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

Area of Science:

• Endocrinology
• Metabolism
• Neurogastroenterology

Background:

• Peripheral muscarinic acetylcholine receptors' role in human glucose homeostasis is unclear.
• Rodent studies suggest these receptors regulate insulin and glucagon release.
• This study investigated peripheral muscarinic signaling in human glucose metabolism.

Purpose of the Study:

• To examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM).
• To assess the effects of bethanechol, a peripheral acetylcholine analogue, on gut hormone release, insulin secretion, and glucose levels.

Main Methods:

• Four liquid meal tolerance tests were conducted in NGT, IGT, and T2DM subjects.
• Oral bethanechol (0, 50, 100, 150 mg) was administered 60 min before a meal.
• Plasma levels of pancreatic polypeptide (PP), GIP, GLP-1, glucose, glucagon, C-peptide, and acetaminophen were measured.
• Insulin secretion rates (ISRs) were calculated from C-peptide levels; acetaminophen and PP served as markers for gastric emptying and cholinergic input.

Main Results:

• The highest bethanechol dose (150 mg) increased PP response in IGT and amplified GLP-1 release in IGT and T2DM groups.
• Bethanechol augmented GIP response only in the NGT group.
• Crucially, bethanechol did not alter ISRs, plasma glucose, or glucagon levels in any group.
• Xenin-25 amplified postprandial PP responses in all subject groups.

Conclusions:

• Peripheral cholinergic input to islets augments insulin secretion in mice but not in humans.
• The mechanisms regulating glucose homeostasis and insulin secretion differ between rodents and humans.
• Further research is needed to fully elucidate the role of peripheral muscarinic signaling in human metabolic disorders.