Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes.
A paradigm for control of insulin secretion is that glucose metabolism elevates cytoplasmic [ATP]/[ADP] in beta cells, closing K(ATP) channels and causing depolarization, Ca2+ entry, and insulin release. Decreased responsiveness of K(ATP) channels to elevated [ATP]/[ADP] should therefore lead to decreased insulin secretion and diabetes. To test this critical prediction, we generated transgenic mice expressing beta cell K(ATP) channels with reduced ATP sensitivity. Animals develop severe hyperglycemia, hypoinsulinemia, and ketoacidosis within 2 days and typically die within 5. Nevertheless, islet morphology, insulin localization, and alpha and beta cell distributions were normal (before day 3), pointing to reduced insulin secretion as causal. The data indicate that normal K(ATP) channel activity is critical for maintenance of euglycemia and that overactivity can cause diabetes by inhibiting insulin secretion.
Koster
J C
JC
The Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Marshall
B A
BA
Ensor
N
N
Corbett
J A
JA
Nichols
C G
CG
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D015870:Gene Expression / Q000502:physiology; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006943:Hyperglycemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007202:Indicators and Reagents / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000172:deficiency; D007515:Islets of Langerhans / Q000737:chemistry / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D010641:Phenotype; D015221:Potassium Channels / Q000032:analysis / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying; D019076:Transgenes / Q000502:physiology
D001786:Blood Glucose; D007202:Indicators and Reagents; D007328:Insulin; D008164:Luminescent Proteins; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D049452:Green Fluorescent Proteins; D020155:3-Hydroxybutyric Acid