Diabetes- 2 Flashcards
Answer B
This patient’s findings suggest overflow incontinence, which is mainly due to impaired detrusor contractility or bladder outlet obstruction (eg, tumor obstructing the urethra). Patients usually develop involuntary and continuous urinary leakage when the bladder is full and often have incomplete emptying. This patient’s overflow incontinence is most likely due to diabetic autonomic neuropathy affecting detrusor muscle innervation, which is common in type 1 diabetics.
Patients initially have infrequent urination due to loss of autonomic afferent innervation and inability to sense a full bladder. Involvement of efferent fibers to the bladder subsequently causes incomplete emptying. Patients can develop recurrent urinary tract infections (UTIs) and overflow incontinence with poor urinary stream and dribbling. Pelvic floor relaxation at night combined with a full bladder can lead to nocturnal enuresis. Postvoid residual (PVR) testing with ultrasound or catheterization can confirm inadequate bladder emptying.
(Choice A) Enlarged prostate on rectal examination may indicate either benign prostatic hyperplasia or prostate cancer, which causes urge incontinence (bladder irritation from the enlarged prostate) or overflow incontinence (urethral obstruction). However, these conditions are commonly seen in older individuals (age >50-60).
(Choice C) Loss of sensation in the perineal area (saddle anesthesia) can indicate cauda equina syndrome, which is commonly due to epidural cord compression from a malignancy. Patients usually develop urinary retention late in the course of the disease, usually associated with fecal incontinence.
(Choices D and E) Cognitive impairment (mini-mental status examination score <22) is often seen in normal pressure hydrocephalus, and lower extremity hyperreflexia would suggest spinal cord disease. Both of these conditions can cause loss of central nervous system inhibition of detrusor contraction, leading to urge incontinence. Urge incontinence is characterized by a sudden desire to urinate. However, absence of other symptoms (eg, gait disturbance) in this patient makes these conditions less likely.
Educational objective:
Diabetic autonomic neuropathy is common in type 1 diabetics and can cause overflow incontinence due to inability to sense a full bladder and incomplete emptying. Postvoid residual (PVR) testing with ultrasound or catheterization can confirm inadequate bladder emptying.
Answer D
This patient has a plantar ulcer under the first metatarsal head. In a patient with chronic, poorly controlled diabetes mellitus, this is likely a neuropathic ulcer due to underlying peripheral sensory neuropathy. Chronic hyperglycemia promotes nerve injury and impairs nerve repair in distal sensory fibers, causing decreased sensation of pain, pressure, and proprioception.
Loss of these protective senses can cause individuals to not recognize an injury due to minor trauma, friction, or pressure. Areas that are particularly susceptible are points of localized pressure created by a shoe or weight-bearing bones of the foot (eg, plantar surface of the first metatarsal head). A wound in this area often goes unnoticed (due to lack of pain sensation and being hidden by socks or shoes) and can develop into a nonhealing foot ulcer.
Loss of proprioception and an increase in ligamentous laxity can also cause chronic pressure-induced joint/skin damage in the feet of patients with diabetic neuropathy, which can lead to calluses or foot deformities (eg, Charcot foot, hammer toe).
(Choice A) Although diabetic patients (especially those who smoke) often have comorbid arterial insufficiency, arterial ulcers are typically painful, sharply demarcated, and located at the tips of the toes. This patient has full distal pulses, which makes clinically significant atherosclerotic disease unlikely to be the primary cause of the ulcer.
(Choice B) Bacterial infection may delay ulcer healing, especially if there is underlying osteomyelitis, but it is not the inciting cause of neuropathic ulcers. In addition, although diabetic ulcers are often colonized by bacteria, this patient has no fever, erythema, or purulent drainage to suggest serious infection.
(Choice C) Irritant contact dermatitis presents with pruritic or painful erythema in areas of exposed skin (eg, hands). It can occasionally cause small vesicles or fissures, but ulcers are not typical.
(Choice E) Systemic vasculitic disorders (eg, polyarteritis nodosa) are an uncommon cause of skin ulcers. Vasculitic ulcers are usually painful and associated with other skin (eg, purpura, nodules) and systemic (eg, fever, fatigue) symptoms.
(Choice F) Ulcers caused by venous insufficiency are most common over the tibias or proximal to the medial malleolus. They present as irregular ulcerations in the setting of stasis dermatitis and/or varicose veins.
Educational objective:
Neuropathic foot ulcers can occur in diabetic patients when loss of pain sensation and proprioception delays recognition of injury due to trauma, friction, or sustained pressure (on plantar surface of foot bones). The risk is greatest in patients with longstanding diabetes who have poor glycemic control.
Answer A
This clinical trial is studying a thiazolidinedione (TZD), a class of medications that decrease insulin resistance, a key pathologic factor in both type 2 diabetes mellitus and nonalcoholic steatohepatitis (NASH).
TZDs (eg, pioglitazone) bind to peroxisome proliferator–activated receptor gamma (PPAR-γ), a transcriptional regulator of genes involved in glucose and lipid metabolism. The activated complex then binds to the transcriptional regulatory sequences to upregulate target genes that enhance insulin sensitivity, including:
Glucose transporter-4, an insulin-responsive, transmembrane glucose transporter expressed in adipocytes and skeletal myocytes that increases glucose uptake by target cells
Adiponectin, a cytokine secreted by fat tissue that increases the number of insulin-responsive adipocytes and stimulates fatty acid oxidation (Choice B)
TZDs are functionally similar to fibrate medications (eg, fenofibrate, gemfibrozil), which bind PPAR-α and are effective in lowering blood triglyceride levels. The PPAR family of transcriptional regulators also plays a significant role in the pathogenesis of metabolic syndrome (obesity, hypertension, dyslipidemia, and insulin resistance), and their activation and subsequent increase in insulin sensitivity are thought to reverse the histologic changes in NASH.
(Choice C) PPAR-γ activation leads to an increase in fat mass secondary to the increased differentiation of preadipocytes into mature adipocytes. The increased movement of free fatty acids into fat cells, along with increased fatty acid oxidation (adiponectin effect), causes circulating free fatty acid levels to decrease.
(Choice D) TZDs do not stimulate insulin secretion; rather, as insulin resistance diminishes, circulating levels of insulin tend to decrease over time.
(Choice E) Leptin is a hormone secreted by fat cells that acts on the hypothalamus to decrease appetite. Although PPAR-γ activation increases fat cell mass, circulating leptin levels remain unchanged or decrease due to the inhibiting effect of PPAR-γ on leptin gene transcription.
Educational objective:
Thiazolidinediones (TZDs) activate peroxisome proliferator–activated receptor gamma, a nuclear receptor that alters the transcription of genes involved in glucose and lipid metabolism. The resulting decrease in insulin resistance lowers blood glucose and can help reverse nonalcoholic steatohepatitis.
Answer A
The beta cells of the pancreas produce basal insulin continuously at a low level to suppress on-going hepatic gluconeogenesis. After meals, insulin secretion increases briefly to control the postprandial rise in blood glucose. Commercial insulin analogues with different pharmacokinetics can be given subcutaneously to replicate physiologic insulin secretion:
Long-acting insulins (eg, glargine) mimic basal insulin secretion; they have an extended duration of action and little or no peak effect. They are typically given once daily and suppress fasting hyperglycemia, which is predominantly caused by inappropriate hepatic gluconeogenesis.
Rapid-acting insulins (eg, lispro, aspart) are given to mimic the effects of postprandial insulin; they peak quickly and are then rapidly cleared. They are given prior to meals so that the peak effect coincides with postmeal glucose excursions; they control postprandial hyperglycemia. Because they are quickly cleared, they have minimal effect on fasting glucose levels.
This patient has normal fasting glucose levels, suggesting that his long-acting basal insulin regimen is appropriate but that he has elevated postprandial glucose. His postprandial hyperglycemia is best treated with a rapid-acting premeal insulin analogue, such as aspart, lispro, or glulisine. Regular insulin also can be given before mealtimes but has a more delayed peak onset and a longer duration of action compared to rapid-acting insulin analogues (which have amino acid changes that accelerate hexamer dissociation compared to regular insulin).
(Choices B, C, and D) Insulins degludec, detemir, and glargine have long durations of action due to structural modifications (eg, polymerizing residues, fatty acid side chains) that delay absorption and distribution. They have minimal peak effect and are used as basal insulin substitutes.
(Choice E) NPH, an intermediate-acting crystalline suspension of insulin with zinc/protamine, can be given twice daily when used as basal insulin. However, unlike other basal insulins, it has a noticeable peak effect and can lead to hypoglycemia if the peak does not correspond to a meal (eg, nocturnal hypoglycemia), making it a less preferable option for this use.
Educational objective:
Long-acting insulin analogues (eg, glargine) have an extended duration of action without a noticeable peak in activity and are typically given once daily to mimic basal insulin secretion. Rapid-acting insulins (eg, aspart, lispro) are quickly absorbed from the injection site and are given at mealtimes to replicate postprandial insulin secretion.
Answer C
This patient with cystic fibrosis (CF) exhibits glucose dysregulation, suggesting clinical onset of endocrine pancreatic failure. In patients with CF, ductal obstruction by thickened secretions leads to exocrine pancreatic insufficiency (eg, fat malabsorption) early in life. Buildup of pancreatic enzymes also results in pancreatic autolysis, chronic inflammation, and fibrosis, with progressive destruction of the endocrine pancreas. Eventually, a form of pancreatogenic diabetes mellitus, referred to as CF-related diabetes (CFRD), can develop.
Nonselective loss of alpha and beta pancreatic islet cells explains this patient’s glucose fluctuations.
Loss of alpha cells leads to glucagon deficiency. Glucagon is the primary counterregulatory hormone. It stimulates glycogenolysis and gluconeogenesis to defend against hypoglycemia in the fasting state (eg, prior to breakfast). Because alpha cells make up only 20% of islet mass, absolute glucagon deficiency occurs earlier in the course of CFRD, often preceding absolute insulin deficiency.
