Abstract
Peripheral muscarinic acetylcholine receptors regulate insulin and glucagon release in rodents but their importance for similar roles in humans is unclear. Bethanechol, an acetylcholine analogue that does not cross the blood-brain barrier, was used to examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT; n = 10), impaired glucose tolerance (IGT; n = 11), and type 2 diabetes mellitus (T2DM; n = 9). Subjects received four liquid meal tolerance tests, each with a different dose of oral bethanechol (0, 50, 100, or 150 mg) given 60 min before a meal containing acetaminophen. Plasma pancreatic polypeptide (PP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucose, glucagon, C-peptide, and acetaminophen concentrations were measured. Insulin secretion rates (ISRs) were calculated from C-peptide levels. Acetaminophen and PP concentrations were surrogate markers for gastric emptying and cholinergic input to islets. The 150 mg dose of bethanechol increased the PP response 2-fold only in the IGT group, amplified GLP-1 release in the IGT and T2DM groups, and augmented the GIP response only in the NGT group. However, bethanechol did not alter ISRs or plasma glucose, glucagon, or acetaminophen concentrations in any group. Prior studies showed infusion of xenin-25, an intestinal peptide, delays gastric emptying and reduces GLP-1 release but not ISRs when normalized to plasma glucose levels. Analysis of archived plasma samples from this study showed xenin-25 amplified postprandial PP responses ~4-fold in subjects with NGT, IGT, and T2DM. Thus, increasing postprandial cholinergic input to islets augments insulin secretion in mice but not humans.Trial Registration: ClinicalTrials.gov NCT01434901
Highlights
Transmitters and peptides released from neurons that innervate islets play important roles in regulating insulin and glucagon release [1,2]
The purpose of the present study is to determine if bethanechol and/or xenin-25 increase postprandial cholinergic input to islets and if this signaling is associated with changes in postprandial glucose, glucosedependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), insulin, C-peptide, glucagon, and PP levels and insulin secretion rates (ISRs) in humans with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM)
The postprandial PP response is similar in humans with and without T2DM
Summary
Transmitters and peptides released from neurons that innervate islets play important roles in regulating insulin and glucagon release [1,2]. Parasympathetic and sympathetic neurons that innervate pancreatic islets increase and inhibit insulin release, respectively [1,2,3,4]. Studies by others using genetically modified mice and/or islets indicate that cholinergic signaling via M3 muscarinic acetylcholine receptors plays an important role in regulating insulin and glucagon release [7,8,9,10,11,12]. Consistent with mouse experiments, studies with the isolated perfused human pancreas have shown that electrical stimulation of the splanchnic nerve in the presence and absence of selective neural inhibitors increases both cholinergic and sympathetic input to islets which in turn, regulates insulin, glucagon, pancreatic polypeptide (PP), and somatostatin release [13,14,15,16,17,18]. The physiologic relevance of the electrical stimulation and human islet studies is not clear
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