Diabetes Case 1

Patient Background:

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 m2 (normal, >90 mL/min/1.73 m2)

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

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

Question 1

Because the eGFR is <30/mL/min/1.73 m2, metformin was discontinued.
Which medication should be avoided given the patient’s eGFR?

Glyburide
Insulin Glargine
Pioglitazone
Linagliptin
Incorrect!
Correct!
Correct Answer
Glyburide

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.

Diabetes Case 2

Patient Background:

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.

Question 1

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

Diabetic polyneuropathy
Diabetic muscle infarction
Diabetic amyotrophy
Statin induced rhabdomyolysis
Incorrect!
Correct!
Correct Answer
Diabetic amyotrophy

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 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.

Question 1

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

Insulin resistance is associated with suppression of low-density lipoprotein (LDL)
Insulin excess causes an increase in lipolysis and circulating levels of free fatty acids (FTAs)
Glucotoxicity results in insulin release
Insufficient insulin can lead to diminished lipoprotein lipase expression.
Incorrect!
Correct!
Correct Answer
Insufficient insulin can lead to diminished lipoprotein lipase expression.

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.

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 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.

Question 1

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

A. Increased glucagon secretion
B. Insulin resistance and beta cell dysfunction
C. Increased peripheral glucose uptake
D. Decreased hepatic gluconeogenesis
E. A and B
Incorrect!
Correct!
Correct Answer
E. A and B

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.

Question 2

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

A. Insulin increases the total number of glucose transporters in the skeletal muscle cell membrane
B. Insulin enhances lipolysis in adipocytes resulting in increased levels of circulating free fatty acid levels
C. In the liver, insulin stimulates glycogenolysis and gluconeogenesis
D. In the pancreas, insulin is co-secreted from alpha cells with glucagon.
Incorrect!
Correct!
Correct Answer
A. Insulin increases the total number of glucose transporters in the skeletal muscle cell membrane

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 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.

Question 1

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

A. Basal rate 0.4 units/hr
B. Carbohydrate ratio: 1 unit/10 grams
C. Sensitivity: 1 unit/40 mg/dL glucose
D. Insulin active time 30 minutes
E. Conversion to regular human insulin for use in the pump
Incorrect!
Correct!
Correct Answer
A. Basal rate 0.4 units/hr

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.

Question 2

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?

A. No changes to pump settings
B. Increase overnight basal rates by 30%
C. Change sensitivity factors to 150
D. Change insulin/carbohydrate ratios to 1 unit/40 grams for most meals
E. Change insulin/carbohydrate ratios to 1 unit/10 grams prior to exercise
Incorrect!
Correct!
Correct Answer
D. Change insulin/carbohydrate ratios to 1 unit/40 grams for most meals

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 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.

Question 1

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

A. Insulin infusion and sodium bicarbonate 50 mEq hourly, added to the saline infusion; repeat chemistry, pH, and electrolytes two hours later
B. Insulin infusion at 0.1 unit/kg/hour; repeat chemistry, pH, and electrolytes two hours later
C. Insulin infusion and 20 mmol/L of potassium hourly, added to the saline infusion, during the first two hours; repeat chemistry, pH, and electrolytes two hours later
D. Insulin infusion and half normal saline (0.45%) at 250 mL per hour; repeat chemistry, pH, and electrolytes two hours later
Incorrect!
Correct!
Correct Answer
C. Insulin infusion and 20 mmol/L of potassium hourly, added to the saline infusion, during the first two hours; repeat chemistry, pH, and electrolytes two hours later

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 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.

 

Question 1

  Which of the following diagnostic tests would you order?

A. Urine analysis
B. Repeat cardiac enzyme and B-type natriuretic peptide
C. Salicylate levels
D. Plasma beta-hydroxybutyrate level
E. CT/MRI (magnetic resonance imaging) scan of the abdomen
Incorrect!
Correct!
Correct Answer
D. Plasma beta-hydroxybutyrate level

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 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.

Question 1

  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?

A. Fatal myocardial infarction
B. Limb amputation
C. Fatal stroke
D. Death from Cardiovascular Causes
Incorrect!
Correct!
Correct Answer
Death from Cardiovascular Causes

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).  

Question 2

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?

A. Accelerates loss of beta cell function
B. Decreased risk of cardiovascular death
C. Average body weight loss of 12%
D. Increased risk of pancreatic cancer
Incorrect!
Correct!
Correct Answer
B. Decreased risk of cardiovascular death

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 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.

