Epidemiology of Heterogenity in Type 2 Diabetes

描述(申请人提供)：有几行证据表明，2型(非胰岛素依赖型)糖尿病是一种异质性疾病，是胰岛素分泌和胰岛素作用异常的综合结果。2型糖尿病患者胰岛素分泌减少的原因尚不完全清楚，但在一组2型糖尿病患者中，这可能与胰岛β细胞的自身免疫破坏有关。我们发现，在2型糖尿病患者中，GAD65抗体的存在与胰岛素治疗的使用密切相关。我们现在提出，我们正在观察的GAD65抗体阳性糖尿病是2型糖尿病的一个独特的亚类，与相对严重的胰岛素缺乏有关。值得注意的是，这些病例都被很好地记录为2型糖尿病，而不是1型糖尿病，而且他们是老年人，显然在临床特征和对胰岛素的需求方面不同于传统的1型糖尿病或年轻人。我们推测，携带GAD65抗体的老年T2 DM患者亚群是独一无二的，因为这与严重的胰岛素缺乏、HLADQ易感性和发展中的微血管疾病有关。相比之下，非GAD65抗体阳性的糖尿病患者可能主要是胰岛素抵抗，血液胰岛素水平升高，并处于大血管疾病的主要风险中。描述罹患这种独特形式的2型糖尿病的风险的个人的特征具有公共卫生意义，因为可以及早制定治疗策略，以预防与高血糖相关的并发症，并可能预防与胰岛素需求开始相关的时间。更恰当地描述这一亚组老年2型糖尿病患者，可能是自身免疫发病机制，将有助于未来对2型糖尿病的病因、自然病程以及治疗的研究。

DESCRIPTION (provided by applicant): Several lines of evidence indicate that Type 2 (non-insulin-dependent) diabetes mellitus is a heterogeneous disease that results from a combination of abnormalities in both insulin secretion and insulin action. The causes of decreased insulin secretion in Type 2 diabetes are still not completely understood, but in a subgroup of Type 2 diabetic patients they may be related to an autoimmune destruction of the pancreatic beta-cells. We showed that in Type 2 diabetic patients the presence of GAD65 antibodies is strongly related to the use of insulin therapy. We now propose that GAD65 antibody-positive diabetes that we are observing is a unique subclass of Type 2 diabetes, which is associated with relatively severe insulin deficiency. It is important to note that these cases are all reasonably well documented as Type 2 diabetes rather than Type 1 and those they are older individuals and, clearly, are different than traditional Type 1 diabetes or young adults in regard to their clinical characteristics and needs for insulin. We hypothesize that this subset of older T2DM patients carrying GAD65 antibodies is unique in that is associated with severe insulin deficiency, with HLADQ susceptibility and with the development micro vascular disease. In contrast, diabetic patients who are not GAD65 antibody positive are probably primarily insulin resistant, have elevated blood insulin levels and are at primary risk for macro vascular disease. As a model for understanding the causes of insulin deficiency in GAD65 antibody positive older patients (>50 yr of age), we plan to evaluate the metabolic and genetic abnormalities in GAD65 autoantibody positive T2DM patients and compare these abnormalities with those of a subgroup of GAD65 antibody negative T2DM patients. The characterization of individuals at risk of developing this unique form of Type 2 diabetes is of public health interest because therapeutic strategies could potentially be instituted early enough to prevent the complications related with hyperglycemia and, possibly, the time of onset of insulin requirement. A more appropriate characterization of this subgroup of older Type 2 diabetic patients, presumably of autoimmune pathogenesis, will be of benefit to future research into the etiology, natural history as well as treatment of Type 2 diabetes mellitus.