Hormonal Responses to Cholinergic Input Are Different in Humans with and without Type 2 Diabetes Mellitus.
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.


BACKGROUND
ClinicalTrials.gov NCT01434901.
Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research Washington University School of Medicine, Saint Louis, MO, United States of America.
Sara
S
Chowdhury
Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research Washington University School of Medicine, Saint Louis, MO, United States of America.
Songyan
S
Wang
Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research Washington University School of Medicine, Saint Louis, MO, United States of America.
Judit
J
Dunai
Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research Washington University School of Medicine, Saint Louis, MO, United States of America.
Rachel
R
Kilpatrick
Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research Washington University School of Medicine, Saint Louis, MO, United States of America.
Lauren Z
LZ
Oestricker
Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO, United States of America.
Michael J
MJ
Wallendorf
Department of Internal Medicine, Division of Nutritional Science, Metabolism and Lipid Research Washington University School of Medicine, Saint Louis, MO, United States of America.
Bruce W
BW
Patterson
Department of Internal Medicine, Division of Nutritional Science, Metabolism and Lipid Research Washington University School of Medicine, Saint Louis, MO, United States of America.
Dominic N
DN
Reeds
Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research Washington University School of Medicine, Saint Louis, MO, United States of America.
Burton M
BM
Wice
D000284:Administration, Oral; D000328:Adult; D018723:Bethanechol / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005749:Gastric Inhibitory Polypeptide / Q000097:blood; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D018149:Glucose Intolerance / Q000097:blood / Q000503:physiopathology; D006728:Hormones / Q000097:blood*; D006801:Humans; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000494:pharmacology; D009496:Neurotensin / Q000008:administration & dosage / Q000494:pharmacology; D065228:Non-Randomized Controlled Trials as Topic; D010191:Pancreatic Polypeptide / Q000097:blood; D019518:Postprandial Period
D001786:Blood Glucose; D002096:C-Peptide; D006728:Hormones; D007328:Insulin; D018721:Muscarinic Agonists; D018723:Bethanechol; C077659:xenin 25; D009496:Neurotensin; D005749:Gastric Inhibitory Polypeptide; D010191:Pancreatic Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon