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Case study: a patient with uncontrolled type 2 diabetes and complex comorbidities whose diabetes care is managed by an advanced practice nurse.

Geralyn Spollett; Case Study: A Patient With Uncontrolled Type 2 Diabetes and Complex Comorbidities Whose Diabetes Care Is Managed by an Advanced Practice Nurse. Diabetes Spectr 1 January 2003; 16 (1): 32–36. https://doi.org/10.2337/diaspect.16.1.32

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The specialized role of nursing in the care and education of people with diabetes has been in existence for more than 30 years. Diabetes education carried out by nurses has moved beyond the hospital bedside into a variety of health care settings. Among the disciplines involved in diabetes education, nursing has played a pivotal role in the diabetes team management concept. This was well illustrated in the Diabetes Control and Complications Trial (DCCT) by the effectiveness of nurse managers in coordinating and delivering diabetes self-management education. These nurse managers not only performed administrative tasks crucial to the outcomes of the DCCT, but also participated directly in patient care. 1

The emergence and subsequent growth of advanced practice in nursing during the past 20 years has expanded the direct care component, incorporating aspects of both nursing and medical care while maintaining the teaching and counseling roles. Both the clinical nurse specialist (CNS) and nurse practitioner (NP) models, when applied to chronic disease management, create enhanced patient-provider relationships in which self-care education and counseling is provided within the context of disease state management. Clement 2 commented in a review of diabetes self-management education issues that unless ongoing management is part of an education program, knowledge may increase but most clinical outcomes only minimally improve. Advanced practice nurses by the very nature of their scope of practice effectively combine both education and management into their delivery of care.

Operating beyond the role of educator, advanced practice nurses holistically assess patients’ needs with the understanding of patients’ primary role in the improvement and maintenance of their own health and wellness. In conducting assessments, advanced practice nurses carefully explore patients’ medical history and perform focused physical exams. At the completion of assessments, advanced practice nurses, in conjunction with patients, identify management goals and determine appropriate plans of care. A review of patients’ self-care management skills and application/adaptation to lifestyle is incorporated in initial histories, physical exams, and plans of care.

Many advanced practice nurses (NPs, CNSs, nurse midwives, and nurse anesthetists) may prescribe and adjust medication through prescriptive authority granted to them by their state nursing regulatory body. Currently, all 50 states have some form of prescriptive authority for advanced practice nurses. 3 The ability to prescribe and adjust medication is a valuable asset in caring for individuals with diabetes. It is a crucial component in the care of people with type 1 diabetes, and it becomes increasingly important in the care of patients with type 2 diabetes who have a constellation of comorbidities, all of which must be managed for successful disease outcomes.

Many studies have documented the effectiveness of advanced practice nurses in managing common primary care issues. 4 NP care has been associated with a high level of satisfaction among health services consumers. In diabetes, the role of advanced practice nurses has significantly contributed to improved outcomes in the management of type 2 diabetes, 5 in specialized diabetes foot care programs, 6 in the management of diabetes in pregnancy, 7 and in the care of pediatric type 1 diabetic patients and their parents. 8 , 9 Furthermore, NPs have also been effective providers of diabetes care among disadvantaged urban African-American patients. 10 Primary management of these patients by NPs led to improved metabolic control regardless of whether weight loss was achieved.

The following case study illustrates the clinical role of advanced practice nurses in the management of a patient with type 2 diabetes.

A.B. is a retired 69-year-old man with a 5-year history of type 2 diabetes. Although he was diagnosed in 1997, he had symptoms indicating hyperglycemia for 2 years before diagnosis. He had fasting blood glucose records indicating values of 118–127 mg/dl, which were described to him as indicative of “borderline diabetes.” He also remembered past episodes of nocturia associated with large pasta meals and Italian pastries. At the time of initial diagnosis, he was advised to lose weight (“at least 10 lb.”), but no further action was taken.

Referred by his family physician to the diabetes specialty clinic, A.B. presents with recent weight gain, suboptimal diabetes control, and foot pain. He has been trying to lose weight and increase his exercise for the past 6 months without success. He had been started on glyburide (Diabeta), 2.5 mg every morning, but had stopped taking it because of dizziness, often accompanied by sweating and a feeling of mild agitation, in the late afternoon.

A.B. also takes atorvastatin (Lipitor), 10 mg daily, for hypercholesterolemia (elevated LDL cholesterol, low HDL cholesterol, and elevated triglycerides). He has tolerated this medication and adheres to the daily schedule. During the past 6 months, he has also taken chromium picolinate, gymnema sylvestre, and a “pancreas elixir” in an attempt to improve his diabetes control. He stopped these supplements when he did not see any positive results.

He does not test his blood glucose levels at home and expresses doubt that this procedure would help him improve his diabetes control. “What would knowing the numbers do for me?,” he asks. “The doctor already knows the sugars are high.”

A.B. states that he has “never been sick a day in my life.” He recently sold his business and has become very active in a variety of volunteer organizations. He lives with his wife of 48 years and has two married children. Although both his mother and father had type 2 diabetes, A.B. has limited knowledge regarding diabetes self-care management and states that he does not understand why he has diabetes since he never eats sugar. In the past, his wife has encouraged him to treat his diabetes with herbal remedies and weight-loss supplements, and she frequently scans the Internet for the latest diabetes remedies.

During the past year, A.B. has gained 22 lb. Since retiring, he has been more physically active, playing golf once a week and gardening, but he has been unable to lose more than 2–3 lb. He has never seen a dietitian and has not been instructed in self-monitoring of blood glucose (SMBG).

A.B.’s diet history reveals excessive carbohydrate intake in the form of bread and pasta. His normal dinners consist of 2 cups of cooked pasta with homemade sauce and three to four slices of Italian bread. During the day, he often has “a slice or two” of bread with butter or olive oil. He also eats eight to ten pieces of fresh fruit per day at meals and as snacks. He prefers chicken and fish, but it is usually served with a tomato or cream sauce accompanied by pasta. His wife has offered to make him plain grilled meats, but he finds them “tasteless.” He drinks 8 oz. of red wine with dinner each evening. He stopped smoking more than 10 years ago, he reports, “when the cost of cigarettes topped a buck-fifty.”

The medical documents that A.B. brings to this appointment indicate that his hemoglobin A 1c (A1C) has never been <8%. His blood pressure has been measured at 150/70, 148/92, and 166/88 mmHg on separate occasions during the past year at the local senior center screening clinic. Although he was told that his blood pressure was “up a little,” he was not aware of the need to keep his blood pressure ≤130/80 mmHg for both cardiovascular and renal health. 11

A.B. has never had a foot exam as part of his primary care exams, nor has he been instructed in preventive foot care. However, his medical records also indicate that he has had no surgeries or hospitalizations, his immunizations are up to date, and, in general, he has been remarkably healthy for many years.

Physical Exam

A physical examination reveals the following:

Weight: 178 lb; height: 5′2″; body mass index (BMI): 32.6 kg/m 2

Fasting capillary glucose: 166 mg/dl

Blood pressure: lying, right arm 154/96 mmHg; sitting, right arm 140/90 mmHg

Pulse: 88 bpm; respirations 20 per minute

Eyes: corrective lenses, pupils equal and reactive to light and accommodation, Fundi-clear, no arteriolovenous nicking, no retinopathy

Thyroid: nonpalpable

Lungs: clear to auscultation

Heart: Rate and rhythm regular, no murmurs or gallops

Vascular assessment: no carotid bruits; femoral, popliteal, and dorsalis pedis pulses 2+ bilaterally

Neurological assessment: diminished vibratory sense to the forefoot, absent ankle reflexes, monofilament (5.07 Semmes-Weinstein) felt only above the ankle

Lab Results

Results of laboratory tests (drawn 5 days before the office visit) are as follows:

Glucose (fasting): 178 mg/dl (normal range: 65–109 mg/dl)

Creatinine: 1.0 mg/dl (normal range: 0.5–1.4 mg/dl)

Blood urea nitrogen: 18 mg/dl (normal range: 7–30 mg/dl)

Sodium: 141 mg/dl (normal range: 135–146 mg/dl)

Potassium: 4.3 mg/dl (normal range: 3.5–5.3 mg/dl)

• Total cholesterol: 162 mg/dl (normal: <200 mg/dl)

• HDL cholesterol: 43 mg/dl (normal: ≥40 mg/dl)

• LDL cholesterol (calculated): 84 mg/dl (normal: <100 mg/dl)

• Triglycerides: 177 mg/dl (normal: <150 mg/dl)

• Cholesterol-to-HDL ratio: 3.8 (normal: <5.0)

AST: 14 IU/l (normal: 0–40 IU/l)

ALT: 19 IU/l (normal: 5–40 IU/l)

Alkaline phosphotase: 56 IU/l (normal: 35–125 IU/l)

A1C: 8.1% (normal: 4–6%)

Urine microalbumin: 45 mg (normal: <30 mg)

Based on A.B.’s medical history, records, physical exam, and lab results, he is assessed as follows:

Uncontrolled type 2 diabetes (A1C >7%)

Obesity (BMI 32.4 kg/m 2 )

Hyperlipidemia (controlled with atorvastatin)

Peripheral neuropathy (distal and symmetrical by exam)

Hypertension (by previous chart data and exam)

Elevated urine microalbumin level

Self-care management/lifestyle deficits

• Limited exercise

• High carbohydrate intake

• No SMBG program

Poor understanding of diabetes

A.B. presented with uncontrolled type 2 diabetes and a complex set of comorbidities, all of which needed treatment. The first task of the NP who provided his care was to select the most pressing health care issues and prioritize his medical care to address them. Although A.B. stated that his need to lose weight was his chief reason for seeking diabetes specialty care, his elevated glucose levels and his hypertension also needed to be addressed at the initial visit.

The patient and his wife agreed that a referral to a dietitian was their first priority. A.B. acknowledged that he had little dietary information to help him achieve weight loss and that his current weight was unhealthy and “embarrassing.” He recognized that his glucose control was affected by large portions of bread and pasta and agreed to start improving dietary control by reducing his portion size by one-third during the week before his dietary consultation. Weight loss would also be an important first step in reducing his blood pressure.

The NP contacted the registered dietitian (RD) by telephone and referred the patient for a medical nutrition therapy assessment with a focus on weight loss and improved diabetes control. A.B.’s appointment was scheduled for the following week. The RD requested that during the intervening week, the patient keep a food journal recording his food intake at meals and snacks. She asked that the patient also try to estimate portion sizes.

Although his physical activity had increased since his retirement, it was fairly sporadic and weather-dependent. After further discussion, he realized that a week or more would often pass without any significant form of exercise and that most of his exercise was seasonal. Whatever weight he had lost during the summer was regained in the winter, when he was again quite sedentary.

A.B.’s wife suggested that the two of them could walk each morning after breakfast. She also felt that a treadmill at home would be the best solution for getting sufficient exercise in inclement weather. After a short discussion about the positive effect exercise can have on glucose control, the patient and his wife agreed to walk 15–20 minutes each day between 9:00 and 10:00 a.m.

A first-line medication for this patient had to be targeted to improving glucose control without contributing to weight gain. Thiazolidinediones (i.e., rosiglitizone [Avandia] or pioglitizone [Actos]) effectively address insulin resistance but have been associated with weight gain. 12 A sulfonylurea or meglitinide (i.e., repaglinide [Prandin]) can reduce postprandial elevations caused by increased carbohydrate intake, but they are also associated with some weight gain. 12 When glyburide was previously prescribed, the patient exhibited signs and symptoms of hypoglycemia (unconfirmed by SMBG). α-Glucosidase inhibitors (i.e., acarbose [Precose]) can help with postprandial hyperglycemia rise by blunting the effect of the entry of carbohydrate-related glucose into the system. However, acarbose requires slow titration, has multiple gastrointestinal (GI) side effects, and reduces A1C by only 0.5–0.9%. 13 Acarbose may be considered as a second-line therapy for A.B. but would not fully address his elevated A1C results. Metformin (Glucophage), which reduces hepatic glucose production and improves insulin resistance, is not associated with hypoglycemia and can lower A1C results by 1%. Although GI side effects can occur, they are usually self-limiting and can be further reduced by slow titration to dose efficacy. 14

After reviewing these options and discussing the need for improved glycemic control, the NP prescribed metformin, 500 mg twice a day. Possible GI side effects and the need to avoid alcohol were of concern to A.B., but he agreed that medication was necessary and that metformin was his best option. The NP advised him to take the medication with food to reduce GI side effects.

The NP also discussed with the patient a titration schedule that increased the dosage to 1,000 mg twice a day over a 4-week period. She wrote out this plan, including a date and time for telephone contact and medication evaluation, and gave it to the patient.

During the visit, A.B. and his wife learned to use a glucose meter that features a simple two-step procedure. The patient agreed to use the meter twice a day, at breakfast and dinner, while the metformin dose was being titrated. He understood the need for glucose readings to guide the choice of medication and to evaluate the effects of his dietary changes, but he felt that it would not be “a forever thing.”

The NP reviewed glycemic goals with the patient and his wife and assisted them in deciding on initial short-term goals for weight loss, exercise, and medication. Glucose monitoring would serve as a guide and assist the patient in modifying his lifestyle.

A.B. drew the line at starting an antihypertensive medication—the angiotensin-converting enzyme (ACE) inhibitor enalapril (Vasotec), 5 mg daily. He stated that one new medication at a time was enough and that “too many medications would make a sick man out of me.” His perception of the state of his health as being represented by the number of medications prescribed for him gave the advanced practice nurse an important insight into the patient’s health belief system. The patient’s wife also believed that a “natural solution” was better than medication for treating blood pressure.

Although the use of an ACE inhibitor was indicated both by the level of hypertension and by the presence of microalbuminuria, the decision to wait until the next office visit to further evaluate the need for antihypertensive medication afforded the patient and his wife time to consider the importance of adding this pharmacotherapy. They were quite willing to read any materials that addressed the prevention of diabetes complications. However, both the patient and his wife voiced a strong desire to focus their energies on changes in food and physical activity. The NP expressed support for their decision. Because A.B. was obese, weight loss would be beneficial for many of his health issues.

Because he has a sedentary lifestyle, is >35 years old, has hypertension and peripheral neuropathy, and is being treated for hypercholestrolemia, the NP performed an electrocardiogram in the office and referred the patient for an exercise tolerance test. 11 In doing this, the NP acknowledged and respected the mutually set goals, but also provided appropriate pre-exercise screening for the patient’s protection and safety.

In her role as diabetes educator, the NP taught A.B. and his wife the importance of foot care, demonstrating to the patient his inability to feel the light touch of the monofilament. She explained that the loss of protective sensation from peripheral neuropathy means that he will need to be more vigilant in checking his feet for any skin lesions caused by poorly fitting footwear worn during exercise.

At the conclusion of the visit, the NP assured A.B. that she would share the plan of care they had developed with his primary care physician, collaborating with him and discussing the findings of any diagnostic tests and procedures. She would also work in partnership with the RD to reinforce medical nutrition therapies and improve his glucose control. In this way, the NP would facilitate the continuity of care and keep vital pathways of communication open.

Advanced practice nurses are ideally suited to play an integral role in the education and medical management of people with diabetes. 15 The combination of clinical skills and expertise in teaching and counseling enhances the delivery of care in a manner that is both cost-reducing and effective. Inherent in the role of advanced practice nurses is the understanding of shared responsibility for health care outcomes. This partnering of nurse with patient not only improves care but strengthens the patient’s role as self-manager.

Geralyn Spollett, MSN, C-ANP, CDE, is associate director and an adult nurse practitioner at the Yale Diabetes Center, Department of Endocrinology and Metabolism, at Yale University in New Haven, Conn. She is an associate editor of Diabetes Spectrum.

Note of disclosure: Ms. Spollett has received honoraria for speaking engagements from Novo Nordisk Pharmaceuticals, Inc., and Aventis and has been a paid consultant for Aventis. Both companies produce products and devices for the treatment of diabetes.

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Case 6–2020: A 34-Year-Old Woman with Hyperglycemia

Presentation of case.

Dr. Max C. Petersen (Medicine): A 34-year-old woman was evaluated in the diabetes clinic of this hospital for hyperglycemia.

Eleven years before this presentation, the blood glucose level was 126 mg per deciliter (7.0 mmol per liter) on routine laboratory evaluation, which was performed as part of an annual well visit. The patient could not recall whether she had been fasting at the time the test had been performed. One year later, the fasting blood glucose level was 112 mg per deciliter (6.2 mmol per liter; reference range, <100 mg per deciliter [<5.6 mmol per liter]).

Nine years before this presentation, a randomly obtained blood glucose level was 217 mg per deciliter (12.0 mmol per liter), and the patient reported polyuria. At that time, the glycated hemoglobin level was 5.8% (reference range, 4.3 to 5.6); the hemoglobin level was normal. One year later, the glycated hemoglobin level was 5.9%. The height was 165.1 cm, the weight 72.6 kg, and the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) 26.6. The patient received a diagnosis of prediabetes and was referred to a nutritionist. She made changes to her diet and lost 4.5 kg of body weight over a 6-month period; the glycated hemoglobin level was 5.5%.

