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Restitution of Defective Glucose-Stimulated Insulin Secretion in Diabetic GK Rat by Acetylcholine Uncovers Paradoxical Stimulatory Effect of ß-Cell Muscarinic Receptor Activation on cAMP Production

¹ Unité Mixte de Recherche (UMR) 7059, National Center for Scientific Research (CNRS) and Paris University 7/D. Diderot, Paris, France
² Department of Genetic Medicine and Development, University Medical Center, Geneva, Switzerland

Because acetylcholine (ACh) is a recognized potentiator of glucose-stimulated insulin release in the normal ß-cell, we have studied ACh’s effect on islets of the Goto-Kakizaki (GK) rat, a spontaneous model of type 2 diabetes. We first verified that ACh was able to restore the insulin secretory glucose competence of the GK ß-cell. Then, we demonstrated that in GK islets 1) ACh elicited a first-phase insulin release at low glucose, whereas it had no effect in Wistar; 2) total phospholipase C activity, ACh-induced inositol phosphate production, and intracellular free calcium concentration ([Ca²⁺]_i) elevation were normal; 3) ACh triggered insulin release, even in the presence of thapsigargin, which induced a reduction of the ACh-induced [Ca²⁺]_i response (suggesting that ACh produces amplification signals that augment the efficacy of elevated [Ca²⁺]_i on GK exocytosis); 4) inhibition of protein kinase C did not affect [Ca²⁺]_i nor the insulin release responses to ACh; and 5) inhibition of cAMP-dependent protein kinases (PKAs), adenylyl cyclases, or cAMP generation, while not affecting the [Ca²⁺]_i response, significantly lowered the insulinotropic response to ACh (at low and high glucose). In conclusion, ACh acts mainly through activation of the cAMP/PKA pathway to potently enhance Ca²⁺-stimulated insulin release in the GK ß-cell and, in doing so, normalizes its defective glucose responsiveness.

Abbreviations: ACh, acetylcholine; BIM, bisindolylmaleimide I; [Ca²⁺]_i, intracellular free calcium concentration; dd-Ado, 2',5'-dideoxyadenosine; H-89, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide; InsP, inositol phosphate; IBMX, isobutyl methylxanthine; KRB, Krebs-Ringer buffer; mAChR, muscarinic ACh receptor; PKA, cAMP-dependent protein kinase; PKC, protein kinase C; PLC, phospholipase C; Rp-8-Br-cAMPS, 8-bromoadenosine-3',5'-cyclic monophosphorothioate, Rp-isomer; SERCA, sarcoendoplasmic reticulum Ca²⁺-ATPase

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