Valitsky Michael, Hoffman Amnon, Unterman Terry, Bar-Tana Jacob
Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.
Institute for Drug Research, Hebrew University Faculty of Medicine, Jerusalem, Israel; and.
Am J Physiol Endocrinol Metab. 2017 Dec 1;313(6):E672-E680. doi: 10.1152/ajpendo.00329.2016. Epub 2017 Mar 7.
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.
胰岛素依赖型1型糖尿病（T1D）由自身免疫性β细胞功能衰竭驱动，而全身对胰岛素的抵抗被认为是非胰岛素依赖型2型糖尿病（T2D）的标志。与这种典型的二分法不同，胰岛素抵抗似乎先于T1D的显性糖尿病阶段并预测其进展，这意味着胰岛素增敏剂可能会改变T1D的病程。然而，此前在动物模型或患者中通过胰岛素增敏剂改善T1D的尝试大多失败了。在T2D动物模型中，甲基取代的长链二羧酸（MEDICA）类似物对胰岛素的增敏作用超过了目前的胰岛素增敏剂，因此激发了我们在T1D背景下探究MEDICA的兴趣。在链脲佐菌素（STZ）诱导的糖尿病大鼠和自身免疫性非肥胖糖尿病（NOD）小鼠中验证了MEDICA在调节T1D病程方面的疗效。在亚治疗剂量胰岛素基础上加用MEDICA治疗可使STZ糖尿病大鼠的显性糖尿病恢复正常，并预防/延缓NOD小鼠的自身免疫性T1D。MEDICA治疗并未改善β细胞胰岛素含量或胰岛炎评分，但其疗效是由全身对胰岛素的显著增敏作用所致。总之，强效胰岛素增敏剂可能抵消自身免疫性T1D的遗传易感性，并将亚治疗剂量胰岛素放大为治疗显性T1D的有效治疗措施。