Six years before this presentation, the patient became pregnant with her first child. Her prepregnancy BMI was 24.5. At 26 weeks of gestation, the result of a 1-hour oral glucose challenge test (i.e., the blood glucose level obtained 1 hour after the oral administration of a 50-g glucose load in the nonfasting state) was 186 mg per deciliter (10.3 mmol per liter; reference range, <140 mg per deciliter [<7.8 mmol per liter]). She declined a 3-hour oral glucose tolerance test; a presumptive diagnosis of gestational diabetes was made. She was asked to follow a meal plan for gestational diabetes and was treated with insulin during the pregnancy. Serial ultrasound examinations for fetal growth and monitoring were performed. At 34 weeks of gestation, the fetal abdominal circumference was in the 76th percentile for gestational age. Polyhydramnios developed at 37 weeks of gestation. The child was born at 39 weeks 3 days of gestation, weighed 3.9 kg at birth, and had hypoglycemia after birth, which subsequently resolved. Six weeks post partum, the patient’s fasting blood glucose level was 120 mg per deciliter (6.7 mmol per liter), and the result of a 2-hour oral glucose tolerance test (i.e., the blood glucose level obtained 2 hours after the oral administration of a 75-g glucose load in the fasting state) was 131 mg per deciliter (7.3 mmol per liter; reference range, <140 mg per deciliter). Three months post partum, the glycated hemoglobin level was 6.1%. Lifestyle modification for diabetes prevention was recommended.

Four and a half years before this presentation, the patient became pregnant with her second child. Her prepregnancy BMI was 25.1. At 5 weeks of gestation, she had an elevated blood glucose level. Insulin therapy was started at 6 weeks of gestation, and episodes of hypoglycemia occurred during the pregnancy. Serial ultrasound examinations for fetal growth and monitoring were performed. At 28 weeks of gestation, the fetal abdominal circumference was in the 35th percentile for gestational age, and the amniotic fluid level was normal. Labor was induced at 38 weeks of gestation; the child weighed 2.6 kg at birth. Neonatal blood glucose levels were reported as stable after birth. Six weeks post partum, the patient’s fasting blood glucose level was 133 mg per deciliter (7.4 mmol per liter), and the result of a 2-hour oral glucose tolerance test was 236 mg per deciliter (13.1 mmol per liter). The patient received a diagnosis of type 2 diabetes mellitus; lifestyle modification was recommended. Three months post partum, the glycated hemoglobin level was 5.9% and the BMI was 30.0. Over the next 2 years, she followed a low-carbohydrate diet and regular exercise plan and self-monitored the blood glucose level.

Two years before this presentation, the patient became pregnant with her third child. Blood glucose levels were again elevated, and insulin therapy was started early in gestation. She had episodes of hypoglycemia that led to adjustment of her insulin regimen. The child was born at 38 weeks 5 days of gestation, weighed 3.0 kg at birth, and had hypoglycemia that resolved 48 hours after birth. After the birth of her third child, the patient started to receive metformin, which had no effect on the glycated hemoglobin level, despite adjustment of the therapy to the maximal dose.

One year before this presentation, the patient became pregnant with her fourth child. Insulin therapy was again started early in gestation. The patient reported that episodes of hypoglycemia occurred. Polyhydramnios developed. The child was born at 38 weeks 6 days of gestation and weighed 3.5 kg. The patient sought care at the diabetes clinic of this hospital for clarification of her diagnosis.

The patient reported following a low-carbohydrate diet and exercising 5 days per week. There was no fatigue, change in appetite, change in vision, chest pain, shortness of breath, polydipsia, or polyuria. There was no history of anemia, pancreatitis, hirsutism, proximal muscle weakness, easy bruising, headache, sweating, tachycardia, gallstones, or diarrhea. Her menstrual periods were normal. She had not noticed any changes in her facial features or the size of her hands or feet.

The patient had a history of acne and low-back pain. Her only medication was metformin. She had no known medication allergies. She lived with her husband and four children in a suburban community in New England and worked as an administrator. She did not smoke tobacco or use illicit drugs, and she rarely drank alcohol. She identified as non-Hispanic white. Both of her grandmothers had type 2 diabetes mellitus. Her father had hypertension, was overweight, and had received a diagnosis of type 2 diabetes at 50 years of age. Her mother was not overweight and had received a diagnosis of type 2 diabetes at 48 years of age. The patient had two sisters, neither of whom had a history of diabetes or gestational diabetes. There was no family history of hemochromatosis.

On examination, the patient appeared well. The blood pressure was 126/76 mm Hg, and the heart rate 76 beats per minute. The BMI was 25.4. The physical examination was normal. The glycated hemoglobin level was 6.2%.

A diagnostic test was performed.

DIFFERENTIAL DIAGNOSIS

Dr. Miriam S. Udler: I am aware of the diagnosis in this case and participated in the care of this patient. This healthy 34-year-old woman, who had a BMI just above the upper limit of the normal range, presented with a history of hyperglycemia of varying degrees since 24 years of age. When she was not pregnant, she was treated with lifestyle measures as well as metformin therapy for a short period, and she maintained a well-controlled blood glucose level. In thinking about this case, it is helpful to characterize the extent of the hyperglycemia and then to consider its possible causes.

CHARACTERIZING HYPERGLYCEMIA

This patient’s hyperglycemia reached a threshold that was diagnostic of diabetes 1 on two occasions: when she was 25 years of age, she had a randomly obtained blood glucose level of 217 mg per deciliter with polyuria (with diabetes defined as a level of ≥200 mg per deciliter [≥11.1 mmol per liter] with symptoms), and when she was 30 years of age, she had on the same encounter a fasting blood glucose level of 133 mg per deciliter (with diabetes defined as a level of ≥126 mg per deciliter) and a result on a 2-hour oral glucose tolerance test of 236 mg per deciliter (with diabetes defined as a level of ≥200 mg per deciliter). On both of these occasions, her glycated hemoglobin level was in the prediabetes range (defined as 5.7 to 6.4%). In establishing the diagnosis of diabetes, the various blood glucose studies and glycated hemoglobin testing may provide discordant information because the tests have different sensitivities for this diagnosis, with glycated hemoglobin testing being the least sensitive. 2 Also, there are situations in which the glycated hemoglobin level can be inaccurate; for example, the patient may have recently received a blood transfusion or may have a condition that alters the life span of red cells, such as anemia, hemoglobinopathy, or pregnancy. 3 These conditions were not present in this patient at the time that the glycated hemoglobin measurements were obtained. In addition, since the glycated hemoglobin level reflects the average glucose level typically over a 3-month period, discordance with timed blood glucose measurements can occur if there has been a recent change in glycemic control. This patient had long-standing mild hyperglycemia but met criteria for diabetes on the basis of the blood glucose levels noted.

Type 1 and Type 2 Diabetes

Now that we have characterized the patient’s hyperglycemia as meeting criteria for diabetes, it is important to consider the possible types. More than 90% of adults with diabetes have type 2 diabetes, which is due to progressive loss of insulin secretion by beta cells that frequently occurs in the context of insulin resistance. This patient had received a diagnosis of type 2 diabetes; however, some patients with diabetes may be given a diagnosis of type 2 diabetes on the basis of not having features of type 1 diabetes, which is characterized by autoimmune destruction of the pancreatic beta cells that leads to rapid development of insulin dependence, with ketoacidosis often present at diagnosis.

Type 1 diabetes accounts for approximately 6% of all cases of diabetes in adults (≥18 years of age) in the United States, 4 and 80% of these cases are diagnosed before the patient is 20 years of age. 5 Since this patient’s diabetes was essentially nonprogressive over a period of at least 9 years, she most likely does not have type 1 diabetes. It is therefore not surprising that she had received a diagnosis of type 2 diabetes, but there are several other types of diabetes to consider, particularly since some features of her case do not fit with a typical case of type 2 diabetes, such as her age at diagnosis, the presence of hyperglycemia despite a nearly normal BMI, and the mild and nonprogressive nature of her disease over the course of many years.

Less Common Types of Diabetes

Latent autoimmune diabetes in adults (LADA) is a mild form of autoimmune diabetes that should be considered in this patient. However, there is controversy as to whether LADA truly represents an entity that is distinct from type 1 diabetes. 6 Both patients with type 1 diabetes and patients with LADA commonly have elevated levels of diabetes-associated autoantibodies; however, LADA has been defined by an older age at onset (typically >25 years) and slower progression to insulin dependence (over a period of >6 months). 7 This patient had not been tested for diabetes-associated autoantibodies. I ordered these tests to help evaluate for LADA, but this was not my leading diagnosis because of her young age at diagnosis and nonprogressive clinical course over a period of at least 9 years.

If the patient’s diabetes had been confined to pregnancy, we might consider gestational diabetes, but she had hyperglycemia outside of pregnancy. Several medications can cause hyperglycemia, including glucocorticoids, atypical antipsychotic agents, cancer immunotherapies, and some antiretroviral therapies and immunosuppressive agents used in transplantation. 8 However, this patient was not receiving any of these medications. Another cause of diabetes to consider is destruction of the pancreas due to, for example, cystic fibrosis, a tumor, or pancreatitis, but none of these were present. Secondary endocrine disorders — including excess cortisol production, excess growth hormone production, and pheochromocytoma — were considered to be unlikely in this patient on the basis of the history, review of symptoms, and physical examination.

Monogenic Diabetes

A final category to consider is monogenic diabetes, which is caused by alteration of a single gene. Types of monogenic diabetes include maturity-onset diabetes of the young (MODY), neonatal diabetes, and syndromic forms of diabetes. Monogenic diabetes accounts for 1 to 6% of cases of diabetes in children 9 and approximately 0.4% of cases in adults. 10 Neonatal diabetes is diagnosed typically within the first 6 months of life; syndromic forms of monogenic diabetes have other abnormal features, including particular organ dysfunction. Neither condition is applicable to this patient.

MODY is an autosomal dominant condition characterized by primary pancreatic beta-cell dysfunction that causes mild diabetes that is diagnosed during adolescence or early adulthood. As early as 1964, the nomenclature “maturity-onset diabetes of the young” was used to describe cases that resembled adult-onset type 2 diabetes in terms of the slow progression to insulin use (as compared with the rapid progression in type 1 diabetes) but occurred in relatively young patients. 11 Several genes cause distinct forms of MODY that have specific disease features that inform treatment, and thus MODY is a clinically important diagnosis. Most forms of MODY cause isolated abnormal glucose levels (in contrast to syndromic monogenic diabetes), a manifestation that has contributed to its frequent misdiagnosis as type 1 or type 2 diabetes. 12

Genetic Basis of MODY

Although at least 13 genes have been associated with MODY, 3 genes — GCK , which encodes glucokinase, and HNF1A and HNF4A , which encode hepatocyte nuclear factors 1A and 4A, respectively — account for most cases. MODY associated with GCK (known as GCK-MODY) is characterized by mild, nonprogressive hyperglycemia that is present since birth, whereas the forms of MODY associated with HNF1A and HNF4A (known as HNF1A-MODY and HNF4A-MODY, respectively) are characterized by the development of diabetes, typically in the early teen years or young adulthood, that is initially mild and then progresses such that affected patients may receive insulin before diagnosis.

In patients with GCK-MODY, genetic variants reduce the function of glucokinase, the enzyme in pancreatic beta cells that functions as a glucose sensor and controls the rate of entry of glucose into the glycolytic pathway. As a result, reduced sensitivity to glucose-induced insulin secretion causes asymptomatic mild fasting hyperglycemia, with an upward shift in the normal range of the fasting blood glucose level to 100 to 145 mg per deciliter (5.6 to 8.0 mmol per liter), and also causes an upward shift in postprandial blood glucose levels, but with tight regulation maintained ( Fig. 1 ). 13 This mild hyperglycemia is not thought to confer a predisposition to complications of diabetes, 14 is largely unaltered by treatment, 15 and does not necessitate treatment outside of pregnancy.

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Key features suggesting maturity-onset diabetes of the young (MODY) in this patient were an age of less than 35 years at the diagnosis of diabetes, a strong family history of diabetes with an autosomal dominant pattern of inheritance, and hyperglycemia despite a close-to-normal body-mass index. None of these features is an absolute criterion. MODY is caused by single gene–mediated disruption of pancreatic beta-cell function. In MODY associated with the GCK gene (known as GCK-MODY), disrupted glucokinase function causes a mild upward shift in glucose levels through-out the day and does not necessitate treatment. 13 In the pedigree, circles represent female family members, squares male family members, blue family members affected by diabetes, and green unaffected family members. The arrow indicates the patient.

In contrast to GCK-MODY, the disorders HNF1A-MODY and HNF4A-MODY result in progressive hyperglycemia that eventually leads to treatment. 16 Initially, there may be a normal fasting glucose level and large spikes in postprandial glucose levels (to >80 mg per deciliter [>4.4 mmol per liter]). 17 Patients can often be treated with oral agents and discontinue insulin therapy started before the diagnosis of MODY. 18 Of note, patients with HNF1A-MODY or HNF4A-MODY are typically sensitive to treatment with sulfonylureas 19 but may also respond to glucagon-like peptide-1 receptor agonists. 20

This patient had received a diagnosis of diabetes before 35 years of age, had a family history of diabetes involving multiple generations, and was not obese. These features are suggestive of MODY but do not represent absolute criteria for the condition ( Fig. 1 ). 1 Negative testing for diabetes-associated autoantibodies would further increase the likelihood of MODY. There are methods to calculate a patient’s risk of having MODY associated with GCK , HNF1A , or HNF4A . 21 , 22 Using an online calculator ( www.diabetesgenes.org/mody-probability-calculator ), we estimate that the probability of this patient having MODY is at least 75.5%. Genetic testing would be needed to confirm this diagnosis, and in patients at an increased risk for MODY, multigene panel testing has been shown to be cost-effective. 23 , 24

DR. MIRIAM S. UDLER’S DIAGNOSIS

Maturity-onset diabetes of the young, most likely due to a GCK variant.

DIAGNOSTIC TESTING

Dr. Christina A. Austin-Tse: A diagnostic sequencing test of five genes associated with MODY was performed. One clinically significant variant was identified in the GCK gene ( {"type":"entrez-nucleotide","attrs":{"text":"NM_000162.3","term_id":"167621407","term_text":"NM_000162.3"}} NM_000162.3 ): a c.787T→C transition resulting in the p.Ser263Pro missense change. Review of the literature and variant databases revealed that this variant had been previously identified in at least three patients with early-onset diabetes and had segregated with disease in at least three affected members of two families (GeneDx: personal communication). 25 , 26 Furthermore, the variant was rare in large population databases (occurring in 1 out of 128,844 European chromosomes in gnomAD 27 ), a feature consistent with a disease-causing role. Although the serine residue at position 263 was not highly conserved, multiple in vitro functional studies have shown that the p.Ser263Pro variant negatively affects the stability of the glucokinase enzyme. 26 , 28 – 30 As a result, this variant met criteria to be classified as “likely pathogenic.” 31 As mentioned previously, a diagnosis of GCK-MODY is consistent with this patient’s clinical features. On subsequent testing of additional family members, the same “likely pathogenic” variant was identified in the patient’s father and second child, both of whom had documented hyperglycemia.

DISCUSSION OF MANAGEMENT

Dr. Udler: In this patient, the diagnosis of GCK-MODY means that it is normal for her blood glucose level to be mildly elevated. She can stop taking metformin because discontinuation is not expected to substantially alter her glycated hemoglobin level 15 , 32 and because she is not at risk for complications of diabetes. 14 However, she should continue to maintain a healthy lifestyle. Although patients with GCK-MODY are not typically treated for hyperglycemia outside of pregnancy, they may need to be treated during pregnancy.

It is possible for a patient to have type 1 or type 2 diabetes in addition to MODY, so this patient should be screened for diabetes according to recommendations for the general population (e.g., in the event that she has a risk factor for diabetes, such as obesity). 1 Since the mild hyperglycemia associated with GCK-MODY is asymptomatic (and probably unrelated to the polyuria that this patient had described in the past), the development of symptoms of hyperglycemia, such as polyuria, polydipsia, or blurry vision, should prompt additional evaluation. In patients with GCK-MODY, the glycated hemoglobin level is typically below 7.5%, 33 so a value rising above that threshold or a sudden large increase in the glycated hemoglobin level could indicate concomitant diabetes from another cause, which would need to be evaluated and treated.

This patient’s family members are at risk for having the same GCK variant, with a 50% chance of offspring inheriting a variant from an affected parent. Since the hyperglycemia associated with GCK-MODY is present from birth, it is necessary to perform genetic testing only in family members with demonstrated hyperglycemia. I offered site-specific genetic testing to the patient’s parents and second child.

Dr. Meridale V. Baggett (Medicine): Dr. Powe, would you tell us how you would treat this patient during pregnancy?

