Metabolism-Excitation Coupling in a Model of KATP Channel Neonatal Diabetes Mellitus

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The KATP channel is critical to pancreatic beta cells, linking glucose metabolism with insulin secretion. KATP channel mutations that reduce ATP-sensitivity lead to neonatal diabetes mellitus (NDM). Expression of these KATP channel mutations in mice also leads to severe diabetes. Beta cell mass and insulin content are initially preserved, but both decrease with time following the prolonged hyperglycemia. When glycemic control is imposed by transplantation of exogenous islets, this secondary loss of beta-cell mass and insulin content is avoided.We have examined various steps of the glucose stimulated insulin secretion pathway in islets that express ATP-insensitive KATP channels, which are either unprotected from hyperglycemia or protected by islet transplantation. In protected islets, expression of mutant KATP channels leads to a severe blunting of glucose stimulated [Ca2+] activity. There remains some sulfonylurea stimulated [Ca2+] and normal KCl stimulated [Ca2+], with insulin secretion following a similar pattern. In unprotected islets, isolated from severely diabetic mice, very similar patterns of [Ca2+] activity are measured but insulin secretion is markedly decreased.Using two-photon microscopy of NAD(P)H we find glucose metabolism is unaltered in protected mutant islets. This suggests that the reduced [Ca2+] elevation and thus mitochondrial Ca2+ uptake has little effect on mitochondrial metabolism. However in unprotected islets, there is elevated basal NAD(P)H and an absence of glucose stimulated NAD(P)H increase, suggesting a disruption of glycolysis and/or mitochondrial metabolism.Finally the low level of glucose stimulated [Ca2+] in mutant islets is partially synchronized, indicating coupling is present. Reduction of gap junction conductance via chemical inhibitors or islet dispersal leads to elevated glucose stimulated Ca2+. This indicates an important role for gap junctions in regulating Ca2+ triggering in the presence of KATP channel mutations.