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.
Pancreatic muscarinic acetylcholine receptors play an important role in stimulating insulin and glucagon secretion from islet cells. To study the potential role of the M 3 muscarinic receptor subtype in cholinergic stimulation of insulin release, we initially examined the effect of the muscarinic agonist, oxotremorine-M (Oxo-M), on insulin secretion from isolated pancreatic islets prepared from wild-type (WT) and M 3 receptor؊deficient mice (M3 ؉/؊ and M3 ؊/؊ mice). At a stimulatory glucose level (16.7 mmol/l), Oxo-M strongly potentiated insulin output from islets of WT mice. Strikingly, this effect was completely abolished in islets from M3 ؊/؊ mice and significantly reduced in islets from M3 ؉/؊ mice. Additional in vitro studies showed that Oxo-M؊mediated glucagon release was also virtually abolished in islets from M3 ؊/؊ mice. Consistent with the in vitro data, in vivo studies showed that M3 ؊/؊ mice displayed reduced serum insulin and plasma glucagon levels and a significantly blunted increase in serum insulin after an oral glucose load. Despite the observed impairments in insulin release, M3؊/؊ mice showed significantly reduced blood glucose levels and even improved glucose tolerance, probably due to the reduction in plasma glucagon levels and the fact that M3 ؊/؊ mice are hypophagic and lean. These findings provide important new insights into the metabolic roles of the M 3 muscarinic receptor subtype. Diabetes 53
The mammalian anx7 gene codes for a Ca 2؉ -activated GTPase, which supports Ca 2؉ ͞GTP-dependent secretion events and Ca 2؉ channel activities in vitro and in vivo. To test whether anx7 might be involved in Ca 2؉ signaling in secreting pancreatic  cells, we knocked out the anx7 gene in the mouse and tested the insulinsecretory properties of the  cells. The nullizygous anx7 (؊͞؊) phenotype is lethal at embryonic day 10 because of cerebral hemorrhage. However, the heterozygous anx7 (؉͞؊) mouse, although expressing only low levels of ANX7 protein, is viable and fertile. The anx7 (؉͞؊) phenotype is associated with a substantial defect in insulin secretion, although the insulin content of the islets, is 8-to 10-fold higher in the mutants than in the normal littermate control. We infer from electrophysiological studies that both glucose-stimulated secretion and voltage-dependent Ca 2؉ channel functions are normal. However, electrooptical recordings indicate that the (؉͞؊) mutation has caused a change in the ability of inositol 1,4,5-trisphosphate (IP3)-generating agonists to release intracellular calcium. The principle molecular consequence of lower anx7 expression is a profound reduction in IP3 receptor expression and function in pancreatic islets. The profound increase in islets,  cell number, and size may be a means of compensating for less efficient insulin secretion by individual defective pancreatic  cells. This is a direct demonstration of a connection between glucoseactivated insulin secretion and Ca 2؉ signaling through IP3-sensitive Ca 2؉ stores.
Insulin secretion from beta-cells of the pancreatic islets of Langerhans is triggered by Ca(2+) influx through voltage-dependent Ca(2+) channels. Electrophysiological and molecular studies indicate that beta-cells express several subtypes of these channels. This review discusses their roles in regulating insulin secretion, focusing on recent studies using beta-cells, exogenous expression systems, and Ca(2+) channel knockout mice. These investigations reveal that L-type Ca(2+) channels in the beta-cell physically interact with the secretory apparatus by binding to synaptic proteins on the plasma membrane and insulin granule. As a result, Ca(2+) influx through L-type channels efficiently and rapidly stimulates release of a pool of insulin granules in close contact with the channels. Thus, L-type Ca(2+) channel activity is preferentially coupled to exocytosis in the beta-cell, and plays a critical role in regulating the dynamics of insulin secretion. Non-L-type channels carry a significant portion of the total voltage-dependent Ca(2+) current in beta-cells and cell lines from some species, but nevertheless account for only a small fraction of insulin secretion. These channels may regulate exocytosis indirectly by affecting membrane potential or second messenger signaling pathways. Finally, voltage-independent Ca(2+) entry pathways and their potential roles in beta-cell function are discussed. The emerging picture is that Ca(2+) channels regulate insulin secretion at multiple sites in the stimulus-secretion coupling pathway, with the specific role of each channel determined by its biophysical and structural properties.
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