Diabetes - Part III Flashcards
Answer E
Prolonged hypoglycemia can lead to irreversible neurologic deficits and death. To prevent injury, counterregulatory systems raise blood glucose in response to hypoglycemia via sympathetic nervous system activation (ie, norepinephrine/epinephrine release) and increase secretion of glucagon, cortisol, and growth hormone.
Symptoms of hypoglycemia fall into 2 general categories: neurogenic (autonomic) and neuroglycopenic.
Neurogenic symptoms are mediated via norepinephrine/epinephrine and acetylcholine release during sympathetic stimulation. Symptoms due to norepinephrine/epinephrine include tremulousness, tachycardia, and anxiety/arousal, whereas acetylcholine causes sweating, hunger, and paresthesias.
Neuroglycopenic symptoms are due to inadequate availability of glucose in the CNS and include behavioral changes, confusion, visual disturbances, stupor, and seizures.
This patient has reduced awareness of hypoglycemia, likely due to the use of a nonselective beta blocker (eg, propranolol) for chronic treatment of migraines and/or hypertension. Nonselective beta blockers attenuate the norepinephrine/epinephrine-mediated symptoms of hypoglycemia, but cholinergic symptoms (eg, hunger) are unaffected. In addition, nonselective beta blockers can contribute to the severity of hypoglycemia; epinephrine stimulates hepatic gluconeogenesis and peripheral glycogenolysis, but this effect is diminished by nonselective beta blockers.
(Choices A and C) Statins (eg, atorvastatin) and hydrochlorothiazide can increase blood glucose levels but would not mask symptoms of hypoglycemia.
(Choice B) Insulin-secreting pancreatic beta cells have alpha-2 and beta-2 receptors; stimulation of alpha-2 receptors inhibits insulin secretion, whereas stimulation of beta-2 receptors increases insulin secretion. Doxazosin is a selective alpha-1 blocker and has no effect on glucose levels.
(Choices D and F) Angiotensin II receptor blockers (eg, losartan) and nondihydropyridine calcium channel blockers (eg, verapamil) do not mask the symptoms of hypoglycemia and have virtually no effect on glucose levels.
Educational objective:
Nonselective beta blockers exacerbate hypoglycemia and mask hypoglycemic symptoms mediated by norepinephrine/epinephrine.
Answer D
This patient has symptomatic hypoglycemia, confirmed by the Whipple triad:
- Symptoms consistent with hypoglycemia (eg, tremor, diaphoresis, confusion)
- Low blood glucose level
- Relief of hypoglycemic symptoms when the blood glucose level is corrected
Insulin is initially synthesized as preproinsulin, after which the signal peptide is removed, yielding proinsulin. In the secretory granules, proinsulin is cleaved into insulin and C-peptide, which are then released together in equimolar amounts. Normally, as blood glucose falls, endogenous insulin secretion is suppressed, and serum levels of both insulin and C-peptide drop.
Hypoglycemia due to excessive endogenous insulin production is associated with elevated levels of C-peptide. This can occur due to autonomous insulin-producing tumors (insulinomas) or intake of insulin secretagogues (eg, sulfonylureas). Self-induced hypoglycemia via oral hypoglycemics is often a manifestation of a factitious disorder and is typically seen in health care workers and family members of patients with diabetes using these medications (which is likely in this patient whose husband has home glucose-testing supplies). Sulfonylurea abuse can be confirmed by testing the urine or blood for specific hypoglycemic agents.
(Choice A) Glucagonoma is a rare tumor of pancreatic alpha cells that secretes excessive amounts of glucagon. This results in hyperglycemia, weight loss, anemia, and necrolytic migratory erythema (a raised, erythematous rash affecting the face, groin, and extremities).
(Choice B) Hypoglycemia due to exogenous insulin injection, which does not contain C-peptide, is associated with an elevated serum insulin level but an undetectable C-peptide level.
(Choice C) Somatostatinoma is a rare tumor of pancreatic delta cells that is associated with hyperglycemia, weight loss, abdominal pain, steatorrhea, cholelithiasis, and hypochlorhydria. These manifestations are due to somatostatin-induced inhibition of insulin, gastrin, secretin, and cholecystokinin secretion, as well as decreased gastrointestinal motility.
(Choice E) VIPomas are non–beta cell pancreatic islet cell tumors that hypersecrete vasoactive intestinal polypeptide (VIP). Features include watery diarrhea, hypokalemia, and impaired gastric acid secretion.
Educational objective:
Hypoglycemia is characterized by tremor, diaphoresis, and confusion in association with a low blood glucose level and resolution of symptoms when the blood glucose level is corrected. Hypoglycemia with elevated insulin and low C-peptide levels suggests exogenous insulin injection, whereas elevated C-peptide suggests an insulin secretagogue or insulin-secreting tumor.
Answer C
This patient with inadequately controlled diabetes on metformin therapy was prescribed a second medication. The new agent is associated with nausea, vomiting, early satiety, and significant weight loss, effects characteristic of a glucagon-like peptide-1 (GLP-1) agonist (eg, exenatide, liraglutide).
