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

恢复胰岛素分泌 (RISE) 研究中的 β 细胞功能和认知

基本信息

批准号：
8702166
负责人：
SUZANNE CRAFT
金额：
$ 45.37万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8702166
关键词：
2,4-thiazolidinedione Achievement Address Adolescent Adult Aftercare Agonist Alzheimer&apos s Disease Amyloid Ancillary Study Antidiabetic Drugs Area Beta Cell Biological Markers Cell physiology Cells Child Childhood Clinical Research Cognition Cognitive Comorbidity Dementia Detection Diabetes Mellitus Disease Management Elderly Episodic memory Evaluation Fasting Glucose Human Hyperglycemia Impaired cognition Insulin Learning Measurement Measures Memory Metabolic Metformin Methods Mission Multi-Institutional Clinical Trial National Institute of Diabetes and Digestive and Kidney Diseases Neurodegenerative Disorders Non-Insulin-Dependent Diabetes Mellitus Occupational Paired-Associate Learning Parents Participant Patients Pharmaceutical Preparations Phase Placebo Control Placebos Plasma Prediabetes syndrome Prevention Randomized Relative (related person)Risk Rodent Short-Term Memory Speed Staging Testing Therapeutic Thiazolidinediones Trail Making Test active method arm cognitive change cognitive function diabetic executive function functional improvement glargine glucagon-like peptide glucose disposal glucose tolerance improved indexing information processing insulin secretion insulin sensitivity interest liraglutide novel strategies novel therapeutic intervention primary outcome public health relevance receptor research study response secondary outcome treatment duration treatment effect two-arm study

项目摘要

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 ?-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 ?-cell function and insulin sensitivity predicts change in cognition and ?-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 ?-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 ?-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 ?-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 ?-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 ?-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 ?-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 ?-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.

描述（由申请人提供）：本申请是为了响应 PAR-12-265（为推进 NIDDK 使命范围内的科学兴趣领域而进行的主要临床研究的辅助研究）而提交的。拟议的辅助研究将检查抗糖尿病治疗对患有前驱糖尿病或早期 2 型糖尿病 (T2DM) 的成人和青少年的认知功能和血浆 β-淀粉样蛋白（与阿尔茨海默病相关的认知能力下降的生物标志物）的影响。恢复胰岛素分泌（RISE）研究的参与者。我们还将研究β-细胞功能和胰岛素敏感性的治疗性调节是否可以预测认知和β-淀粉样蛋白的变化。成人 RISE 研究是一项安慰剂对照、多中心临床试验，在 255 名患有前驱糖尿病和早期 T2DM 的受试者中进行，该试验将解决这样的假设：强化血糖调节控制将恢复 β 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通过二甲双胍。在整个 12 个月的治疗期间将进行强化评估，以评估 β 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 个月的治疗后评估。一项平行的 RISE 研究将在 90 名青少年中进行，这些青少年将被随机分配服用二甲双胍或二甲双胍加利拉鲁肽。拟议的辅助研究将通过添加一系列记忆和精神运动速度的敏感测量（连续配对副学习测试、单卡）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。 RISE 研究中的学习测试、检测和识别测试、跟踪测试）和血浆 β-淀粉样蛋白测量。我们将测试这样的假设：与安慰剂组的参与者相比，三个积极治疗组中的成年人在 12 个月时的认知评分将表现出更大的改善，血浆 β-淀粉样蛋白相对于基线降低，并且二甲双胍组中的成人和青少年参与者相对于其他积极治疗组，加利拉鲁肽组将显示出更大的改善。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 β 细胞功能测量，源自第二阶段和 AIRmax 反应）和敏感性（胰岛素调整的葡萄糖处理率）的变化与认知能力相关。和β-淀粉样蛋白变化。最后，我们将检查治疗停止后认知和生物标志物的变化是否持续。这项辅助研究将解决糖尿病早期治疗是否可以改善认知以及治疗结束后是否能维持改善的重要问题。该研究还将探讨认知状态与代谢机制的关系，例如胰岛素分泌和敏感性受损，这些代谢机制可能导致认知能力下降和与糖尿病前期和 T2DM 相关的神经退行性疾病风险增加，从而提出治疗和预防认知能力下降的新方法患有这些疾病的患者。