Question 1

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

A. Monthly screening examinations
B. Panretinal photocoagulation (laser treatment)
C. Aggressive diabetes control
D. Vitrectomy surgery
E. Topical steroid drops
Incorrect!
Correct!
Correct Answer
B. Panretinal photocoagulation (laser treatment

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 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.

Question 1

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

A. Continued reinforcement of dietary counselling and increasing carbohydrate restriction is recommended.
B. Start GLP-1 receptor agonist therapy for diabetes and weight loss given the concern for obesity.
C. Patient should repeat the oral glucose tolerance test as the results may have been an error.
D. Patient should be initiated on basal and bolus insulin therapy at this time.
Incorrect!
Correct!
Correct Answer
D. Patient should be initiated on basal and bolus insulin therapy at this time.

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 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/m2. 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).

 

 

 

 

 

Question 1

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

A. Insulin pump therapy is not working for her and she should go back to multiple daily injections with insulin pens
B. Add a continuous glucose monitoring (CGM) device for more advanced monitoring
C. Switch her to a sensor augmented insulin pump therapy so that risk of hypoglycemia can be minimised
D. Modify her pump settings with attention to insulin distribution
Incorrect!
Correct!
Correct Answer
D. Modify her pump settings with attention to insulin distribution

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.

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 12

A 55 yo Caucasian male is referred to endocrinology for evaluation of an elevated A1c. His main complaint is intermittent nausea, for which work up is ongoing. He underwent renal transplant 12 months ago, for hypertensive kidney disease. Prior to transplant, he tried metformin for prediabetes and stopped it due to complaints of diarrhea. His father suffered type 2 diabetes mellitus. His current medications include tacrolimus, prednisone 5 mg, mycophenolic acid and metoprolol. BMI is 32 kg/m2. Rest of the vital signs. Physical examination are normal except for trace edema in lower extremities.  His lab results show fasting blood glucose of 135mg/dl (1 month prior to clinic visit), A1c of 7.6% (1 week prior to clinic visit), eGFR of 48 mL/min/1.73m2 (1 week prior to clinic visit).

Question 1

Along with lifestyle changes, what is the best next step?

A. Empagliflozin
B. Pioglitazone
C. Sitagliptin
D. Acarbose
Incorrect!
Correct!
Correct Answer
C. Sitagliptin

DPP-4 inhibitors (Sitagliptin, Linagliptin) have been shown to be safe and effective in retrospective and one small prospective study, for use in Post-Transplant Diabetes Mellitus. Thus, choice #3 is the correct option.  Pioglitazone has been shown to be safe and effective in glycemic control after transplant in small studies, but carries a known risk for weight gain, edema, heart failure and reduce bone mass. This patient has edema and is at high risk for fracture, as he is a kidney transplant recipient. There are no safety and efficacy studies to date for use of SGLT2-inhibitors and alpha-glucosidase inhibitors after transplant. Thus, choices, A, B, and D are incorrect.

 

References:

  1. Lane JT, Odegaard DE, Haire CE, Collier DS, Wrenshall LE, Stevens RB. Sitagliptin therapy in kidney transplant recipients with new-onset diabetes after transplantation. Transplantation. 2011;92(10):e56-e57. doi:10.1097/TP.0b013e3182347ea4
  2. Shivaswamy V, Boerner B, Larsen J. Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes. Endocr Rev. 2016;37(1):37-61. doi:10.1210/er.2015-1084

DPP-4 inhibitors (Sitagliptin, Linagliptin) have been shown to be safe and effective in retrospective and one small prospective study, for use in Post-Transplant Diabetes Mellitus. Thus, choice #3 is the correct option.  Pioglitazone has been shown to be safe and effective in glycemic control after transplant in small studies, but carries a known risk for weight gain, edema, heart failure and reduce bone mass. This patient has edema and is at high risk for fracture, as he is a kidney transplant recipient. There are no safety and efficacy studies to date for use of SGLT2-inhibitors and alpha-glucosidase inhibitors after transplant. Thus, choices, A, B, and D are incorrect.

References:

  1. Lane JT, Odegaard DE, Haire CE, Collier DS, Wrenshall LE, Stevens RB. Sitagliptin therapy in kidney transplant recipients with new-onset diabetes after transplantation. Transplantation. 2011;92(10):e56-e57. doi:10.1097/TP.0b013e3182347ea4
  2. Shivaswamy V, Boerner B, Larsen J. Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes. Endocr Rev. 2016;37(1):37-61. doi:10.1210/er.2015-1084