Secondary Consequences of β Cell Inexcitability: Identification and Prevention in a Murine Model of KATP-Induced Neonatal Diabetes Mellitus

ATP-insensitive K ATP channel mutations cause neonatal diabetes mellitus (NDM). To explore the mechanistic etiology, we generated transgenic mice carrying an ATP-insensitive mutant K ATP channel subunit. Constitutive expression in pancreatic β-cells caused neonatal hyperglycemia and progression to s...

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Veröffentlicht in:Cell metabolism 2009-02, Vol.9 (2), p.140-151
Hauptverfasser: Remedi, Maria Sara, Kurata, Harley T., Scott, Alexis, Wunderlich, F. Thomas, Rother, Eva, Kleinridders, Andre, Tong, Ailing, Brüning, Jens C., Koster, Joseph C., Nichols, Colin G.
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Sprache:eng
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Zusammenfassung:ATP-insensitive K ATP channel mutations cause neonatal diabetes mellitus (NDM). To explore the mechanistic etiology, we generated transgenic mice carrying an ATP-insensitive mutant K ATP channel subunit. Constitutive expression in pancreatic β-cells caused neonatal hyperglycemia and progression to severe diabetes and growth retardation with loss of islet insulin content and β-cell architecture. Tamoxifen-induced expression in adult β-cells led to diabetes within 2-weeks, with similar secondary consequences. Diabetes was avoided by transplantation of normal islets under the kidney capsule, before induction. Moreover, the endogenous islets maintained normal insulin content and secretion in response to sulfonylureas, but not glucose, consistent with reduced ATP sensitivity of β-cell K ATP channels. In NDM, transfer to sulfonylurea therapy is less effective in older patients. This may result from poor glycemic control or lack of insulin, since glibenclamide treatment prior to tamoxifen-induction prevented diabetes and secondary complications in mice, but failed to halt disease progression after diabetes had developed.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2008.12.005