Improving beta-cell function in Mexican American women with prediabetes

描述（由申请人提供）：在美国，不同种族人群在肥胖和糖尿病方面存在重大健康差异。墨西哥裔美国人（MA）女性特别受前驱糖尿病的困扰，因为45%的MA女性肥胖，年龄调整后的糖尿病发病率为9.3%，而白人女性肥胖率为33%，糖尿病发病率为5.4%。胰腺细胞功能障碍是糖尿病前期向糖尿病转化的主要因素。到2型糖尿病被诊断出来时，80%的β细胞功能丧失;而到糖尿病前期发展时，50%的β细胞功能丧失。因此，至少在糖尿病前期阶段进行早期干预至关重要。强有力的证据表明，胰高血糖素样肽-1（GLP-1）保护β细胞功能。我们的目标是确定在有和没有GLP-1类似物的情况下，强烈的生活方式改变是否会改善患有糖尿病前期的MA女性的β细胞功能，停药后是否会维持这种效果，以及遗传变异是否可以预测这种反应。预测基因很可能被识别出来，因为大多数与糖尿病相关的基因都会影响β细胞的功能。细胞功能的改善可以潜在地防止受贫困、教育有限和健康差距困扰的MA中代谢疾病的螺旋式下降。1.我们假设生活方式的改变加上GLP-1类似物比单独改变生活方式更能改善糖尿病前期肥胖患者的β细胞功能。我们将比较在使用和不使用利拉鲁肽的情况下，代餐（MR）和文化敏感的生活方式改变计划的效果。主要终点将是改善β-细胞功能，通过急性胰岛素反应（AIRg）测量，AIRg由频繁采样的静脉葡萄糖耐量试验（FSIGT）确定。还将计算DI（空气和胰岛素敏感性的指标）。次要终点包括β细胞标志物（C肽、胰岛素生成指数（IGI）、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;以及代谢综合征组分。2.我们假设与β细胞功能障碍相关的遗传变异将预测β细胞对干预的反应。我们将在代谢芯片上使用一组选定的SNP，将目标1中利拉鲁肽治疗受试者中β细胞功能障碍相关的T2 DM相关基因多态性与胰岛素反应和其他表型相关联。这项调查针对高度脆弱，快速增长的人群中代谢疾病的严重健康差异，测试新的以文化为重点的干预策略，并确定β细胞对靶向胰腺β细胞的药理干预反应的遗传生物标志物。这些数据最终为预防糖尿病的干预试验奠定了基础，糖尿病是一种主要的慢性和昂贵的疾病，在MA，这可以大大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.