Preservation of Beta Cell Function in Prediabetes Early Type 2 Diabetes

描述(由申请人提供)：这项研究将是多中心合作努力的一部分，测试在糖尿病前期/早期实现持久β细胞保存的不同策略。 T2D(RFA DK-10-013)。最终干预设计和测量终点将在选定参与地点后在联合体内协调。我们建议研究受试者在口服葡萄糖耐量试验后糖化血红蛋白5.7-7.0%和2小时血糖140 mg/dL。受试者最初将接受胰岛素治疗，以达到90-100 mg/dL的空腹血糖读数。然后，受试者将随机接受为期6个月的治疗，使用贝塔细胞支持/卸载策略(使用利拉鲁肽+吡格列酮)或贝塔细胞休息/保护策略(使用甘精胰岛素+IL-1受体拮抗剂Anakinra)。我们将进行高血糖钳夹来测量第一时相和第二时相葡萄糖刺激的胰岛素分泌，并使用精氨酸刺激来测量最大分泌量作为β细胞质量的替代物。我们还将使用口服葡萄糖耐量试验来测量综合生理性胰岛素反应，包括对2小时血糖读数的影响。这些测试将在基线(葡萄糖毒性缓解后)和随机治疗3个月和6个月后进行。所有受试者将从6个月到24个月(研究结束)过渡到二甲双胍单一疗法，并在12个月和24个月接受重复测量。治疗反应(第一阶段胰岛素分泌的改善幅度)和持久性(在随机分组时，第一阶段胰岛素分泌保持改善的受试者的比例高于他们自己的基线)将被评估为共同的终点。我们将使用上述每个终点的高响应者和低响应者的基线血液样本，利用蛋白质组学进行生物标记物的发现工作。高通量LC/MS/MS方法将用于无偏见地发现和随后识别与这些结果密切相关的循环蛋白。来自当地受试者的样本将用于发现阶段，来自整个联盟的样本将用于验证阶段。

DESCRIPTION (provided by applicant): This study will be part of a multicenter collaborative effort testing different strategies to achieve durable beta cell preservation in pre-diabetes/early T2D (RFA DK-10-013). The final intervention design and measurement endpoints will be harmonized within the consortium following selection of participating sites. We propose to study subjects with HbA1c 5.7-7.0% and 2 hour glucose >140 mg/dL following an oral glucose tolerance test. Subjects will initially be treated with insulin to achieve fasting glucose readingsof 90-100 mg/dL. Subjects will then be randomized to 6 month's treatment using either a strategy of beta cell support/unloading (using liraglutide plus pioglitazone) or one of beta cell rest/protection (using insulin Glargine plus the IL-1 receptor antagonist Anakinra). We will perform hyperglycemic clamps to measure first phase and second phase glucose-stimulated insulin secretion and use arginine stimulation to measure maximal secretory capacity as a surrogate of beta cell mass. We will also use oral glucose tolerance testing to measure integrated physiologic insulin responses including effects on the 2hr glucose reading. These tests will be performed at baseline (after relief of glucose toxicity) and after 3 and 6 months of randomized treatments. All subjects will transition to metformin monotherapy from months 6 to 24 (end of study), and undergo repeat measurements at 12 and 24 months. The treatment Response (magnitude of improvement in first-phase insulin secretion) and Durability (proportion of subjects maintaining improvements in first phase insulin secretion at 24 months greater than their own baseline at randomization) will be evaluated as coprimary endpoints. We will use baseline blood samples from the high and low responders from each of the above endpoints to undertake a biomarker discovery effort using proteomics. A high-throughput LC/MS/MS approach will be used for unbiased discovery and subsequent identification of circulating proteins that are robustly associated with these outcomes. Samples from local subjects will be used in the discovery phase, and samples from across the consortium will be used in the validation phase.