Dr. Camille E. Powe: During the patient’s first pregnancy, routine screening led to a presumptive diagnosis of gestational diabetes, the most common cause of hyperglycemia in pregnancy. Hyperglycemia in pregnancy is associated with adverse pregnancy outcomes, 34 and treatment lowers the risk of such outcomes. 35 , 36 Two of the most common complications — fetal overgrowth (which can lead to birth injuries, shoulder dystocia, and an increased risk of cesarean delivery) and neonatal hypoglycemia — are thought to be the result of fetal hyperinsulinemia. 37 Maternal glucose is freely transported across the placenta, and excess glucose augments insulin secretion from the fetal pancreas. In fetal life, insulin is a potent growth factor, and neonates who have hyperinsulinemia in utero often continue to secrete excess insulin in the first few days of life. In the treatment of pregnant women with diabetes, we strive for strict blood sugar control (fasting blood glucose level, <95 mg per deciliter [<5.3 mmol per liter]; 2-hour postprandial blood glucose level, <120 mg per deciliter) to decrease the risk of these and other hyperglycemia-associated adverse pregnancy outcomes. 38 – 40

In the third trimester of the patient’s first pregnancy, obstetrical ultrasound examination revealed a fetal abdominal circumference in the 76th percentile for gestational age and polyhydramnios, signs of fetal exposure to maternal hyperglycemia. 40 – 42 Case series involving families with GCK-MODY have shown that the effect of maternal hyperglycemia on the fetus depends on whether the fetus inherits the pathogenic GCK variant. 43 – 48 Fetuses that do not inherit the maternal variant have overgrowth, presumably due to fetal hyperinsulinemia ( Fig. 2A ). In contrast, fetuses that inherit the variant do not have overgrowth and are born at a weight that is near the average for gestational age, despite maternal hyperglycemia, presumably because the variant results in decreased insulin secretion ( Fig. 2B ). Fetuses that inherit GCK-MODY from their fathers and have euglycemic mothers appear to be undergrown, most likely because their insulin secretion is lower than normal when they and their mothers are euglycemic ( Fig. 2D ). Because fetal overgrowth and polyhydramnios occurred during this patient’s first pregnancy and neonatal hypoglycemia developed after the birth, the patient’s first child is probably not affected by GCK-MODY.

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Pathogenic variants that lead to GCK-MODY, when carried by a fetus, change the usual relationship of maternal hyperglycemia to fetal hyperinsulinemia and fetal overgrowth. GCK-MODY–affected fetuses have lower insulin secretion than unaffected fetuses in response to the same maternal blood glucose level. In a hyperglycemic mother carrying a fetus who is unaffected by GCK-MODY, excessive fetal growth is usually apparent (Panel A). Studies involving GCK-MODY–affected hyperglycemic mothers have shown that fetal growth is normal despite maternal hyperglycemia when a fetus has the maternal GCK variant (Panel B). The goal of treatment of maternal hyperglycemia when a fetus is unaffected by GCK-MODY is to establish euglycemia to normalize fetal insulin levels and growth (Panel C); whether this can be accomplished in the case of maternal GCK-MODY is controversial, given the genetically determined elevated maternal glycemic set point. In the context of maternal euglycemia, GCK-MODY–affected fetuses may be at risk for fetal growth restriction (Panel D).

In accordance with standard care for pregnant women with diabetes who do not meet glycemic targets after dietary modification, 38 , 39 the patient was treated with insulin during her pregnancies. In her second pregnancy, treatment was begun early, after hyperglycemia was detected in the first trimester. Because she had not yet received the diagnosis of GCK-MODY during any of her pregnancies, no consideration of this condition was given during her obstetrical treatment. Whether treatment affects the risk of hyperglycemia-associated adverse pregnancy outcomes in pregnant women with known GCK-MODY is controversial, with several case series showing that the birth weight percentile in unaffected neonates remains consistent regardless of whether the mother is treated with insulin. 44 , 45 Evidence suggests that it may be difficult to overcome a genetically determined glycemic set point in patients with GCK-MODY with the use of pharmacotherapy, 15 , 32 and affected patients may have symptoms of hypoglycemia when the blood glucose level is normal because of an enhanced counterregulatory response. 49 , 50 Still, to the extent that it is possible, it would be desirable to safely lower the blood glucose level in a woman with GCK-MODY who is pregnant with an unaffected fetus in order to decrease the risk of fetal overgrowth and other consequences of mildly elevated glucose levels ( Fig. 2C ). 46 , 47 , 51 In contrast, there is evidence that lowering the blood glucose level in a pregnant woman with GCK-MODY could lead to fetal growth restriction if the fetus is affected ( Fig. 2D ). 45 , 52 During this patient’s second pregnancy, she was treated with insulin beginning in the first trimester, and her daughter’s birth weight was near the 16th percentile for gestational age; this outcome is consistent with the daughter’s ultimate diagnosis of GCK-MODY.

Expert opinion suggests that, in pregnant women with GCK-MODY, insulin therapy should be deferred until fetal growth is assessed by means of ultrasound examination beginning in the late second trimester. If there is evidence of fetal overgrowth, the fetus is presumed to be unaffected by GCK-MODY and insulin therapy is initiated. 53 After I have counseled women with GCK-MODY on the potential risks and benefits of insulin treatment during pregnancy, I have sometimes used a strategy of treating hyperglycemia from early in pregnancy using modified glycemic targets that are less stringent than the targets typically used during pregnancy. This strategy attempts to balance the risk of growth restriction in an affected fetus (as well as maternal hypoglycemia) with the potential benefit of glucose-lowering therapy for an unaffected fetus.

Dr. Udler: The patient stopped taking metformin, and subsequent glycated hemoglobin levels remained unchanged, at 6.2%. Her father and 5-year-old daughter (second child) both tested positive for the same GCK variant. Her father had a BMI of 36 and a glycated hemoglobin level of 7.8%, so I counseled him that he most likely had type 2 diabetes in addition to GCK-MODY. He is currently being treated with metformin and lifestyle measures. The patient’s daughter now has a clear diagnosis to explain her hyperglycemia, which will help in preventing misdiagnosis of type 1 diabetes, given her young age, and will be important for the management of any future pregnancies. She will not need any medical follow-up for GCK-MODY until she is considering pregnancy.

FINAL DIAGNOSIS

Maturity-onset diabetes of the young due to a GCK variant.

Acknowledgments

We thank Dr. Andrew Hattersley and Dr. Sarah Bernstein for helpful comments on an earlier draft of the manuscript.

This case was presented at the Medical Case Conference.

No potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org .

diabetes complications case study

Case Studies of Patients with Type 2 Diabetes Mellitus: Exercises in Problem Solving

David M. Quillen, MD, is a clinical associate professor in the department of community health and family medicine at the University of Florida in Gainesville, FL.

Louis Kuritzky, MD, is clinical assistant professor emeritus in the department of community health and family medicine at the University of Florida in Gainesville, FL.

ABSTRACT: Primary care clinicians are often at the front line in the management of type 2 diabetes mellitus (T2DM), and they regularly face the challenge of making the best choices in an increasingly complex field. This article presents a series of hypothetical case studies that represent some of the more common therapeutic dilemmas that primary care clinicians face in their daily management of patients with T2DM.

Diabetes mellitus currently affects 6.4% or 285 million adults worldwide, and that number is expected to increase to 7.7% or 439 million by 2030. 1 In the United States, the prevalence of diabetes in adults increased from 11.3% in 2010 to 12.3% in 2012. 2 The current type 2 diabetes mellitus (T2DM) epidemic is closely associated with a parallel obesity epidemic, with more than 85% of patients with diabetes being overweight or obese. 3 Furthermore, many glucose-lowering treatments only complicate weight management by causing patients to gain even more weight. 4 The increase in the prevalence of diabetes, along with its comorbidities and complications, places a substantial burden on society and primary care providers. In the United States, diabetes now represents 1 in 10 visits to primary care physicians 5 and was reported as the seventh leading cause of death during 2010, with some suggesting that the true figure may be even higher. 2

The American Diabetes Association (ADA) provides recommendations on targets for glycemic control in T2DM. A glycated hemoglobin (HbA1c) treatment goal of <7.0% is suggested for most patients, with less (<8.0%) or more (<6.5%) stringent goals applied in special situations such as when patients have particularly short or long projected lifespans, respectively. 6,7 Despite evidence linking good disease control with improved outcomes, glycemic control in patients with T2DM remains suboptimal. 8-13 One important reason for this is the adverse events associated with glucose-lowering therapies, particularly weight gain and hypoglycemia, 14 which may have an impact on medication adherence. 9,11 Other patient-related reasons for suboptimal glycemic control include limited disease knowledge, 9,10,14 high emotional burden of T2DM, 9 lack of acceptance of the disease, 9 reluctance to intensify medications, 10,14 and confusion related to complex treatment regimens. 8,10 Clinician behaviors can also present barriers to good glycemic control—including failure to intensify treatment in a timely fashion (commonly termed clinical inertia), 11 insufficient time with patients to fully explore and/or explain treatment advancement options, 9 and emphasis on comorbidities (eg, hypertension, dyslipidemia, and obesity).

Recognizing that diabetes management is often suboptimal, and understanding the diversity of potential reasons behind this, the ADA and the European Association for the Study of Diabetes issued a joint position statement in 2012, which was updated in 2015. 4,6 Central to this communication was the principle that therapy should be individualized, taking into account each patient’s characteristics and preferences as much as possible. In particular, age, weight, risk of hypoglycemia, costs, problematic medication side effects, comorbid conditions, and existing medications should all be considered.

If lifestyle intervention is insufficient to maintain adequate glycemic control, monotherapy with metformin is generally the recommended initial pharmacotherapy (in the absence of contraindications or tolerability issues). However, since diabetes is generally a progressive disorder, combination therapy is likely to be required at some point for the vast majority of patients. There are now many glucose-lowering treatment options available, targeting a wide range of pathologies underlying T2DM. When choosing combination therapy, the use of agents with complementary mechanisms of action ( Table and Figure ) maximizes the potential for good glycemic control. 6,15,16

Primary care clinicians are often at the front line of T2DM management and face the day-to-day challenge of making the best choices for patients. This article presents a series of representative hypothetical case studies describing some of the more common challenges faced in the management of T2DM.

diabetes complications case study

Case 1: Failure of Metformin Monotherapy

A 68-year-old male patient with T2DM has received optimal metformin monotherapy for the last 2 years (current dose of 2000 mg/day) and tolerates the treatment well. Hypoglycemia has not been an issue to date. His body mass index (BMI) is 28 kg/m 2 , which he has worked hard to reduce from 35 kg/m 2 over the last 2 years. He has mild hypertension, which is well- controlled on a thiazide plus an angiotensin-converting enzyme inhibitor. His blood lipids are well-controlled on atorvastatin 10 mg daily.

He now presents at the clinic with an HbA1c of 7.6%. During consultation, the patient mentions that he has seen advertisements for canagliflozin (Invokana) and questioned its efficacy.

After reviewing the available therapeutic choices and using a shared decision-making model, a dipeptidyl peptidase-4 (DPP-4) inhibitor is selected as add-on therapy based upon simplicity of use, tolerability, and the patient’s wish to avoid anything that might cause weight gain. Because he is an uncircumcised male, he decided against canagliflozin once informed of the potential side effect of balanitis.

diabetes complications case study

A common challenge faced in primary care is how to manage patients whose glycemic control has declined on monotherapy, but not to a gross extent. Before stepping up pharmacotherapy with add-on medication, it is imperative to ensure that current treatments are being used in an optimal way. The clinician should assess whether improvements could be achieved through increased adherence or as a result of more intensive lifestyle changes (eg, diet and exercise).

In this case, the patient has already done very well in terms of weight reduction and maintenance. At this point, add-on therapy may be needed to improve glycemic control. Where the patient was only modestly above his ADA-recommended HbA1c goal of 7.0%, aggressive therapy—which may be associated with adverse effects—was not warranted. Although not obese, this patient was concerned about body weight; therefore, treatments associated with weight gain—eg, sulfonylureas (SUs) and insulin—may not be suitable. 17

Patients in the United States may be exposed to direct-to-consumer advertising of pharmaceuticals, and it is common for patients to express opinions about named drugs. In these situations, it is important to listen carefully to the patient’s thoughts. Allowing the patient a role in the decision-making process may help obviate some of the patient-related barriers to optimal glycemic control, and it improves the chances of good adherence and disease understanding. 4 In situations where the treatment requested by the patient is not ideal, time spent on patient education is critical. The reasons why the suggested therapy is not preferred should be outlined and the patient should be involved as much as possible in the choice of an alternative therapy.

In this case, the patient and doctor opted for a DPP-4 inhibitor as add-on treatment. Other reasonable options might include a 3-month trial of lifestyle modification, a glucagon-like peptide-1 receptor agonist (GLP-1RA), a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or an alpha-glucosidase inhibitor. Because the patient was disinclined to use an injectable agent, GLP-1RAs were not the best choice. Although SGLT-2 inhibitors would be a consideration and the patient specifically mentioned that class, because he is uncircumcised, he may be at increased risk to incur one of the genital mycotic infections seen with this class of agents. Such infections are less common in men than in women, but the risk in men may be increased in uncircumcised individuals. Tolerability of alpha-glucosidase inhibitors is substantially less than DPP-4 inhibitors, hence the shared decision to use this class of agents.

Case 2: Failure of Metformin and a DPP-4 Inhibitor

A 65-year-old female patient with a 10-year history of T2DM presents with an HbA1c of 9.0% despite receiving metformin (2000 mg/d) plus a DPP-4 inhibitor for the last 12 months. Her BMI is 29 kg/m 2 . Renal function is near normal (estimated glomerular filtration rate [eGFR] of 64 mL/min/1.73 m 2 ). She has mild dyslipidemia controlled with a statin and hypertension controlled with an angiotensin II receptor blocker (blood pressure ≤140/90 mm Hg).

Because of concerns of hypoglycemia, the patient elects to avoid insulin.

Appropriate therapies in this case could include an add-on GLP-1RA or SGLT-2 inhibitor. The patient chooses to add an SGLT-2 inhibitor.

This case features a patient with a marked loss of glycemic control, suggesting a need for treatment intensification. When deciding on triple therapy, agents with complementary mechanisms of action should be considered. 4 Most oral agents lower HbA1c, on average, by approximately 1.0%, which means that achieving a goal of <7.0% may be difficult without significant lifestyle modification in this case. Triple therapy is an intensive approach, with an increased potential for adverse events and drug interactions. Furthermore, decreased patient adherence to therapy is an issue associated with multidrug regimens. 4 For these reasons, the patient in this case should be closely monitored.

In the case presented, the patient opted for an add-on SGLT-2 inhibitor. Combining a DPP-4 inhibitor with a GLP-1RA might seem counterintuitive, since both agents work through modulation of GLP-1, but a single trial has indicated that the combination does provide a further 0.68% reduction of HbA1c, 18 which may be useful in some cases. In the presented case, this degree of glucose lowering would be insufficient to attain HbA1c goals.

diabetes complications case study

Case 3: Recurrent Hypoglycemic Episodes

A 62-year-old patient with T2DM had been uncontrolled with metformin plus SU (HbA1c of 8.6%). Add-on basal neutral Protamine hagedorn (NPH) insulin/regular insulin 70/30 (a schedule of two-thirds in the morning/one-third in the afternoon) was initiated and titrated to goal. This choice was driven by the need for a low cost, high-efficacy agent, but this resulted in a few mild hypoglycemia episodes (fasting blood glucose or overnight glucose of >56 mg/dL to <70 mg/dL not requiring assistance). As insulin titration progressed, hypoglycemic episodes were more frequent but not severe.

In an effort to reduce hypoglycemia and simplify the regimen, the SU was discontinued. After re-titration of insulin and implementation of very careful meal management, glycemic control was achieved without hypoglycemic episodes.

In such case, an important goal is to eliminate the hypoglycemic episodes. The severity of hypoglycemia should be assessed, as well as the conditions under which the episodes occurred. Hypoglycemia is often seen when patients take their medications as prescribed without eating. An irregular eating pattern and volume could be implicated in this scenario. In the presented case, the patient was receiving 2 agents that have a propensity to cause hypoglycemia (SU and insulin). The SU was withdrawn and the insulin re-titrated. As control becomes tighter during re-titration, the potential for hypoglycemia between meals and at night could increase. For between-meal hypoglycemia, small snacks can help but have an additional caloric burden. Nighttime hypoglycemia can be managed by decreasing the evening dose and moving away from the fixed two-thirds in the morning/one-third in the afternoon dosing.

Cost considerations drove this patient to use NPH basal insulin. While basal insulins (NPH, detemir, glargine, and degludec) all offer similar levels of fasting blood glucose control, “second-generation” (more expensive) basal insulins (detemir, glargine, and degludec) offer a flatter insulin profile, with less nocturnal hypoglycemia.

An alternative approach in this case could be to start the patient on a basal insulin alone until fasting blood glucose goals are attained, followed by the addition of a rapid-acting insulin at appropriate meals.

Case 4: Deteriorating Kidney Function

A 70-year-old obese female presents with stage 3 chronic kidney disease (CKD) and treatment-naïve T2DM (HbA1c of 7.6%). Her current eGFR is 45 mL/min/1.73 m 2 (ie, “moderate” renal impairment). She is normotensive.

Insulin and GLP-1RAs are considered; she elects to try a GLP-1RA.

CKD is a common condition in patients with T2DM that complicates the management of these patients. Drug clearance is often impaired, leading to prolonged exposure to increased drug levels. 19 As such, kidney function should be assessed before starting glucose-lowering therapy, and the patient should be carefully monitored for hypoglycemia (which may indicate increased drug levels) during treatment. 20 Many available glucose-lowering drugs are contraindicated, or should be used with caution, in patients with T2DM and CKD. 19,20 For example, the standard first-line glucose-lowering therapy (metformin) is contraindicated in patients with an eGFR <60 mL/min/1.73 m 2 . GLP-1RAs can be used with caution in patients with CKD as long as the eGFR is >30 mL/min/1.73 m 2 , and DPP-4 inhibitors can be used at reduced doses. 20 SGLT-2 inhibitors act by inhibiting reabsorption of glucose from the renal tubules into the bloodstream, thereby increasing urinary glucose excretion. Thus, as eGFR decreases, the ability of SGLT-2 inhibitors to lower blood glucose by this mechanism will also decrease. SGLT-2 inhibitors are not indicated in patients with an eGFR <45 mL/min/1.73 m 2 . 21,22 All forms of insulin are safe to use in mild to severe renal failure including dialysis, although healthcare providers and patients should be aware that dosage adjustments may be needed as renal function changes.

