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When Translation Meets Metabolism: Multiple Links to Diabetes

Endocrine Research (Y.S., S.I.T.), Infectious Diseases (S.-L.T.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285; and Department of Biochemistry and McGill Cancer Center (N.S.), McGill University, Montréal, Quebéc H3G 1Y6, Canada

Correspondence: Address all correspondence and requests for reprints to: Dr. Nahum Sonenberg, Department of Biochemistry, McGill University, McIntyre Medical Services Building, 3655 Drummond Street, Room 807, Montréal, Quebéc H3G 1Y6, Canada. E-mail: nsonen{at}med.mcgill.ca; or to Dr. Yuguang Shi, Endocrine Research DC 0545, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana 46033. E-mail: shi_yuguang{at}lilly.com

Type 2 diabetes is a polygenic disorder characterized by multiple biochemical defects including transcriptional, translational, and posttranslational abnormalities. Although major progress has been made in elucidation of factors at the transcriptional and posttranslational levels, defects at the translational level remain elusive. Mutation of a kinase that regulates translation initiation has been implicated in the etiology of a monogenic form of diabetes known as Wolcott-Rallison syndrome. Characterization of mice rendered deficient in eukaryotic initiation factors has provided model systems to study the involvement of translation in regulating insulin synthesis and secretion, hepatic function, peripheral insulin resistance, and diabetic complications. Recent progress in the understanding of endoplasmic reticulum overload by unfolded proteins has begun to uncover mechanisms leading to pancreatic ß-cell exhaustion. Future advances in this area may lead to identification of the missing links in the pathogenesis of ß-cell failures due to conditions such as hyperinsulinemia, hyperglycemia, and long-term treatment with sulfonylureas, and thus may identify novel therapeutic targets for diabetes.

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