Loss of beta cells leads to insulin deficiency, contributing to hyperglycemia and catabolic symptoms (eg, weight loss). This patient’s postprandial hyperglycemia indicates failure of the beta-cell response to dietary carbohydrate intake.
This early loss of glucagon accounts for more frequent episodes of hypoglycemia compared to patients with non-pancreatogenic (eg, type 2) diabetes mellitus. A similar phenomenon also affects patients following pancreas resection (eg, Whipple procedure).
(Choice A) Decreased insulin clearance causes hypoglycemia in patients with renal insufficiency who are receiving exogenous insulin therapy.
(Choice B) Ectopic insulin secretion (eg, insulinoma) can cause fasting and paroxysmal hypoglycemia but would not explain this patient’s hyperglycemia, polyuria (osmotic diuresis), or weight loss, which are signs of insulin deficiency, rather than excess.
(Choice D) Decreased (rather than increased) pancreatic trypsinogen production contributes to dietary protein malabsorption and low skeletal muscle mass in patients with CF (eg, this patient’s sarcopenia and low BMI).
(Choice E) Decreased cortisol production (eg, primary adrenal insufficiency) can precipitate hypoglycemia, especially in the setting of physiologic stress (eg, infection). However, adrenal steroid synthesis is unaffected by CF, and cortisol deficiency would not explain the patient’s hyperglycemia.
Educational objective:
Pancreatic disease in cystic fibrosis is characterized by nonselective destruction of alpha and beta cells. Because alpha cells make up the minority of islet mass, glucagon deficiency and fasting hypoglycemia occur early in the diabetic disease course.
Answer E
Glucose uptake in skeletal muscle occurs by facilitated diffusion via glucose transporter (GLUT) 4. In the fed state, insulin induces muscular glucose uptake by stimulating translocation of GLUT4 from intracellular depots to the plasma membrane and T tubules. As circulating glucose and insulin levels fall in the fasting state, GLUT4 is resequestered, and muscle becomes increasingly dependent on internal stores of glucose and glycogen and, subsequently, on fatty acids released by lipolysis in the liver.
However, translocation of GLUT4 is also induced by muscle contraction, allowing insulin-independent glucose uptake during exercise. Over time, regular exercise also causes increased expression of GLUT4 and greater insulin-dependent GLUT4 translocation, leading to increased skeletal muscle glucose uptake at any given insulin level (ie, increased insulin sensitivity) and therefore lower blood glucose.
This patient has been engaging in a regular exercise program and is likely experiencing rapid uptake of glucose while exercising. As blood glucose levels fall, counterregulatory factors (eg, glucagon, epinephrine) are activated, leading to his symptoms (eg, palpitations, sweating), which are then relieved by the intake of sugar. Exercise-induced hypoglycemia is common in patients with diabetes mellitus due to the lack of physiologic insulin regulation along with insufficient carbohydrate supplementation.
(Choice A) As blood glucose levels fall during fasting or exercise, glucagon and epinephrine stimulate hepatic glycogenolysis and gluconeogenesis, leading to increased (not decreased) glucose production.
(Choice B) Glucokinase phosphorylates glucose to glucose-6-phosphate, primarily for glycogen synthesis. It is expressed mainly in the liver and is stimulated by rising, not falling, glucose levels.
(Choice C) Glucose-6-phosphatase catalyzes the hydrolysis of glucose-6-phosphate to glucose during gluconeogenesis, thereby helping to maintain glucose levels in the fasting state; increased activity would improve hypoglycemic symptoms by increasing circulating glucose levels.
(Choice D) GLUT2 is found primarily in the liver and pancreatic beta cells, where it facilitates insulin-independent glucose uptake. It is not expressed significantly in muscle or translocated in response to muscle contraction.
Educational objective:
Glucose uptake in skeletal muscle occurs primarily via glucose transporter (GLUT) 4. Muscle contraction and insulin induce translocation of GLUT4 to the cell surface, increasing glucose uptake during exercise and the fed state, respectively. Over time, regular exercise causes increased expression of GLUT4, leading to increased skeletal muscle glucose uptake at any given insulin level and therefore lower blood glucose levels.
Answer D
Glucagon increases serum glucose by increasing hepatic glucose production via glycogenolysis (breakdown of glycogen) and gluconeogenesis (production of glucose from noncarbohydrate sources). Glucagon-induced glycogenolysis is the predominant initial means of rapidly increasing blood glucose levels during hypoglycemia.
Glucagon functions by stimulating G protein–coupled receptors on hepatocytes, increasing intracellular cAMP concentration and activating protein kinase A. This leads to activation of the key glycogenolytic enzyme, glycogen phosphorylase. It also stimulates gluconeogenesis by activating rate-limiting gluconeogenetic enzymes (eg, pyruvate carboxylase, phosphoenolpyruvate carboxykinase) and decreasing intracellular fructose-2,6-bisphosphate levels (inhibiting glycolysis).
(Choices A, B, and F) Epinephrine from the adrenals increases glucose by multiple mechanisms, including increased glycogenolysis and gluconeogenesis in the liver and decreased glucose uptake by skeletal muscle. Epinephrine also causes increased alanine release from skeletal muscle, which serves as a source of gluconeogenesis in the liver. In adipose tissue, epinephrine increases the breakdown of triglycerides, thereby increasing circulating free fatty acids and glycerol that can be utilized as gluconeogenetic substrates.
