Epidemiology of Heterogenity in Type 2 Diabetes

2 型糖尿病异质性流行病学

• 批准号: 7119943
• 负责人: MASSIMO T PIETROPAOLO
• 金额: $ 51.95万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7119943
• 关键词: African American; age difference; autoantibody; autoimmunity; biomarker; caucasian American; clinical research; epidemiology; gender difference; gene expression; gene mutation; genetic susceptibility; glucose clamp technique; glucose tolerance; human middle age (35-64); human subject; immunopathology; insulin sensitivity /resistance; longitudinal human study; noninsulin dependent diabetes mellitus; pancreatic islets; patient oriented research; photon absorptiometry; racial /ethnic difference; radioimmunoassay

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.

描述（由申请人提供）：多项证据表明 2 型（非胰岛素依赖性）糖尿病是一种异质性疾病，由胰岛素分泌和胰岛素作用异常共同导致。 2 型糖尿病中胰岛素分泌减少的原因尚不完全清楚，但在 2 型糖尿病患者的亚组中，这些原因可能与胰腺 β 细胞的自身免疫性破坏有关。我们发现，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，我们观察到的 GAD65 抗体阳性糖尿病是 2 型糖尿病的一个独特亚类，它与相对严重的胰岛素缺乏有关。值得注意的是，这些病例都被相当详细地记录为 2 型糖尿病而不是 1 型，而且这些病例都是老年人，而且显然在临床特征和胰岛素需求方面与传统 1 型糖尿病或年轻人不同。我们假设携带 GAD65 抗体的老年 T2DM 患者亚群是独特的，因为它与严重的胰岛素缺乏、HLADQ 易感性和微血管疾病的发生有关。相比之下，GAD65 抗体不呈阳性的糖尿病患者可能主要存在胰岛素抵抗，血液胰岛素水平升高，并且处于大血管疾病的主要风险中。作为了解 GAD65 抗体阳性老年患者（>50 岁）胰岛素缺乏原因的模型，我们计划评估 GAD65 自身抗体阳性 T2DM 患者的代谢和遗传异常，并将这些异常与 GAD65 抗体阴性 T2DM 患者亚组的异常进行比较。对有患这种独特形式 2 型糖尿病风险的个体进行特征分析具有公共卫生意义，因为可以尽早制定治疗策略，以预防与高血糖相关的并发症，并可能预防胰岛素需求的开始时间。对这一老年 2 型糖尿病患者亚组（可能具有自身免疫发病机制）进行更适当的表征，将有利于未来对 2 型糖尿病的病因学、自然史以及治疗的研究。