Case 5: Fear of Injections

A female patient presents with an HbA1c of 9.5% and has received metformin plus SU for the last 2 years. During a discussion of therapeutic options, the patient expresses anxiety about using injectable therapy, but her target HbA1c goal has not been attained with any of the multiple oral regimens she has tried.

Once the patient actually experiences an injection in the office, she is much less apprehensive. The idea of a once-weekly GLP-1RA appeals to her more than daily basal insulin.

In this case, it was important to help the patient overcome her fear of injections because adding a third oral agent had not been successful. Although it can sometimes be a challenge, there is value in determining the reasons why patients are anxious about injectable therapy and if there are any potential trade-offs that would make it more attractive (eg, weight loss or the need for only once-weekly administration). An injection trial, even with saline, in the office can sometimes help patients overcome their fear and become more willing to try injectable therapies. Where insulin is required, a strategy to assist patients in overcoming their fear of injections is to start with very low-dose basal insulin. Many patients can accept basal insulin but fear multiple mealtime injections. In such cases, taking a stepwise approach may be helpful, such as starting with just evening mealtime insulin.

Simplifying Treatment Decision-Making

Choosing the right therapy for the right patient is important to create a positive cycle of change for patients, enabling them to improve their glycemic control while increasing exercise, eating healthier, and losing weight. The requirement for additional medication is an unwanted burden for patients, and the way in which the clinician presents further treatment to the patient is of utmost importance. It is critical that patients are aware that diabetes is typically a progressive disorder and that the requirement to augment treatment is an anticipated part of the process, despite a patient’s best efforts. Factors that should be considered when deciding on therapy options include efficacy, side effect profile, cost, contraindications, previous therapy/adverse events, therapy delivery route/regimen, and patient preferences and perceptions. A positive patient–clinician relationship, which incorporates shared decision-making, can increase the likelihood of successful treatment. Clinician awareness of these factors should lead to better treatment choice, improved adherence, and improved outcomes for patients.

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Diabetes Quiz 18

A 78 year old male presents to endocrine clinic for diabetes evaluation after recent hospital stay for a heart failure exacerbation. His past medical history is significant for ESRD on hemodialysis, HFrEF with an EF of 35%, CAD s/p multiple stents, COPD on home O2, hypertension, and hyperlipidemia.

His diabetes medication regimen is presently lantus 20 units qHS, lispro 7 units TID AC, and glipizide XL 10mg qday.

His wife is concerned about several low blood sugar readings since discharge from the hospital. He has had numerous blood sugar readings in the 50-60s mg/dL in the morning along with before meals during the day. He has classic hypoglycemic symptoms during these episodes.

Physical exam is significant for the following: BMI 28kg/M 2 , BP 117/68mmHg, Heart rate 82bpm along with +2 pitting edema in the lower extremities bilaterally.

His most recent labs from 1 month ago were significant for a HbA1C of 5.9% and eGFR 7ml/minute/1.73m 2 .

In addition to stopping glipizide and lowering insulin doses, you counsel the patient and his wife that his target HbA1C % and blood sugars should be which of the following:

Given this patient is elderly with multiple end stage chronic diseases, the goal of diabetes therapy is to minimize any significant hypoglycemic events that may be occurring. The target HbA1C can be adjusted to <8.0-8.5% in these patients with a less stringent fasting and preprandial blood sugar goal of 100-180 mg/dL. Since he has ESRD, sulfonylureas can predispose patients on dialysis to hypoglycemia and should be used very cautiously especially while on insulin therapy.

In older adults treatment goals for glycemic control should be modified over time based on comorbidities, functional and cognitive status, and patient/caregiver preferences.

Standards of Care

12. Older Adults: Standards of Medical Care in Diabetes—2021

American Diabetes Association

Diabetes Care 2021 Jan; 44(Supplement 1): S168-S179. https://doi.org/10.2337/dc21-S012

Diabetes Case 17

A 45 year old male with type 2 diabetes comes to see his endocrinologist. His Hba1c had been 6.7 last visit 6 months back. HIs A1c has now has gone up to 8.2 on recent labs. He is currently on metformin 1000mg bid. The patient had been following carb counting but has been non-compliant with his diet lately. He reports fasting glucose in 150-230 range most days. He checks before dinner occasionally and reports glucose usually over 200. He denies any hypoglycemia.

The patient has gained 15 lbs. weight in past 6 months and has a BMI of 39. He does not have any long term CV complications at this time. Family history is remarkable for both parents with type 2 diabetes and dad with coronary artery disease and unilateral above knee amputation. The patient is tolerating metformin well. His BP is well controlled on lisinopril 10mg daily.

In addition to diet modification, which of the following would be the next best treatment option for optimizing this patient’s diabetes management?

This patient has a Hba1c of 8.0. He is obese and currently does not have any CV complications. The best treatment option for him would be to choose a medication that will address not only his high glucose but also his obesity and risk of complications.

The first choice for a second-line therapy by the new American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) guidelines is GLP1 RAs or SGLT-2 inhibitors for patients with atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease. For patients without these conditions, the ADA/EASD lists five options of noninsulin second-line therapy. On the other hand, the 2019 consensus statement from the American Association of Clinical Endocrinologists/American College of Endocrinology lists nine options, with GLP1 RAs as the first recommended therapy, followed by SGLT2 inhibitors and dipeptidyl peptidase 4 (DPP4) inhibitors, and sulfonylurea as the last option.

Currently Trulicity is the only GLP-1 agent that in addition to improving glucose and having the weight loss benefit will also provide primary prevention for CV disease.

Adding basal / bolus regime is currently not needed as many other options are available. Moreover, adding insulin will not provide the weight loss benefit and primary prevention CV benefit.

-Adding SGLT-2 inhibitor may be a good option however based on the above guidelines and primary prevention benefit associated with Trulicity once weekly GLP-1 seems like the best option. And it will also help him lose weight.

1-Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC.

2-Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double‐blind, randomised placebo‐controlled trial. Lancet. 2019;394(10193):121‐130.

3-Gerstein HC, Colhoun HM, Dagenais GR, et al. Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide. Diabetes Obese Metab. 2018;20(1):42‐49.

Diabetes Case 16

Michael is a 48-year-old gentleman with T2DM since age of 38. He has background of ischemic heart disease, mixed hyperlipidemia and hypertension. He had a delayed presentation of an inferior myocardial infarction 3 months ago. He is currently treated with Metformin XR 1g twice daily, Sitagliptin 100mg once daily, perindopril 5mg once daily, bisoprolol 2.5mg once daily Atorvastatin 80mg once daily. His most recent labs showed:

Creatinine 1.1mg/dL (97.3umol/L), eGFR 76ml/minute/1.73m2, fasting glucose 145mg/dL (8mmol/L), HbA1C 7.6% (60mmol/mol), Albumin/creatinine 28 mg/g (normal<30mg/g), total cholesterol 150mg/dL (3.9mmol/L), with HDL-C 40mg/dL (1.04mmol/L), NT-pro-BNP 754pg/ml (normal for age <125pg/ml).

His clinic checks showed height 172cm, weight 73kg, BMI 24.7kg/m 2 , BP 134/82mmHg.

You explain to him that he has sub-optimal diabetes control and a HbA1C <7.0% should be sought.

Which of the following therapy interventions is most appropriate?

Lifestyle modifications are important and should be optimized regardless of treatment modality but should be adjunct to other therapy modifications given the importance of achieving target as soon and safe as possible.

Gliclazide may help improve his diabetes control but will put him at risk of hypoglycemia which can be detrimental in his condition. Also, Gliclazide promotes weight gain which is better avoided in this patient.

Switching to a GLP1RA is a reasonable option especially with the cardiovascular benefits, however, most likely GLP1RA cause nausea, at least during the initiation period and are given as SC injections which can reduce compliance.

Given the late presentation of his inferior MI and the mild rise in NT-pro-BNP the risk of heart failure is high. Dapagliflozin, and SGLT2 inhibitor with diuretic and glucosuric properties, would suit the patient very well with proven cardiovascular benefits including heart failure, ease of intake (oral), minimal risk of hypoglycemia, and weight reduction potential.

Diabetes Case 15

A 64 year-old female presents to your clinic for management of type 2 diabetes mellitus diagnosed fifteen years ago. Her medical history includes coronary artery disease (s/p CABG) and ischemic cardiomyopathy (ejection fraction 45%) complicated by two hospital admissions for congestive heart failure exacerbation within the past year. She was recently diagnosed with diabetic gastroparesis.

Her glucose-lowering regimen solely comprises Lantus 30 units daily. Fingerstick glucose data discloses infrequent fasting hypoglycemia.

Physical examination: BP 125/76 mmHg, heart rate 72 bpm, BMI 36 kg/m 2 . Sensation is intact to monofilament testing in both feet.

Pre-clinic lab assessment:

Which of the following would be the next best treatment option?

Canagliflozin is an SGLT2 inhibitor that has been approved by the FDA to reduce the risk of major cardiovascular events in adults with type 2 diabetes and established cardiovascular disease 1 . Moreover, it is also indicated to reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria. Relative to placebo, participants who received canagliflozin in the CREDENCE trial experienced a 30% reduction in the risk of the primary composite endpoint, which included end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death 2 .

Dulaglutide is a once weekly injectable glucagon-like peptide-1 receptor agonist (GLP-1 RA). It received FDA approval for the reduction of major cardiovascular events (MACE) in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors 3 . Long-term use of dulaglutide is also associated with reduced composite renal outcomes - defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy - in people with type 2 diabetes 4 . Nevertheless, dulaglutide would be an unsuitable option in this scenario due to the presence of gastroparesis. GLP-1 RAs slow down gastric emptying and could therefore exacerbate gastroparesis.

Saxagliptin, a DPP4 inhibitor, is unsuitable for the lady in question, who has experienced systolic congestive heart failure exacerbations. Results from the SAVOR-TIMI 53 trial demonstrated an increased risk of heart failure hospitalization with the use of saxagliptin 5 .

Increasing the dose of Lantus would be a reasonable option, but not the best next step. As it is, she already experiences some degree of hypoglycemia. Thus, increasing the dose of insulin could increase the frequency of hypoglycemic episodes. Furthermore, monotherapy with insulin would not address the presence of CKD secondary to diabetic nephropathy or cardiovascular disease.

Diabetes Case 14

A 29 year old female with T1DM since age of 11, treated with multiple daily injection using Insulin Detemir 20 units at night and Insulin Aspart 1 unit per 10 grams of carbohydrates per meal.

She informs you that she is pregnant at 8 weeks gestation and she is asking your support. She has impaired hypoglycemia awareness with GOLD score of 5 with a recent history of severe hypoglycaemia requiring administration of Glucagon injection by partner. She has mild background diabetic retinopathy and raised microalbuminuria. A trial of insulin pump in the past was not successful as patient found it too intrusive. Her pre-clinic labs assessments showed:

eGFR 68ml/minute/1.73m 2

ACR 145mg/mmol/ (Normal <30)

Hb 112g/L (Female 120-160g/L)

On examination you find:

Heart rate 82bpm

Injection site examination reveals multiple lipohypertrophy legions in the abdomen, but not the thighs or upper arms.

Which of the following is likely to make the most difference to her diabetes and pregnancy outcomes?

Continuous glucose monitoring (CGM) will be of great utility for this lady during her pregnancy. Intensification of therapy is required in order to achieve HbA1C target of <6.5% and postprandial glucose target of <120 mg/dL (6.7 mmol/L) (Management of Diabetes in Pregnancy: Standards of Medical Care in Diabetes—2020, https://doi.org/10.2337/dc20-S014). CGM can enable close glucose monitoring as well as alarms for hyperglycemia and hypoglycemia which would be particularly useful for this lady given her hypoglycemia awareness impairment. The CONCEPTT trial (Feig et al, Lancet 2017, DOI: 10.1016/S0140-6736(17)32400-5) demonstrated significant reduction in maternal hyperglycemia and improved neonatal outcomes with CGMs use in comparison to standard of care.

Insulin Detemir is licensed for use during pregnancy, and while longer acting insulin analogues have evidence for hypoglycemia risk reduction the patient can achieve better outcomes by avoiding lipohypertrophy sites when injecting insulin. Sensor augmented pump can reduce risk of hypoglycemia, but given patient’s previous experience it is not recommended to explore this again in pregnancy unless recurrent hypoglycemia becomes problematic. The patient is doing carbohydrates counting already and a refresher training session will be helpful but not likely to make a difference on its own.

Diabetes Case 13

68-year-old female with a 17 year history of type 2 diabetes is seen in follow-up. She does have hypertension, hyperlipidemia with known coronary disease with prior PTCA/stent 2 years ago. She did have an ophthalmology evaluation where there was no evidence of background retinopathy.

Medications include: Metformin 850 mg twice daily, Actos 30 mg daily, sitagliptin 100 mg daily

On physical examination, blood pressure is 130/70, heart rate = 82, body mass index = 34, afebrile

She has evidence of acanthosis nigricans on physical examination. There were no thyroid nodules palpable or a bruit.

Laboratory data:

hemoglobin A1c = 7.5%, serum creatinine = 1.4 mg/dl, eGFR 51 ML/Min/1.73m2; urine albumin: Creatinine ratio(UACR) to 32 mg/g, unchanged from prior evaluation 6 months ago.

Based on the data described above, does this patient have diabetic kidney disease?

The diagnosis of diabetic kidney disease is based on the presence of albuminuria, defined as UACR > or equal to 300, or UACR 30-299 mg/g WITH the presence of diabetic retinopathy and/or having type 1 diabetes greater than or equal to 10 years in duration, OR demonstrated reduced kidney function and the presence of diabetes as defined as an sGFR <60 mL/min/1.73m2-.,of course, in the absence of any other causes of kidney damage.

Diabetes Case 12

A 42 year-old woman with type 1 diabetes for 22 years was married recently, and she and her husband have decided to have a child. Neither had children previously. The woman has hypertension treated with an angiotensin converting enzyme (ACE) inhibitor and a diuretic with maintenance of blood pressure at 120/80 mm Hg. She recently had a 24 hour urine test, and the results showed a total protein of 3 grams (normal, <80 mg) and creatinine clearance of 70 mL/minute (normal, 88-128 mL/minute). Her glycated hemoglobin (HbA1c) is 6.7% (normal, <5.7%). Her insulin doses are all administered through a continuous insulin infusion pump using insulin aspart. Her present weight is 60 kg; thus, her insulin requirement was calculated as 0.6 times her weight in kilograms = 36 units per day with 1/2 basal and 1/2 bolus. She reported that she would try to become pregnant next month.

What do you advise her?

The risk of congenital defects is clearly related to hyperglycemia in the first trimester. A meal plan that may minimize postprandial excursions could be achieved by redistribution of carbohydrate intake into three small-to-moderate meals and 2-4 snacks, with a meal plan calculated as 30 kcal per kg. During preconception planning, the Endocrine Society recommends obtaining an HbA1c as close to normal as possible, if this can be safely achieved. For women with pre-existing diabetes, the American Diabetes Association recommends attempting to optimize glycemic control prior to conception, with a goal of HbA1c <6.5%, a level associated with the lowest risk of congenital anomalies. Glycemic control later in pregnancy affects the risk for large-for-gestational age (size) and other complications. In the later stages of pregnancy, the HbA1c normally declines. As a result, the American Diabetes Association recommends a target of 6-6.5% for pregnant women with diabetes as pregnancy progress, although <6% may be optimal, with precautions to avoid hypoglycemia. The following targets are suggested:

A fasting target = 90 mg/dL is considered optimal if it can be safely achieved, with the caveat that significant hypoglycemia could be reason to modify the targets.

Because of the risk of teratogenic effects, ACE inhibitors and angiotensin receptor blocker (ARB) therapy should be discontinued and/or replaced, if necessary for control of hypertension, as part of pre-pregnancy planning. If treatment is required, antihypertensive medications that can be used effectively and safely during pregnancy include methyldopa, labetalol, diltiazem, clonidine, and prazosin. Diuretic therapy is not recommended due to the risk of volume depletion. Statin use is similarly contraindicated in pregnancy.

A fasting target ≤ 90 mg/dL is considered optimal if it can be safely achieved, with the caveat that significant hypoglycemia could be reason to modify the targets.

