Total insulin and IGF-I resistance in pancreatic cells causes overt diabetes

Kohjiro Ueki^1, 6, 7, Terumasa Okada^1, 6, Jiang Hu¹, Chong Wee Liew¹, Anke Assmann¹, Gabriella M Dahlgren², Jennifer L Peters², Jonathan G Shackman², Min Zhang³, Isabella Artner⁴, Leslie S Satin³, Roland Stein⁴, Martin Holzenberger⁵, Robert T Kennedy², C Ronald Kahn¹ & Rohit N Kulkarni¹

¹  Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.

²  Departments of Chemistry & Pharmacology, University of Michigan, Michigan 48109, USA.

³  Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA.

⁴  Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

⁵  INSERM U515, Hopital Saint-Antoine, Paris 12, France.

⁶  These authors contributed equally to this work.

⁷  Current address: Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.

An appropriate cell mass is pivotal for the maintenance of glucose homeostasis¹. Both insulin and IGF-1 are important in regulation of cell growth and function (reviewed in ref. 2). To define the roles of these hormones directly, we created a mouse model lacking functional receptors for both insulin and IGF-1 only in cells (DKO), as the hormones have overlapping mechanisms of action and activate common downstream proteins. Notably, DKO mice were born with a normal complement of islet cells, but 3 weeks after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants^{3, 4}. Normoglycemic 2-week-old DKO mice manifest reduced cell mass, reduced expression of phosphorylated Akt and the transcription factor MafA, increased apoptosis in islets and severely compromised cell function. Analyses of compound knockouts showed a dominant role for insulin signaling in regulating cell mass. Together, these data provide compelling genetic evidence that insulin and IGF-I–dependent pathways are not critical for development of cells but that a loss of action of these hormones in cells leads to diabetes. We propose that therapeutic improvement of insulin and IGF-I signaling in cells might protect against type 2 diabetes.

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