GLP-1 is secreted by intestinal L cells in response to food intake and regulates glucose by slowing gastric emptying, suppressing glucagon secretion, and increasing glucose-dependent insulin release (ie, insulin release in response to food intake), which lowers the risk for hypoglycemia. It acts through cell surface receptors that are coupled with a G protein–adenylyl cyclase system. Native GLP-1 is degraded by dipeptidyl peptidase-4 (DPP-4), but synthetic GLP-1 agonists are more resistant to degradation, prolonging their therapeutic effect.
Although insulin secretion is increased by GLP-1 agonists, most patients lose weight due to suppressed appetite caused by the following:
Slowed gastric emptying
Nausea and vomiting
Increased satiety (mediated by receptors in the hypothalamus)
These effects are also seen in patients without diabetes, a reason that certain GLP-1 agonists are also approved for the primary indication of weight loss.
(Choice A) Basal-bolus insulin therapy is typically used to treat patients with severe diabetes mellitus (eg, hemoglobin A1c >10%). Insulin therapy is not associated with gastrointestinal side effects but causes significant weight gain.
(Choice B) DPP-4 inhibitors (eg, sitagliptin) are oral agents that block the degradation of endogenous GLP-1. Because they act indirectly on the GLP-1 receptor, their effects (eg, antihyperglycemic, weight loss–related) are less pronounced compared to GLP-1 agonists, which act directly on the receptor. Therefore, these agents do not result in weight loss but are considered weight neutral.
(Choice D) Sulfonylureas directly stimulate pancreatic insulin secretion independent of circulating glucose levels, resulting in significant weight gain and risk for hypoglycemia.
(Choice E) Thiazolidinediones (eg, pioglitazone) increase the transcription of certain insulin-responsive genes and decrease insulin resistance. Weight gain and fluid retention are common side effects; weight loss is not seen.
Educational objective:
Glucagon-like peptide-1 (GLP-1) agonists slow gastric emptying, suppress glucagon secretion, and increase glucose-dependent insulin release. These agents cause significant weight loss by suppressing the appetite and increasing satiety.
Answer A
Cystic fibrosis (CF) is an autosomal recessive disorder caused by a mutation (eg, ΔF508) in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. CFTR normally regulates the transport of chloride ions across secretory epithelial cells; a defect in this protein leads to the accumulation of thick, inspissated secretions in ducts throughout the body (eg, lungs, pancreas, gastrointestinal tract, vas deferens).
In the pancreas, dehydrated, viscous secretions block the lumen of the pancreatic ducts, causing both exocrine (ie, malabsorption) and endocrine dysfunction. Endocrine dysfunction is due to pancreatic fibrosis and fat infiltration, which cause progressive encroachment, disruption, and destruction of pancreatic islet cells. This injury results in decreased insulin production and CF-related diabetes (CFRD). In the initial stages, glucose is typically normal when fasting (ie, able to produce some insulin) but elevated after a glycemic load, as seen in this patient. As the disease progresses, there is fasting hyperglycemia and increasing hemoglobin A1c levels.
Because early diagnosis and treatment with insulin are associated with improved pulmonary status and overall survival, all CF patients should undergo regular screening with oral glucose tolerance tests.
(Choice B) Decreased insulin production due to pancreatic islet cell autoantibodies describes the pathogenesis of type 1 diabetes mellitus. Islet cell destruction in CFRD is not an autoimmune process.
(Choice C) Although glucagon increases in response to starvation, chronic malnutrition is likely to result in glucagon resistance. In addition, glucagon-producing alpha islet cells are damaged along with beta cells in patients with CF, resulting in decreased glucagon secretion.
(Choices D and E) Stress-induced hyperglycemia and insulin resistance can occur in times of acutely increased metabolic demand (eg, trauma, burn, sepsis) due to the release of cortisol, epinephrine, and glucagon. Patients with late-stage CFRD may have a component of insulin resistance during times of acute stress and inflammation (eg, pulmonary exacerbation); however, this is not the primary mechanism of CFRD.
Educational objective:
Cystic fibrosis (CF) causes the accumulation of thick, viscous secretions in ducts throughout the body. CF-related diabetes occurs after the progressive destruction of pancreatic islet cells leads to decreased insulin production.
Answer B
Sodium-glucose cotransporter-2 (SGLT-2) is a low-affinity, high-capacity transport protein that reabsorbs 90% of filtered glucose in the proximal tubule. SGLT-2 inhibitors (eg, canagliflozin, dapagliflozin) are oral antidiabetic agents that decrease renal reabsorption of sodium and glucose and thereby decrease blood glucose levels. They are used primarily as a combination therapy (eg, with metformin), especially in patients with atherosclerotic cardiovascular disease (eg, prior myocardial infarction), heart failure, or nephropathy (eg, albuminuria).
Because SGLT-2 inhibitors rely on adequate renal glucose filtration to exert their antihyperglycemic effect, they become less effective or ineffective as renal function declines (eg, when estimated glomerular filtration rate [eGFR] falls <30-45 mL/min/1.73 m2). Therefore, checking serum creatinine (used to calculate eGFR) is recommended prior to medication initiation.
