Metabolic regulation of islet hormone secretion in diabetes

糖尿病胰岛激素分泌的代谢调节

• 批准号: 10513317
• 负责人: Matthew J. Merrins
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513317
• 关键词: Adjuvant Therapy; Advanced Development; Affect; Age; Agonist; Alpha Cell; American; Amino Acids; Antidiabetic Drugs; Beta Cell; Biological Availability; Blood Circulation; Blood Glucose; Caring; Cell membrane; Cell physiology; Cell secretion; Cellular Metabolic Process; Country; Cyclic AMP; Diabetes Mellitus; Dose; Electrophysiology (science); Enzymes; Failure; Fatty Liver; Functional disorder; G-Protein-Coupled Receptors; GLP-I receptor; General Population; Genetic; Glucagon; Gluconeogenesis; Glucose; Health; Healthcare; Hormone secretion; Hormones; Human; Image; Impairment; Insulin; Islets of Langerhans; Knock-out; Lipids; Liver; Membrane; Metabolic; Metabolic Diseases; Metabolism; Methods; Mission; Mitochondria; Modeling; Molecular; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Oral; Paracrine Communication; Patients; Phase III Clinical Trials; Phosphoenolpyruvate; Physiological; Physiology; Plasma; Potassium Channel; Pre-Clinical Model; Prevalence; Prevention; Production; Pyruvate; Pyruvate Kinase; Regulation; Research; Role; Shapes; Signal Transduction; Structure of beta Cell of islet; Testing; Therapeutic; Three-Dimensional Imaging; United States; Veterans; Work; antagonist; cell type; diabetes mellitus therapy; effectiveness testing; exenatide; glucagon-like peptide 1; human old age (65+); imaging platform; impaired glucose tolerance; improved; in vivo; insight; insulin secretion; insulin sensitivity; islet; knock-down; military veteran; novel; novel therapeutic intervention; pharmacologic; physiologic model; pre-clinical; predictive modeling; prevent; programs; pyruvate kinase deficiency; response; sensor; small molecule; sound

Over 29 million Americans suffer from diabetes, including 25% of Veterans seeking VA healthcare. A strong contributor to type 2 diabetes (T2D) is that obesity rates have increased dramatically in the last 3 decades, now reaching over 30% in many parts of the country with rates over 40% in Veterans, who are disproportionally affected by diabetes. In the United States, nearly 1 in 4 Veterans receiving care from the VA, and 20% of Veterans overall have diabetes (compared to 9% in the general population). The prevalence of diabetes is even higher in Veterans over the age of 65, and across all ages the prevalence of diabetes in Veterans is climbing by 2% every year. Developing new methods for properly treating the failure of insulin secretion in T2D patients is therefore a high priority for the Veteran population. One molecule that is at the cornerstone of our research program, the glycolytic enzyme pyruvate kinase (PK), has strong potential to be of protective and therapeutic value. We have discovered that small-molecule PK activators control multiple cell types in the pancreatic islet and enhance insulin secretion, including in human islets from obese and T2D donors. The objective of this proposal is to identify the mechanisms by which PK activation is able to enhance insulin secretion at the cellular and molecular level. Based on our preliminary studies, our central hypothesis is that PK controls both α- and β- cell hormone secretion by closing ATP-sensitive K+ channels (KATP). The physiological model being tested is that islet α-cells, which are activated by amino acids, supercharge β-cell secretion to lower postprandial blood glucose. We will test our central hypothesis in multiple pre-clinical models of diabetes, and accomplish the objective of this proposal by completing the following specific aims: 1) Determine the effect of PK activation on α-cell metabolism and hormone secretion, 2) Determine how α-cell hormones enhance the β-cell response to PK activators, and 3) Assess the therapeutic potential of combining PK activators with Glp1 receptor agonists to prevent and rescue obesity/T2D. With the completion of these aims, we will gain a significantly more comprehensive understanding of PK function in the pancreatic islet, and take the critical next steps in evaluating PK as a new target for the prevention and treatment of type 2 diabetes.

超过 2900 万美国人患有糖尿病，其中 25% 的退伍军人正在寻求 VA 医疗服务。 导致 2 型糖尿病 (T2D) 的一个因素是过去 3 年来肥胖率急剧增加，现在 该国许多地区的这一比例超过 30%，其中退伍军人的比例超过 40%，而退伍军人的比例则不成比例。 在美国，近四分之一的退伍军人接受退伍军人管理局的护理，20% 的退伍军人接受糖尿病治疗。 退伍军人总体患有糖尿病（与普通人群的 9% 相比）。 65 岁以上的退伍军人中糖尿病患病率更高，而且在所有年龄段中，退伍军人中糖尿病的患病率均呈上升趋势 每年开发适当治疗 T2D 患者胰岛素分泌障碍的新方法。 因此，对于退伍军人来说，这是我们研究的基石之一。 糖酵解酶丙酮酸激酶 (PK) 程序具有强大的保护和治疗潜力 我们发现小分子 PK 激活剂控制胰岛中的多种细胞类型。 并增强胰岛素分泌，包括来自肥胖和 T2D 捐献者的人类胰岛。 该提案的目的是确定 PK 激活能够增强细胞胰岛素分泌的机制。 根据我们的初步研究，我们的中心假设是 PK 控制 α- 和 β-。 通过关闭 ATP 敏感 K+ 通道 (KATP) 来分泌细胞激素 正在测试的生理模型是： 被氨基酸激活的胰岛 α 细胞可增强 β 细胞的分泌，从而降低餐后血液 我们将在多个糖尿病临床前模型中测试我们的中心假设，并实现 通过完成以下具体目标来实现本提案的目标： 1) 确定 PK 激活对 α 细胞代谢和激素分泌，2) 确定 α 细胞激素如何增强 β 细胞对 PK 激活剂，以及 3) 评估 PK 激活剂与 Glp1 受体激动剂相结合的治疗潜力 预防和拯救肥胖/T2D 随着这些目标的完成，我们将获得更多的成果。 全面了解胰岛的 PK 功能，并采取关键的后续步骤进行评估 PK作为防治2型糖尿病的新靶点。