Physiological and Pharmacological Mechanisms through which the DPP-4 Inhibitor Sitagliptin Regulates Glycemia in Mice

Abstract

Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressed on the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemic DPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r(-/-) and Gipr(-/-) mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an i.v. infusion of the corresponding receptor antagonist exendin (9-39). The role of the dipeptides His-Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitro on isolated islets. We demonstrate that very low doses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but not systemic DPP-4 activity. The glucoregulatory action of sitagliptin was associated with increased vagus nerve activity and was diminished in wild-type mice treated with the GLP-1R antagonist exendin (9-39) and in Glp1r(-/-) and Gipr(-/-) mice. Furthermore, the dipeptides liberated from GLP-1 (His-Ala) and GIP (Tyr-Ala) deteriorated glucose tolerance, reduced insulin, and increased portal glucagon levels. The predominant mechanism through which DPP-4 inhibitors regulate glycemia involves local inhibition of intestinal DPP-4 activity, activation of incretin receptors, reduced liberation of bioactive dipeptides, and activation of the gut-to-pancreas neural axis.

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

“…Thus it has been demonstrated in subjects with type 2 diabetes both for sitagliptin (14) and vildagliptin (49) that insulin secretion also after intravenous glucose administration is stimulated during DPP-4 inhibition with no or only minimal increase in circulating GLP-1 levels, which would suggest contribution by autonomic nerves and/or other bioactive peptides. A finding by Salehi et al that GLP-1 receptor antagonism reduces the insulin response to intravenous glucose in humans may support the neural hypothesis (50).…”

“…They demonstrated that administration of low oral doses of sitagliptin (40-120 mg) improved glucose tolerance and increased circulating insulin without affecting DPP-4 activity in peripheral plasma. It should be emphasized that even though DPP-4 activity was not altered in peripheral plasma, the glucose-lowering effect of sitagliptin was still GLP-1 dependent since the effect was lost in mice with genetic deletion of GLP-1 receptors (14). While not inhibiting DPP-4 activity in peripheral plasma, these low doses of sitagliptin inhibited DPP-4 activity locally in the duodenum, jejunum, and ileum.…”

“…This idea was initially presented by Waget et al in 2011 in acute studies in nondiabetic mice (14). They demonstrated that administration of low oral doses of sitagliptin (40-120 mg) improved glucose tolerance and increased circulating insulin without affecting DPP-4 activity in peripheral plasma.…”

Hormonal Signaling in the Gut

“…For example, oral administration of low doses of DPP-4 inhibitor, sitagliptin, aimed at selectively inhibiting intestinal, but not systemic, DPP-4 activity still resulted in enhanced glycemic control and plasma insulin levels through activation of local GLP-1R on the vagus nerve. This indicates a predominant role for enhancement of the GLP-1 gut-brain-periphery axis in the ability of sitagliptin to reduce local intestinal DPP4 activity and regulate glycemia (43). Furthermore, the rapid remission of type 2 diabetes following gastric bypass surgeries has been hypothesized to be mediated by GLP-1 (44,45).…”

Dipeptidyl peptidase 4 (DPP-4) is expressed in mouse and human islets and its activity is decreased in human islets from individuals with type 2 diabetes

“…Thus, oral administration of a low dose of DPP-4 inhibitor to mice reduced glucose without inhibiting the circulating DPP-4 activity [7,8]. This would suggest that local DPP-4 activity is also important for the glucose-lowering action of DPP-4 inhibitors.…”