(Choices A and E) Although SGLT-2 inhibitors increase the risk for genitourinary infections (eg, candidiasis, urinary tract infection), screening for infection with a leukocyte count and urinalysis in asymptomatic patients (eg, no dysuria or fever) is unnecessary.
(Choice C) Certain drugs such as diuretics (eg, thiazide, loop) reduce renal uric acid clearance and may precipitate gout. However, SGLT-2 inhibitors are associated with increased renal uric acid clearance and are not expected to increase the risk for gout.
(Choice D) Thyroid function tests are routinely performed on patients taking lithium and amiodarone, which can alter thyroid hormone metabolism. However, thyroid function tests are not required for antidiabetic medications.
Educational objective:
Sodium-glucose cotransporter-2 inhibitors (eg, canagliflozin, dapagliflozin) lower glucose levels by decreasing renal reabsorption of glucose and have cardioprotective and renoprotective effects. Checking serum creatinine is recommended prior to initiation because the antihyperglycemic effect of these medications becomes less pronounced as renal function declines.
Answer B
This patient’s persistent hypoglycemia indicates excessive insulin secretion caused by her diabetes medication, which is most likely a sulfonylurea (eg, glyburide, glimepiride). Sulfonylureas bind to a receptor on pancreatic beta cells and inhibit the ATP-sensitive potassium channel, altering the cell’s resting potential and resulting in calcium influx stimulating exocytosis of insulin secretory granules. The increased insulin secretion occurs independent of blood glucose concentrations (ie, even when blood glucose concentrations are low).
Hypoglycemia with sulfonylureas can be induced by exercise, missed meals, or initiation of additional antidiabetic medications. The risk is greater in the elderly population and in patients with chronic kidney disease or hepatic impairment (due to slower drug metabolism and clearance). The hypoglycemia may reoccur following successful initial treatment until the drug has been fully cleared.
(Choice A) Acarbose is an alpha-glucosidase inhibitor that decreases intestinal carbohydrate digestion and glucose absorption, thereby blunting postprandial hyperglycemia. It is not associated with hypoglycemia because the medication does not induce insulin secretion.
(Choice C) Metformin is a biguanide that decreases hepatic gluconeogenesis and intestinal glucose absorption and increases peripheral glucose uptake and use. Because metformin does not increase endogenous insulin production, it is not associated with hypoglycemia.
(Choice D) Thiazolidinediones (eg, pioglitazone) increase insulin sensitivity by increasing glucose use and decreasing glucose production in adipose tissue, muscle, and liver. Thiazolidinediones do not increase endogenous insulin production and therefore carry a low risk of hypoglycemia.
(Choice E) Unlike sulfonylureas, dipeptidyl peptidase-4 inhibitors (eg, sitagliptin) and glucagon-like peptide-1 agonists (eg, exenatide) increase glucose-dependent insulin release from the pancreatic beta cells. The effects on insulin release diminish as glucose levels approach normal (eg, fasting state), and therefore, hypoglycemia risk is very low.
Educational objective:
Sulfonylureas (eg, glyburide, glimepiride) increase insulin secretion by pancreatic beta cells independent of blood glucose concentration. These medications have a high incidence of hypoglycemia, especially in the elderly population.
Answer B
The patient described in this vignette has type 2 diabetes mellitus (advanced age, obesity, prolonged non-compliance with treatment without immediate life-threatening consequences). The two cardinal defects involved in the pathophysiology of type 2 diabetes mellitus are increased insulin resistance and defective insulin secretion. Although still controversial, many researchers believe that increased insulin resistance is the primary abnormality in type 2 diabetes mellitus. Early in the pathogenesis of type 2 diabetes, glucose tolerance is thought to remain normal because of a compensatory increase in insulin secretion from beta cells. This compensatory insulin response by beta cells ultimately fails, causing poor glucose tolerance. A number of genetic and acquired factors are implicated in the beta-cell dysregulation of type 2 diabetes. Islet amyloid polypeptide (amylin) is one factor thought to be responsible for this beta cell dysfunction. Amylin is stored in insulin secretory granules and is co-secreted with insulin from pancreatic beta cells. Deposits of amylin are universally seen in the pancreatic islets of patients with type 2 diabetes mellitus. Amylin may play a causative role in beta cell apoptosis and defective insulin secretion; however, this theory is still controversial.
Type 1 and type 2 diabetes mellitus have very strong genetic components. Twin studies have shown a concordance rate of 50% in identical twins for diabetes mellitus type 1, and around 80% for diabetes mellitus type 2. The genes involved in the pathogenesis of diabetes mellitus type 2 remain largely unknown. Gene polymorphism within the major histocompatibility complex contributes to type 1 diabetes mellitus disease in humans. HLA-DQ and -DR are the most important determinants of type 1 diabetes mellitus. In the general population, DR3 and DR4 are seen in approximately 40% of subjects; however, in patients with type 1 diabetes mellitus, DR3 and DR4 haplotypes are seen in more than 90% of subjects.
