The role of endogenous incretin secretion as amplifier of glucose-stimulated insulin secretion in healthy subjects and patients with type 2 diabetes

Abstract

In order to quantify the role of incretins in first- and second-phase insulin secretion (ISR) in type 2 diabetes mellitus (T2DM), a double-blind, randomized study with 12 T2DM subjects and 12 healthy subjects (HS) was conducted using the hyperglycemic clamp technique together with duodenal nutrition perfusion and intravenous infusion of the glucagon-like peptide 1 (GLP-1) receptor antagonist exendin(9-39). Intravenous glucose alone resulted in a significantly greater first- and second-phase ISR in HS compared with T2DM subjects. Duodenal nutrition perfusion augmented both first- and second-phase ISR but first-phase ISR more in T2DM subjects (approximately eight- vs. twofold). Glucose-related stimulation of ISR contributed only 20% to overall ISR. Infusion with exendin(9-39) significantly reduced first- and second-phase ISR in both HS and T2DM subjects. Thus, both GLP-1 and non-GLP-1 incretins contribute to the incretin effect. In conclusion, both phases of ISR are impaired in T2DM. In particular, the responsiveness to glucose in first-phase ISR is blunted. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretions are unaltered. The absolute incretin effect is reduced in T2DM; its relative importance, however, appears to be increased, highlighting its role as an important amplifier of first-phase ISR in T2DM.

Trial registration: ClinicalTrials.gov NCT01449019.

FIG. 1.

Overview on study design. Red arrows indicate the blood samples for measuring plasma hormones; red asterisks indicate the time points of blood samples for glucose measurement. The asterisk in the term “glucose*” represents the time points of blood samples for glucose measurement that are indicated as asterisks in contrast to the arrows, which indicate the blood samples for measuring plasma hormones. (A high-quality color representation of this figure is available in the online issue.)

FIG. 2.

Plasma insulin (A and B) and C-peptide (C and D) in response to hyperglycemic isoglycemic clamp experiments with intravenous (IV) saline plus duodenal meal (blue triangles), exendin(9-39) (ex[9-39]) IV plus duodenal meal (yellow squares), and isoglycemic IV glucose experiments without intraduodenal meal perfusion (red circles) in HS (A and C) and patients with T2DM (B and D). Blood glucose concentrations are shown in A and B (black and white symbols). n = 12 per group; mean ± SEM. See Tables 2 and 3 for statistical analysis.

FIG. 3.

Plasma insulin (A and B), incretin effect (C and D), and percentage contribution of the incretin effect to the total insulin response (E and F) in response to hyperglycemic isoglycemic clamp experiments during first-phase ISR (A, C, and E) and second-phase ISR (B, D, and F) with intravenous (IV) isoglycemic glucose experiments without intraduodenal meal perfusion (isoglycemic fasting control, white bars), with saline IV plus duodenal meal (black bars), and with exendin(9-39) (ex[9-39]) IV plus duodenal meal (striated bars) in HS and patients with T2DM. n = 12 per group; mean ± SEM of incremental AUC. *P < 0.05 vs. isoglycemic fasting control; #P < 0.05 vs. saline IV plus duodenal meal. See Tables 2 and 3 for further statistical analysis.

FIG. 4.

Plasma GLP-1 (A and B) and GIP (C and D) concentration in response to hyperglycemic isoglycemic clamp experiments with intravenous (IV) saline plus duodenal meal (blue triangles) or exendin(9-39) (ex[9-39]) IV plus duodenal meal (yellow squares) and isoglycemic IV glucose experiments without intraduodenal meal perfusion (red circles) in HS (A and C) and patients with T2DM (B and D). n = 12 per group; mean ± SEM. See Table 3 for statistical analysis.

FIG. 5.

Plasma glucagon concentration in response to hyperglycemic isoglycemic clamp experiments with intravenous (IV) saline plus duodenal meal (blue triangles) or exendin(9-39) (ex[9-39]) IV plus duodenal meal (yellow squares) and isoglycemic IV glucose experiments without intraduodenal meal perfusion (red circles) in HS (A) and patients with T2DM (B). n = 12 per group; mean ± SEM. See Table 3 for statistical analysis.