Epidemiology of Heterogenity in Type 2 Diabetes

2 型糖尿病异质性流行病学

• 批准号: 6968683
• 负责人: MASSIMO T PIETROPAOLO
• 金额: $ 48.74万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6968683
• 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（由申请方提供）：多项证据表明，2型（非胰岛素依赖型）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的组合引起。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2型糖尿病患者的一个亚组中，它们可能与胰腺β细胞的自身免疫性破坏有关。我们发现，在2型糖尿病患者中，GAD 65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GAD 65抗体阳性糖尿病是2型糖尿病的一个独特亚类，与相对严重的胰岛素缺乏有关。重要的是要注意，这些病例都有合理的证据证明是2型糖尿病，而不是1型糖尿病，而且他们是老年人，显然，在临床特征和胰岛素需求方面不同于传统的1型糖尿病或年轻人。我们假设携带GAD 65抗体的老年T2DM患者的这一亚组是独特的，因为其与严重胰岛素缺乏、HLADQ易感性和微血管疾病的发展相关。相比之下，GAD 65抗体不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，并且是大血管疾病的主要风险。作为了解GAD 65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GAD 65自身抗体阳性T2DM患者的代谢和遗传异常，并将这些异常与GAD 65抗体阴性T2DM患者亚组的异常进行比较。对具有发展这种独特形式的2型糖尿病风险的个体的表征具有公共卫生利益，因为治疗策略可能足够早地制定，以预防与高血糖症相关的并发症，并且可能是胰岛素需求开始的时间。对老年2型糖尿病患者亚组的更适当的表征，可能是自身免疫发病机制，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。