Abstract
We previously demonstrated that infusion of an intestinal peptide called xenin-25 (Xen) amplifies the effects of glucose-dependent insulinotropic polypeptide (GIP) on insulin secretion rates (ISRs) and plasma glucagon levels in humans. However, these effects of Xen, but not GIP, were blunted in humans with type 2 diabetes. Thus, Xen rather than GIP signaling to islets fails early during development of type 2 diabetes. The current crossover study determines if cholinergic signaling relays the effects of Xen on insulin and glucagon release in humans as in mice. Fasted subjects with impaired glucose tolerance were studied. On eight separate occasions, each person underwent a single graded glucose infusion- two each with infusion of albumin, Xen, GIP, and GIP plus Xen. Each infusate was administered ± atropine. Heart rate and plasma glucose, insulin, C-peptide, glucagon, and pancreatic polypeptide (PP) levels were measured. ISRs were calculated from C-peptide levels. All peptides profoundly increased PP responses. From 0 to 40 min, peptide(s) infusions had little effect on plasma glucose concentrations. However, GIP, but not Xen, rapidly and transiently increased ISRs and glucagon levels. Both responses were further amplified when Xen was co-administered with GIP. From 40 to 240 min, glucose levels and ISRs continually increased while glucagon concentrations declined, regardless of infusate. Atropine increased resting heart rate and blocked all PP responses but did not affect ISRs or plasma glucagon levels during any of the peptide infusions. Thus, cholinergic signaling mediates the effects of Xen on insulin and glucagon release in mice but not humans.
Highlights
Xenin-25 (Xen) is a 25-amino acid neurotensin-related peptide produced by a subset of enteroendocrine cells [1,2]
Atropine completely inhibited the pancreatic polypeptide responses to Xen alone, glucose-dependent insulinotropic polypeptide (GIP) alone, and the combination of GIP plus Xen, it had little effect on rapid and transient (0 to 40 minutes) and glucose-regulated (40 to 240 minutes) insulin and glucagon responses, regardless of peptide(s) administered. Consistent with these results, we recently demonstrated that bethanechol, a muscarinic acetylcholine agonist that works only in the periphery, increased the postprandial pancreatic polypeptide response in humans with impaired glucose tolerance but had no effect on insulin secretion rates (ISRs) or plasma glucagon levels [16]
The glucose concentration within the Effects of cholinergic signaling on islet hormone release islets during the start of the graded glucose infusion is unknown, our results strongly suggest that this rapid response to peptides is largely independent of circulating plasma glucose levels
Summary
Xenin-25 (Xen) is a 25-amino acid neurotensin-related peptide produced by a subset of enteroendocrine cells [1,2]. Xen administration delays gastric emptying [3], reduces. Effects of cholinergic signaling on islet hormone release. Washington University Nutrition Obesity Research Center Grant (P30DK056341) from the National Institute of Diabetes and Digestive and Kidney Diseases; the Washington University Digestive Disease Research Core Center (P30 DK52574-16); the Washington University Clinical and Translational Science Award (UL1 TR000448) from the National Center for Advancing Translational Sciences (NCATS); and the Biologic Therapy Core Facility of the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, Mo. (NCI Cancer Center Support Grant P30 CA91842). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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