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

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, Ca²⁺ 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.