Diabetes Case 11

A 37 years old female with T1DM since age of 24. She has mild background diabetic retinopathy and microalbuminuria. She attended structured education for carbohydrates counting and insulin management few years ago. She moved from multiple daily injections to insulin pump therapy 4 months ago due to inadequate diabetes control and fear of hypoglycaemia. She had one episode of severe hypoglycemia 2 years ago requiring paramedics attendance and intervention. She has intact hypoglycaemia awareness. She does exercise 3 times a week, one hour each in the afternoon with mixed aerobic and anaerobic activities preceded by carb loading (30 grams). When seen in clinic her BP was 132/82mmHg, weight was 84kg with BMI 29.7kg/m 2 . Her most recent labs showed:

Hb 132g/L (115-165g/L)

MCV 83fL (Ref 80-103fL)

HbA1C 12.5% (113mmol/mol)

Creatinine 105µmol/L (1.19mg/dL) (ref 46-115µmol/L)

Urea 6.4mmol/L (17.9mg/dL) (ref 2.7-8.3mmol/L)

Total cholesterol 4.6mmol/L (185mg/dL) (ref <5.3mmol/L)

Albumin/ creatinine 122mg/g (<30mg/g)

TSH 2.4 µIU/L (ref 0.31-4.5uIU/L)

Her current medications include: Insulin Aspart in the insulin pump, Perindopril 4mg daily, Combined Oral Contraceptive Pill. Her basal rates are outlined in the figure below. Her bolus calculator settings are: insulin to carbohydrates ratio (ICR)= 1 unit per 10 grams of carbohydrates, Insulin sensitivity factor (ISF)= I unit to reduce glucose by 3 mmol/L. Duration of insulin action = 5 hours. Glucose target: 7mmol/L (125mg/dL).

A typical day of her insulin pump download is shown below (an exercise day).

What would you advise in regard to her insulin pump therapy?

The patient appears to be very engaged with her insulin pump with numerous daily glucose checks and multiple bolus administrations. Despite that, her readings are elevated, more so in the afternoon and evening. By focusing on insulin distribution, we note a major imbalance between basal and bolus insulin with majority of her total daily dose (TDD) of insulin coming from bolus insulin leaving her fire-fighting trying to catch up with high glucose. It is too early to stop insulin pump therapy as she has been on it for only 4 months so far and the problem is not with patient management. While adding CGM would help with hypoglycemia early detection and fear alleviation; at this stage the patient is doing adequate glucose monitoring and she has not had hypoglycemia while on insulin pump. The effect of adding CGM on improving diabetes control would be minimal as the problem is not lack of monitoring. Switching to a sensor augmented insulin pump would have been the correct course of action if she has been experiencing recurrent hypoglycemia, which is not the case.

There is a considerable scope for improvement. She seems to have a degree of insulin resistance and the basal insulin setting is too conservative. Moreover, the excessive rise in glucose in the afternoon and evening is likely due to a combination of low basal insulin rate, inadequate ICR and anerobic exercise. Expected TDD for her weight is 58 units/24 hours (84 [weight in kg] X 0.7), with basal rate being 29 units (50% of TDD), equivalent to 1.2unit/hour. For protection against nocturnal hypoglycemia a 20% lower basal rate (1.0unit/hour) from midnight till 4:00AM is recommended. Moreover, advice on using temporary basal reduction by 50% 1 hour before exercise and for the duration of exercise should be given. Revision of bolus calculator settings should be explored after few days of instituting the basal rate changes.

Diabetes Case 10

A 39 year old woman presents for evaluation of gestational diabetes (GDM) at 18 weeks gestation. She reports a history of a prior pregnancy 6 year ago, during which she was previously diagnosed with GDM but was managed with diet control. She reports that an oral glucose tolerance test was performed following the last pregnancy, and that it was normal. HbA1c checked at her first prenatal visit of the current pregnancy was 5.4%. Due to her prior history of GDM her obstetrician ordered a 75g oral glucose tolerance test in the early second trimester which showed:

Fasting glucose 97 mg/dl (normal 60 - 92 mg/dl)

1 hour glucose 191 mg/dl (normal 60 - 180 mg/dl)

2 hour glucose 165 mg/dl (normal 60 - 153 mg/dl)

The patient subsequently met with a certified diabetes educator and was provided with glucometer training and dietary counselling. She has been monitoring point of care glucose levels at home fasting and one hour postprandial. Her fasting glucose is now ranging from 99-110 mg/dl, and her 1 hour postprandial glucose is ranging from 150-170 mg/dl. Physical exam is normal other than BMI of 33.

Which of the following statements is true regarding her current glucose levels in pregnancy?

This patient has been diagnosed with gestational diabetes based on failed values for all time points on her oral glucose tolerance test. Despite a normal HbA1c reflecting her lack of diabetes prior to pregnancy, she has developed GDM at this point in her pregnancy. Her elevated glucose values above pregnancy targets are also confirmed on home glucose monitoring despite already receiving dietary counselling. Overly aggressive dietary counselling is not appropriate as pregnant patients should maintain adequate calorie and carbohydrate intake to sustain the pregnancy and avoid ketosis which can lead to preterm labor. GLP-1 receptor agonist therapy has not been studied in pregnancy and is not a recommended therapy option.

Although metformin and glyburide can be used in pregnancy, opting for insulin therapy is the most likely to be successful at rapidly controlling glucose levels and maintaining glucose control for the duration of the pregnancy in this patient. Tight glycemic control in pregnancy has been correlated with improved maternal and fetal outcomes.

Diabetes Case 8

A 28 year-old male patient with a 20-year history of type 1 diabetes mellitus presents with complaints of new onset floaters in his right eye. He reports that his diabetes has been poorly controlled with his most recent glycated hemoglobin (HbA1c) at 12% (normal, Examination shows 20/20 acuity in both eyes. Dilated fundus examination of both eyes shows mild vitreous hemorrhage. Scattered retinal hemorrhages, neovascularization of the disc, and multiple areas of neovascularization in the mid-peripheral retina are also present. No macular edema is observed, and the retina is attached in both eyes.

What is the most appropriate course for treating diabetic retinopathy for this patient?

Numerous studies have shown that regular screening and early intervention slow the progression of retinopathy. Only 40% of patients achieve their target HbA1c even two years after starting insulin treatment. Frequent dilated fundus examinations performed by an ophthalmologist serve to assess the degree of retinopathy, educate patients on the potential complications, and reinforce the need for optimal metabolic control. While screening examinations are the cornerstone of managing diabetic retinopathy, this would not be the most appropriate management for this patient.

The patient has proliferative diabetic retinopathy, which can lead to severe vision loss if left untreated. This patient requires treatment for his proliferative retinopathy rather than just on-going screening. Regular screening examinations would be appropriate if the patient had non-proliferative diabetic retinopathy.Panretinal photocoagulation (PRP) is the appropriate management for proliferative diabetic retinopathy. PRP has been shown to reduce the risk of severe vision loss in such patients.

The patient in the clinical vignette above has neovascularization at the disc and in the peripheral retina along with evidence of bleeding (vitreous hemorrhage) from these abnormal vessels. The goal of PRP is to cause regression of neovascularization, and thus, reduce the risk of vision loss. Aggressive metabolic control would help reduce long-term complications in this patient, although it is not likely to have an immediate beneficial effect on retinopathy. Metabolic control is an effective method of slowing the progression of diabetic retinopathy. Intensive metabolic control, as reflected by the HbA1c value, not only reduces the mean risk of developing retinopathy, but also lowers the risk of progression. Stringent goals may reduce long-term diabetes complications, coincident with an increased risk of hypoglycemia, especially in patients with type 1 diabetes mellitus. However, some patients might experience worsening of retinopathy with initiation of aggressive control after years of suboptimally controlled diabetes. In the ACCORD trial, overall mortality was noted to be slightly higher in patients with type 2 diabetes who were randomized to aggressive glycemic control with a target HbA1c less than 6%.

The American Diabetes Association (ADA) recommends individualized HbA1c goals for patients. Young patients with a long life expectancy, low risk of hypoglycemia, and the absence of cardiovascular risk factors can have aggressive HbA1c goals (6%-6.5%), while older patients with a long duration of poorly controlled diabetes and the presence of cardiovascular disease may benefit from less stringent HbA1c goals (7.5%-8%). Also, less-intensive glycemic goals may be indicated in patients with severe or frequent hypoglycemia.Vitrectomy surgery would not be the most appropriate management for proliferative diabetic retinopathy in this patient. Vitrectomy is a surgical procedure that involves removal of the vitreous gel from the eye and relieves areas of vitreo-retinal adhesions. Indications for vitrectomy in diabetic retinopathy include non-clearing vitreous hemorrhage, retinal detachment threatening the macula, and traction on the macula leading to edema.Steroids are potent anti-inflammatory agents that have a role in treating diabetic macular edema but would not be beneficial in the clinical scenario described above. Anti-vascular endothelial growth factor (VEGF) agents also have a role in treating diabetic macular edema, but their role in managing diabetic retinopathy is currently being investigated in clinical trials.

Diabetes Case 9

A 67 year-old woman recently moved to your city and presents to you in clinic for the first time. She has had type 2 diabetes for about 14 years and has been taking glyburide 10 mg daily and metformin 1000 mg bid. She states that she has known retinopathy and neuropathy. She has coronary artery disease and has had two intracoronary stents placed last year. She is taking losartan for blood pressure control and to “protect” her kidneys, as well as atorvastatin 40 mg and clopidogrel 75 mg daily. Her examination is significant for a body mass index (BMI) of 34 kg/m2 (normal, 18.5 to 24.9 kg/m2), a blood pressure (BP) of 138/84 mm Hg, microaneurysms on eye exam, decreased vibratory sensation in her feet, and absent Achilles reflexes. Laboratory testing shows a glycated hemoglobin (HbA1c) of 7.9% (normal, In addition to healthy lifestyle, you discuss adding another medication for glycemic control, including alternatives for intensification of therapy.

If the patient opts for adding empagliflozin, evidence would suggest that its inclusion as a component of therapy may reduce the likelihood of which of the following outcomes?

Diabetes is a major cause of cardiovascular disease (CVD), and individuals with chronic kidney disease (CKD) often die of CVD; it is the major cause of death in this patient population. The presence of microalbuminuria, albuminuria, and declining glomerular filtration rate (GFR) are all known predictors of CVD. In the EMPA-REG OUTCOME trial, approximately 7000 subjects were randomized to empagliflozin or placebo and followed for a median of 3.1 years. Those who received empagliflozin had fewer cardiovascular events, defined as the primary outcome (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) compared to placebo (10.5% vs. 12.1%, HR 0.86, 95% CI 0.74-0.99, P=0.04 for superiority).

The rate of hospitalization for heart failure was also lower in the empagliflozin group. Use was associated with a significant reduction in incident or worsening nephropathy (defined as progression to macroalbuminuria, doubling of serum creatinine level, initiation of renal replacement therapy, or death from renal disease) (12.7% vs. 18.8%; HR 0.61, 95% CI 0.53-0.70, P<0.001).

In your discussion of treatment alternatives, you describe potential complications of sodium glucose co-transporter 2 (SGLT-2) inhibitor therapy. The patient then mentions her past history of recurrent vaginal yeast infections and decides against using empagliflozin. You also mention liraglutide 1.8 mg daily injection.

Which of the following has been shown with Liraglutide 1.8 mg daily therapy?

Liraglutide tends to improve both fasting and postprandial control and promote weight loss, but a side effect may be nausea, which may be transitory or dose dependent. In the LEADER trial, over 9000 subjects were randomized to liraglutide or placebo and followed for a median of 3.8 years. The primary outcome was time to first occurrence of composite endpoint (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke).

Those receiving liraglutide had fewer primary outcome events (13.0% vs. 14.9%; HR 0.87, 95% CI 0.78-0.97). At the present time there is insufficient evidence to confirm an increased risk of pancreatic cancer with GLP-1 agonist therapy. There is some evidence in animal models that GLP-1 may decrease the rate of beta cell failure. Mean weight loss while on the 1.8mg dose of liraglutide was found to be 4.7% (5 kg).

Diabetes Case 7

A 58 year-old retired truck driver with type 2 diabetes underwent bariatric surgery three days ago for treatment of obesity. He has a 12-year history of type 2 diabetes, well controlled with metformin 1000 mg bid, sitagliptin 100 mg/d, dapagliflozin 10 mg/d, and 35 units of glargine insulin at bedtime. His glycated hemoglobin (HbA1c) levels have ranged between 6.8% and 7.4% during the past two years. The patient was recently diagnosed with sleep apnea and has developed increasing fatigue, along with knee pain due to left osteoarthritis. He also had a history of hypertension and hyperlipidemia, well-controlled with lisinopril 40 mg/day, amlodipine 10 mg/day, and atorvastatin 40 mg/day. He has a long history of obesity since his early 30's when he used to drive a delivery truck, eating in fast-food restaurants 5 days a week combined with a lack of exercise for over 25 years. His body mass index (BMI) was calculated at 42 kg/m2 (normal, 18.5 to 24.9 kg/m2). Prior to surgery, his blood pressure was 139/75 mm Hg; pulse was 84 beats/minute; respirations were 16 breaths/minute, and his temperature was 37°C. Physical examination was unremarkable except for generalized obesity. The surgery went well and without complications. His blood glucose (BG) was 144 mg/dL before surgery and 168 mg/dL repeated two hours after surgery. Antidiabetic drugs were stopped the day of surgery, except for glargine insulin at 30 units/day plus correction doses with lispro every 6 hours. During the first two days after surgery, the patient's BG ranged between 120 and 220 mg/dL (normal random, <140 mg/dL). In the evening of the 2nd post-op day, he developed tachycardia (114 beats/minute), mild dyspnea, and fatigue. His blood pressure was 100/74 mm Hg, and his respiratory rate was 18 breaths/minute, SpO2 was 96%. He was afebrile. The resident on call evaluated the patient and ordered the following tests: stat EKG reported as sinus tachycardia and non-specific T wave abnormalities. The patient had normal cardiac enzymes and a negative chest-X-ray. Figure 1 Despite an IV bolus of normal saline of 500 mL over two hours and hydration at 200 mL/hr, he remained tachycardic (heart rate of 110-120 beats/minute), with mild-shortness of breath and diffuse abdominal pain. Blood glucose (BG) continued to be around 160-240 mg/dL during the 3rd day post-op.

Which of the following diagnostic tests would you order?

Diabetic ketoacidosis (DKA) is most commonly reported in patients with type 1 diabetes, but it can also occur in patients with poorly controlled type 2 diabetes in the presence of stress and concomitant medical and surgical illnesses. Drugs that affect carbohydrate metabolism such as corticosteroids, sympathomimetics, and atypical antipsychotics might also precipitate the development of DKA. In recent years, an association between the use of sodium glucose co-transporter 2 (SGLT-2)-inhibitors and DKA has been reported in patients with type 1 and type 2 diabetes.

The US Food and Drug Administration (FDA) and European Medicines Agency have both issued warning statements listing DKA as a rare adverse reaction of SGLT-2-inhibitor treatment. In clinical trials of patients with type 1 diabetes treated with SGLT-2 inhibitors, about 10% of patients developed ketosis and 5-6% required hospitalization for DKA. In patients with type 2 diabetes, DKA is rare, reported in 0.1-0.8 per 1,000 patients. Most cases of DKA occur among patients with a concomitant precipitating cause, such as surgery, alcohol abuse, insulin pump malfunction, and poor adherence to medications. Awareness among healthcare professionals, as well as patient education, might facilitate early detection of DKA during SGLT-2 inhibitor treatment or even prevent development of this diabetes emergency.

Potential strategies include routine monitoring of blood and urine ketone bodies during acute illness, periods of starvation, and in the presence of hyperglycemia. Until more information is available, the use of SGLT-2 inhibitors should be avoided during severe illness, major surgical procedures, and when ketone bodies are detected despite increases in insulin dose. For patients taking an SGLT-2 inhibitor who present with symptoms suggestive of DKA, such as abdominal pain, nausea, vomiting, fatigue, and dyspnea, a diagnosis of DKA should be considered and an appropriate work-up carried out. Although a low bicarbonate and/or the presence of positive urinary ketones may be suggestive of DKA, these measures may be inaccurate.

Therefore, the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) recommends direct measurement of blood ketones (beta-hydroxybutyrate) and arterial pH as necessary to confirm the diagnosis. Normal or modestly elevated blood glucose does not exclude the diagnosis of DKA during SGLT-2 inhibitor use. For management of DKA in patients taking SGLT-2 inhibitors, stop the drug immediately and proceed with traditional DKA treatment protocols. Note that although the drug is discontinued, SGLT-2 inhibitor-mediated increases in urinary glucose loss may persist for several days. To minimize the risk of DKA associated with SGLT-2 inhibitors, AACE/ACE recommends stopping the SGLT-2 inhibitor at least 24 hours prior to elective surgery, planned invasive procedures, or anticipated severe stressful physical activity such as running a marathon. Routine measurement of urine ketones is not recommended during use of SGLT-2 inhibitors because this measurement can be misleading. Instead, measurement of blood ketones is preferred for diagnosis of DKA in asymptomatic patients.

Diabetes Case 6

You are called Sunday morning by the emergency medicine physician for a 28 year-old male with a 13-year history of poorly controlled type 1 diabetes and recurrent episodes of diabetic ketoacidosis (DKA). He has a history of non-proliferative diabetic retinopathy and hypoglycemia unawareness. His mother found him confused and lethargic at home and called EMS (Emergency Medical Service). While waiting for EMS, she gave him half a glass of regular soda with no improvement in mentation. EMS performed capillary blood glucose (BG) and found that it was greater than 600 mg/dL (normal random, <140 mg/dL). Normal saline was started, and he was transported to the nearest ER (emergency room). His mother states that he has been taking insulin glargine and lispro insulin. He had four hospital admissions during the past year due to hypoglycemia and three episodes of DKA. The patient drinks beer and vodka during the weekends. Physical examination: Patient is a well-developed lean male; blood pressure is 92/45 mm Hg; pulse is 116 beats/minute; respirations are 22 breaths/minute, and temperature is 35ºC. Neck was supple; lungs were clear. Cardiovascular (CV) exam revealed tachycardia, but no S3 or S4 gallops. Abdomen was diffusely tender with mild rebound pain. Neurological exam results were as follows: stupor, no focal findings, moving four extremities, and appropriate response to pain.