(Choices A, C, D & E) These are features of type 1 diabetes mellitus. Type 1 diabetes occurs when an autoimmune response is triggered by an environmental insult in genetically susceptible individuals. Patients with type 2 diabetes retain at least some beta cell function, but patients with type 1 diabetes mellitus develop absolute deficiency of insulin secondary to immune destruction of pancreatic beta cells. These patients need insulin for survival. Discontinuation of insulin treatment results in ketoacidosis.
Educational objective:
Pancreatic islet amyloid deposition is characteristic of type 2 diabetes mellitus. A strong linkage with HLA class II gene makeup, pancreatic islet infiltration with leukocytes (insulitis), and antibodies against islet antigens are frequently seen in type 1 diabetes.
Answer C
Glucose-induced insulin release from pancreatic beta cells requires the following steps:
Glucose enters the beta cell through glucose transporter type 2 (GLUT-2).
Glucose is metabolized by glucokinase to glucose-6-phosphate.
Glucose-6-phosphate enters glycolysis to produce ATP.
Increased ATP levels causes closure of ATP-sensitive potassium (KATP) channels.
Depolarization of beta cells triggers opening of voltage-dependent calcium channels.
Influx of calcium causes insulin release.
Glucokinase has a lower glucose affinity than other hexokinases, which allows it to limit the rate of glucose entry into the glycolytic pathway based on blood glucose levels. It therefore functions as a glucose sensor for beta cells in controlling insulin release.
Heterozygous mutations of the glucokinase gene that decrease the activity or affinity of the enzyme cause a decrease in beta cell glucose metabolism, leading to reduced ATP formation and insulin secretion at any given glucose level. Glucokinase mutations are one cause of maturity-onset diabetes of the young (MODY), an autosomal dominant disorder characterized by mild hyperglycemia that often worsens with pregnancy-induced insulin resistance. In contrast to those with more common type 2 diabetes mellitus, patients with MODY are typically younger and nonobese, and the condition is nonprogressive, even without treatment.
(Choices A, B, E, and G) Glycolytic enzyme deficiencies (eg, aldolase A, enolase, phosphofructokinase, pyruvate kinase) generally present with hemolytic anemia because red blood cells rely completely on anaerobic glycolysis for energy production.
(Choice D) Lactate dehydrogenase is present in most cells and catalyzes the conversion of pyruvate to lactate during anaerobic glycolysis. Deficiency can cause decreased exercise tolerance and muscle stiffness.
(Choice F) Pyruvate carboxylase, one of the gluconeogenesis pathway enzymes in the mitochondria, catalyzes the conversion of pyruvate to oxaloacetate. Deficiency of pyruvate carboxylase causes lactic acidosis and fasting hypoglycemia.
Educational objective:
Insulin release by pancreatic beta cells is stimulated by increased glucose metabolism and ATP production. Glucokinase functions as a glucose sensor in pancreatic beta cells by controlling the rate of glucose entry into the glycolytic pathway. Mutations in the glucokinase gene lead to a state in which higher glucose levels are required to stimulate insulin secretion and are a cause of maturity-onset diabetes of the young.
Answer E
Insulin, a polypeptide hormone synthesized by pancreatic beta cells, is released in response to elevated glucose levels. Insulin mRNA codes for preproinsulin, a larger precursor molecule that begins with a hydrophobic N-terminal signal peptide. Shortly after translation begins, this signal sequence interacts with cytosolic signal recognition peptide, which halts protein synthesis until the ribosome translocates to the rough endoplasmic reticulum (RER). Once bound to the RER, translation resumes and the growing peptide chain is extruded into the RER. The N-terminal signal peptide is then cleaved from preproinsulin to yield proinsulin.
Proinsulin undergoes conformational changes and the addition of 3 disulfide bonds in the RER. Proinsulin is then transported to the Golgi apparatus, where it is packed into secretory granules. Endopeptidases in the secretory granules cleave proinsulin into insulin and C-peptide, which are then stored within the granules until they are secreted from the cell via exocytosis (Choices A, B, and C).
Exogenous insulin administered to patients with diabetes does not contain C-peptide. However, C-peptide released from beta cells remains in the circulation with a half-life of approximately 35 minutes and can be assayed as a surrogate marker for endogenous insulin production.
(Choice D) Most proteins destined for the extracellular space have a signaling sequence that directs them to the RER/Golgi apparatus, where they are packaged into secretory vesicles. However, a few proteins, such as interleukin-1, lack a signaling sequence and are secreted directly from the cytoplasm via an unconventional mechanism.
Educational objective:
Cleavage of proinsulin in pancreatic beta-cell secretory granules yields insulin and C-peptide, which are stored in the granules until they are secreted in equimolar amounts.
Answer D
This patient has incipient diabetic nephropathy with moderately increased albuminuria (ie, 30-300 mg/g). Although patients with more advanced diabetic kidney disease typically have reduced glomerular filtration (rising serum creatinine), in earlier stages, filtration is normal to increased and serum creatinine may be normal.
