Transgenic overexpression of active calcineurin in beta-cells results in decreased beta-cell mass and hyperglycemia.
BACKGROUND
Glucose modulates beta-cell mass and function through an initial depolarization and Ca(2+) influx, which then triggers a number of growth regulating signaling pathways. One of the most important downstream effectors in Ca(2+) signaling is the calcium/Calmodulin activated serine threonine phosphatase, calcineurin. Recent evidence suggests that calcineurin/NFAT is essential for beta-cell proliferation, and that in its absence loss of beta-cells results in diabetes. We hypothesized that in contrast, activation of calcineurin might result in expansion of beta-cell mass and resistance to diabetes.


RESULTS
To determine the role of activation of calcineurin signaling in the regulation of pancreatic beta-cell mass and proliferation, we created mice that expressed a constitutively active form of calcineurin under the insulin gene promoter (caCn(RIP)). To our surprise, these mice exhibited glucose intolerance. In vitro studies demonstrated that while the second phase of Insulin secretion is enhanced, the overall insulin secretory response was conserved. Islet morphometric studies demonstrated decreased beta-cell mass suggesting that this was a major component responsible for altered Insulin secretion and glucose intolerance in caCn(RIP) mice. The reduced beta-cell mass was accompanied by decreased proliferation and enhanced apoptosis.


CONCLUSIONS
Our studies identify calcineurin as an important factor in controlling glucose homeostasis and indicate that chronic depolarization leading to increased calcineurin activity may contribute, along with other genetic and environmental factors, to beta-cell dysfunction and diabetes.
Bernal-Mizrachi
Ernesto
E
Division of Metabolism, Endocrinology, Diabetes, The Brehm Center for Type 1 Diabetes, University of Michigan, Ann Arbor, Michigan, United States of America. ebernal@umich.edu
Cras-Méneur
Corentin
C
Ye
Bo Ra
BR
Johnson
James D
JD
Permutt
M Alan
MA
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019703:Calcineurin / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D048429:Cell Size; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics* / Q000473:pathology*; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D019076:Transgenes / Q000235:genetics*
D007328:Insulin; D019703:Calcineurin; D005947:Glucose