Based on the clinical presentation, your initial orders should include which of the following?

Diabetic ketoacidosis (DKA) is the most serious life-threatening hyperglycemic emergency in patients with diabetes. Infections are the most common cause of DKA around the world; however, poor adherence to insulin treatment is the most common precipitating cause of DKA in young patients with type 1 diabetes (T1D) and in inner city populations. Other causes include newly diagnosed diabetes, non-infectious illnesses such as acute myocardial infarction or neurovascular accidents, alcohol use, pancreatitis, and psychological disorders such as depression and eating disorders. Further causes include insulin pump malfunction and certain medications (corticosteroids, sodium glucose co-transporter 2 (SGLT-2)-inhibitors).

The syndrome of DKA consists of the triad of hyperglycemia, ketonemia, and metabolic acidosis. Diagnostic criteria include a blood glucose >250 mg/dL, bicarbonate 12 mmol/L. Although the majority of patients present with plasma glucose levels >250 mg/dL, some patients exhibit only mild elevations in plasma glucose levels. This ‘euglycemic DKA' can be seen during pregnancy, prolonged fasting, or with SGLT-2 inhibitor use.

Treatment goals include correction of dehydration, hyperglycemia, and hyperosmolality, electrolyte imbalance, increased ketonemia, and identification and treatment of precipitating event(s). During treatment, laboratory measurements of glucose and electrolytes, venous pH, bicarbonate, and anion gap should be repeated every 2-4 hours. Intravenous (IV) fluids are a critical aspect of DKA treatment. Treatment with IV fluids alone expands intravascular volume, restores renal perfusion, and reduces insulin resistance by decreasing circulating counter-regulatory hormone levels. Isotonic saline (0.9% NaCL) is the preferred solution and is given at an initial rate of 500-1000 mL/hour during the first 2-4 hours. Most patients with DKA present with a normal or elevated serum potassium level despite a total body potassium deficit. Insulin therapy lowers serum potassium levels by promoting the movement of potassium back into the intracellular compartment. Thus, potassium replacement should be started when the serum concentration is This patient presented with severe DKA, hyperglycemia, and hypokalemia. His serum potassium was 3.0 mmol/L. Due to the risk of aggravating the patient's hypokalemia, insulin therapy should be delayed, and the patient should receive IV fluids plus potassium for the first two hours. Serum potassium should be repeated in two hours, and insulin should be delayed until serum potassium is greater than 3.3-3.5 mmol/L. Option A is incorrect since there is no proven benefit from administering bicarbonate in patients with DKA in the absence of severe metabolic acidosis.

Option B is incorrect since insulin alone without concurrent normal saline and potassium infusion would only worsen hypokalemia and fail to restore circulatory volume for better renal perfusion. Option D is incorrect because half normal saline alone would neither correct hypovolemia nor correct hypokalemia.

Diabetes Case 5

A 32 year-old woman with a 10-year history of type 1 diabetes is referred to you to discuss insulin pump therapy. She has a very erratic schedule of activity and eating due to work and having a toddler at home. She is also interested in another pregnancy in the next year. Her current insulin regimen consists of insulin glargine 14 units at bedtime and insulin lispro 4 units with each meal. Self-monitoring of blood glucose shows values ranging between 60-250 mg/dL (normal random, <140 mg/dL).

Hypoglycemia occurs infrequently, and she has reliable symptoms. Her height is 64 inches (162.56 cm), and her weight is 132 lbs (60 kg). Her body mass index (BMI) is 23 kg/m2 (normal, 18.5 to 24.9 kg/m2). Physical examination findings were unremarkable. Recent glycated hemoglobin (HbA1c) measurement was 6.4% (normal, <5.7%). You discuss glucose goals for pregnancy and refer to diabetes education to review carbohydrate counting and basal-bolus therapy.

Which of the following would you anticipate she would need, as a conservative starting point, when she transitions to the insulin pump?

It is essential to understand how to convert from multiple daily injections of insulin to a continuous infusion of insulin through an insulin pump. Equations commonly used for determining the basal rates, carbohydrate to insulin ratios, and correctional doses are listed below. These equations are not only useful to determine initial doses of insulin, but can also be useful for long-standing pump users as you review their pump settings and make adjustments based on total doses of insulin and patterns of use.To determine the total daily dose (TDD) of insulin, basal and bolus doses on average should be added together.

To reduce the risk of hypoglycemia, the total dose may be decreased by 20-25% to determine the “pump TDD”. An alternative method suggested by the 2014 American Association of Clinical Endocrinologists (AACE) consensus statement suggests “pump TDD” can be calculated from the patient's weight in kilograms multiplied by 0.5. Both calculations need adjustment based on baseline HbA1c and hypoglycemia history.Calculations for pump settings:1. Basal rate: Pump TDD x 0.5, divided by 24 to determine the hourly rate2. Carbohydrate ratio: 450 divided by pump TDD3. Insulin sensitivity factor: 1700/pump TDDBased on her TDD of 26 units (14 + 12), which would be reduced by 20% (due to her low HbA1c), her TDD would be approximately 20 units per day.20 x 0.5 = 10 divided by 24 hours would be a basal rate of 0.4 units per hour.Carbohydrate ratio would be 450 divided by 20 = 22.5 (rounded up to 25).Sensitivity factor would be 1700/20 = 85.

She now returns for follow up one year after transitioning to insulin pump therapy, which went smoothly. She is currently using insulin lispro in her pump. She no longer plans to have any more children and had an intrauterine device (IUD) placed by her primary care physician (PCP).

Her basal rates are 0.45 units per hour; her insulin to carbohydrate ratio is 1:20 with all meals, and her insulin sensitivity factor is 85, with a target of 120 mg/dL. Her main concern is a 15 lb weight gain (6.8 kg) since transitioning to the insulin pump. Because of this gain, she is unwilling to increase her insulin doses, but is frustrated that her glycated hemoglobin (HbA1c) has increased compared to her last visit. She is interested in pramlintide injections. You suggest adding pramlintide before each meal, starting with 15 mg and titrating the dose every three days as tolerated to a maximal dose of 60 mg before each meal.

With the start of pramlintide, what changes would you suggest to her pump settings?

Pramlintide is a synthetic analog of human amylin, a neuroendocrine hormone co-secreted from the beta cell that lowers postprandial glucose levels by suppressing postprandial glucagon secretion and slowing gastric emptying, thus reducing the rate of glucose absorption from the gastrointestinal tract. Like insulin, it is deficient in those with type 1 diabetes. Studies in patients with type 1 diabetes note that adding pramlintide to injected insulin or continuous subcutaneous insulin infusion (CSII) can blunt glycemic excursions, reduce HbA1c levels by 0.2-0.4%, improve satiety, and produce modest weight loss of 0.5-1 kg.

Upon initiation, pramlintide should only be used with meals containing at least 30 grams of carbohydrate, and mealtime insulin doses are initially decreased by 50% to avoid hypoglycemia. The most common side effect is nausea, which can be minimized by titrating the drug from a lower starting dose. Pramlintide is only available in pens.The correct answer is option C; with initiation of pramlintide, you would decrease bolus amounts by up to 50%, which would mean increasing the carbohydrate ratio. Other factors would not be appropriate to adjust

Diabetes Case 4

Case Background:

A 21 year-old man with a 7-year history of type 2 diabetes mellitus (T2DM) presents for follow-up. He was diagnosed with T2DM at age 14 years. At that time, his body mass index (BMI) was in the 99th percentile for his age. His mother has a history of gestational diabetes mellitus during her pregnancy with him and was diagnosed with T2DM in her early forties, when he was ten years old. His current BMI is 41 kg/m2 (normal, 18.5 to 24.9 kg/m2). He has been treated with metformin and insulin analogues, but he has not been taking the insulin recently because he feels unwell after he exercises with symptoms of shakiness, sweatiness, and hunger. His glycated hemoglobin (HbA1c) is 9.2% (normal, <5.7%). He wants to know more about diabetes mellitus and asks if there are other medication options for him.

Q1. The pathophysiology of the diabetes mellitus of this patient is characterized by which of the following?

Rationale: Insulin, produced and secreted by beta cells located in clusters of pancreatic cells called the islets of Langerhans, is the most potent anabolic hormone, promoting the uptake, utilization, and storage of both glucose and lipids. T2DM is characterized by resistance to the actions of insulin in target tissues. Pancreatic beta cells compensate by increasing insulin secretion, and patients with insulin resistance initially have high circulating levels of insulin and maintain normal serum levels of glucose. Eventually, however, pancreatic beta cells start to fail. When they can no longer supply enough insulin to meet these increased requirements, T2DM develops. It is believed that the chronic demand for elevated insulin secretion in insulin resistant subjects unmasks a secondary defect in the beta cells, resulting in progressive loss of beta cell function. Thus, both insulin resistance and insufficiency of beta cell function are important features in T2DM pathogenesis. In addition, glucagon secretion by pancreatic alpha cells appears to be inappropriately elevated in many patients with T2DM, and thus, a decreased insulin:glucagon ratio may also contribute to hyperglycemia in these patients.

Q2. Which of the following statements is correct regarding insulin and its actions?

Rationale : Insulin acts by acutely modulating rate-controlling enzymes of metabolism and by inducing longer-term changes through its effects upon gene expression. The three main targets of insulin in the body are skeletal muscle and liver, which help maintain plasma glucose homeostasis, and adipose tissue, which is regulated hormonally to ensure delivery of plasma free fatty acids (FFAs) to and removal of triglycerides from the circulation, as appropriate to condition. Insulin binding to a single receptor is able to differentially control energy metabolism in these three tissues in part through the unique, tissue-specific expression of protein isoforms. In response to an elevation of circulating glucose levels after a meal and other stimuli associated with eating, pancreatic beta cells increase insulin secretion until plasma glucose levels return to the pre-meal physiological set point. Insulin binds to a cell surface receptor on target cells, which causes a conformation change that is transduced across the cell membrane and disinhibits an intrinsic tyrosine kinase activity present in the intracellular portion of the receptor. The activation of the insulin receptor tyrosine kinase results in the autophosphorylation of the receptor on tyrosine residues and the recruitment of several signaling molecules, which are then phosphorylated by the insulin receptor. The most important of these substrates is a family of insulin receptor substrate (IRS) proteins. The tyrosine phosphorylation of IRS proteins activates numerous signaling cascades that mediate the plethora of responses in target cells. Insulin's effects can be broadly divided into two categories: mitogenic, those promoting cell growth and division, and metabolic, those promoting glucose and triglyceride uptake, utilization, and storage. The principal physiological effect of insulin secretion is to reduce plasma glucose levels. Enhanced glucose uptake in skeletal muscle accounts for up to 90% of insulin-mediated glucose disposal in peripheral tissues, making it a critical step in the maintenance of blood glucose levels. Skeletal muscle is also a key site for the development of insulin resistance preceding diabetes. Insulin promotes glucose uptake in muscle by stimulating the translocation of specialized vesicles containing the facilitative glucose transporter isoform GLUT4 from the perinuclear region to the cell surface. The liver is the principal organ responsible for maintaining plasma glucose levels during times of fasting or increased demand, such as during exercise. When blood glucose levels start to fall, counter-regulatory hormones such as glucagon elevate cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) activity, which stimulate glycogen breakdown and gluconeogenesis (de novo production of glucose), increasing hepatic glucose output. In contrast, insulin suppresses hepatic glucose production and promotes glucose storage as glycogen in hepatocytes. The ratio of insulin to glucagon levels dictates whether the liver will store glucose (high insulin) or produce glucose for use by the rest of the body (low insulin). Hepatocytes express an insulin-insensitive glucose transporter isoform termed GLUT2 that is always present at the cell surface, enabling glucose uptake during hyperglycemia and glucose release into the bloodstream during episodes of hypoglycemia. Thus, insulin does not directly stimulate glucose uptake by liver cells. However, insulin does increase rate-limiting enzymes controlling glycogen metabolism and promotes glucose storage as glycogen. Additionally, if hepatic glycogen stores are full, excess glucose can be converted to fatty acids and shipped within triglycerides on very low density lipoproteins (VLDLs) via the circulation to adipose tissue for long-term storage. Thus, the liver is the second most important peripheral tissue after skeletal muscle for clearance of plasma glucose following a meal. The adipocyte is the third major site of insulin action. Insulin promotes glucose uptake in the fat cell through the translocation of GLUT4 storage vesicles similar to that found in muscle cells. However, the glucose that adipocytes take up is not stored as glycogen, but rather partially metabolized down the glycolytic pathway to form glycerol-3-phosphate, which is the backbone for triglycerides.

Diabetes Case 3

Patient Background:

A 52 year-old woman presents to the emergency department reporting severe abdominal pain. She describes the pain as a 10, with 10 being the worst pain, and points to the epigastric area, stating that the pain sometimes feels as though it is moving towards her back. Her pain is associated with nausea, but no vomiting. She reports no known medical history other than being told that she might have “borderline” or “prediabetes” eight to ten years ago, but she has not followed up regularly with her doctor. She does not smoke or drink alcohol. In the emergency department, she is found to have a blood glucose level of 718 mg/dL (normal random, <140 mg/dL) and a glycated hemoglobin (HbA1c) of 15.8% (normal, <5.7%). Biochemical evaluation is significant for slight lactic acidosis and a markedly elevated serum lipase, but no evidence of ketosis. Because her blood sample appeared lipemic, her triglycerides are measured and found to be over 2000 mg/dL (desirable, <150 mg/dL).

The patient receives fluid resuscitation and is started on intravenous insulin in normal saline. Her blood glucose and triglyceride levels improve while her pain resolves and her appetite returns. After recovery, she understands that she is being discharged on insulin therapy and asks how diabetes mellitus may have contributed to her high triglyceride levels.

Which of the following best explains the relationship between type 2 diabetes mellitus and hypertriglyceridemia-induced pancreatitis?

Insulin promotes glucose uptake in the fat cell through the translocation of GLUT4 storage vesicles similar to that found in muscle cells. However, the glucose that adipocytes take up is not stored as glycogen, but rather partially metabolized down the glycolytic pathway to form glycerol-3-phosphate. This key metabolic intermediary serves as a backbone to which three FFAs are esterified to form triglyceride, which is then stored in the lipid droplet occupying most of the fat cell. Lipids are delivered to the fat cell through the circulation. Lipoprotein lipase located on the outside of the fat cell cleaves triglycerides to FFAs; these free fatty acids are taken up by adipocytes where they are re-esterified. Insulin enhances adipose tissue lipoprotein lipase expression. Insufficient insulin can contribute to excess levels of circulating FFAs and triglycerides.

Diabetes Case 2

A 75 year-old man with type 2 diabetes (T2D) for 8 years presents to the endocrinology office with pain and weakness of his thighs. He initially noted pain and weakness in his right thigh two months ago, but now has pain and weakness in both legs. He denies any back pain. He has difficulty getting up from the chair and has been using a wheelchair recently. He also reports that he has been losing weight. He currently takes glipizide 5 mg twice daily, metformin 1 g twice daily, aspirin 81 mg daily, rosuvastatin 40 mg daily, and enalapril 10 mg daily. Apart from diabetes and hypertension, he has no other known medical problems. He does not smoke or drink and is married. He denies any fever, trauma, or low back pain.

On examination, his height is 5' 9”, and his weight is 125 lb. His blood pressure is 130/80 mm Hg; his pulse is 60 beats per minute and regular. He is afebrile. He has 2/5 strength in both quadriceps and absent patellar reflexes bilaterally. No swelling, masses, or tenderness of the thigh muscles is noted, and distal pulses are normal. Straight leg raising produces no symptoms. Electrodiagnostic studies show markedly reduced amplitudes of sensory nerve and compound muscle action potentials with only mild slowing of conduction velocity in the motor fibers of femoral nerves bilaterally. Electromyogram of the paraspinal muscles is normal. His glycated hemoglobin (HbA1c) is 7.2% (normal, <5.7%); his serum creatinine is 1.0 mg/dL (normal, 0.8-1.3 mg/dL), and his creatine kinase levels are normal.

Which of the following disorders is the most likely diagnosis in this patient?

The patient has the classic presentation of diabetic amyotrophy. Diabetic amyotrophy (lumbosacral plexopathy, diabetic lumbosacral radiculoplexus neuropathy) presents classically in older type 2 diabetes patients with acute onset, asymmetric, focal pain in one thigh followed by weakness, which then progresses to involve the other leg over the next several months.

Patients with diabetic amyotrophy often have unintentional weight loss and may have autonomic symptoms, with or without associated peripheral neuropathy. This often presents in patients with relatively recent onset diabetes, which is usually in fair control. The exact pathogenesis is unclear, but likely involves ischemia, metabolic, and inflammatory factors. An ischemic nonsystemic vasculitis has been hypothesized as the cause. Electrodiagnostic studies (EDS) reveal markedly reduced amplitudes of sensory nerve and compound muscle action potentials with only mild slowing of nerve conduction velocities.

The proximal distribution of the pain in this case contrasts with the distribution that characterizes diabetic polyneuropathy, in which distal symptoms are typically greater than proximal symptoms. Sensory symptoms are not prominent with chronic inflammatory demyelinating polyradiculoneuropathy.

