A role and regulation of glucose responsive lipolysis in pancreatic beta cells

点击翻译按钮获取中文摘要

T2D is a major health problem for US veterans that imposes significant physical, financial, and emotional tolls. Thus, there is a strong and urgent need for an effective and widely applicable therapy. Excessive accumulation of lipids in beta cells is considered to contribute to the development of T2D. Experimental data supports that lipid overload activates multiple stress pathways including inflammation, ER stress, oxidative stress, and mitochondrial dysfunction ultimately leading to the loss of functional beta cell mass. We have found evidence that the accumulation of triglycerides (TG) in human islets from T2D donors is associated with dysregulation of lipolysis, a previously unrecognized defect in T2D islets that accelerates TG accumulation in T2D islets. Glucose activates lipolysis in non-diabetic human islets but not in T2D islets. Furthermore, our preliminary data indicates that the dysregulation of lipolysis impairs insulin secretion by reducing the stability of syntaxin1a (Stx1a), one of the SNARE complex proteins important for exocytosis. When we tested the impact of dysregulation of lipolysis using human pseudoislets in which the expression of the principal TG lipase (ATGL) is down-regulated, ATGL deficient human pseudoislets showed excessive lipid droplet (LD) accumulation and impaired insulin secretion along with proteasomal degradation of Stx1a. Importantly, the reduction of Stx1a is a defect reported in human T2D islets. Thus, we hypothesize that the dysregulation of lipolysis in response to glucose reduces the stability of Stx1a and impairs insulin secretion in T2D islets. To understand molecular mechanism behind the defects in T2D islets, it will be imperative to determine how glucose upregulates lipolysis in beta cells, why glucose fails to upregulate lipolysis in T2D islets, and how the impairment in lipolysis reduces Stx1a. We will approach our questions using human pseudoislets and INS1 cells as models since they exhibit similarity with human islets in LD formation, the regulation of lipolysis, and phenotypes of ATGL deficiency. We expect to obtain novel information regarding how dysregulation of lipid mobilization causes beta cell dysfunction in T2D through the following aims. Specific aim 1: Determine a mechanism by which ATGL increases lipolysis in response to glucose in non-diabetic beta cells We will systematically test potential targets by which glucose increases lipolysis in INS1 cells and non-diabetic human beta cells. Aim 1a will test which glucose generated signals regulates lipolysis in beta cells. Aim 1b-d will test whether glucose increases lipolysis by modifying ATGL, co-lipases, or perilipins. Specific aim 2: Determine a mechanism by which lipolysis is dysregulated in type 2 diabetic beta cells Aim 1 dissects a mechanism by which glucose regulates lipolysis in beta cells. Leveraging on the information from Aim 1, we will determine why T2D islets are unable to increase lipolysis in response to glucose and how we can restore lipolysis in T2D islets. Specific Aim 3: Test the hypothesis that defective lipolysis destabilizes stx1a in T2D islets Stx1a is proposed to contribute to the impairment of insulin secretion in T2D as Stx1a is reduced in islets of T2D models and human islets affected by T2D. However, it has been unknown why Stx1a is reduced in T2D islets. Our preliminary data implicates that the impairment of lipolysis may cause the reduction of Stx1a in T2D islets. Thus, we will test the hypothesis that reduced lipolysis contributes to the reduction of Stx1a in T2D islets through accelerating degradation of Stx1a due to reduced palmitoylation. Our study combines pharmacological and molecular approaches to increase our understanding of the pathogenesis of beta cell dysfunction in T2D. The information obtained will potentially lead us to a novel target that improves beta cell function in T2D by restoring LD mobilization in beta cells.