title: Insulin sensitizer prevents and ameliorates experimental type 1 diabetes.
abstract: Insulin-dependent type-1 diabetes (T1D) is driven by autoimmune β-cell failure, whereas systemic resistance to insulin is considered the hallmark of insulin-independent type-2 diabetes (T2D). In contrast to this canonical dichotomy, insulin resistance appears to precede the overt diabetic stage of T1D and predict its progression, implying that insulin sensitizers may change the course of T1D. However, previous attempts to ameliorate T1D in animal models or patients by insulin sensitizers have largely failed. Sensitization to insulin by MEthyl-substituted long-chain DICArboxylic acid (MEDICA) analogs in T2D animal models surpasses that of current insulin sensitizers, thus prompting our interest in probing MEDICA in the T1D context. MEDICA efficacy in modulating the course of T1D was verified in streptozotocin (STZ) diabetic rats and autoimmune nonobese diabetic (NOD) mice. MEDICA treatment normalizes overt diabetes in STZ diabetic rats when added on to subtherapeutic insulin, and prevents/delays autoimmune T1D in NOD mice. MEDICA treatment does not improve β-cell insulin content or insulitis score, but its efficacy is accounted for by pronounced total body sensitization to insulin. In conclusion, potent insulin sensitizers may counteract genetic predisposition to autoimmune T1D and amplify subtherapeutic insulin into an effective therapeutic measure for the treatment of overt T1D.
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Valitsky
authors.affiliation: Institute for Drug Research, Hebrew University Faculty of Medicine, Jerusalem, Israel; and.
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
authors.affiliation: Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois.
authors.forename: Terry
authors.initials: T
authors.lastname: Unterman
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel; jacobb@ekmd.huji.ac.il.
authors.forename: Jacob
authors.initials: J
authors.lastname: Bar-Tana
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000517:prevention & control*; D003998:Dicarboxylic Acids / Q000008:administration & dosage* / Q000737:chemistry; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000008:administration & dosage*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin
chemical_list: D003998:Dicarboxylic Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D013311:Streptozocin
keywords: AMPK; NOD mice; diabetes type 1; insulin resistance; streptozotocin