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（主要正在进行的临床研究的辅助研究，以推进NIDDK使命内的科学兴趣领域）提交的。拟议的辅助研究将检查抗糖尿病治疗对参与恢复胰岛素分泌（RISE）研究的成人和青少年前驱糖尿病或早期2型糖尿病（T2DM）患者的认知功能和血浆ß-淀粉样蛋白（与阿尔茨海默病相关的认知能力下降的生物标志物）的影响。我们还将研究ß-细胞功能和胰岛素敏感性的治疗性调节是否能预测认知和ß-淀粉样蛋白的变化。父母成人RISE研究是一项安慰剂对照、多中心的临床试验，在255名糖尿病前期和早期T2DM患者中进行，该试验将解决强化血糖调节控制将恢复ß-细胞功能的假设，并且恢复效果将在停止治疗后持续存在。参与者将随机分为4个治疗组：安慰剂、二甲双胍、二甲双胍加利拉鲁肽或甘精胰岛素加二甲双胍。在整个12个月的治疗期间，将进行强化评估，以评估ß-细胞功能、胰岛素敏感性和葡萄糖耐量，随后进行治疗后3个月和9个月的评估。一项平行的RISE研究将对90名青少年进行，他们将被随机分配到二甲双胍或二甲双胍加利拉鲁肽组。拟议的辅助研究将评估治疗对认知和ß-淀粉样蛋白的影响，以及内分泌变化与认知变化的关系，通过在RISE研究中增加一系列记忆和精神运动速度的敏感测量（连续配对联想学习测试、一张学习测试、检测和识别测试、轨迹测试）和血浆ß-淀粉样蛋白测量。我们将检验以下假设：与安慰剂分配的参与者相比，三个积极治疗组的成年人在12个月时相对于基线在认知评分和血浆ß-淀粉样蛋白降低方面表现出更大的改善，二甲双胍加利拉鲁肽组的成人和青少年参与者相对于其他积极治疗组将表现出更大的改善。我们还将测试胰岛素分泌的变化（胰岛素敏感性调整ß-细胞功能测量来源于第二阶段和AIRmax反应）和敏感性（胰岛素调节葡萄糖处置率）在治疗12个月后将与认知和ß-淀粉样蛋白变化有关的假设。最后，我们将检查停止治疗后认知和生物标志物的变化是否维持。辅助研究将解决糖尿病早期治疗是否能改善认知的重要问题，以及治疗结束后是否能保持改善。该研究还将研究认知状态与代谢机制的关系，如胰岛素分泌和敏感性受损，这可能是糖尿病前期和2型糖尿病患者认知能力下降和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能力下降的新方法。

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.