(Choice C) During the first 12 hours of fasting, hepatic glycogenolysis is the source for most of the body’s glucose. When hypoglycemia is sustained, gluconeogenesis in the renal cortex becomes an important glucose source. Epinephrine is more effective than glucagon in stimulating renal gluconeogenesis.
(Choice E) Glucagon and insulin are pancreatic hormones that act as key blood glucose regulators. Insulin decreases blood glucose levels and suppresses glucagon secretion. Although it sounds counterintuitive, glucagon stimulates insulin secretion by acting on the pancreatic beta cells (allowing glucose to be taken up by insulin-sensitive tissues).
(Choice G) The treatment of choice in hypoglycemic patients without an altered sensorium is to administer glucose orally as glucose is a monosaccharide that gets absorbed rapidly from the gastrointestinal tract.
Educational objective:
Glucagon increases serum glucose by increasing hepatic glycogenolysis and gluconeogenesis. Glucagon also stimulates insulin secretion from the pancreas. Unlike epinephrine, glucagon has an insignificant effect on glucose homeostasis in the skeletal muscle, adipose tissue, and renal cortex.
Answer B
Incretins are gastrointestinal hormones produced by the gut mucosa that stimulate pancreatic insulin secretion in response to sugar-containing meals. This response is independent of blood glucose levels, and typically occurs prior to any elevation in blood glucose level following a meal. Two hormones with incretin effects are glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (glucose-dependent insulinotropic peptide, GIP). Insulin levels will also increase following intravenous administration of glucose due to the sensitivity of the pancreatic beta-cells to increases in blood glucose, but this increase will not be as marked as that seen following oral glucose administration because the effect of incretin is absent.
(Choice A) Insulin-like growth factor-1 is produced by the liver in response to stimulation by growth hormone. It functions as a mitogen and as an inhibitor of apoptosis.
(Choice C) Somatostatin is produced by cells in the stomach, small bowel and pancreas and inhibits the production and release of most other gastrointestinal hormones, including insulin.
(Choice D) Secretin is a hormone produced in the duodenum in response to increased luminal acidity. It stimulates the release of bicarbonate-rich secretions from the pancreas, gallbladder and duodenum. It also increases the activity of cholecystokinin.
(Choice E) Cholecystokinin is produced by the duodenum in response to a fat or protein-rich meal. It has many functions including inhibition of further gastric emptying, stimulation of pancreatic enzyme secretion and stimulation of bile production and gallbladder contraction.
Educational objective:
Incretin functions by stimulating insulin release following oral consumption of glucose. Incretin-stimulated insulin release is independent of the increase in insulin secretion brought on by elevations in the blood glucose level.
Answer D
Stress hyperglycemia is a transiently elevated blood glucose level in the context of severe illness in patients without preexisting diabetes mellitus. It is common in the intensive care unit and is typically seen in those with sepsis and other severe infections, burns, trauma, or major hemorrhage.
Severe metabolic stress is associated with increased production of cortisol, catecholamines (primarily epinephrine and norepinephrine), glucagon, and proinflammatory cytokines (eg, IL-1, IL-6, tumor necrosis factor-alpha). Cortisol, catecholamines, and glucagon act on the liver to increase glycogenolysis and gluconeogenesis, stimulating release of glucose from the liver into the blood.
In addition, the release of proinflammatory cytokines is associated with increased expression of glucose transporter (GLUT) 1 in the CNS and macrophages, along with decreased expression of GLUT4 (which mediates insulin-induced glucose uptake in peripheral tissues). This facilitates increased glucose uptake by the brain and immune cells responsible for fighting infection.
(Choice A) During trauma resuscitation, most patients are given isotonic fluids (eg, normal saline, Ringer lactate), which are unlikely to cause hyperglycemia. Even if mild fluid-induced hyperglycemia occurs, blood glucose levels typically normalize quickly after fluid boluses.
(Choice B) Norepinephrine stimulates peripheral lipolysis, releasing glycerol, which can be taken up by the liver for use in gluconeogenesis. Therefore, stress increases, not decreases, the hepatic glycerol supply.
(Choice C) Severe illness is often associated with increased anaerobic glycolysis due to systemic or local tissue hypoxia (blood loss in this patient). Increased conversion of glucose to lactate in ischemic tissues raises plasma lactate levels. Glucose levels are often concurrently elevated due to stress hyperglycemia, but anaerobic glycolysis itself depletes glucose.
(Choice E) The renal cortex can convert lactate to glucose via gluconeogenesis. However, it makes a significantly smaller contribution to circulating glucose levels than hepatic gluconeogenesis.
Educational objective:
Stress hyperglycemia is transiently elevated blood glucose levels in the context of severe illness (eg, sepsis, burns, major hemorrhage) in patients without preexisting diabetes mellitus. Cortisol and catecholamines released in response to severe metabolic stress act on the liver to increase glycogenolysis and gluconeogenesis.
Answer B
This patient’s polyuria, polydipsia, fatigue, and weight loss despite increased food intake are suggestive of type 1 diabetes mellitus. Patients often develop these characteristic symptoms over an acute to subacute time frame and may occasionally present with diabetic ketoacidosis (nausea/vomiting, abdominal pain, decreased mental status, fruity odor to breath). Although most patients with type 1 diabetes mellitus are diagnosed before age 10, onset in adolescence and adulthood is not uncommon.
Appropriate initial tests and related diagnostic criteria for diabetes include:
Fasting plasma glucose ≥126 mg/dL
Hemoglobin A1c ≥6.5%
Random (nonfasting) glucose ≥200 mg/dL in a patient with symptoms of hyperglycemia (eg, polyuria, polydipsia)
Oral glucose tolerance test with plasma glucose ≥200 mg/dL 2 hours after glucose ingestion (preferred for diagnosis of gestational diabetes)
(Choice A) Colon cancer in a first-degree relative increases an individual’s risk for this disease. However, because this patient’s father was at an advanced age at diagnosis, the patient’s risk is not significantly elevated.
(Choice C) Acute HIV presents as an acute viral syndrome with nonspecific symptoms and signs (eg, weight loss, fatigue). However, polyuria and polydipsia suggest diabetes rather than acute HIV.
(Choice D) It is possible that weight loss and polyuria are due to thyrotoxicosis, but the absence of other symptoms of thyroid disease (eg, palpitations, heat intolerance, excessive sweating) makes this less likely.
(Choice E) Acute cystitis can cause frequent urination but the total urine volume is not increased, and polydipsia and weight loss are more suggestive of diabetes mellitus. Although urinalysis can detect glucosuria, it has low sensitivity for diabetes and should not be used to confirm the diagnosis.
(Choice F) Although surreptitious drug abuse can be considered in patients with weight loss or other unexplained symptoms, a hemoglobin A1c test is more likely to be diagnostic in light of this patient’s polyuria and polydipsia.
Educational objective:
Type 1 diabetes mellitus typically presents subacutely with polyuria and polydipsia accompanied by fatigue and weight loss. The diagnosis can be confirmed with a fasting blood glucose or hemoglobin A1c measurement.
Answer E
Sodium-glucose cotransporter-2 (SGLT2) is a high-capacity transport protein that reabsorbs 90% of filtered glucose in the proximal tubule. SGLT2 inhibitors (eg, canagliflozin, dapagliflozin) are oral antidiabetic agents that decrease renal reabsorption of glucose and sodium, leading to urinary glucose loss and decreased blood glucose levels. The decreased reabsorption of sodium and glucose also induces osmotic diuresis and natriuresis, leading to a decrease in blood pressure and a lower rate of hospitalization for heart failure.
However, the glycosuria induced by SGLT2 inhibitors creates a more favorable environment for pathogenic bacteria and fungi in the genitourinary tract and perineum. This leads to an increased risk for urinary tract infections (eg, pyelonephritis), genital mycotic infections (eg, vaginitis), and necrotizing fasciitis of the perineum (ie, Fournier gangrene). Other adverse effects include hypovolemia, which can lead to orthostatic hypotension and acute kidney injury.
(Choice A) Glucagon-like peptide-1 agonists (eg, exenatide, dulaglutide) lower blood glucose levels by increasing glucose-dependent insulin secretion and suppressing glucagon secretion. Adverse effects include delayed gastric emptying and a possible increased risk for pancreatitis.
(Choice B) Thiazolidinediones (eg, pioglitazone) increase the reabsorption of sodium in the renal collecting tubule; this can lead to significant fluid retention, particularly in patients with heart failure. In contrast, SGLT2 inhibitors reduce fluid retention.
(Choices C and F) Exogenous insulin and sulfonylureas (eg, glimepiride), which stimulate endogenous insulin secretion, can cause hypoglycemia and weight gain. SGLT2 inhibitors carry a low risk for hypoglycemia because the glucose-lowering effect is proportionate to the filtered glucose load. In addition, renal glucose wasting typically induces mild weight loss.
(Choice D) Metformin inhibits hepatic gluconeogenesis, leading to the accumulation of lactate. Patients with decreased lactate clearance (eg, renal or hepatic dysfunction, congestive heart failure) can have excessive accumulation of lactate, leading to lactic acidosis.
Educational objective:
Sodium-glucose cotransporter-2 inhibitors (eg, canagliflozin, dapagliflozin) decrease renal reabsorption of glucose, leading to urinary glucose loss and decreased blood glucose levels. However, the resultant glycosuria can lead to genitourinary tract infections and genital mycotic infections.
Answer C
This patient has symptomatic hypoglycemia following initiation of a sulfonylurea medication (ie, glipizide) for diabetes mellitus. Sulfonylureas inhibit the ATP-sensitive potassium channel on the pancreatic beta cell membrane, inducing depolarization with opening of L-type calcium channels (ie, increased Ca2+ influx), stimulating insulin release. Sulfonylurea-induced stimulation of beta cells is independent of blood glucose and occurs even when blood glucose levels are normal, increasing the risk for hypoglycemia.
