ATP-Sensitive K+ Channel Signaling in Glucokinase-Deficient Diabetes

ATP-Sensitive K + Channel Signaling in Glucokinase-Deficient Diabetes Maria S. Remedi , Joseph C. Koster , Brian L. Patton and Colin G. Nichols From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri Address correspondence and reprint requests to Colin G. Nichols, the Department of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. E-mail: cnichols{at}cellbio.wustl.edu Abstract As the rate-limiting controller of glucose metabolism, glucokinase represents the primary β-cell “glucose sensor.” Inactivation of both glucokinase (GK) alleles results in permanent neonatal diabetes; inactivation of a single allele causes maturity-onset diabetes of the young type 2 (MODY-2). Similarly, mice lacking both alleles (GK −/− ) exhibit severe neonatal diabetes and die within a week, whereas heterozygous GK +/− mice exhibit markedly impaired glucose tolerance and diabetes, resembling MODY-2. Glucose metabolism increases the cytosolic [ATP]-to-[ADP] ratio, which closes ATP-sensitive K + channels (K ATP channels), leading to membrane depolarization, Ca 2+ entry, and insulin exocytosis. Glucokinase insufficiency causes defective K ATP channel regulation, which may underlie the impaired secretion. To test this prediction, we crossed mice lacking neuroendocrine glucokinase (nGK +/− ) with mice lacking K ATP channels (Kir6.2 −/− ). Kir6.2 knockout rescues perinatal lethality of nGK −/− , although nGK −/− Kir6.2 −/− animals are postnatally diabetic and still die prematurely. nGK +/− animals are diabetic on the Kir6.2 +/+ background but only mildly glucose intolerant on the Kir6.2 −/− background. In the presence of glutamine, isolated nGK +/− Kir6.2 −/− islets show improved insulin secretion compared with nGK +/− Kir6.2 +/+ . The significant abrogation of nGK −/− and nGK +/− phenotypes in the absence of K ATP demonstrate that a major factor in glucokinase deficiency is indeed altered K ATP signaling. The results have implications for understanding and therapy of glucokinase-related diabetes. DMEM, Dulbecco’s modified Eagle medium GSIS, glucose-stimulated insulin secretion KATP channel, ATP-sensitive K+ channel MODY-2, maturity-onset diabetes of the young type 2 Footnotes Accepted July 7, 2005. Received May 3, 2005. DIABETES