A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo.
One of the hallmarks of type 2 diabetes is that pancreatic beta cells fail to release sufficient amounts of insulin in the presence of elevated blood glucose levels. Insulin secretion is modulated by many hormones and neurotransmitters including acetylcholine, the major neurotransmitter of the peripheral parasympathetic nervous system. The physiological role of muscarinic acetylcholine receptors expressed by pancreatic beta cells remains unclear at present. Here, we demonstrate that mutant mice selectively lacking the M3 muscarinic acetylcholine receptor subtype in pancreatic beta cells display impaired glucose tolerance and greatly reduced insulin release. In contrast, transgenic mice selectively overexpressing M3 receptors in pancreatic beta cells show a profound increase in glucose tolerance and insulin release. Moreover, these mutant mice are resistant to diet-induced glucose intolerance and hyperglycemia. These findings indicate that beta cell M3 muscarinic receptors play a key role in maintaining proper insulin release and glucose homeostasis.
Gautam
Dinesh
D
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
Han
Sung-Jun
SJ
Hamdan
Fadi F
FF
Jeon
Jongrye
J
Li
Bo
B
Li
Jian Hua
JH
Cui
Yinghong
Y
Mears
David
D
Lu
Huiyan
H
Deng
Chuxia
C
Heard
Thomas
T
Wess
Jürgen
J
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004032:Diet; D005947:Glucose / Q000008:administration & dosage; D018149:Glucose Intolerance / Q000378:metabolism; D005951:Glucose Tolerance Test / Q000379:methods; D006706:Homeostasis; D006946:Hyperinsulinism / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism; D007295:Inositol Phosphates / Q000096:biosynthesis; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D010641:Phenotype; D043587:Receptor, Muscarinic M3 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
D001786:Blood Glucose; D007295:Inositol Phosphates; D007328:Insulin; D018721:Muscarinic Agonists; D043587:Receptor, Muscarinic M3; D005947:Glucose