Xenin-25 amplifies GIP-mediated insulin secretion in humans with normal and impaired glucose tolerance but not type 2 diabetes

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-stimulated insulin secretion (GSIS). This response is blunted in type 2 diabetes (T2DM). Xenin-25 is a 25-amino acid neurotensin-related peptide that amplifies GIP-mediated GSIS in hyperglycemic mice. This study determines if xenin-25 amplifies GIP-mediated GSIS in humans with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or T2DM. Each fasting subject received graded glucose infusions to progressively raise plasma glucose concentrations, along with vehicle alone, GIP, xenin-25, or GIP plus xenin-25. Plasma glucose, insulin, C-peptide, and glucagon levels and insulin secretion rates (ISRs) were determined. GIP amplified GSIS in all groups. Initially, this response was rapid, profound, transient, and essentially glucose independent. Thereafter, ISRs increased as a function of plasma glucose. Although magnitudes of insulin secretory responses to GIP were similar in all groups, ISRs were not restored to normal in subjects with IGT and T2DM. Xenin-25 alone had no effect on ISRs or plasma glucagon levels, but the combination of GIP plus xenin-25 transiently increased ISR and plasma glucagon levels in subjects with NGT and IGT but not T2DM. Since xenin-25 signaling to islets is mediated by a cholinergic relay, impaired islet responses in T2DM may reflect defective neuronal, rather than GIP, signaling.

Trial registration: ClinicalTrials.gov NCT00798915.

Figures

FIG. 1.

A and B: Plasma levels of IR-GIP and xenin-25 during GGIs. Subjects with NGT were administered GGIs with a primed-continuous intravenous infusion of GIP alone, xenin-25 (Xen) alone, or the combination of GIP plus xenin-25. IR peptide levels (group average ± SEM) in subjects with IGT and T2DM were similar to those shown for subjects with NGT.

FIG. 2.

A–L: Xenin-25 amplifies the effects of GIP on plasma insulin, C-peptide, and glucose levels and ISRs in humans with NGT and IGT but not T2DM. Subjects with NGT, IGT, or T2DM were administered GGIs with albumin alone (Alb), GIP alone (GIP), xenin-25 alone (Xen), or the combination of GIP plus xenin-25 (G+X). Group average values ± SEM for insulin, C-peptide, ISR, and glucose are shown.

FIG. 3.

A–F: Xenin-25 amplifies the insulin secretory response to GIP in humans with NGT and IGT but not T2DM. In A, C, and E, group average ISRs (from G–I in Fig. 2) were plotted vs. group average plasma glucose levels (from J–L in Fig. 2) for the indicated infusions. To simplify plots, error bars and symbols are not shown but are the same for ISR and plasma glucose as those shown in Fig. 2G–I for ISR and Fig. 2J–L for plasma glucose. In B, D, and F, the ratios of ISR iAUC to glucose iAUC are shown for subjects with NGT, IGT, and T2DM. Albumin alone, Alb; GIP alone, GIP; xenin-25 alone, Xen; combination of GIP plus xenin-25, G+X.

FIG. 4.

Xenin-25 rapidly and transiently amplifies GIP-mediated ISR in humans with NGT and IGT but not T2DM. Data are shown for the first 40 min of each GGI. A–C: ISR iAUCs. D–F: Values for ISR total AUC (tAUC) divided by the glucose tAUC. Albumin alone, Alb; GIP alone, GIP; xenin-25 alone, Xen; combination of GIP plus xenin-25, G+X.

FIG. 5.

Xenin-25 amplifies the effects of GIP on plasma glucagon levels in humans with NGT and IGT but not T2DM. A, D, and G: Group average changes in plasma glucagon ± SEM. Changes in plasma glucagon levels during the first 40 min (B, E, and H) or the entire 240 min (C, F, and I). Albumin alone, Alb; GIP alone, GIP; xenin-25 alone, Xen; combination of GIP plus xenin-25, G+X.