Improving beta-cell function in Mexican American women with prediabetes

描述(申请人提供)：在美国的不同种族中，肥胖和糖尿病之间存在着严重的健康差距。墨西哥裔美国人(MA)女性尤其受糖尿病前期的困扰，因为45%的MA女性肥胖，经年龄调整后的糖尿病发病率为9.3%，而高加索女性的肥胖率和糖尿病发病率分别为33%和5.4%。胰腺�细胞功能障碍是糖尿病前期转化为糖尿病的主要因素。当诊断为2型糖尿病时，80%的�细胞功能丧失；而当糖尿病前期发展时，50%的细胞功能丧失。因此，至少在糖尿病前期进行早期干预是至关重要的。强有力的证据表明，胰升糖素样肽-1(GLP-1)具有保护�细胞功能的作用。我们的目标是确定在使用和不使用GLP-1类似物的情况下，剧烈的生活方式变化是否改善了患有糖尿病前期的MA女性的�细胞功能，这种影响是否在停药后保持，以及基因变异是否可以预测这种反应。预测基因很可能被识别出来，因为大多数被识别为糖尿病相关特征的基因都会影响�细胞的功能。�细胞功能的改善可能会防止因贫困、教育有限和健康差距而困扰的MA代谢性疾病的螺旋式下降。1.我们假设，生活方式的改变加上一种GLP-1类似物比单独改变生活方式更能改善患有糖尿病前期的肥胖患者的�细胞功能。我们将比较饮食替代(MR)和文化敏感的生活方式改变计划在使用和不使用利拉鲁肽的情况下的效果。主要终点将是改善�细胞功能，通过急性胰岛素反应来衡量，AIR G由频繁采样的静脉葡萄糖耐量试验确定)。Di(衡量空气和胰岛素敏感性的指标)也将被计算出来。次要终点包括�细胞标志物(C-肽、胰岛素基因指数、胰高血糖素)的变化；预测糖尿病和炎症的新型血浆生物标志物；以及代谢综合征成分。2.我们假设与�细胞功能障碍相关的基因变异将预测�细胞对干预的反应。我们将使用代谢芯片上选定的一组SNPs，将�细胞功能障碍中T2 DM相关基因的多态与来自Aim 1的利拉鲁肽治疗对象的胰岛素反应和其他表型相关联。这项研究针对高度脆弱、快速增长的人群中代谢性疾病方面的严重健康差异，测试新的以文化为重点的干预策略，并确定�细胞对针对胰腺�细胞的药物干预的遗传生物标记物。这些数据最终为在MA预防糖尿病的干预试验奠定了基础，这是一种主要的慢性和昂贵的疾病，可能会显著改善与肥胖和糖尿病相关的健康差距。

DESCRIPTION (provided by applicant): Major health disparities exist in obesity and diabetes among ethnic groups in the US. Mexican American (MA) women are particularly afflicted by prediabetes as 45% of MA women are obese and have an age-adjusted 9.3% diabetes rate, compared to 33% obesity and 5.4% diabetes rates in Caucasian women. Pancreatic �-cell dysfunction is a major factor in the conversion of pre-diabetes to diabetes. By the time type 2 diabetes is diagnosed, 80% of �-cell function is lost; while 50% is lost by the time prediabetes develops. Thus, early intervention at least by the prediabetes stage is critical. Strong evidence suggests that glucagon-like peptide-1 (GLP-1) preserves �-cell function. Our goal is to determine whether intense lifestyle change with and without a GLP-1 analog improves �-cell function in MA women with pre-diabetes, whether the effect is maintained after drug discontinuation, and whether genetic variations predict this response. Predictive genes are likely to be identified because most genes identified for diabetes-related traits influence �-cell function. Improvement in �- cell function can potentially prevent the downward spiral of metabolic disease in MA plagued by poverty, limited education, and health disparities. 1. We hypothesize that lifestyle change plus a GLP-1 analog improves �-cell function in obese individuals with pre-diabetes more than lifestyle change alone. We will compare the effects of a meal replacement (MR) and culturally sensitive lifestyle modification program with and without liraglutide. The primary endpoint will be improved �-cell function, measured by the acute insulin response, AIRg, determined from the frequently sampled intravenous glucose tolerance test, FSIGT). DI (a measure of AIR and insulin sensitivity) will also be calculated. Secondary endpoints include changes in �-cell markers (C-peptide, insulin genic index (IGI), glucagon); novel plasma biomarkers that predict diabetes and inflammation; and metabolic syndrome components. 2. We hypothesize that genetic variations that are associated with �-cell dysfunction will predict the �- cell response to intervention. We will use a selected group of SNPs on the Metabochip to correlate polymorphisms of T2DM-related genes implicated in �-cell dysfunction with insulin responses and other phenotypes in liraglutide-treated subjects from Aim 1. This investigation targets serious health disparities in metabolic disease in a highly vulnerable, rapidly growing population, testing novel culturally-focused intervention strategies and identifying genetic biomarkers of �-cell response to a pharmacologic intervention that targets the pancreatic �-cell. These data ultimately set the stage for an intervention trial to prevent diabetes, a major chronic and costly disease, in MA, which could substantially improve the health disparity associated with obesity and diabetes.