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(正在进行的主要临床研究的辅助研究，以推进NIDDK任务中的科学兴趣领域)而提交的。这项拟议的辅助研究将考察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糖尿病前期或早期2型糖尿病(T2 DM)患者认知功能和血浆β-淀粉样蛋白(与阿尔茨海默病相关的认知功能下降的生物标志物)的影响。我们还将研究，是否治疗调节？细胞功能和胰岛素敏感性可以预测认知和？淀粉样蛋白的改变。父母成人RISE研究是一项在255名糖尿病前期和早期T2 DM患者中进行的安慰剂对照、多中心临床试验，将解决这样的假设，即强化的血糖调节控制将恢复？细胞功能，并且恢复效果在治疗停止后将持续存在。参与者将被随机分成4个治疗组：安慰剂、二甲双胍、二甲双胍+利拉鲁肽，或甘精胰岛素+二甲双胍。在为期12个月的治疗期间，将进行密集的评估，以评估ü细胞功能、胰岛素敏感性和葡萄糖耐量，随后将进行3个月和9个月的治疗后评估。一项平行的RISE研究将对90名青少年进行，他们将被随机分为二甲双胍或二甲双胍+利拉鲁肽。这项拟议的辅助研究将通过在RISE研究中增加一系列记忆和精神运动速度的敏感测量(连续配对联合学习测试、一卡式学习测试、检测和识别测试、跟踪测试)和血浆淀粉样蛋白测量，来评估治疗对认知和β-淀粉样蛋白的影响，以及内分泌变化与认知变化的关系。我们将测试这样的假设，即与安慰剂分配的参与者相比，在12个月时，三个积极治疗组的成年人在认知分数方面将显示出比安慰剂分配的参与者更大的认知分数改善和血浆β-淀粉样蛋白的降低，而与其他积极治疗组相比，二甲双胍+利拉鲁肽组的成年人和青少年参与者将表现出更大的改善。我们还将测试这一假设，即治疗12个月后胰岛素分泌的变化(来自第二阶段和Airmax反应的胰岛素敏感度调整细胞功能指标)和敏感度(胰岛素调整后的葡萄糖处置速率)将与认知和ç-淀粉样蛋白的变化有关。最后，我们将检查认知和生物标志物的变化在治疗停止后是否保持不变。这项辅助研究将解决一些重要问题，即糖尿病早期治疗是否可以改善认知能力，以及治疗结束后是否保持改善。这项研究还将研究认知状态与代谢机制的关系，如胰岛素分泌受损和敏感性，这可能是与糖尿病前期和T2 DM相关的认知衰退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衰退的新方法。

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.