scholarly journals A critical role for β cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo

2006 ◽  
Vol 3 (6) ◽  
pp. 449-461 ◽  
Author(s):  
Dinesh Gautam ◽  
Sung-Jun Han ◽  
Fadi F. Hamdan ◽  
Jongrye Jeon ◽  
Bo Li ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Insulin Release ◽  
Glucose Homeostasis ◽  
Acetylcholine Receptors ◽  
Critical Role ◽  
Muscarinic Acetylcholine Receptors ◽  
Β Cell ◽  
Muscarinic Acetylcholine ◽  
Blood Glucose Homeostasis

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

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5185-5194 ◽  
Author(s):  
Dinesh Gautam ◽  
Inigo Ruiz de Azua ◽  
Jian Hua Li ◽  
Jean-Marc Guettier ◽  
Thomas Heard ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Transgenic Mice ◽  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Metabolic Effects ◽  
Β Cells ◽  
Β Cell ◽  
Muscarinic Acetylcholine

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.

scholarly journals Imaging Muscarinic Cholinergic Receptors in Human Brain in vivo with SPECT, [123I]4-Iododexetimide, and [123I]4-Iodolevetimide

1992 ◽  
Vol 12 (4) ◽  
pp. 562-570 ◽  
Author(s):  
Hans W. Müller-Gärtner ◽  
Alan A. Wilson ◽  
Robert F. Dannals ◽  
Henry N. Wagner ◽  
J. James Frost
Keyword(s):  
Human Brain ◽  
Muscarinic Receptor ◽  
Muscarinic Receptors ◽  
Acetylcholine Receptors ◽  
Brain Regions ◽  
Muscarinic Acetylcholine Receptors ◽  
Emission Computed Tomography ◽  
Nonspecific Binding ◽  
Muscarinic Acetylcholine

A method to image muscarinic acetylcholine receptors (muscarinic receptors) noninvasively in human brain in vivo was developed using [123I]4-iododexetimide ([123I]IDex), [123I]4-iodolevetimide ([123I]ILev), and single photon emission computed tomography (SPECT). [123I]IDex is a high-affinity muscarinic receptor antagonist. [123I]ILev is its pharmacologically inactive enantiomer and measures nonspecific binding of [123I]IDex in vitro. Regional brain activity after tracer injection was measured in four young normal volunteers for 24 h. Regional [123I]IDex and [123I]ILev activities were correlated early after injection, but not after 1.5 h. [123I]IDex activity increased over 7–12 h in neocortex, neostriatum, and thalamus, but decreased immediately after the injection peak in cerebellum. [123I]IDex activity was highest in neostriatum, followed in rank order by neocortex, thalamus, and cerebellum. [123I]IDex activity correlated with muscarinic receptor concentrations in matching brain regions. In contrast, [123I]ILev activity decreased immediately after the injection peak in all brain regions and did not correspond to muscarinic receptor concentrations. [123I]IDex activity in neocortex and neostriatum during equilibrium was six to seven times higher than [123I]ILev activity. The data demonstrate that [123I]IDex binds specifically to muscarinic receptors in vivo, whereas [123I]ILev represents the nonspecific part of [123I]IDex binding. Subtraction of [123I]ILev from [123I]IDex images on a pixel-by-pixel basis therefore reflects specific [123I]IDex binding to muscarinic receptors. Owing to its high specific binding, [123I]IDex has the potential to measure small changes in muscarinic receptor characteristics in vivo with SPECT. The use of stereoisomerism directly to measure nonspecific binding of [123I]IDex in vivo may reduce complexity in modeling approaches to muscarinic acetylcholine receptors in human brain.

Synthesis,18F-Labeling, and Biological Evaluation of Piperidyl and Pyrrolidyl Benzilates as in Vivo Ligands for Muscarinic Acetylcholine Receptors

2000 ◽  
Vol 43 (23) ◽  
pp. 4552-4562 ◽  
Author(s):  
Marc B. Skaddan ◽  
Michael R. Kilbourn ◽  
Scott E. Snyder ◽  
Phil S. Sherman ◽  
Tim J. Desmond ◽  
...  
Keyword(s):  
Acetylcholine Receptors ◽  
Biological Evaluation ◽  
Muscarinic Acetylcholine Receptors ◽  
Muscarinic Acetylcholine

scholarly journals A Whole-Body Model for Glycogen Regulation Reveals a Critical Role for Substrate Cycling in Maintaining Blood Glucose Homeostasis

2011 ◽  
Vol 7 (12) ◽  
pp. e1002272 ◽  
Author(s):  
Ke Xu ◽  
Kevin T. Morgan ◽  
Abby Todd Gehris ◽  
Timothy C. Elston ◽  
Shawn M. Gomez
Keyword(s):  
Blood Glucose ◽  
Glucose Homeostasis ◽  
Critical Role ◽  
Whole Body ◽  
Body Model ◽  
Blood Glucose Homeostasis ◽  
Whole Body Model

Effects of Autoantibodies against M2 Muscarinic Acetylcholine Receptors on Rabbit Atria in vivo

Cardiology ◽  
2009 ◽  
Vol 112 (3) ◽  
pp. 180-187 ◽  
Author(s):  
Chang Ming Hong ◽  
Qiang Sun Zheng ◽  
Xiong Tao Liu ◽  
Fu Jun Shang ◽  
Hong Tao Wang ◽  
...  
Keyword(s):  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Muscarinic Acetylcholine ◽  
Rabbit Atria
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