Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis.
Type 2 diabetes is a disorder of hyperglycemia resulting from failure of beta cells to produce adequate insulin to accommodate an increased metabolic demand. Here we show that regulation of mRNA translation through phosphorylation of eukaryotic initiation factor 2 (eIF2alpha) is essential to preserve the integrity of the endoplasmic reticulum (ER) and to increase insulin production to meet the demand imposed by a high-fat diet. Accumulation of unfolded proteins in the ER activates phosphorylation of eIF2alpha at Ser51 and inhibits translation. To elucidate the role of this pathway in beta-cell function we studied glucose homeostasis in Eif2s1(tm1Rjk) mutant mice, which have an alanine substitution at Ser51. Heterozygous (Eif2s1(+/tm1Rjk)) mice became obese and diabetic on a high-fat diet. Profound glucose intolerance resulted from reduced insulin secretion accompanied by abnormal distension of the ER lumen, defective trafficking of proinsulin, and a reduced number of insulin granules in beta cells. We propose that translational control couples insulin synthesis with folding capacity to maintain ER integrity and that this signal is essential to prevent diet-induced type 2 diabetes.
Howard Hughes Medical Institute, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, Michigan 48109, USA.
Donalyn
D
Scheuner
Dirk
D
Vander Mierde
Benbo
B
Song
Daisy
D
Flamez
John W M
JW
Creemers
Katsura
K
Tsukamoto
Mark
M
Ribick
Frans C
FC
Schuit
Randal J
RJ
Kaufman
D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology; D004033:Diet Fads; D018752:Diet, Fat-Restricted; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics; D006360:Heat-Shock Proteins / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D018832:Molecular Chaperones / Q000378:metabolism; D009765:Obesity / Q000235:genetics; D010766:Phosphorylation; D011384:Proinsulin / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics*
D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D007328:Insulin; D018832:Molecular Chaperones; D011384:Proinsulin; D005947:Glucose