Role of the incretin pathway in the pathogenesis of type 2 diabetes mellitus.
Nutrient intake stimulates the secretion of the gastrointestinal incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which exert glucose-dependent insulinotropic effects and assist pancreatic insulin and glucagon in maintaining glucose homeostasis. GLP-1 also suppresses glucose-dependent glucagon secretion, slows gastric emptying, increases satiety, and reduces food intake. An impaired incretin system, characterized by decreased responsiveness to GIP and markedly reduced GLP-1 concentration, occurs in individuals with type 2 diabetes mellitus (T2DM). The administration of GLP-1 improves glycemic control, but GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). Exenatide, a DPP-4-resistant exendin-4 GLP-1 receptor agonist, exhibits the glucoregulatory actions of GLP-1 and reduces body weight in patients with T2DM. It may possess cardiometabolic actions with the potential to improve the cardiovascular risk profile of patients with T2DM. DPP-4 inhibitors such as sitagliptin and saxagliptin increase endogenous GLP-1 concentration and demonstrate incretin-associated glucoregulatory actions in patients with T2DM. DPP-4 inhibitors are weight neutral. A growing understanding of the roles of incretin hormones in T2DM may further clarify the application of incretin-based treatment strategies.
Freeman
Jeffrey S
JS
Division of Endocrinology and Metabolism, Philadelphia College of Osteopathic Medicine, 4190 City Ave., Suite 324, Philadelphia, PA 19131-1626, USA. jeffreyfreemando@aol.com
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005972:Glutaminase / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D054795:Incretins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D015398:Signal Transduction; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology
D001786:Blood Glucose; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D054795:Incretins; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D011719:Pyrazines; C421249:TAX1BP3 protein, human; D014230:Triazoles; D014688:Venoms; D052216:Glucagon-Like Peptide 1; C502994:saxagliptin; D000077270:Exenatide; D005972:Glutaminase; D000218:Adamantane; D000068900:Sitagliptin Phosphate