Incorrect: The clinical picture is not characteristic of statin-induced rhabdomyolosis, and the creatine kinase (CK) levels are normal. Diagnosis is based on classic clinical presentation in a diabetes patient with supporting EDS.

Incorrect: Diabetic muscle infarction usually presents with unilateral, acute onset pain and tenderness of thigh (or calf); swelling and tenderness of the affected muscle usually occurs. CK levels are often elevated; magnetic resonance imaging (MRI) reveals increased signal on T2- weighted images.

Incorrect: Spinal disc herniation is unlikely with absence of low back pain and normal straight leg raising test, and diabetic radiculopathy can be discounted based on the normal electromyogram of the paraspinal muscles.

Diabetes Case 1

A 64 year-old Caucasian woman with an 11-year history of type 2 diabetes is referred to you for further management. She is currently taking metformin 1000 mg bid, rosuvastatin 10 mg daily, and irbesartan 150 mg daily. Menopause was at age 47, and she has never taken any estrogen replacement therapy. Her examination is significant for a body mass index (BMI) of 32 kg/m2 (normal, 18.5 to 24.9 kg/m2), a blood pressure (BP) of 142/86 mm Hg, and decreased vibratory sensation in her feet with absent Achilles reflexes and pedal pulses. The patient does not have lower extremity edema.

Laboratory Results:

Glycated hemoglobin (A1c): 8.2% (normal, <5.7%)

Serum creatinine: 1.8 mg/dl (normal, 0.5 to 1.1 mg/dL)

Estimated glomerular filtration rate (eGFR): 28 mL/min/1.73 m 2 (normal, >90 mL/min/1.73 m 2 )

Urine microalbumin/creatinine ratio of 62 mg/g (normal, <30 mg/g)

Low density lipoprotein (LDL) cholesterol: 93 mg/dL (normal, <100 mg/dL)

Because the eGFR is <30/mL/min/1.73 m 2 , metformin was discontinued. Which medication should be avoided given the patient’s eGFR?

The risk of hypoglycemia is greatly increased with use of glimepiride and glyburide with an eGFR <60 mL/min/1.73 m2 due to the presence of two active metabolites cleared in part by the kidney. Thus, use of glyburide should be avoided with an eGFR <60 mL/min/1.73 m2.

Insulin doses often need to be adjusted as renal function declines, but insulin can still be used in patients with chronic kidney disease (CKD). No dose adjustment is indicated with thiazolidinediones such as pioglitazone in patients with CKD. However, thiazolidinediones are associated with fluid retention, and they should be used with caution if edema is present. Only a small amount of linagliptin is cleared renally; thus, no dose adjustment is indicated in patients with a reduced eGFR.

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Learning Tools - Case Studies

Patient M is a white woman, 32 years of age, presenting to her primary care physician with complaints of polyuria for the past four weeks. Further assessment reveals an upcoming appointment with her optometrist for new onset blurred vision. The patient is 5 feet 5 inches tall and weighs 142 pounds; her calculated BMI is 23.6 kg/m 2 . She confirms a family history of diabetes on her father's side and admits to a generally sedentary occupation and lifestyle. A random finger stick reveals a blood glucose level of 257 mg/dL.

Rationale and comments : Patient M's evaluation has resulted in adequate findings to diagnose diabetes. Any random blood glucose greater than 200 mg/dL with additional symptoms (in this case, polyuria and blurred vision) is considered diagnostic for diabetes.

Patient M is referred for fasting blood work, which reveals the following results:

HbA1c: 8.5% (estimated average glucose: 197 mg/dL)

Fasting blood glucose: 147 mg/dL

Two-hour glucose level (after 75 g oral glucose tolerance test): 240 mg/dL

Triglycerides: 152 mg/dL

Low-density lipoprotein (LDL): 97 mg/dL

Liver function tests: Within normal limits

Renal function: Within normal limits

Patient M is referred to an ADA-recognized diabetes education program for further education in diabetes self-management, self-monitoring of blood glucose (SMBG), and exercise and meal planning education [55] .

Patient M returns to her primary care physician after three months. Her follow-up HbA1c demonstrates minimal change, with a result of 8.2% (estimated average glucose: 189 mg/dL) and a fasting blood glucose level of 156 mg/dL. SMBG records reveal blood glucose levels consistently between 135 mg/dL and 160 mg/dL fasting and between 230 mg/dL and 300 mg/dL postprandial. Patient M states that she is following her meal and exercise planning goals with little success.

The patient's physician evaluates all of her blood work and patient history information and determines that the best course of treatment would be to initiate sulfonylurea therapy. Patient M is started on glipizide 5 mg each morning, and continuation with her meal and exercise plans is emphasized.

Rationale and comments : This is an appropriate treatment plan for Patient M because, although she has a sedentary occupation, she is not considered obese. She has been adherent to her meal and exercise plan without success. Her fasting blood glucose levels are elevated, but it is the postprandial levels that have instigated the elevated HbA1c levels. The sulfonylurea secretagogue glipizide should improve the high postprandial levels resulting from loss of first-phase insulin release.

Patient L is an African American man, 52 years of age, presenting to his primary care physician with complaints of frequent urination and excessive thirst, particularly in the late afternoon and early evening. He is a truck driver and works 12 hours each day. Patient L is 6 feet 1 inch tall and weighs 215 pounds, with a calculated BMI of 28.4 kg/m 2 . He confirms a family history of diabetes on both his father's and mother's sides. A random finger stick results in a blood glucose level of 243 mg/dL.

Rationale and comments : The information gained from Patient L's initial examination indicates diabetes. Again, any random blood glucose greater than 200 mg/dL, accompanied by symptoms (polyuria and excessive thirst for this patient), is considered diagnostic for diabetes.

Patient L is referred for fasting blood work, which reveals the following:

HbA1c: 9.1% (estimated average glucose: 214 mg/dL)

Fasting blood glucose: 132 mg/dL

Two-hour glucose level (after 75 g oral glucose tolerance test): 310 mg/dL

Triglycerides: 147 mg/dL

Patient L is diagnosed with type 2 diabetes and is referred to an ADA-recognized diabetes education program. A follow-up appointment in three months is scheduled.

Upon the follow-up primary care appointment, Patient L's HbA1c shows minimal change, with a result of 8.8% (estimated average glucose: 206 mg/dL) and a fasting blood glucose level of 148 mg/dL. The patient's SMBG records reveal fasting blood glucose levels consistently between 150 mg/dL and 165 mg/dL and postprandial levels steadily between 230 mg/dL and 290 mg/dL. Patient L states that he has difficulty eating meals at consistent times due to his profession and exercises when he is able. There has been little change in his weight since his last visit.

Patient L's physician determines that the best course of therapy would be to initiate nonsulfonylurea secretagogue therapy. The patient is started on repaglinide 2 mg 15 minutes prior to his first three main meals. He is advised not to take the medication if he does not eat the meal. He is strongly encouraged to continue with his meal and exercise plans.

Rationale and comments : This is an appropriate choice of medication for Patient L due to his inconsistent eating habits and continued postprandial hyperglycemia, his sedentary occupation, and his weight (not considered obese). His postprandial levels are the problematic factor, and repaglinide will allow Patient L the freedom to adjust his medication therapy to his eating schedule.

Patient V is a Hispanic man, 61 years of age, presenting to the primary care physician with complaints of polydipsia, polyphagia, and fatigue for the past month. Upon further assessment, he states that he has recently had his eyeglass prescription adjusted due to blurred vision. He is 5 feet 10 inches tall and weighs 245 pounds; his calculated BMI is 35.2 kg/m 2 . The patient reveals a family history of diabetes on both sides. He works a physical job in a warehouse lifting 50-pound boxes. A random finger stick reveals a blood glucose level of 220 mg/dL. As previously discussed, this is sufficient information to diagnose diabetes.

Patient V's fasting blood work reveals the following:

HbA1c: 8.7% (estimated average glucose: 203 mg/dL)

Fasting blood glucose: 151 mg/dL

Two-hour glucose level (after 75 g oral glucose tolerance test): 233 mg/dL

Triglycerides: 210 mg/dL

Patient V is referred to an ADA-recognized diabetes education program and is instructed to return for follow-up in three months.

When the patient returns to his primary care physician, his follow-up HbA1c demonstrates minimal change with the result of 8.2% (estimated average glucose: 189 mg/dL) and a fasting blood glucose level of 156 mg/dL. SMBG records reveal fasting blood glucose levels consistently between 135 mg/dL and 160 mg/dL and postprandial levels steadily between 220 mg/dL and 248 mg/dL. His lipid levels remain greater than goal as well. Patient V indicates that he has been following his meal and exercise planning goals but has experienced minimal success.

After evaluation of the patient's blood work, history, and progress to date, the physician decides to utilize the alpha-glucosidase inhibitor, acarbose. Patient V is started on acarbose 25 mg with each meal, and adherence to his culturally specific meal and exercise plans is stressed.

Rationale and comments : Although not commonly utilized, acarbose is appropriate for Patient V due to his elevated lipid levels and postprandial hyperglycemia. His fasting blood glucose levels are above normal, and the physician has determined that his postprandial levels are the cause of the elevated HbA1c levels. Acarbose should improve the patient's postprandial glucose levels and his lipid levels.

Patient K is a white woman, 71 years of age, presenting to her primary care physician with complaints of fatigue, polyuria, polyphagia, and polydipsia for the past few months. She is 5 feet 4 inches tall and weighs 205 pounds, with a calculated BMI of 35.3 kg/m 2 . She confirms a family history of diabetes on her mother's side, a personal history of having given birth to a child weighing more than 9 pounds, and arthritis of her bilateral knees. A finger stick reveals a blood glucose level of 198 mg/dL.

Rationale and comments : Based on the information gathered during the initial examination, Patient K cannot be definitively diagnosed with diabetes. Although symptoms of diabetes are present, a blood glucose level of 198 mg/dL is not diagnostic unless further laboratory testing is completed.

In order to gain additional information, Patient K is referred for a complete blood work-up. The results of this work-up reveal:

HbA1c: 8.0% (estimated average glucose: 183 mg/dL)

Fasting blood glucose: 195 mg/dL

Two-hour glucose level (after 75-g oral glucose tolerance test): 160 mg/dL

Triglycerides: 167 mg/dL

Based on this additional information, Patient K is diagnosed with type 2 diabetes and is referred to an ADA-recognized diabetes education program. At her three-month follow-up appointment, the patient's HbA1c level has increased to 8.6% (estimated average glucose: 200 mg/dL) and her fasting blood glucose level is 205 mg/dL. Sporadic SMBG records reveal fasting levels consistently between 180 mg/dL and 210 mg/dL and postprandial levels between 150 mg/dL and 170 mg/dL. Patient K states she did not attend the education class as recommended but has attempted to limit her sugar intake. She denies starting an exercise program because of the pain she experiences in her knees when she tries to walk.

It is determined, taking into account Patient K's blood glucose level and failure to make lifestyle changes, that the best course of treatment is medication therapy utilizing metformin. The patient is prescribed metformin 500 mg each evening and water aerobics for exercise. Her physician again stresses the importance of SMBG and participation in diabetes self-management education.

Rationale and comments : The therapy prescribed is appropriate for Patient K for many reasons. Her fasting blood glucose levels are higher than normal, her postprandial levels are slightly elevated, and she is suspected to have insulin resistance. She is obese and has been non-adherent to her meal and exercise plans. Her SMBG has been erratic. Metformin will positively impact the patient's fasting blood glucose levels by decreasing the liver's production of endogenous glucose, decreasing insulin resistance, and decreasing the reabsorption of carbohydrates in the gut.

Let us revisit Patient K, who has been taking metformin to control her type 2 diabetes. One year ago, Patient K was started on metformin 500 mg each evening with recommendations to attend diabetes self-management education. Since then, her dosage has been titrated up, and she currently takes metformin 1,000 mg twice per day. At her scheduled appointment, Patient K has an HbA1c level of 8.8% (estimated average glucose: 206 mg/dL) and claims to be adherent with her meal and exercise plan the majority of the time. Occasional SMBG indicates fasting levels between 145 mg/dL and 170 mg/dL and postprandial levels between 180 mg/dL and 230 mg/dL. Although the metformin achieved a small decrease in Patient K's blood glucose levels, she has not obtained satisfactory results. More intensive therapy, with a second antihyperglycemic agent, is necessary, and the physician prescribes glyburide 2.5 mg daily. Upon hearing this, the patient becomes teary-eyed and expresses concerns about the cost of the new medication. She states she is on a fixed income and can barely make ends meet. The physician offers to prescribe a combination medication that is less expensive than the two agents separately. Patient K agrees and is prescribed Glucovance 2.5 mg/500 mg in the morning and continues with metformin 1,000 mg in the evening.

Patient K returns for a three-month follow-up. Her HbA1c demonstrates a decrease, with the result of 8.1% (estimated average glucose: 186 mg/dL) and a fasting blood glucose level of 110 mg/dL. SMBG records show fasting blood glucose levels consistently between 98 mg/dL and 120 mg/dL and postprandial levels between 160 mg/dL and 200 mg/dL. The patient has also made great improvements in adhering to meal plans, exercise goals, and SMBG. However, the physician stresses the need for Patient K's HbA1c level to be less than 7.0%, and they agree to change therapy to Glucovance 2.5 mg/500 mg twice per day. The patient agrees to wake at 3 a.m. at least twice in the first week to test her morning blood glucose level to assess for nocturnal hypoglycemia.

Rationale and comments : Patient K's morning blood glucose levels are close to optimal, but her postprandial levels remain elevated and her HbA1c level remains suboptimal. She has demonstrated greater adherence to her meal, exercise, and SMBG plans. Metformin will continue to impact her fasting and mid-day blood glucose levels by decreasing the liver's production of endogenous glucose, decreasing insulin resistance, and decreasing the reabsorption of carbohydrates in the gut. In addition, glyburide will assist the pancreas in the production of insulin. Patient K will require education regarding the importance of determining the presence of nocturnal hypoglycemia, signs and symptoms of hypoglycemia, and conditions that require communication with her primary care physician.

Patient H is an African American woman, 38 years of age, presenting to her primary care physician for a routine physical with complaints of fatigue and constant hunger. She is 5 feet 7 inches tall and weighs 235 pounds, with a calculated BMI of 36.9 kg/m 2 . She has a strong history of diabetes and coronary artery disease on both sides of her family, a personal history of gestational diabetes with her last two children, and is employed as a legal secretary. A finger stick reveals a blood glucose level of 213 mg/dL. A diagnosis of diabetes is made, and the patient is referred for fasting blood work, which reveals:

HbA1c: 7.8% (estimated average glucose: 177 mg/dL)

Fasting blood glucose: 137 mg/dL

Two-hour glucose level (after 75-g oral glucose tolerance test): 187 mg/dL

Triglycerides: 178 mg/dL

The physician refers Patient H to an ADA-recognized diabetes education program so she may receive information regarding blood glucose monitoring and exercise and meal planning. At her follow-up appointment, the patient's HbA1c has not significantly changed, with a result of 7.7% (estimated average glucose: 174 mg/dL) and a fasting blood glucose level of 172 mg/dL. SMBG records reveal fasting blood glucose levels consistently between 155 mg/dL and 190 mg/dL and postprandial levels steadily between 190 mg/dL and 213 mg/dL. Patient H claims to be adherent to her meal and exercise planning goals but is struggling with weight loss and hunger. As a result, her physician initiates her on TZD therapy. The patient is prescribed pioglitazone 15 mg each morning, and she is advised to continue with her meal and exercise plans. Patient H is also given instructions to report any signs of sudden weight gain, shortness of breath, or chest pains, as these could be signs of excessive fluid retention related to TZD therapy.

Rationale and comments : Patient H has been adherent to her meal and exercise plan with little success and growing frustration. Her morning and postprandial blood glucose levels are above normal, and both contribute to the elevated HbA1c levels. TZD therapy is indicated for Patient H because of her family history of coronary heart disease, obesity, and suspected insulin resistance.

Patient B is a Pacific Islander woman, 64 years of age, presenting to the primary care physician with complaints of a urinary tract infection (UTI) and fatigue. She attributes the fatigue to waking frequently at night due to the UTI. The patient denies any recent history of febrile states or pain with urination. She is 5 feet 1 inch tall and weighs 170 pounds, with a calculated BMI of 32.2 kg/m 2 . She confirms a family history of diabetes on her mother's side and admits to a sedentary lifestyle.

Patient B's urine sample is negative for infection. A random finger stick reveals a blood glucose level of 207 mg/dL. She is diagnosed with type 2 diabetes based on her blood glucose level and the characteristic symptoms (polyuria and fatigue).

In order to gain additional information, Patient B is referred for fasting blood work. The results of this blood work indicate:

Patient B is referred to an ADA-recognized diabetes education program and is initiated on treatment for dyslipidemia based on her very high LDL level and borderline high triglycerides.

When Patient B returns for her three-month follow-up appointment, she acknowledges compliance to her meal and exercise planning goals with very little success. Her repeat HbA1c demonstrates minimal change with a result of 7.6% (estimated average glucose: 171 mg/dL) and a fasting blood glucose level of 165 mg/dL. Her fasting levels during SMBG are generally between 145 mg/dL and 170 mg/dL; her postprandial levels are between 170 mg/dL and 190 mg/dL.

DPP-4 therapy is determined to be the best treatment choice to control Patient B's diabetes. She is started on sitagliptin 100 mg each morning and continues her meal plan and exercise program.

