Beneficial Metabolic Effects Caused by Persistent Activation of β-Cell M3 Muscarinic Acetylcholine Receptors in Transgenic Mice

Author:

Gautam Dinesh1,de Azua Inigo Ruiz1,Li Jian Hua1,Guettier Jean-Marc1,Heard Thomas1,Cui Yinghong1,Lu Huiyan2,Jou William3,Gavrilova Oksana3,Zawalich Walter S.4,Wess Jürgen1

Affiliation:

1. Molecular Signaling Section (D.G., I.R.A., J.H.L., J.-M.G., T.H., Y.C., J.W.), National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892

2. Laboratory of Bioorganic Chemistry, Mouse Transgenic Core Facility (H.L.), National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892

3. Laboratory of Mouse Metabolic Core Facility (W.J., O.G.), National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892

4. Yale University School of Nursing (W.S.Z.), New Haven, Connecticut 06519

Abstract

Previous studies have shown that β-cell M3 muscarinic acetylcholine receptors (M3Rs) play a key role in maintaining blood glucose homeostasis by enhancing glucose-dependent insulin release. In this study, we tested the hypothesis that long-term, persistent activation of β-cell M3Rs can improve glucose tolerance and ameliorate the metabolic deficits associated with the consumption of a high-fat diet. To achieve the selective and persistent activation of β-cell M3Rs in vivo, we generated transgenic mice that expressed the Q490L mutant M3R in their pancreatic β-cells (β-M3-Q490L Tg mice). The Q490L point mutation is known to render the M3R constitutively active. The metabolic phenotypes of the transgenic mice were examined in several in vitro and in vivo metabolic tests. In the presence of 15 mm glucose and the absence of M3R ligands, isolated perifused islets prepared from β-M3-Q490L Tg mice released considerably more insulin than wild-type control islets. This effect could be completely blocked by incubation of the transgenic islets with atropine (10 μm), an inverse muscarinic agonist, indicating that the Q490L mutant M3R exhibited ligand-independent signaling (constitutive activity) in mouse β-cells. In vivo studies showed that β-M3-Q490L Tg mice displayed greatly improved glucose tolerance and increased serum insulin levels as well as resistance to diet-induced glucose intolerance and hyperglycemia. These results suggest that chronic activation of β-cell M3Rs may represent a useful approach to boost insulin output in the long-term treatment of type 2 diabetes.

Publisher

The Endocrine Society

Subject

Endocrinology

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