title: Impairment of GLP1-induced insulin secretion: role  of genetic background, insulin resistance and hyperglycaemia.
abstract: One major risk factor of type 2 diabetes is the impairment of glucose-induced insulin secretion which is mediated by the individual genetic background and environmental factors. In addition to impairment of glucose-induced insulin secretion, impaired glucagon-like peptide (GLP)1-induced insulin secretion has been identified to be present in subjects with diabetes and impaired glucose tolerance, but little is known about its fundamental mechanisms. The state of GLP1 resistance is probably an important mechanism explaining the reduced incretin effect observed in type 2 diabetes. In this review, we address methods that can be used for the measurement of insulin secretion in response to GLP1 in humans, and studies showing that specific diabetes risk genes are associated with resistance of the secretory function of the β-cell in response to GLP1 administration. Furthermore, we discuss other factors that are associated with impaired GLP1-induced insulin secretion, for example, insulin resistance. Finally, we provide evidence that hyperglycaemia per se, the genetic background and their interaction result in the development of GLP1 resistance of the β-cell. We speculate that the response or the non-response to therapy with GLP1 analogues and/or dipeptidyl peptidase-4 (DPP-IV) inhibitors is critically dependent on GLP1 resistance.
authors.affiliation: Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Herzberg-Schäfer
authors.forename: M
authors.initials: M
authors.lastname: Heni
authors.forename: N
authors.initials: N
authors.lastname: Stefan
authors.forename: H-U
authors.initials: HU
authors.lastname: Häring
authors.forename: A
authors.initials: A
authors.lastname: Fritsche
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000627:therapeutic use*; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D008297:Male
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4