Xenin-25 Potentiates Glucose-dependent Insulinotropic Polypeptide Action via a Novel Cholinergic Relay Mechanism

Abstract

The intestinal peptides GLP-1 and GIP potentiate glucosemediated insulin release. Agents that increase GLP-1 action are effective therapies in type 2 diabetes mellitus (T2DM). However, GIP action is blunted in T2DM, and GIP-based therapies have not been developed. Thus, it is important to increase our understanding of the mechanisms of GIP action. We developed mice lacking GIP-producing K cells. Like humans with T2DM, "GIP/DT" animals exhibited a normal insulin secretory response to exogenous GLP-1 but a blunted response to GIP. Pharmacologic doses of xenin-25, another peptide produced by K cells, restored the GIP-mediated insulin secretory response and reduced hyperglycemia in GIP/DT mice. Xenin-25 alone had no effect. Studies with islets, insulin-producing cell lines, and perfused pancreata indicated xenin-25 does not enhance GIP-mediated insulin release by acting directly on the ␤-cell. The in vivo effects of xenin-25 to potentiate insulin release were inhibited by atropine sulfate and atropine methyl bromide but not by hexamethonium. Consistent with this, carbachol potentiated GIP-mediated insulin release from in situ perfused pancreata of GIP/DT mice. In vivo, xenin-25 did not activate c-fos expression in the hind brain or paraventricular nucleus of the hypothalamus indicating that central nervous system activation is not required. These data suggest that xenin-25 potentiates GIP-mediated insulin release by activating non-ganglionic cholinergic neurons that innervate the islets, presumably part of an enteric-neuronal-pancreatic pathway. Xenin-25, or molecules that increase acetylcholine receptor signaling in ␤-cells, may represent a novel approach to overcome GIP resistance and therefore treat humans with T2DM.The entero-insulin axis is a physiologic system composed of peptides secreted from the gastrointestinal tract that play an important role in regulating insulin secretion from pancreatic islet ␤-cells (1, 2). To date, attention has focused on two intestinal peptides, glucagon-like peptide-1 (GLP-1) 2 and glucosedependent insulinotropic polypeptide (GIP). GIP is produced predominantly by intestinal K cells located in the proximal small intestine, whereas GLP-1 is produced primarily by intestinal L-cells present in the distal bowel (3-5). Release of GLP-1 and GIP is controlled by nutrient levels in the lumen of the gut rather than the bloodstream. Both hormones are released into the bloodstream immediately after ingestion of a meal and then potentiate glucose-stimulated insulin release. This increase in insulin secretion has been termed the incretin effect. Importantly, the incretin effect occurs only in the presence of elevated blood glucose and does not cause postprandial hypoglycemia.An increase in circulating GLP-1 activity has significant therapeutic benefit in patients with T2DM (1, 2, 6 -10). Two major classes of drugs that accomplish this goal have recently been introduced into the market with substantial success. Long acting analogs of GLP-1 potentiate glucose-stimulated insulin secretion leadin...

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].…”

Characterisation of the biological activity of xenin-25 degradation fragment peptides

“…Xenin-25 is considered as having potential for future treatment of type 2 diabetes based on encouraging findings from cellular and animal models (Taylor et al 2010, Wice et al 2010, Martin et al 2012. However, the rapid degradation of xenin-25 by plasma enzymes and consequent short biological half-life (Taylor et al 2010) is a major factor that hampers possible therapeutic use of the peptide.…”

Dietary steamed wheat bran increases postprandial fat oxidation in association with a reduced blood glucose-dependent insulinotropic polypeptide response in mice

“…This finding implies the existence of another non-GIP mechanism regulating postprandial insulin secretion after consumption of the steamed WB and arabinoxylan. Glucagon-like peptide-type 1 (GLP-1) and xenin also stimulate insulin secretion [50,51]. Postprandial levels of xenin, which is co-released from K cells with GIP and amplifies GIP-mediated insulin secretion, did not differ after WB consumption (data not shown).…”