Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 114, Issue 2, Pages 214-223Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200421645
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Funding
- NIDDK NIH HHS [DK58282, R01 DK057539, DK63608, DK57539, R37 DK058282, P30 DK063608, R01 DK058282] Funding Source: Medline
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The role of different tissues in insulin action and their contribution to the pathogenesis of diabetes remain unclear. To examine this question, we have used genetic reconstitution experiments in mice. Genetic ablation of insulin receptors causes early postnatal death from diabetic ketoacidosis. We show that combined restoration of insulin receptor function in brain, liver, and pancreatic beta cells rescues insulin receptor knockout mice from neonatal death, prevents diabetes in a majority of animals, and normalizes adipose tissue content, lifespan, and reproductive function. In contrast, mice with insulin receptor expression limited to brain or liver and pancreatic beta cells are rescued from neonatal death, but develop lipoatrophic diabetes and die prematurely. These data indicate, surprisingly, that insulin receptor signaling in noncanonical insulin target tissues is sufficient to maintain fuel homeostasis and prevent diabetes.
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