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

• 批准号: 8560429
• 负责人: SUZANNE CRAFT
• 金额: $ 58.13万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/8560429
• 关键词: 2,4-thiazolidinedione; Achievement; Address; Adolescent; Adult; Aftercare; Agonist; Alzheimer' 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

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。拟议的辅助研究将检查抗糖尿病治疗对认知功能和血浆？淀粉样蛋白（与阿尔茨海默病相关的认知衰退的生物标志物），在参与恢复胰岛素分泌（RISE）研究的患有前驱糖尿病或早期2型糖尿病（T2DM）的成人和青少年中。我们还将研究是否治疗调制？-细胞功能和胰岛素敏感性预测认知和？淀粉样蛋白母体成人RISE研究是一项安慰剂对照、多中心、临床试验，在255例前驱糖尿病和早期T2DM受试者中开展，旨在解决强化血糖调节控制将恢复？细胞功能，恢复效果将持续治疗停止后。受试者将随机分为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组，随后 通过二甲双胍。强化评估评估？-细胞功能、胰岛素敏感性和葡萄糖耐量将在整个12个月的治疗期间发生，随后是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。拟议的辅助研究将评估治疗对认知和？淀粉样蛋白，以及内分泌变化与认知变化的关系，通过增加一系列敏感的记忆和心理速度测量（连续配对联想学习测试，单卡学习测试，检测和识别测试，线索制作测试）和血浆？淀粉样蛋白测量与RISE研究。我们将检验以下假设，即三个活性治疗组中的成人将显示认知评分的更大改善和血浆？与安慰剂分配的受试者相比，二甲双胍+利拉鲁肽组的成人和青少年受试者在12个月时相对于基线的淀粉样蛋白水平将显示出更大的改善，并且相对于其他活性治疗组，二甲双胍+利拉鲁肽组的成人和青少年受试者将显示出更大的改善。我们还将检验胰岛素分泌的变化（胰岛素敏感性调整？治疗12个月后，来自第二阶段和AIRmax反应的细胞功能测量）和敏感性（胰岛素调整的葡萄糖处置率）将与认知和？淀粉样蛋白变化。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T2DM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。