TY - JOUR
T1 - ATP-sensitive K+ channel signaling in glucokinase-deficient diabetes
AU - Remedi, Maria S.
AU - Koster, Joseph C.
AU - Patton, Brian L.
AU - Nichols, Colin G.
PY - 2005/10
Y1 - 2005/10
N2 - 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 (KATP channels), leading to membrane depolarization, Ca2+ entry, and insulin exocytosis. Glucokinase insufficiency causes defective KATP channel regulation, which may underlie the impaired secretion. To test this prediction, we crossed mice lacking neuroendocrine glucokinase (nGK +/-) with mice lacking KATP 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 KATP demonstrate that a major factor in glucokinase deficiency is indeed altered KATP signaling. The results have implications for understanding and therapy of glucokinase-related diabetes.
AB - 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 (KATP channels), leading to membrane depolarization, Ca2+ entry, and insulin exocytosis. Glucokinase insufficiency causes defective KATP channel regulation, which may underlie the impaired secretion. To test this prediction, we crossed mice lacking neuroendocrine glucokinase (nGK +/-) with mice lacking KATP 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 KATP demonstrate that a major factor in glucokinase deficiency is indeed altered KATP signaling. The results have implications for understanding and therapy of glucokinase-related diabetes.
UR - http://www.scopus.com/inward/record.url?scp=25844454853&partnerID=8YFLogxK
U2 - 10.2337/diabetes.54.10.2925
DO - 10.2337/diabetes.54.10.2925
M3 - Article
C2 - 16186394
AN - SCOPUS:25844454853
SN - 0012-1797
VL - 54
SP - 2925
EP - 2931
JO - Diabetes
JF - Diabetes
IS - 10
ER -