The risk for hypoglycemia associated with sulfonylureas is increased in the setting of skipped meals (as in this patient), in excessively high medication doses, and with concurrent renal or hepatic disease (which decreases drug metabolism and clearance). Although hypoglycemia can occur with any sulfonylurea medication, the risk is highest with longer-acting sulfonylureas (eg, glyburide).
(Choice A) Metformin inhibits the mitochondrial enzymes required for gluconeogenesis, leading to decreased hepatic glucose production and lower circulating glucose levels. It also increases peripheral glucose uptake and improves insulin sensitivity by activating AMP-activated protein kinase. Metformin does not increase endogenous insulin secretion and therefore is not associated with hypoglycemia.
(Choice B) Thiazolidinediones (eg, pioglitazone) decrease insulin resistance by binding to peroxisome proliferator–activated receptor gamma, a transcriptional regulator of genes involved in glucose and lipid metabolism.
(Choice D) Glucagon-like polypeptide-1 (GLP-1) is secreted by the intestine in response to food intake and slows gastric emptying and increases glucose-dependent insulin release. GLP-1 agonists (eg, exenatide) act through cell surface receptors that are coupled with a G protein–adenylyl cyclase system. Because the effects of GLP-1 agonists are glucose dependent (eg, occur primarily in the presence of food), these medications are not typically associated with hypoglycemia.
(Choice E) Insulin acts by binding to a cell surface receptor consisting of 2 alpha and 2 beta subunits. The alpha subunits are located extracellularly and provide binding sites for insulin. The membrane-spanning beta subunits contain the intracellular tyrosine kinase domains.
Educational objective:
Sulfonylureas inhibit the ATP-sensitive potassium channel on the pancreatic beta cell membrane, inducing depolarization Ca2+ influx, and insulin release independent of blood glucose concentrations. Sulfonylureas can induce hypoglycemia because they stimulate insulin secretion even when blood glucose levels are normal.
Answer A
This patient has cataracts, a vision-impairing opacification of the lens that causes loss of the red reflex with decreased visualization of retinal details on ophthalmoscopic evaluation. The incidence of cataracts increases with age; other risk factors include smoking, excessive sunlight exposure, diabetes mellitus, and glucocorticoid use. In this patient, long-term hyperglycemia most likely contributed to cataract formation by causing oversaturation of the polyol pathway.
The first step in the polyol pathway (an alternative route of glucose metabolism) is the conversion of glucose into sorbitol by aldose reductase. Sorbitol cannot readily cross cell membranes and is therefore trapped inside the cells where it forms. The second enzyme in the pathway, sorbitol dehydrogenase, is able to convert sorbitol into fructose at a sufficient rate to prevent accumulation when glucose levels are normal. However, the process is slow; in long-standing hyperglycemia, sorbitol accumulates in tissues with lower sorbitol dehydrogenase activity, such as the retina, lens, kidney, and peripheral nerves.
Sorbitol accumulation increases cellular osmotic and oxidative stress and contributes to the pathogenesis of diabetic retinopathy, neuropathy, and nephropathy. In lens cells, the increased stress leads to the development of hydropic lens fibers that degenerate, eventually resulting in lens opacification and cataract formation.
(Choices B and C) Another function of aldose reductase is the conversion of galactose into galactitol (ie, this enzyme converts sugars into their corresponding sugar alcohols). Galactitol production via this pathway is normally insignificant. In galactosemia (galactose-1-phosphate uridyltransferase deficiency), an increased amount of galactitol is produced, resulting in congenital cataracts.
(Choice D) The end product of sorbitol metabolism in most cells is fructose (not glucose), which is then excreted by the cells and taken up by the liver to produce glucose and triglycerides.
(Choice E) Xylulose is an intermediate in the pentose phosphate pathway, which is used to generate NADPH (for cholesterol and fatty acid synthesis) and ribose 5-phosphate (for nucleotide synthesis).
Educational objective:
In the polyol pathway, aldose reductase converts glucose into sorbitol, which is slowly metabolized into fructose by sorbitol dehydrogenase. Chronic hyperglycemia overwhelms this pathway, causing intracellular sorbitol accumulation and increased osmotic/oxidative stress. This accelerates cataract development in patients with diabetes, and contributes to the pathogenesis of diabetic retinopathy, neuropathy, and nephropathy.
Answer A
Sodium-glucose cotransporter-2 (SGLT-2) is a transport protein that reabsorbs 90% of filtered glucose in the proximal renal tubule. SGLT-2 inhibitors (eg, canagliflozin, dapagliflozin) are oral antidiabetic agents that decrease renal reabsorption of glucose and sodium, lowering blood glucose and causing osmotic diuresis. Because of their diuretic effects, SGLT-2 inhibitors consequently:
decrease blood pressure (due to intravascular volume reduction)
lower mortality for heart failure (due to preload/afterload reduction)
slow progression of diabetic nephropathy (due to natriuresis, which reduces glomerular hyperfiltration)
In elderly patients taking diuretics (eg, furosemide) and antihypertensives, SGLT-2 inhibitors should be used with caution due to concern for orthostatic hypotension, which can lead to falls and acute kidney injury. Because of increased renal glucose excretion, patients typically experience a mild reduction in weight (often desirable) but may be at increased risk for genitourinary infections (eg, vaginal candidiasis).