Rationale and comments : Patient B's higher than normal fasting and postprandial blood glucose levels are contributing to the elevated HbA1c levels, and she has been adherent to her meal plan and exercise program with minimal success. This treatment is appropriate for Patient B because DPP-4 therapy assists in weight loss while impacting blood glucose levels.

Patient A is a white man, 19 years of age, with a history of type 1 diabetes. He is currently in the end of his first year of college and studying for his final examinations. He has been unable to exercise due to the amount of time devoted to studying. His eating has been erratic, and he has forgotten to cover his meals with insulin aspart. He presents to the emergency department with a six-hour history of abdominal pain, nausea, and confusion as reported by his roommate. The roommate also recalls a fruity odor to Patient A's breath and knows he has not been consuming alcohol. When asked questions regarding his blood glucose levels, Patient A is confused and unable to recall any past history of testing. The roommate states he did not witness the patient assessing any glucose levels. The patient's laboratory evaluation reveals:

Blood glucose: 531 mg/dL

Strong serum ketones

Bicarbonate: 3 mEq/L

Arterial pH: 7.1

CO 2 : 10 mmol/L

Rationale and Comments : Diabetic ketoacidosis should be the expected diagnosis. Signs and symptoms that support this diagnosis include:

History of type 1 diabetes

High level of stress related to upcoming examinations

Erratic eating patterns

Not covering carbohydrates with insulin

Acetone breath, confusion, nausea

Laboratory glucose, bicarbonate, pH, CO 2 , and serum ketone levels

Based on the laboratory values and patient history, the attending physician diagnoses diabetic ketoacidosis and orders insulin therapy: a bolus of regular insulin at 0.1 units/kg followed by an insulin infusion of 0.1 units/kg/hour. An infusion of 0.9% sodium chloride at 20 mL/kg/hour is administered for the first hour. Blood glucose levels are monitored hourly, and adjustments to the infusion are made based on hospital policy.

Eighteen hours after admission, Patient A awakes. His blood glucose is well controlled on the insulin infusion, and his acidosis is resolved. One hour prior to discontinuation of the insulin infusion, he is started on his home dose of insulin glargine, as his HbA1c level was assessed to be 7.1%. The next morning, the patient remains stable and his glucose status is controlled.

Before Patient A is discharged, important patient education points are reviewed and reinforced. The nurse assesses the patient's insulin administration technique by allowing him to demonstrate drawing up and administering his insulin injections. An overview of the onset, peak action times, and duration of all prescribed insulin preparations is provided. The need for injection site rotation and appropriate storage of insulin vials are stressed. The nurse also provides Patient A with information on stress management techniques. Finally, the nurse gives the patient written information regarding sick day management and encourages him to share the handout with his roommate or anyone else who will be involved with his care or well-being.

Patient T is a defense attorney in a busy prestigious law firm. She has dealt with type 1 diabetes since the age of 13 years. She was started on an insulin pump in order to improve her blood glucose control and her overall health. Patient T has been happy with the results achieved with the pump, with the exception of a recent weight gain of 10 pounds and increases in her postprandial blood glucose levels. She confers with her endocrinologist regarding options to decrease the postprandial levels and alleviate any further weight gain.

The endocrinologist suggests treatment with exenatide. However, Patient T is concerned with returning to a twice-daily injection, which is one reason she appreciates insulin pump therapy. The patient and her endocrinologist discuss this option, and although she is hesitant to return to daily injections, the patient chooses to attempt the therapy. The endocrinologist prescribes exenatide 5 mcg twice daily.

After four weeks of therapy with exenatide, Patient T returns for follow-up. She states that although she initially experienced nausea, her weight is starting to trend down and her postprandial levels are improving. Patient T indicates she would like to continue with the exenatide therapy based on seen benefits.

CASE STUDY 1

Patient W is a Native American woman, 48 years of age, who is admitted to the hospital with complaints of chest pain. She is 5 feet 6 inches tall and weighs 256 pounds; her BMI is 41.4 kg/m 2 . Her vital signs are assessed; her heart rate is 122 beats per minute, regular rate and rhythm, blood pressure is 198/101 mm Hg, and oral temperature is 37.4 degrees Celsius. Her past medical history is positive for gestational diabetes with her fourth child (five years previous), bilateral arthritis of the knees, and tobacco use. Patient W denies use of recreational drugs and homeopathic pharmaceuticals, but she does admit to occasional alcohol usage, generally two beers per day on the weekend. Her family history includes diabetes, heart disease, stroke, lung cancer, and alcohol abuse. Although her electrocardiogram is negative for myocardial infarction, her stress test reveals left coronary artery ischemia. Her cardiac enzymes are negative, but other significant laboratory results include:

Triglycerides: 250 mg/dL

Blood urea nitrogen (BUN): 35 mg/dL

Creatinine: 1.5 mg/dL

Random blood glucose: 310 mg/dL

HbA1c: 9.5% (estimated average glucose: 226 mg/dL)

eGFR: 43 mL/min/1.73 m 2

Patient W is admitted for a cardiac catheterization and further cardiac work-up. She is started on blood glucose monitoring before meals and at bedtime with weight-based insulin correction with analog (rapid-acting) insulin, a calorie-controlled cardiac diet, antihypertensive medication, a statin for lipid management, an angiotensin-converting enzyme inhibitor, and pain medications as needed for chest pain or discomfort.

On hospital day 2, Patient W has a fasting blood glucose of 210 mg/dL. She receives rapid-acting insulin coverage per weight-based protocol even though she is being prepared for cardiac catheterization in the late morning and has not eaten. At approximately 10 a.m., the patient is taken for a cardiac catheterization, which reveals a 90% blockage of the left coronary artery, and subsequently undergoes percutaneous coronary intervention (PCI). A drug-eluting stent is placed. Postprocedure, Patient W returns to her room mildly sedated with an arterial line in place and a blood glucose level of 201 mg/dL, for which she receives weight-based coverage. At 5 p.m., the patient is alert and hungry. Her arterial line is discontinued, and her blood glucose is 220 mg/dL, for which she again receives weight-based coverage. At 9 p.m., Patient W has been pain free throughout the day and is ready to sleep. Her blood glucose level is 201 mg/dL. She is given insulin and is instructed to notify the nurse of any pain, palpitations, sweating, shakiness, and/or dizziness.

On hospital day 3, Patient W awakens with a blood glucose level of 248 mg/dL. Her physician initiates basal insulin to obtain better glucose control. She is cleared for discharge by her cardiologist, but her primary care physician would prefer to monitor her glucose levels for one more day, including her two-hour postprandial level after her evening meal. Throughout the day, the following blood glucose levels are documented:

7 a.m.: 248 mg/dL

11 a.m.: 121 mg/dL

5 p.m.: 118 mg/dL

7 p.m. (two-hour postprandial): 210 mg/dL

9 p.m.: 178 mg/dL

The following morning, Patient W is discharged to home with a prescription for glyburide 2.5 mg twice a day for her newly diagnosed type 2 diabetes. She is also referred to an ADA-recognized education program. She receives survival skills education prior to leaving the hospital and is encouraged to contact the outpatient education center within the first week after discharge. Patient W agrees with her discharge plan and states understanding of all instructions given.

Rationale and comments : The treatment approach appears appropriate to manage Patient W's diabetes. Patient education will be extensive for this patient given the many new medications and changes associated with the PCI and her various conditions. Education specific to the glyburide should include instructions to eat meals at a consistent time (not skipping meals) and information regarding the signs, symptoms, and treatment of hypoglycemia.

At her follow-up appointment, Patient W has completed her self-management education and set personal behavior change goals for meal planning and exercise. She is demonstrating competent SMBG assessment; her fasting levels are between 140 mg/dL and 170 mg/dL, and her postprandial levels range from 160 mg/dL to 200 mg/dL. The patient's occasional two-hour postprandial readings range from 190 mg/dL to 230 mg/dL. Her fasting laboratory results are as follows:

Fasting blood glucose: 167 mg/dL

HbA1c: 8.6% (estimated average glucose: 200 mg/dL)

Triglycerides: 220 mg/dL

In order to improve Patient W's blood glucose control, her physician chooses to increase her glyburide to 5 mg twice a day with instruction to return for follow-up in one month to assess the efficacy of treatment. In one month, Patient W continues to have difficulties achieving optimal control on monotherapy. The decision is made to start combination therapy with pioglitazone, a TZD.

Rationale and comments : Combination therapy with a TZD is the correct choice for Patient W because her BUN and creatinine levels are too high to safely utilize metformin. Furthermore, her casual use of alcohol on the weekends can be an area of concern with the potential for liver dysfunction. Pioglitazone will address the issue of insulin resistance in the presence of the metabolic syndrome and has beneficial effects on coronary artery disease in the presence of type 2 diabetes.

Prior to leaving the physician's office, the nurse reviews the signs and symptoms of hypoglycemia with Patient W. The patient is instructed to alert her primary care physician of frequent episodes of hypoglycemia. She is also counseled regarding the need to eat meals at spaced intervals throughout the day to decrease the chances of developing hypoglycemia.

The heart failure risks associated with TZD use are discussed as well as the need to report any weight increase of 3 to 5 pounds over a two-day period to her primary care physician. Patient W is also advised to contact her primary care physician if she experiences any symptoms related to liver dysfunction/failure, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Finally, the patient is reminded of the need to monitor her liver function by venipuncture periodically while on pioglitazone.

CASE STUDY 2

Patient O is a Hispanic male, 48 years of age, with a seven-year history of type 2 diabetes. He presents to his primary care physician's office for a routine follow-up appointment to assess his diabetes control. His only complaint at the time of his appointment is an occasional burning sensation in his bilateral lower extremities.

Patient O's past medical history is positive for type 2 diabetes diagnosed at 41 years of age, hypertension for the past two years, and new onset of hyperlipidemia within the past six months. He is negative for renal disease, retinopathy, and peripheral vascular disease. The patient's family history is positive for type 2 diabetes, coronary artery disease, cerebral vascular accident, hyperlipidemia, and obesity.

During the physical assessment, Patient O is alert and oriented. His height (5 feet 10 inches), weight (239 pounds), and BMI (34.4 kg/m 2 ) are measured and documented. Blood pressure is 128/68 mm Hg on medications, pulse is 74 beats per minute, and oral temperature is 37 degrees Celsius. Lungs are clear to auscultation, and heart sounds are clear without rubs or murmurs. The patient's abdomen is soft and nontender at all quadrants. Peripheral pulses are present at +2 at all extremities, and feet are free from lesions with a positive Babinski reflex. All extremities are warm to touch and responsive to monofilament test.

Patient O's laboratory results include:

HbA1c: 8.1% (estimated average glucose: 186 mg/dL)

Fasting blood glucose: 155 mg/dL

Creatinine: 1.3 mg/dL

Triglycerides: 201 mg/dL

Microalbuminuria: 312 mcg/mg

The patient is currently prescribed captopril 25 mg twice a day, simvastatin 40 mg daily at bedtime, metformin 1,000 mg twice per day, and glipizide extended-release 20 mg daily. He has previously met with a registered nurse certified diabetes educator and registered dietitian certified diabetes educator regarding self-care management, blood glucose monitoring, behavior change, meal planning, and goal setting. He tests his blood glucose levels twice a day at various times.

At this visit, Patient O receives the results of his blood work and has expressed concerns regarding his recent SMBG numbers and new onset of burning in his lower extremities. He presents verbalizing frustration and feeling like a failure. It is vital to actively listen to the patient regarding his frustrations and fears related to his diabetes. It is also important to educate him regarding the progressive nature of diabetes, regardless of the attentiveness a person gives to the care of the disease [2] .

The nurse reviews Patient O's eating and exercise habits to see if any changes could be made to optimize control. Furthermore, sources of stress are discussed. Patient O is told that worrying about the progression of his diabetes and having anxiety regarding adherence to his meal or exercise plan is normal, but it is possible for this additional stress and anxiety to result in increased blood glucose levels [7] . Patient O states that he was unaware of the impact stress was having on his body.

Due to the continued elevated blood glucose levels, the primary care physician wants to maximize oral medication therapy, most likely by adding a DPP-4 inhibitor, an alpha-glucosidase inhibitor, or a TZD [2] . In order to make a decision regarding the most appropriate agent, each of the classes' benefits and risks should be considered with Patient O in mind. The addition of a DPP-4 inhibitor has been shown to be weight neutral, occasionally demonstrating a reduction in weight. The dose can be decreased for safe use in those individuals who have some renal impairment, such as Patient O [57] . The greatest drawback of DPP-4 inhibitor therapy is the cost.

The addition of an alpha-glucosidase inhibitor is a less expensive option and would benefit Patient O by decreasing the absorption of complex carbohydrates in the intestinal tract. The alpha-glucosidase inhibitors do have objectionable side effects, such as recurrent flatulence, that some patients are unable to tolerate [56] . Patient education needs for those taking alpha-glucosidase inhibitors include timing of medication with meals, gastrointestinal side effects, and the treatment of hypoglycemia [42, 56, 60] .

The addition of a TZD would reduce insulin resistance and reduce cardiovascular risk factors, including markers of vascular inflammation [2] . However, precautions should be taken when this therapy is prescribed. Weight gain and liver damage are possible, and laboratory levels should be regularly monitored. Patient education regarding weight gain and shortness of breath is necessary as these are signs of impending heart failure.

The final option for Patient O would be to continue current therapy and add basal insulin. This would provide long-acting coverage to allow the metformin and extended-release glipizide to have a greater effect. This also has obstacles to acceptance, including fear of injection, fear of acute hypoglycemia, and misconceptions about insulin therapy. All therapy choices would be viable options for Patient O, and as a healthcare provider, understanding of all available agents is needed to support the final decision.

CASE STUDY 3

Patient F is a black female resident of a local long-term care facility. She is 87 years of age and has had type 2 diabetes for the past 25 years. In addition to diabetes, Patient F has a past medical history of hypertension, cardiovascular disease, peripheral neuropathy, and mild Alzheimer disease. Her son and daughter-in-law came to visit and found the patient confused, wet with foul urine, and begging for water. She had a temperature of 38.5 degrees Celsius. The family requested her transfer to the emergency department for evaluation and treatment.

Upon admission to the emergency department, Patient F is increasingly confused and combative, with a body temperature of 38.8 degrees Celsius. She is started on oxygen at 2 liters for an oxygen saturation of 88%. Laboratory samples are obtained, and an infusion of 0.9% sodium chloride is initiated at 75 mL/hour for observed signs of dehydration. The laboratory results indicate:

Blood glucose: 1179 mg/dL

Potassium: 5.2 mEq/L

Phosphorus: 3.4 mmol/L

Ketones: Minimal

Serum osmolality: 420 mOsm/kg

White blood cell count: 46,000

Urinalysis: Positive for bacteria

Based on this information, a diagnosis of HHS is made. Because HHS is characterized by profound dehydration, management is initially focused on rehydration. The physician orders an increase in the current 0.9% sodium chloride infusion to 100 mL/hour. Because there are no dysrhythmias noted on the telemetry monitor, the physician continues to monitor the potassium level with subsequent laboratory assessments. Patient F is also started on empirical antibiotic therapy for a suspected UTI until the results of urine and blood culture are known. An additional intravenous access is initiated in order to administer insulin. A regular insulin bolus of 0.1 units/kg followed by an infusion of regular insulin is ordered to run at a rate of 0.1 units/kg/hour.

Patient F's blood glucose levels slowly drop to 275 mg/dL, but her osmolality is 365 mOsm/kg and she remains confused. Because the patient's osmolality remains greater than 350 mOsm/kg and her confusion is unresolved, her blood glucose levels should be maintained between 250 mg/dL and 300 mg/dL. Her potassium level stabilizes without intravenous therapy and is currently 4.2 mEq/L. Her telemetry readings remain in sinus rhythm.

After 36 hours of therapy, Patient F has an osmolality of less than 315 mOsm/kg, and she is back to her baseline mentation. Her blood glucose level is 225 mg/dL, and she is getting prepared to transfer off of the insulin infusion.

Rationale and comments : Several considerations should be made in order to continue to achieve optimal glycemic control. The patient's HbA1c is 11.9%, which is considered uncontrolled. If a long-acting insulin is not started, the glucose levels will rebound. Also, it is vital that hydration status is maintained. Basal insulin should be given at least one hour prior to the discontinuation of the insulin infusion in order to prevent rebound hyperglycemia, which is a risk due to Patient F's continuing UTI and high HbA1c.

Patient F is maintained on 0.9% sodium chloride 75 mL/hour until adequate oral intake is established. She also starts insulin detemir 0.2 units/kg (total dose: 15 units) to be given once per day at night, which should provide weight-based coverage for correction of glucose elevations.

After three days, Patient F's HHS has been resolved, and the team is preparing the patient for discharge. However, she continues to have blood glucose levels between 280 mg/dL and 400 mg/dL.

Rationale and comments : There are several available options for Patient F. Insulin detemir may be continuously increased to desired effect and/or split to a twice daily schedule. If glycemic control is not achieved on the long-acting insulin preparation, addition of bolus insulin therapy may be necessary. Because the patient is a resident of a long-term care facility and has a history of cognitive impairment, the better option for her may be combination therapy.

To combat the consistently high blood glucose levels, Patient F's insulin detemir dose is increased to 15 units twice a day. The next day, the patient has the following glucose results: 146 mg/dL, 175 mg/dL, 188 mg/dL, and 136 mg/dL. Her primary care provider is satisfied with these readings and plans to discharge her the following day.

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