Metabolic regulation of islet hormone secretion in diabetes

超过2900万美国人患有糖尿病，其中25%的退伍军人寻求退伍军人医疗保健。一个坚强的人 导致2型糖尿病(T2D)的原因是肥胖率在过去30年里急剧上升，现在 在该国许多地区达到30%以上，退伍军人的比例超过40%，他们的比例不成比例 受到糖尿病的影响。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 退伍军人总体上患有糖尿病(相比之下，普通人群的这一比例为9%)。糖尿病的患病率持平。 65岁以上的退伍军人糖尿病患病率更高，在所有年龄段，退伍军人的糖尿病患病率正在攀升 每年2%。正在开发适当治疗T2D患者胰岛素分泌失败的新方法 因此，对于退伍军人来说，这是一个高度优先的问题。一种分子是我们研究的基石 程序，糖酵解酶丙酮酸激酶(PK)，具有很强的保护和治疗潜力 价值。我们发现小分子PK激活剂控制着胰岛中的多种细胞类型 并增加胰岛素的分泌，包括来自肥胖和T2D捐赠者的人类胰岛。这样做的目的是 建议确定PK激活能够促进细胞内胰岛素分泌的机制 和分子水平。基于我们的初步研究，我们的中心假设是PK同时控制α-和β- 通过关闭ATP敏感的K+通道(KATP)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，通过增加β细胞的分泌来降低餐后血 葡萄糖。我们将在多种糖尿病临床前模型中测试我们的中心假设，并完成 本方案的目的是通过完成以下具体目标：1)确定PK激活对 α-细胞代谢和激素分泌，2)决定α-细胞激素如何增强β-细胞对 PK激动剂，以及3)评估PK激动剂与GLP1受体激动剂联合治疗的潜力 预防和挽救肥胖/T2D。随着这些目标的实现，我们将获得更多 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.