In the kidneys, glucose is freely filtered in the glomerulus and is normally reabsorbed with sodium by sodium-glucose cotransporter-2 (SGLT2) in the proximal tubule. In patients with diabetes mellitus, the increased filtered glucose load leads to the following pathophysiologic changes:
Reabsorption of the excess tubular glucose causes increased co-reabsorption of sodium by SGLT2.
This results in decreased tubular sodium delivery to the macula densa, stimulating renin secretion by the juxtaglomerular apparatus and, ultimately, increasing angiotensin II levels.
Angiotensin II induces relative vasoconstriction in the renal efferent arterioles, increasing hydrostatic pressure in the glomerular capillaries, contributing to glomerular hyperfiltration.
SGLT2 inhibitors (eg, empagliflozin) lower blood glucose levels by decreasing the reabsorption of glucose (and sodium) in the proximal tubule, causing urine glucose wasting and increased sodium excretion. The concurrent increase in tubular sodium delivery to the macula densa leads to decreased renin secretion, lower glomerular pressure, reduced hyperfiltration, and delayed progression of nephropathy.
(Choice A) Glucose is absorbed in the intestine primarily via SGLT1 (not SGLT2), which is not significantly affected by empagliflozin.
(Choices B and C) SGLT2 inhibitors lower blood glucose levels, leading to decreased secretion of insulin by pancreatic beta cells. Most patients taking SGLT2 inhibitors experience modest weight loss, not gain, due to urinary glucose wasting and lower circulating insulin levels.
(Choice E) SGLT2 inhibitors are associated with increased, not suppressed, glucagon secretion, possibly due to lower blood glucose and insulin levels or a direct effect on pancreatic alpha cells. Glucagon-like peptide-1 agonists (eg, exenatide) lower blood glucose levels by increasing glucose-dependent insulin secretion and suppressing glucagon secretion.
Educational objective:
In patients with diabetes mellitus, excess glucose in the proximal tubule causes increased concurrent reabsorption of sodium by sodium-glucose cotransporter-2 (SGLT2). This leads to decreased sodium delivery to the macula densa and increased renin secretion, which increases glomerular filtration pressure and promotes glomerular hyperfiltration. SGLT2 inhibitors increase sodium delivery to the macula densa, decreasing renin production and reducing hyperfiltration.
Answer E
This patient is presenting with diabetic ketoacidosis, a condition that most commonly affects patients with type 1 diabetes mellitus due to their absolute insulin deficiency. Type 1 diabetes mellitus occurs in genetically susceptible individuals who are exposed to triggering environmental factors (eg, viral infections, environmental toxins, dietary components). This results in an autoimmune response against pancreatic beta cells that leads to progressive loss of beta cell mass. Overt manifestations of diabetes mellitus tend to develop once >90% of beta cells are destroyed. Although antibodies against islet antigens are detected in a large number of patients, they are thought to play a permissive role in disease pathogenesis; the destruction of beta cells occurs primarily through cell-mediated immunity. Infiltration of islets by inflammatory cells is called insulitis and is more prominent during the early stages of disease.
(Choices A and B) Abdominal fat deposition and excessive body weight are important contributors to insulin resistance and development of type 2 diabetes mellitus. Intra-abdominal visceral fat is more strongly related to insulin resistance than is subcutaneous fat.
(Choice C) Maturity-onset diabetes of the young is an autosomal dominant disease caused by mutations that impair glucose sensing and insulin secretion by pancreatic beta cells. It presents as non-insulin-dependent diabetes at a young age (<25) and accounts for <5% of all cases of diabetes mellitus.
(Choice D) Islet amyloid polypeptide is secreted along with insulin from pancreatic beta cells. Amyloid deposition occurs in the islets of patients with type 2 diabetes mellitus, although its role as a causative agent of beta cell dysfunction remains unknown. Patients with type 1 diabetes mellitus have low circulating levels of islet amyloid polypeptide due to extensive beta cell destruction.
Educational objective:
Autoimmune insulitis with progressive beta cell loss is the most common cause of type 1 diabetes mellitus. Insulin resistance accompanied by relative insulin deficiency is the main cause of type 2 diabetes mellitus.
Answer B
As blood glucose levels fall through the physiologic range, insulin secretion by pancreatic beta cells decreases, leading to reduced peripheral uptake and utilization of glucose. At the same time, alpha cells increase secretion of glucagon, which is the primary counterregulatory hormone to insulin and acts on the liver to rapidly increase glycogenolysis and gluconeogenesis and decrease glycolysis.
Patients with type 1 diabetes mellitus are at increased risk of hypoglycemia because exogenous insulin is not subject to the same regulation as endogenous insulin and will continue to be absorbed from the injection site despite falling glucose levels. Those with long-standing diabetes (ie, >5 years) frequently also have alpha cell failure with decreased glucagon secretion and therefore have an even greater risk of rapid hypoglycemia. Patients with pancreatogenic diabetes (eg, secondary to chronic pancreatitis) also typically have inadequate alpha cell reserve and can experience frequent hypoglycemia.
