title: ATP-sensitive K+ channel signaling in glucokinase-deficient diabetes.
abstract: As the rate-limiting controller of glucose metabolism, glucokinase represents the primary beta-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.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Remedi
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Koster
authors.forename: Brian L
authors.initials: BL
authors.lastname: Patton
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000032:analysis; D003433:Crosses, Genetic; D003920:Diabetes Mellitus / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D005838:Genotype; D005941:Glucokinase / Q000172:deficiency* / Q000502:physiology; D005973:Glutamine / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction; D000099161:Kcnj11 Channel
chemical_list: D001786:Blood Glucose; D005941:Glucokinase; D005973:Glutamine; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel