title: mTORC1-independent reduction of retinal protein synthesis in type 1 diabetes.
abstract: Poorly controlled diabetes has long been known as a catabolic disorder with profound loss of muscle and fat body mass resulting from a simultaneous reduction in protein synthesis and enhanced protein degradation. By contrast, retinal structure is largely maintained during diabetes despite reduced Akt activity and increased rate of cell death. Therefore, we hypothesized that retinal protein turnover is regulated differently than in other insulin-sensitive tissues, such as skeletal muscle. Ins2(Akita) diabetic mice and streptozotocin-induced diabetic rats exhibited marked reductions in retinal protein synthesis matched by a concomitant reduction in retinal protein degradation associated with preserved retinal mass and protein content. The reduction in protein synthesis depended on both hyperglycemia and insulin deficiency, but protein degradation was only reversed by normalization of hyperglycemia. The reduction in protein synthesis was associated with diminished protein translation efficiency but, surprisingly, not with reduced activity of the mTORC1/S6K1/4E-BP1 pathway. Instead, diabetes induced a specific reduction of mTORC2 complex activity. These findings reveal distinctive responses of diabetes-induced retinal protein turnover compared with muscle and liver that may provide a new means to ameliorate diabetic retinopathy.
authors.affiliation: Kellogg Eye Center, Departments of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI patricef@umich.edu.
authors.forename: Patrice E
authors.initials: PE
authors.lastname: Fort
authors.affiliation: Kellogg Eye Center, Departments of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI.
authors.forename: Mandy K
authors.initials: MK
authors.lastname: Losiewicz
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.affiliation: Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA.
authors.forename: Leonard S
authors.initials: LS
authors.lastname: Jefferson
authors.affiliation: Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA.
authors.forename: Scot R
authors.initials: SR
authors.lastname: Kimball
authors.affiliation: Kellogg Eye Center, Departments of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Abcouwer
authors.affiliation: Kellogg Eye Center, Departments of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gardner
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D005136:Eye Proteins / Q000096:biosynthesis*; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D010695:Phlorhizin / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012335:RNA, Ribosomal / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D012160:Retina / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D038202:alpha-Crystallin A Chain / Q000096:biosynthesis; D038206:beta-Crystallin B Chain / Q000096:biosynthesis
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; D005136:Eye Proteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D012335:RNA, Ribosomal; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; C572458:Rptor protein, rat; D038202:alpha-Crystallin A Chain; D038206:beta-Crystallin B Chain; C550254:rictor protein, rat; D010695:Phlorhizin; D011972:Receptor, Insulin; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
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