(Choice A) Progressive hypoglycemia prompts a catecholamine (eg, epinephrine) surge, which increases hepatic glucose production and triggers many of the characteristic hypoglycemic symptoms (eg, arousal, tremor). Patients with long-standing diabetes often have a blunted autonomic response to hypoglycemia, with reduced hypoglycemic awareness, but catecholamines are less important than glucagon in raising blood glucose levels.
(Choice C) Prolonged hypoglycemia can stimulate secretion of cortisol and growth hormone, which increase glucose levels. These hormones typically act over longer timescales (eg, days/weeks) and are less important than glucagon in preventing acute hypoglycemia.
(Choice D) Chronic exposure to high circulating insulin levels leads to downregulation of insulin receptors and reduced insulin sensitivity. This effect promotes hyperglycemia, not hypoglycemia.
(Choice E) Repeated hypoglycemia causes downregulation of beta-adrenergic receptors, which contributes to reduced hypoglycemic awareness. Depending on the systems involved, upregulation of beta-adrenergic receptors would generally reduce hypoglycemia and increase awareness.
Educational objective:
Patients with type 1 diabetes mellitus are at increased risk of hypoglycemia because exogenous insulin will continue to be absorbed from the injection site despite falling glucose levels. Those with long-standing diabetes may also have decreased glucagon secretion and therefore have an even greater risk of rapid hypoglycemia.
Answer E
Insulin decreases blood glucose levels by increasing glucose uptake into skeletal muscle and adipocytes. In addition to having glucose lowering effects, insulin is an anabolic hormone that promotes synthesis of glycogen, triglycerides, nucleic acids, and proteins. Furthermore, insulin inhibits glycogenolysis and gluconeogenesis.
The surface receptor for insulin is a transmembrane protein with intrinsic tyrosine kinase activity in its cytoplasmic domain. Insulin binding activates tyrosine kinase, leading to phosphorylation of insulin receptor substrate 1 (IRS-1). IRS-1 then activates several intracellular pathways that induce the physiologic effects of insulin. Activation of the MAP kinase pathway promotes mitogenic functions such as DNA synthesis and cell growth. In contrast, activation of phosphatidylinositol-3-kinase (PI3K) stimulates metabolic functions such as translocation of GLUT-4 to the cell membrane, glycogen synthesis, and fat synthesis. PI3K promotes glycogen synthesis by activating protein phosphatase, an enzyme that dephosphorylates glycogen synthase, leading to its activation.
(Choice A) Janus kinase (JAK) is a component of the second messenger system for various peptide hormones (eg, growth hormone, prolactin) and cytokines (eg, interferon, interleukin). JAK has tyrosine kinase activity; however, it is a cytoplasmic enzyme that is not part of a cell surface receptor (non-receptor tyrosine kinase).
(Choice B) Lipoxygenase is an enzyme involved in arachidonic acid metabolism and is responsible for the arm of that pathway that synthesizes leukotrienes.
(Choice C) Phospholipase C is activated in the G-protein/inositol triphosphate (IP3)/calcium second messenger system. Hormone-receptor binding activates a G-protein that in turn activates phospholipase C to degrade phospholipids into IP3 and diacylglycerol. Both diacylglycerol and the increased intracellular calcium caused by IP3 lead to protein kinase C activation.
(Choice D) Protein kinase A is the primary intracellular effector enzyme in the G-protein/adenylate cyclase second messenger system. Glucagon acts through this pathway to stimulate glycogen breakdown. Protein kinase A activates glycogen phosphorylase via activation of glycogen phosphorylase kinase.
Educational objective:
Insulin is an anabolic hormone that acts via receptor tyrosine kinase signaling to increase the synthesis of glycogen, proteins, fatty acids, and nucleic acids. Tyrosine kinase/phosphatidylinositol-3-kinase stimulation promotes glycogen synthesis by activating protein phosphatase, an enzyme that dephosphorylates (activates) glycogen synthase.
Answer B
This patient has uncontrolled type 2 diabetes mellitus and is appropriately given metformin, which is the preferred first-line medication for most patients. Metformin has a number of important metabolic effects:
Reduced hepatic gluconeogenesis: metformin inhibits mitochondrial glycerophosphate dehydrogenase, which reduces the availability of substrates for gluconeogenesis (eg, glycerol, lactate).
Increased insulin-dependent peripheral glucose uptake and utilization.
Reduced circulating lipid levels: metformin upregulates AMP-activated protein kinase in hepatocytes, which inhibits lipogenesis.
Circulating levels of endogenous insulin are unchanged or slightly decreased by metformin; therefore, metformin carries low risk of hypoglycemia. In addition, it reduces caloric intake due to decreased appetite and decreased absorption of glucose, leading to modest weight loss in most patients.
(Choice A) Sulfonylureas (eg, glyburide, glimepiride) stimulate beta cell insulin release, leading to decreased glycogenolysis and gluconeogenesis and increased peripheral uptake of glucose; the higher circulating insulin levels also confer an increased risk of hypoglycemia and weight gain.
