When translation meets metabolism: multiple links to diabetes.
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 beta-cell exhaustion. Future advances in this area may lead to identification of the missing links in the pathogenesis of beta-cell failures due to conditions such as hyperinsulinemia, hyperglycemia, and long-term treatment with sulfonylureas, and thus may identify novel therapeutic targets for diabetes.
Shi
Yuguang
Y
Endocrine Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. shi_yuguang@lilly.com
Taylor
Simeon I
SI
Tan
Seng-Lai
SL
Sonenberg
Nahum
N
D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics; D018955:CD36 Antigens / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000503:physiopathology; D008099:Liver / Q000378:metabolism; D010766:Phosphorylation; D019893:Ribosomal Protein S6 Kinases; D019892:eIF-2 Kinase
D018955:CD36 Antigens; D015852:Eukaryotic Initiation Factor-2; D039561:Eukaryotic Initiation Factor-4E; D005947:Glucose; D019893:Ribosomal Protein S6 Kinases; D019892:eIF-2 Kinase