Metabolic regulation of islet hormone secretion in diabetes

超过2900万美国人患有糖尿病，其中包括25%寻求VA医疗保健的退伍军人。一个强大 2型糖尿病（T2 D）的一个重要原因是肥胖率在过去30年中急剧增加，现在 在全国许多地区达到30%以上，退伍军人的比例超过40%，他们是自愿的。 受糖尿病影响。在美国，近四分之一的退伍军人接受退伍军人事务部的护理，20%的 退伍军人总体上患有糖尿病（相比之下，普通人群中有9%）。糖尿病的患病率甚至 在65岁以上的退伍军人中，糖尿病的患病率更高，在所有年龄段的退伍军人中，糖尿病的患病率都在攀升， 每年2%。开发适当治疗2型糖尿病患者胰岛素分泌衰竭的新方法， 因此，退伍军人的优先事项。我们研究的基础分子 糖酵解酶丙酮酸激酶（PK）具有很强的保护和治疗作用 值我们已经发现小分子PK激活剂控制胰岛中的多种细胞类型 并增强胰岛素分泌，包括在来自肥胖和T2 D供体的人类胰岛中。的目的 建议是确定PK激活能够增强细胞胰岛素分泌的机制， 分子水平。基于我们的初步研究，我们的中心假设是PK控制α-和β- 通过关闭ATP敏感性K+通道（KATP）来调节细胞激素分泌。正在测试的生理模型是， 胰岛α细胞被氨基酸激活，使β细胞分泌增加，从而降低餐后血糖 葡萄糖我们将在糖尿病的多个临床前模型中检验我们的中心假设， 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，和3）评估PK激活剂与Glp 1受体激动剂组合以治疗糖尿病的治疗潜力。 预防和挽救肥胖/T2 D。随着这些目标的实现，我们将获得更大的 全面了解胰岛中的PK功能，并采取关键的后续步骤， PK作为2型糖尿病防治的新靶点。

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.