Preservation of Beta Cell Function in Prediabetes Early Type 2 Diabetes

描述（由申请人提供）：本研究将是多中心合作研究的一部分，该研究测试了不同的策略，以在糖尿病前期/早期糖尿病患者中实现持久的β细胞保存。 T2D（RFA DK-10-013）。最终的干预设计和测量终点将在选择参与研究中心后在联盟内协调一致。我们建议研究口服葡萄糖耐量试验后HbA 1c 5.7-7.0%且2小时血糖>140 mg/dL的受试者。受试者最初将接受胰岛素治疗，以使空腹血糖读数达到90-100 mg/dL。然后将受试者随机分配至6个月的治疗组，使用β细胞支持/卸载策略（使用利拉鲁肽+吡格列酮）或β细胞静息/保护策略（使用甘精胰岛素+IL-1受体拮抗剂阿那白滞素）。我们将进行高血糖钳夹以测量葡萄糖刺激的胰岛素分泌的第一阶段和第二阶段，并使用精氨酸刺激来测量最大分泌能力作为β细胞质量的替代。我们还将使用口服葡萄糖耐量试验来测量综合生理胰岛素反应，包括对2小时葡萄糖阅读的影响。这些检查将在基线（葡萄糖毒性缓解后）以及随机治疗3个月和6个月后进行。所有受试者将从第6个月至第24个月（研究结束）过渡至二甲双胍单药治疗，并在第12个月和第24个月接受重复测量。将评价治疗应答（第一时相胰岛素分泌改善的幅度）和耐久性（第24个月时维持第一时相胰岛素分泌改善大于随机化时自身基线的受试者比例）作为共同主要终点。我们将使用来自上述每个终点的高应答者和低应答者的基线血液样本，使用蛋白质组学进行生物标志物发现工作。高通量LC/MS/MS方法将用于无偏发现和随后鉴定与这些结果稳健相关的循环蛋白质。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.