Educational objective:
Metformin reduces hepatic gluconeogenesis and release of glucose into circulation; increases peripheral glucose uptake and utilization; and reduces circulating lipid levels. Circulating insulin levels are unchanged or slightly decreased; therefore, metformin carries low risk of hypoglycemia. In addition, metformin reduces caloric intake due to decreased appetite and decreased absorption of glucose, leading to modest weight loss.
A 34-year-old woman is brought to the emergency department in the early morning with confusion, tremor, and sweating. Her husband reports that she did not wake to her alarm clock and was difficult to arouse. Over the past week, the patient has had similar episodes in the morning before eating and after exercise. Past medical history is unremarkable. Blood pressure is 135/95 mm Hg, pulse is 110/min, and respirations are 24/min. The patient is arousable to voice but does not follow commands. Cranial nerve examination, muscle tone, and deep tendon reflexes are normal. A bedside fingerstick glucose level is 35 mg/dL. The patient is given an intravenous infusion of glucose, which rapidly improves her mental status. Further evaluation reveals that her episodes of hypoglycemia are due to increased levels of an endogenous hormone. This hormonal imbalance is most likely causing the patient’s symptoms by stimulating which of the following conversions?
(Refer to picture for answer options)
Answer C
This patient has developed hypoglycemia secondary to increased levels of an endogenous hormone. Hypoglycemia can develop due to insulin excess (either endogenous [eg, insulinoma] or exogenous [eg, inadvertent overdose, surreptitious insulin/secretagogue use]) as well as deficiency of counterregulatory hormones (eg, glucagon, epinephrine, cortisol).
Insulin lowers plasma glucose by increasing glucose uptake in fat, muscle, and liver. In addition, insulin causes an increase in glycolysis by activating phosphofructokinase-2 (PFK2), the enzyme that produces fructose 2,6-bisphosphate. The intracellular concentration of fructose 2,6-bisphosphate is the major regulator of phosphofructokinase-1 (PFK1), which converts fructose 6-phosphate to fructose 1,6-bisphosphate in the rate-limiting step of glycolysis. Fructose 2,6-bisphosphate stimulates PFK1 while inhibiting the reverse enzyme, fructose 1,6-bisphosphatase. As a result, the rise in fructose 2,6-bisphosphate levels caused by insulin leads to an increase in glycolysis and inhibition of gluconeogenesis, with a corresponding decrease in circulating glucose levels.
(Choice A) Insulin promotes the storage of glucose by inhibiting glycogen phosphorylase (breaks down glycogen into glucose-6-phosphate) and stimulating glycogen synthase (incorporates UDP-glucose into glycogen).
(Choices B, D, and E) Glucose 6-phosphate is converted to fructose 6-phosphate by phosphoglucose isomerase. Fructose 1,6-bisphosphate is converted to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate by fructose bisphosphate aldolase. Glyceraldehyde 3-phosphate is converted to phosphoenolpyruvate through the action of multiple enzymes. These steps are readily reversible and not regulated by insulin.
(Choice F) Oxaloacetate is converted to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase during gluconeogenesis; this reaction is downregulated by high insulin levels.
Educational objective:
Phosphofructokinase-1 (PFK1) catalyzes the rate-limiting step in glycolysis, and the most potent stimulator of PFK1 is fructose 2,6-bisphosphate. Insulin increases production of fructose 2,6-bisphosphate by phosphofructokinase-2 (PFK2), thereby stimulating glycolysis.
Answer C
Metformin is the preferred initial medication for most patients with type 2 diabetes due to its low cost, lack of weight gain, and low risk of hypoglycemia. However, metformin can cause gastrointestinal side effects (eg, nausea, diarrhea), which may be severe enough to warrant therapeutic change. Sulfonylureas are not typically preferred second-line agents; however, they are affordable and may be used as add-on therapy or as a replacement for metformin when cost is a major concern.
Sulfonylureas inhibit the ATP-sensitive potassium channel on the pancreatic beta cell membrane, inducing depolarization and L-type calcium channel opening. The increased Ca2+ influx stimulates beta cell insulin release independent of blood glucose concentrations (eg, even when blood glucose levels are normal or low). Therefore, a main associated risk is hypoglycemia. Circumstances that can lead to hypoglycemia include exercise, missed meals, or initiation of additional antidiabetic medications. Longer-acting sulfonylureas (eg, glyburide) are more prone to causing hypoglycemia than shorter-acting drugs (eg, glipizide) and are therefore not preferred.
(Choice A) Glucagon-like peptide-1 (GLP-1) helps regulate glucose by slowing gastric emptying and increasing insulin release in response to food intake. Pharmacologic GLP-1 agonists (eg, exenatide) lower blood glucose and promote weight loss; these agents are associated with acute pancreatitis.
(Choice B) In patients with poor oral intake (eg, gastroenteritis) or in those who are on concurrent diuretics (eg, furosemide), osmotic diuresis caused by sodium-glucose cotransporter 2 (SGLT2) inhibitors can lead to additional dehydration, resulting in acute kidney injury. In the long term, however, SGLT2 inhibitors have renoprotective effects and are recommended in patients with diabetic nephropathy.
