title: Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and GLP-1 receptor blockade.
abstract: Understanding the incretin pathway has led to significant advancements in the treatment of type 2 diabetes (T2D). Still, the exact mechanisms are not fully understood. In a randomized, placebo-controlled, four-period, crossover study in 24 patients with T2D, dipeptidyl peptidase-4 (DPP-4) inhibition and its glucose-lowering actions were tested after an oral glucose tolerance test (OGTT). The contribution of GLP-1 was examined by infusion of the GLP-1 receptor (GLP-1r) antagonist exendin-9. DPP-4 inhibition reduced glycemia and enhanced insulin levels and the incretin effect (IE). Glucagon was suppressed, and gastric emptying (GE) was decelerated. Exendin-9 increased glucose levels and glucagon secretion, attenuated insulinemia and the IE, and accelerated GE. With the GLP-1r antagonist, the glucose-lowering effects of DPP-4 inhibition were reduced by ∼ 50%. However, a significant effect on insulin secretion remained during GLP-1r blockade, whereas the inhibitory effects of DPP-4 inhibition on glucagon and GE were abolished. Thus, in this cohort of T2D patients with a substantial IE, GLP-1 contributed ∼ 50% to the insulin excursion after an OGTT with and without DPP-4 inhibition. Thus, a significant DPP-4-sensitive glucose-lowering mechanism contributes to glycemic control in T2D patients that may be not mediated by circulating GLP-1.
authors.affiliation: Department of Internal Medicine II, Clinical Research Unit, Clinical Center of the Ludwig-Maximilians University, Campus Grosshadern, Munich, Germany.
authors.forename: Benedikt A
authors.initials: BA
authors.lastname: Aulinger
authors.forename: Anne
authors.initials: A
authors.lastname: Bedorf
authors.forename: Gabriele
authors.initials: G
authors.lastname: Kutscherauer
authors.forename: Jocelyn
authors.initials: J
authors.lastname: de Heer
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Jörg
authors.initials: J
authors.lastname: Schirra
mesh_terms: D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000097:blood; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005215:Fasting / Q000378:metabolism; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006801:Humans; D054795:Incretins; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D007328:Insulin; D011719:Pyrazines; D018027:Receptors, Glucagon; D014230:Triazoles; D052216:Glucagon-Like Peptide 1; D000068900:Sitagliptin Phosphate