TY - JOUR
T1 - Targeted overactivity of β cell K(ATP) channels induces profound neonatal diabetes
AU - Koster, J. C.
AU - Marshall, B. A.
AU - Ensor, N.
AU - Corbett, J. A.
AU - Nichols, C. G.
N1 - Funding Information:
We thank Rebecca Dunlap for technical assistance with these experiments. We are grateful to Tom Broekelmann for expert advice in immunohistochemical techniques and Carina Ämmälä for expert advice regarding in β cell isolation. This work was primarily supported by National Institutes of Health grants DK55282 (C. G. N.), DK02339 (B. A. M), and the Washington University Diabetes Research and Training Center (DK20579, fellowship support of J. C. K.). We are grateful for additional support from a grant from the Hardison Family Foundation (B. A. M.), a Career Development Award from the American Diabetes Association (B. A. M.), National Institutes of Health grant DK52194 (J. A. C.), and a Career Development Grant from Juvenile Diabetes Foundation International (J. A. C.). B. A. M. is a scholar of the Child Health and Research Center of Excellence in Developmental Biology at Washington University School of Medicine.
PY - 2000/3/17
Y1 - 2000/3/17
N2 - A paradigm for control of insulin secretion is that glucose metabolism elevates cytoplasmic [ATP]/[ADP] in β 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 β 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 α and β 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.
AB - A paradigm for control of insulin secretion is that glucose metabolism elevates cytoplasmic [ATP]/[ADP] in β 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 β 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 α and β 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.
UR - http://www.scopus.com/inward/record.url?scp=0034677634&partnerID=8YFLogxK
U2 - 10.1016/S0092-8674(00)80701-1
DO - 10.1016/S0092-8674(00)80701-1
M3 - Article
C2 - 10761930
AN - SCOPUS:0034677634
SN - 0092-8674
VL - 100
SP - 645
EP - 654
JO - Cell
JF - Cell
IS - 6
ER -