Treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin improves fasting islet-cell function in subjects with type 2 diabetes

Abstract

Context: Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes mellitus (T2DM) by prolonging the activity of the circulating incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Consistent with this mechanism of action, DPP-4 inhibitors improve glucose tolerance after meals by increasing insulin and reducing glucagon levels in the plasma. However, DPP-4 inhibitors also reduce fasting blood glucose, an unexpected effect because circulating levels of active GIP and GLP-1 are low in the postabsorptive state.

Objective: The objective of the study was to examine the effects of DPP-4 inhibition on fasting islet function.

Design: We conducted a randomized, double-blind, placebo-controlled trial.

Setting: The study was performed in General Clinical Research Centers at two University Hospitals.

Subjects: Forty-one subjects with T2DM were treated with metformin or diet, having good glycemic control with glycosylated hemoglobin values of 6.2-7.5%.

Intervention: Subjects were treated with vildagliptin (50 mg twice daily) or placebo for 3 months, followed by a 2-wk washout. Major Outcome Measure: We measured insulin secretion in response to iv glucose and arginine before and after treatment and after drug washout.

Results: There were small and comparable reductions in glycosylated hemoglobin in both groups over 3 months. Vildagliptin increased fasting GLP-1 levels in subjects taking metformin, but not those managed with diet, and raised active GIP levels slightly. DPP-4 inhibitor treatment improved the acute insulin and C-peptide responses to glucose (50 and 100% respectively; P < 0.05) and increased the slope of the C-peptide response to glucose (33%; P = 0.023).

Conclusion: Vildagliptin improves islet function in T2DM under fasting conditions. This suggests that DPP-4 inhibition has metabolic benefits in addition to enhancing meal-induced GLP-1 and GIP activity.

Trial registration: ClinicalTrials.gov NCT00351585.

Figures

Figure 1

Fasting levels of intact GIP (A) and GLP-1(B) concentrations, and DPP-4 activity (C) in diabetic subjects treated with vildagliptin (black bars) or placebo (white bars). Measurements are shown from pretreatment (0 wk) and posttreatment (12 wk) studies. *, Posttreatment values that are significantly different from pretreatment results (P < 0.05).

Figure 2

Plasma glucose concentrations in pretreatment (closed circles) and posttreatment (open circles) studies of diabetic subjects receiving placebo (A) or vildagliptin (B). The protocol included a frequently sampled IVGTT from 0–240 min, a graded glucose infusion from 260 to 320 min, and an arginine bolus from 320 to 335 min. The acute insulin (C and D) and C-peptide (E and F) responses to an iv glucose bolus are shown for subjects receiving placebo (C and E) and vildagliptin (D and F).

Figure 3

Plasma glucagon concentrations from the pretreatment (closed circles) and posttreatment (open circles) studies in diabetic subjects treated with placebo (A) or vildagliptin (B). *, Posttreatment values that are significantly different from pretreatment results (P < 0.05).

Figure 4

The acute insulin (A) and C-peptide (B) responses to glucose in diabetic subjects treated with placebo (white bars) or vildagliptin (black bars). For each measure, the results are shown for pretreatment (0 wk), posttreatment (12 wk), and after drug washout (14 wk). *, Posttreatment values that are significantly different from pretreatment results (P < 0.05).