Xenin-25 delays gastric emptying and reduces postprandial glucose levels in humans with and without Type 2 diabetes

Abstract

Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine cells. In animals, Xen regulates gastrointestinal function and glucose homeostasis, typically by initiating neural relays. However, little is known about Xen action in humans. This study determines whether exogenously administered Xen modulates gastric emptying and/or insulin secretion rates (ISRs) following meal ingestion. Fasted subjects with normal (NGT) or impaired (IGT) glucose tolerance and Type 2 diabetes mellitus (T2DM; n = 10-14 per group) ingested a liquid mixed meal plus acetaminophen (ACM; to assess gastric emptying) at time zero. On separate occasions, a primed-constant intravenous infusion of vehicle or Xen at 4 (Lo-Xen) or 12 (Hi-Xen) pmol · kg(-1) · min(-1) was administered from zero until 300 min. Some subjects with NGT received 30- and 90-min Hi-Xen infusions. Plasma ACM, glucose, insulin, C-peptide, glucagon, Xen, GIP, and glucagon-like peptide-1 (GLP-1) levels were measured and ISRs calculated. Areas under the curves were compared for treatment effects. Infusion with Hi-Xen, but not Lo-Xen, similarly delayed gastric emptying and reduced postprandial glucose levels in all groups. Infusions for 90 or 300 min, but not 30 min, were equally effective. Hi-Xen reduced plasma GLP-1, but not GIP, levels without altering the insulin secretory response to glucose. Intense staining for Xen receptors was detected on PGP9.5-positive nerve fibers in the longitudinal muscle of the human stomach. Thus Xen reduces gastric emptying in humans with and without T2DM, probably via a neural relay. Moreover, endogenous GLP-1 may not be a major enhancer of insulin secretion in healthy humans under physiological conditions.

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

“…More encouraging, recent studies have highlighted the possibility that xenin, a hormone co-secreted with GIP from a subset of enteroendocrine K cells, could amplify the insulin-secretory response of GIP [9]. In agreement, observations from our laboratory and others confirm the GIP-potentiating effects of xenin under normal and type 2 diabetes conditions [10][11][12][13]. Furthermore, there is also evidence to suggest that xenin acts as a satiety hormone in animals [10,[14][15][16][17] and humans [18].…”

“…For GIP, the first 14 N-terminal amino acid residues contain the bioactive domain important for insulin-secretory function [25,26]. Based on this knowledge, we constructed a novel GIP/xenin hybrid peptide, (DAla 2 )GIP/xenin-8-Gln, by linking GIP (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) to xenin-8-Gln, retaining the regions of each peptide known to be important for biological activity (see electronic supplementary material [ESM] Table 1). Importantly, since GIP is a substrate for dipeptidyl peptidase-4 (DPP-4) [27], the hybrid peptide includes substitution of the naturally occurring alanine L isomer residue by a D isomer at position 2 [28,29].…”

Inter-organ communication and regulation of beta cell function

“…However, co-treatment with recombinant xenin-25 and GIP reduces postprandial glycemia by delaying gastric emptying in humans with or without type 2 diabetes (15). Thus, while GIP is considered an incretin hormone, its mechanisms of action and its significance in glucoregulation remain to be fully understood.…”

Metabolic responses to xenin-25 are altered in humans with Roux-en-Y gastric bypass surgery

“…In human studies, our laboratory has shown that intravenous administration of Xen amplified the effects of GIP on insulin, glucagon, and pancreatic polypeptide release during graded glucose infusions [17,18]. During liquid mixed meal tolerance tests, Xen infusion delayed gastric emptying, reduced postprandial glycemia, and inhibited glucagon-like peptide-1 (GLP-1) release and insulin secretion [19]. Importantly, the reduced insulin secretion was a consequence of lower glucose levels and not an inhibition of insulin release per se.…”