A 56-year-old man comes to the office for follow-up of type 2 diabetes mellitus. The patient has had inadequate glycemic control with metformin monotherapy, and a new medication that inhibits dipeptidyl peptidase-4 was prescribed 3 months ago. He feels well and reports no adverse effects from the new therapy. The patient also has hypertension, for which he takes ramipril. He does not use tobacco, alcohol, or illicit drugs. The patient says he is generally compliant with dietary guidance but occasionally eats fast foods. Blood pressure is 126/74 mm Hg and pulse is 76/min. BMI is 31.4 kg/m². Physical examination shows no abnormalities. Laboratory results show a hemoglobin A1c of 6.8%. The newly prescribed medication most likely improved this patient's glycemic control through which of the following direct mechanisms?

Question

Quizplus · Accepted Answer

11ec160b_3bb4_8470_9249_27c28a8ec642_MD0001_00 Glucagon-like peptide-1 (GLP-1) is secreted by intestinal L cells in response to food intake and regulates glucose levels by slowing gastric emptying, suppressing glucagon secretion, and increasing glucose-dependent insulin release. 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). DPP-4 inhibitors (eg, sitagliptin, saxagliptin) inhibit the degradation of GLP-1, prolonging its effects and leading to improved glycemic control (eg, reduction in hemoglobin A1c). GLP-1's effect on insulin secretion is glucose-dependent: as glucose levels fall, so does insulin secretion. Therefore, DPP-4 inhibitors have a low risk of hypoglycemia. Major side effects include nasopharyngitis and other upper respiratory symptoms. GLP-1 agonists that are intrinsically resistant to degradation by DPP-4 are also available and have a similar (but more potent) effect in lowering blood glucose with a low risk of hypoglycemia. (Choice A) Alpha-glucosidase inhibitors (eg, acarbose) directly impair the hydrolysis of polymeric carbohydrates, leading to decreased postprandial glucose absorption. Although DPP-4 inhibitors can indirectly slow digestion of carbohydrates due to delayed gastric emptying, they do not directly affect intestinal carbohydrate metabolism. (Choice B) Sodium-glucose cotransporter-2 inhibitors (eg, canagliflozin, dapagliflozin) act in the kidney to decrease reabsorption of filtered glucose. (Choice C) GLP-1 acts directly on pancreatic islet cells to suppress glucagon secretion, an effect that is enhanced by DPP-4 inhibitors. (Choice E) 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. Educational objective: Glucagon-like peptide-1 (GLP-1) regulates glucose by slowing gastric emptying, suppressing glucagon secretion, and increasing glucose-dependent insulin release. Dipeptidyl peptidase-4 inhibitors (eg, sitagliptin, saxagliptin) decrease the breakdown of GLP-1 and improve glycemic control in patients with type 2 diabetes. Because the effect on insulin is glucose-dependent, these medications have a low risk of hypoglycemia. __________ References: Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus. (http://www.ncbi.nlm.nih.gov/pubmed/26173919)

A 56-Year-Old Man Comes to the Office for Follow-Up of Type