(Choice B) SGLT-2 inhibitors may decrease (not increase) bone density, possibly because decreased sodium reabsorption is associated with increased phosphate reabsorption in the proximal tubule, resulting in increased parathyroid hormone secretion and, subsequently, increased bone resorption.
(Choice C) Thiazolidinediones (eg, pioglitazone) are antidiabetic medications associated with fluid retention. In contrast, SGLT-2 inhibitors induce a net loss of sodium and fluid.
(Choice D) Glucagon-like peptide-1 (GLP-1) regulates glucose by slowing gastric emptying and increasing glucose-dependent insulin release. Pharmacologic GLP-1 agonists (eg, exenatide) increase postprandial satiety, which leads to weight loss, and are used in the treatment of type 2 diabetes mellitus.
(Choice E) Because renal glucose filtration is proportional to blood glucose level (eg, less glucose is filtered if serum glucose is normal or low, such as in a fasting state), SGLT-2 inhibitors carry a low risk for hypoglycemia. In addition, they do not increase pancreatic insulin secretion, further reducing the risk for hypoglycemia.
Educational objective:
Sodium-glucose cotransporter-2 inhibitors (eg, canagliflozin, dapagliflozin) decrease renal reabsorption of glucose and sodium. The resultant osmotic diuresis and natriuresis lead to reduced blood pressure, decreased mortality in heart failure, and slowed progression of diabetic nephropathy.
Answer B
Insulin therapy for diabetes mellitus commonly causes weight gain due to increased peripheral glucose uptake, increased adipose lipid deposition, and reduced renal glucose loss (due to normalization of blood glucose, which reduces the filtered glucose load). Behavioral factors, including snacking and less rigorous adherence to dietary recommendations, can also contribute. Weight gain is especially pronounced in patients with type 2 diabetes who typically have high circulating levels of insulin and preexisting obesity.
This patient has experienced weight gain after initiating a long-acting insulin analogue (ie, insulin glargine). Insulin normally suppresses appetite, but this patient reports increased need to eat, which suggests that the weight gain may not be simply due to the metabolic effects of insulin. Specifically, this patient may be eating more to suppress feelings of hypoglycemia.
To address this patient’s insulin-induced weight gain, the clinician should obtain additional history to elicit the patient’s perspective on appetite, recent changes in dietary patterns, and associated hypoglycemic symptoms. Once the causes are better understood, several strategies, including dietary modification and changes to the insulin regimen, can mitigate insulin-induced weight gain.
(Choice A) Periodic review of exercise habits is recommended for patients with diabetes. However, this patient has already stated that appetite is her primary concern, so this should be explored first.
(Choice C) Patients can gain weight due to a variety of factors. In addition to physiologic factors, stress often alters diet and exercise habits, leading to weight gain. However, this patient’s weight gain is temporally associated with the initiation and titration of insulin, which makes insulin the most reasonable culprit. If the issue is not resolved after addressing the patient’s insulin regimen, other factors can be explored.
(Choice D) Although the benefits of improved glycemic control with insulin generally outweigh the negative effects of weight gain, this statement does not address the patient’s concerns and could miss an opportunity to improve the insulin program.
Educational objective:
Insulin can cause weight gain due to physiologic (eg, increased peripheral glucose uptake, reduced renal loss of glucose) and behavioral (eg, increased snacking in response to hypoglycemia, less rigorous attention to diet) factors. Counseling should elicit the patient’s perspective on appetite, changes in dietary patterns, and hypoglycemic symptoms.
Answer C
Several studies have shown that diabetes mellitus is one of the strongest risk factors for coronary heart disease. Cardiovascular mortality is increased by 2- to 4-fold in patients with type 2 diabetes mellitus, and approximately 40% of patients die secondary to coronary heart disease. For a person with type 2 diabetes mellitus, the risk of dying from coronary heart disease exceeds the risk of dying from any of the other listed causes, even in the absence of other major risk factors for coronary heart disease.
(Choice A) The risk of breast cancer is not increased in patients with diabetes mellitus. Although this patient has a family history of breast cancer, her risk is not significantly increased since her mother was at an advanced age when the cancer occurred.
(Choice B) Diabetic ketoacidosis (DKA) and hyperosmolar coma are acute complications of untreated diabetes mellitus. Hyperosmolar coma is seen mainly with type 2 diabetes mellitus and is characterized by very high blood sugar levels without ketoacidosis. The mortality of hyperosmolar coma is higher than DKA; however, very few patients with diabetes die directly from DKA or hyperosmolar coma.
(Choice D) Diabetes mellitus is the leading cause of end-stage renal disease (ESRD), followed by hypertension. However, approximately 50% of patients with ESRD die due to cardiovascular disease, with infections being the next most common cause.
(Choice E) The risk of stroke is increased in patients with diabetes mellitus. However, cerebrovascular accidents account for about 10% of total mortality in patients with type 2 diabetes mellitus versus 40% from coronary heart disease.
