Impact of incretin therapy on islet dysfunction: an underlying defect in the pathophysiology of type 2 diabetes.
Glucose homeostasis is governed by a complex interplay of hormonal signaling and modulation. Insulin, glucagon, amylin, the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and other hormones and enzymes interact to maintain glucose homeostasis and normal cellular metabolism. Derangements in these hormonal interactions, particularly insulin deficits and impaired insulin action, result in the development of type 2 diabetes-but only in individuals who have experienced significant dysfunction or loss of beta-cells, located in the pancreatic islets of Langerhans. Much less is known about the impact of alpha-cell dysregulation on glucose homeostasis, although it has been demonstrated that glucagon-secreting alpha-cells, also located in the pancreatic islets, play an important role in glucose metabolism. Because beta-cell dysfunction occurs early in the course of type 2 diabetes and is progressive, early intervention with therapies that improve beta-cell function is desirable. In addition to reducing HbA1c and fasting plasma glucose, the recently developed diabetes therapies GLP-1 receptor agonists (eg, exenatide, liraglutide) and dipeptidyl peptidase-4 (DPP-4) inhibitors (eg, sitagliptin, vildagliptin) appear to have beneficial effects on beta-cell dysfunction and, possibly, on alpha-cell dysregulation.
McGill
Janet B
JB
Division of Endocrinology Metabolism and Lipid Research, Washington University in St. Louis, St. Louis, MO 63110, USA. JMCGILL@DOM.wustl.edu
D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D054795:Incretins / Q000494:pharmacology* / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000503:physiopathology*; D008297:Male; D018027:Receptors, Glucagon / Q000819:agonists* / Q000502:physiology
D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D018027:Receptors, Glucagon; D005947:Glucose