Beta-cell Function and Cognition in the Restoring Insulin Secretion (RISE) Study

描述（由申请人提供）：本申请是根据PAR-12-265（NIDDK使命内推进科学兴趣领域的主要正在进行的临床研究的辅助研究）提交的。拟定的辅助研究将在参与恢复胰岛素分泌（RISE）研究的糖尿病前期或早期2型糖尿病（T2 DM）成人和青少年中检查抗糖尿病治疗对认知功能和血浆β-淀粉样蛋白（与阿尔茨海默病相关的认知下降的生物标志物）的影响。我们还将研究β-细胞功能和胰岛素敏感性的治疗调节是否能预测认知和β-淀粉样蛋白的变化。母体成人RISE研究是一项在255例前驱糖尿病和早期T2 DM受试者中进行的安慰剂对照、多中心临床试验，该研究将阐述强化葡萄糖调节控制将恢复胰岛细胞功能以及治疗停止后恢复作用将持续存在的假设。受试者将被随机分配至4个治疗组：安慰剂组、二甲双胍组、二甲双胍+利拉鲁肽组或甘精胰岛素+二甲双胍组。在整个12个月的治疗期间，将进行强化评价，以评估胰岛细胞功能、胰岛素敏感性和葡萄糖耐量，然后进行3个月和9个月的治疗后评价。将在90名青少年中进行一项平行RISE研究，这些青少年将随机接受二甲双胍或二甲双胍+利拉鲁肽治疗。拟定的辅助研究将通过在RISE研究中增加一系列记忆和心理速度的敏感指标（连续配对联想学习测试、单卡学习测试、检测和识别测试、连线测试）和血浆β-淀粉样蛋白测量，评估治疗对认知和β-淀粉样蛋白的影响，以及内分泌变化与认知变化的关系。我们将检验以下假设：与安慰剂分配的受试者相比，三个活性治疗组中的成人在12个月时相对于基线的认知评分改善和血浆β-淀粉样蛋白降低更大，二甲双胍+利拉鲁肽组中的成人和青少年受试者相对于其他活性治疗组的改善更大。我们还将检验以下假设：治疗12个月后胰岛素分泌（胰岛素敏感性调整的胰岛β细胞功能测量，来自第二时相和AIRmax反应）和敏感性（胰岛素调整的葡萄糖处置率）的变化将与认知和β淀粉样蛋白变化相关。最后，我们将检查认知和生物标志物的变化是否在治疗停止后保持。辅助研究将解决糖尿病早期治疗是否可以改善认知的重要问题，以及治疗结束后是否可以保持改善。该研究还将检查认知状态与代谢机制的关系，如胰岛素分泌和敏感性受损，这可能是认知下降和与前驱糖尿病和T2 DM相关的神经退行性疾病风险增加的基础，从而提出治疗和预防这些疾病患者认知下降的新方法。

DESCRIPTION (provided by applicant): This application is submitted in response to PAR-12-265 (Ancillary Studies to Major Ongoing Clinical Research Studies to Advance Areas of Scientific Interest within the Mission of the NIDDK). The proposed ancillary study will examine the effects of anti-diabetic treatment on cognitive function and plasma ß-amyloid (a biomarker of cognitive decline related to Alzheimer's disease), in adults and adolescents with prediabetes or early Type 2 Diabetes Mellitus (T2DM) who are participants in the Restoring Insulin Secretion (RISE) Study. We will also examine whether therapeutic modulation of ß-cell function and insulin sensitivity predicts change in cognition and ß-amyloid. The parent adult RISE Study is a placebo-controlled, multi-center, clinical trial in 255 subjects with prediabetes and early T2DM that will address the hypothesis that intensive glucoregulatory control will restore ß-cell functio, and that restorative effects will persist after treatment cessation. Participants will be randomize into 4 treatment arms: placebo, metformin, metformin plus liraglutide, or insulin glargine followed by metformin. Intensive evaluations to assess ß-cell function, insulin sensitivity, and glucose tolerance will occur throughout a 12-month treatment period, followed by 3- and 9-month post-treatment evaluations. A parallel RISE study will be conducted with 90 adolescents who will be randomized to metformin or metformin plus liraglutide. The proposed ancillary study will assess the effects of treatment on cognition and ß-amyloid, and the relationship of endocrinologic changes to changes in cognition, by adding a battery of sensitive measures of memory and psychomotor speed (Continuous Paired Associate Learning Test, One-Card Learning Test, Detection and Identification Test, Trail-Making Test) and plasma ß-amyloid measurement to the RISE studies. We will test the hypotheses that adults in the three active treatment arms will show greater improvement in cognitive scores and lowering of plasma ß-amyloid at 12-months relative to baseline compared with placebo-assigned participants, and that adult and adolescent participants in the metformin plus liraglutide arm will show greater improvement relative to the other active treatment groups. We will also test the hypothesis that changes in insulin secretion (insulin sensitivity-adjusted ß-cell function measures derived from second phase and AIRmax responses) and sensitivity (insulin-adjusted glucose disposal rate) after 12-months of treatment will be related to cognitive and ß-amyloid changes. Finally, we will examine whether cognitive and biomarker changes are maintained after treatment cessation. The ancillary study will address the important questions of whether therapy at early stages of diabetes can improve cognition, and whether improvement is maintained after treatment ends. The study will also examine the relationship of cognitive status with metabolic mechanisms such as impaired insulin secretion and sensitivity that may underlie the increased risk of cognitive decline and neurodegenerative disease associated with prediabetes and T2DM, and thereby suggest novel approaches to treatment and prevention of cognitive decline in patients with these conditions.