Educational objective:
Patients with noncoronary atherosclerotic disease, diabetes mellitus, or chronic kidney disease are at the same risk of cardiovascular events (eg, myocardial infarction, stroke) as patients with known coronary heart disease. Coronary heart disease is the most common cause of death in patients with diabetes mellitus.
Answer A
This patient with diabetes mellitus has postprandial nausea, vomiting of undigested food, bloating, and early satiety, raising strong suspicion for diabetic gastroparesis, an autonomic neuropathy of the gastrointestinal tract marked by delayed gastric emptying in the absence of mechanical obstruction (eg, normal esophagogastroduodenoscopy [EGD]). Metoclopramide, a dopamine 2 receptor antagonist, can improve symptoms but is occasionally associated with extrapyramidal side effects (eg, dystonia) and tardive dyskinesia (eg, involuntary movements).
For patients with gastroparesis who cannot tolerate metoclopramide, erythromycin, a macrolide antibiotic, can be used as an alternate prokinetic agent. The prokinetic effects of erythromycin stem from the activation of the motilin receptor in the smooth muscle of the upper digestive tract, which results in coordinated peristaltic contractions that begin in the stomach and move through the entire upper digestive system (thereby propelling food into the colon).
When used as an antibiotic, erythromycin can cause significant abdominal cramping, but in the setting of gastroparesis, the prokinetic effects can be leveraged to improve gastric emptying and ameliorate gastroparesis symptoms. However, the agonist effects of erythromycin diminish over time (tachyphylaxis) so it is generally used for short periods (<4 weeks).
(Choices B and C) Patients with irritable bowel syndrome (IBS) who have significant gastrointestinal bloating symptoms can be treated with antispasmodic medications (eg, dicycloverine) that block gastrointestinal muscarinic receptors. Those with constipation-predominant IBS are sometimes treated with lubiprostone, a chloride channel activator, to increase intestinal fluid secretion. IBS is usually marked by periods of diarrhea and/or constipation and abdominal bloating; early satiety and vomiting of undigested food would be atypical.
(Choice D) Peptic ulcer disease (PUD) is treated with medications (eg, proton pump inhibitor, sucralfate) that have a protective effect on the gastrointestinal mucosa. Although PUD can occasionally cause nausea, vomiting, and early satiety due to gastric outlet obstruction, most patients have significant upper abdominal pain. In addition, an EGD would show a gastric or duodenal ulcer.
(Choice E) Patients with small intestinal bacterial overgrowth (SIBO)—colonization of the small intestine with colonic bacteria—often develop bloating, abdominal discomfort, flatulence, and/or diarrhea. However, early satiety and vomiting of undigested food would be atypical. In addition, SIBO is generally treated with rifaximin or neomycin.
Educational objective:
Erythromycin stimulates upper gastrointestinal motility by acting as an agonist on motilin receptors in the muscularis externa. Therefore, it can be used to treat gastroparesis (ie, delayed gastric emptying), a condition that frequently occurs in patients with long standing diabetes mellitus.
Answer D
Metformin lowers blood glucose by decreasing hepatic gluconeogenesis and increasing insulin-dependent peripheral glucose uptake. It functions by inhibiting mitochondrial glycerol-3-phosphate dehydrogenase, which reduces availability of gluconeogenesis substrates (eg, glycerol, lactate). Metformin also upregulates AMP-activated protein kinase, which inhibits lipogenesis and subsequently lowers circulating lipid levels.
Metformin is the preferred first-line medication for type 2 diabetes mellitus. It does not increase endogenous insulin secretion and therefore carries a low risk of hypoglycemia. In addition, it also leads to modest weight loss in most patients.
However, the inhibition of gluconeogenesis by metformin results in increased lactate production. Patients with significant renal dysfunction or other disorders that reduce lactate clearance (eg, hepatic impairment) are at risk for metformin-induced lactic acidosis. For this reason, the glomerular filtration rate should be estimated using serum creatinine measurement prior to the initiation of metformin.
(Choice A) Metformin can cause vitamin B12 deficiency (leading to macrocytic anemia), likely due to decreased intestinal absorption. However, this is a chronic effect seen after long-term use, and pretreatment testing is not needed.
(Choice B) The oral glucose tolerance test is used for the initial diagnosis of diabetes mellitus, primarily gestational diabetes. This patient’s diagnosis has been confirmed with elevated fasting glucose and hemoglobin A1c; additional diagnostic testing is not necessary.
(Choice C) Plasma lactate levels are used to confirm acute lactic acidosis; measurement of a baseline level is not useful.
(Choice E) Monitoring serum potassium is not necessary with metformin use. Serum potassium is routinely monitored with diuretics (especially loop diuretics), spironolactone, ACE inhibitors, and angiotensin II receptor blockers.
(Choice F) Thyroid function tests routinely performed in patients taking lithium and amiodarone but are not required for antidiabetic medications, including metformin.
Educational objective:
Metformin lowers blood glucose by reducing hepatic gluconeogenesis and increasing insulin-dependent peripheral glucose uptake. Lactic acidosis is a rare complication of metformin therapy; the risk is increased in patients with underlying renal insufficiency.
