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, placebocontrolled, 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.

Effects of Sitagliptin on Glycemia, Incretin Hormones, and Antropyloroduodenal Motility in Response to Intraduodenal Glucose Infusion in Healthy Lean and Obese Humans and Patients With Type 2 Diabetes Treated With or Without Metformin

“…This might relate to the effects of peptide YY (PYY), whose degradation from PYY1-36 to PYY3-36, which has more potent effects to slow gastric emptying, is prevented by DPP-4 inhibition (50). The current data are thus in keeping with the majority of evidence that DPP-4 inhibition does not influence gastric emptying (17)(18)(19)21,22), although a recent study reported slowing of oral glucose emptying after sitagliptin in type 2 diabetic patients (20). Metformin was reported to slow gastric emptying in mice (25), but we did not observe any effect on APD motility in the current experimental setting.…”

“…The lack of glucose lowering with sitagliptin in type 2 diabetic subjects, therefore, supports the hypothesis of a defective glucoregulatory capacity of endogenous GIP in this group and is consistent with the marked impairment of glucose lowering by sitagliptin in type 2 diabetic patients after oral glucose during GLP-1 antagonism with exendin-(9-39) (20). Although insulin response to exogenous GIP can be partly restored with strict glycemic control in type 2 diabetes, its insulinotropic effect is not associated with improvement in glucose disposal during hyperglycemic clamp studies (41).…”

“…The majority of studies have reported a lack of effect of DPP-4 inhibitors on gastric emptying for unclear reasons (16)(17)(18)(19)(20)(21)(22). Although endogenous GLP-1 slows gastric emptying through suppression of antral motility and stimulation of pyloric contractions (6,7), the effect of DPP-4 inhibitors on these motor mechanisms has not been assessed.…”

Pleiotropic Mechanisms for the Glucose-Lowering Action of DPP-4 Inhibitors

“…Indeed, several biological peptides apart from the GLP-1 are potentially substrates for DPP-4 although most of these findings are not relevant in vivo (4). Indirect evidence that other peptides than GLP-1 may contribute to the effects of DPP-4 inhibition was recently presented by Aulinger et al (38). They showed that the GLP-1 receptor antagonist exendin-9 could inhibit the effect of sitagliptin on glucose and insulin secretion by only ;50% after 4 weeks of treatment with the DPP-4 inhibitor in type 2 diabetes.…”

DPP-4 Inhibition and the Known Unknown

“…In patients with type 2 diabetes, insulinogenic indices (based on insulin, C-peptide, or insulin secretory rates) were increased by vildagliptin and reduced by exendin , but, importantly, the difference between these conditions was only ;50%. Hence, as concluded by Aulinger et al (10) who evaluated the effects of sitagliptin, only about half of the insulinotropic effect of DPP-4 inhibition could be attributed to GLP-1. Exendin also accelerated gastric emptying, whereas vildagliptin apparently had no effect.…”