(Choice D) Metformin can decrease absorption of vitamin B12, leading to B12 deficiency in long-term use. Sulfonylureas do not have a significant effect on vitamin B12 metabolism.
(Choice E) SGLT2 inhibitors (eg, dapagliflozin) decrease renal reabsorption of glucose, leading to increased urinary glucose loss and lower blood glucose levels. The excess glucose in the urine can increase the risk of urinary tract infections and vulvovaginal candidiasis.
Educational objective:
Sulfonylureas inhibit the ATP-sensitive potassium channel on the pancreatic beta cell membrane, inducing depolarization and L-type calcium channel opening. The increased Ca2+ influx stimulates beta cell insulin release independent of blood glucose concentrations, increasing the risk of hypoglycemia when meals are missed or during exercise.
Answer A
Pancreatic beta cells secrete insulin in response to elevated glucose levels. Glucose enters beta cells via glucose transporter 2 (GLUT-2) and is metabolized via glycolysis and the citric acid cycle to generate ATP. ATP then binds to the regulatory subunit of the ATP-sensitive potassium channel (KATP channel). KATP channels are normally open at rest and maintain membrane polarization by allowing outward movement of potassium from the beta cells; however, on binding ATP, the KATP channels close. Increased intracellular ATP therefore leads to decreased potassium efflux and membrane depolarization. This triggers opening of voltage-dependent calcium channels, increased intracellular calcium levels, and subsequent insulin release.
Mutations in the KATP channel causing increased affinity for ATP result in fewer open channels and depolarization at lower glucose concentrations. This causes continued secretion of insulin despite falling blood glucose levels, leading to congenital hypoglycemia. Conversely, mutations of the KATP channels that decrease ATP affinity prevent appropriate depolarization in response to rising glucose levels, causing a familial form of neonatal diabetes mellitus. These patients can be treated successfully with sulfonylureas, which bind to KATP channels and cause closure independent of ATP.
(Choices B, D, and G) Citrate, fumarate, and malate are intermediate products in the citric acid cycle. During this process, energy is stored as NADH and FADH2. ATP is then produced when NADH and FADH2 enter oxidative phosphorylation. However, these intermediates do not directly interact with KATP channels.
(Choices C, F, and H) Fructose-6-phosphate and pyruvate are products of the glycolytic pathway. Lactate is produced from pyruvate during anaerobic glycolysis. Glycolysis raises intracellular ATP levels, but these glycolytic intermediates do not act on KATP channels directly.
(Choice E) Glucose induces insulin release from beta cells via ATP formation but does not interact with KATP channels directly.
Educational objective:
Oxidative metabolism of glucose in pancreatic beta cells generates ATP. ATP-induced closure of the ATP-sensitive potassium channels leads to membrane depolarization and subsequent insulin release.
Answer D
This patient has an elevated hemoglobin A1c, confirming a diagnosis of type 2 diabetes mellitus; he has altered mentation (eg, lethargy), dehydration (eg, dry mucous membranes), and severe hyperglycemia that is consistent with a hyperosmolar hyperglycemic state. After acute management (eg, intravenous fluids and insulin infusion), he needs to transition to chronic (subcutaneous) insulin therapy.
A variety of commercial insulin analogues with different pharmacokinetics are available; the ideal regimen mimics normal insulin secretion using separate injections of the following:
Long-acting insulins (eg, glargine) mimic continuous, steady-level basal insulin secretion by the pancreas that suppresses hepatic gluconeogenesis; they have an extended duration of action and little or no peak effect. They are typically given once daily and are used to control fasting hyperglycemia that is attributable to inappropriate hepatic gluconeogenesis.
Rapid-acting insulins (eg, lispro, aspart) mimic rapid-onset, short-lived postprandial insulin surges in response to meals; they peak and are cleared quickly. They are given multiple times daily, just before each meal, so that the peak effect coincides with postprandial glucose surges.
(Choice A) Insulin aspart alone can replicate postprandial insulin secretion but does not provide a basal insulin effect.
(Choices B and C) Insulins detemir and glargine are long-acting basal insulins without significant peak effects; because of detemir’s shorter duration of action (ie, <24 hr), it is sometimes given twice daily to ensure 24-hour coverage. These medications do not treat postprandial hyperglycemia.
(Choice E) NPH is an intermediate-acting insulin; it can be used as a basal insulin if given twice daily to provide 24-hour coverage. Unlike physiologic basal insulin secretions, NPH has a significant peak effect that increases the risk for hypoglycemia. In addition, premixing with regular insulin does not easily allow for premeal bolus adjustments. Therefore, a combined formulation of NPH and regular insulin (usually in a 70/30 ratio) is less representative of physiologic insulin secretion compared to separate injections of basal and rapid-acting premeal insulin.
Educational objective:
Physiologic insulin secretion can be approximated by separate administrations of long-acting and rapid-acting insulin analogues. Long-acting preparations (eg, glargine) replicate basal insulin secretion, whereas premeal, rapid-acting insulin (eg, lispro) replicates meal-related insulin surges.
