Lipid Sensing in Pancreatic Alpha Cells

胰腺α细胞中的脂质感应

• 批准号: 9444831
• 负责人: WILLIAM L HOLLAND
• 金额: $ 40.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2018-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9444831
• 关键词: Ablation; Adipose tissue; Agonist; Alpha Cell; Apoptosis; Area; Atherosclerosis; Attenuated; B-Lymphocytes; Beta Cell; Carbohydrates; Catabolism; Cell Line; Cell physiology; Cells; Ceramidase; Ceramides; Data; Deposition; Development; Diabetes Mellitus; Diabetes prevention; Enzymes; FGF21 gene; FOXO1A gene; Fatty acid glycerol esters; Functional disorder; G(M3) Ganglioside; Glucagon; Glucagon Receptor; Gluconeogenesis; Glucose; Glucose Intolerance; Glucosylceramides; Grant; Hamsters; Heart failure; Hepatic; Hormones; Human; Hyperglycemia; Impairment; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Knockout Mice; Leptin; Link; Lipids; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolism; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Palmitoyl Coenzyme A; Pancreas; Peptides; Perfusion; Peripheral; Pharmacologic Substance; Physiological; Plasma; Prevention; Production; Recombinants; Regulation; Reporting; Resistance; Rodent; Role; Serum; Signal Transduction; Skeletal Muscle; Somatostatin; Sphingolipids; Structure of alpha Cell of islet; Testing; Therapeutic; Therapeutic Intervention; Tissues; Work; adiponectin; blood glucose regulation; desensitization; diabetic; fibroblast growth factor 21; galactosylgalactosylglucosylceramidase; gamma-Aminobutyric Acid; glucose production; hyperglucagonemia; improved; in vivo; insulin secretion; insulin sensitivity; insulin signaling; islet; lipid mediator; mimetics; mouse model; novel; overexpression; pancreatic juice; preproglucagons; prevent; promoter; receptor; small molecule; targeted treatment; uptake

Abstract Sphingolipid Accumulation in the Pancreatic Alpha Cell Links Insulin Resistance to Hyperglycemia This grant evaluates the contribution of lipid metabolite accumulation in the pancreatic alpha cell to the aberrant production of the pancreatic peptide glucagon and glucagon’s ensuing hyperglycemic effects. Pancreatic islets secrete both insulin and glucagon in a manner which is tightly juxtaposed. The hormone glucagon, which promotes hepatic glucose production, has long been underestimated as a contributor to metabolic disease. Diabetes mellitus results from insufficient insulin secretion to match insulin demands by various tissues. This includes a demand by the alpha cell for insulin to diminish glucagon production and secretion. Our preliminary data suggest that impaired insulin action within the alpha cell can promote hyperglucagonemia, which drives hyperglycemia, aberrant gluconeogenesis, and excess glucose efflux from the liver. Sphingolipids, such as ceramides and glucosylceramides, are an important class of bioactive lipids which may impair insulin signal transduction in the alpha cell. Most recently, we demonstrated that ceramide is sufficient to impair insulin-induced suppression of glucagon from alpha cells. The levels of these lipids change as a function of adipose tissue mass and functionality, and are partially driven by cellular availability of palmitoyl-CoA. Aberrant accumulation of sphingolipids has been implicated in a multitude of metabolic processes, including atherosclerosis, insulin resistance, lipotoxic heart failure, beta cell apoptosis and beta cell dysfunction. The adipose-derived secretory factor adiponectin promotes an increase in ceramide catabolism, which is dependent on adiponectin receptors 1 and 2 (AdipoR1/R2). The associated ceramidase activity promotes ceramide degradation and correlates with the suppression of hepatic glucose efflux. Fibroblast growth factor 21 (FGF21, a reported glucagon suppressor), rapidly stimulates adiponectin secretion and improves glycemia by harnessing adiponectin’s ceramide-lowering potential. Preliminary results suggest that novel small molecule mimetics of adiponectin (currently in pharmaceutical development) may offer the same potential therapeutic benefits of adiponectin to improve glucose homeostasis by decreasing ceramide excess and glucagon secretion. Here, we will test the following 3 questions via 3 interrelated aims: 1)Does the alpha cell become insulin, leptin, or GABA resistant in a sphingolipid-dependent manner? 2) Does adiponectin act as a glucagon suppressor via adiponectin receptor-induced ceramidase activity and ceramide-lowering within the alpha cell? 3) Does FGF21 have a direct effect on the alpha cell or does it rely on adiponectin to blunt glucagon secretion? We propose that ceramide within the alpha cell is a key link between insulin resistance and diabetes and serves as a critical physiologic node for regulation of glycemia; this would be a prime target for therapeutic intervention for the treatment and prevention of type-2 diabetes

摘要 胰腺α细胞中鞘脂的积聚与胰岛素抵抗和高血压的关系 该基金评估了胰腺α细胞中脂质代谢物积累对胰腺癌的作用。 胰肽胰高血糖素的异常产生和胰高血糖素随后的高血糖效应。 胰岛以紧密并列的方式分泌胰岛素和胰高血糖素。激素 胰高血糖素，促进肝脏葡萄糖的产生，长期以来一直被低估为一个贡献者， 代谢性疾病糖尿病是由于胰岛素分泌不足以满足胰岛素需求， 各种组织。这包括α细胞对胰岛素的需求，以减少胰高血糖素的产生， 分泌物我们的初步数据表明，α细胞内受损的胰岛素作用可以促进 高胰高血糖素血症，其驱动高血糖症、异常的胰高血糖素生成和从胰高血糖素血症中过量的葡萄糖流出。 肝脏神经酰胺和葡萄糖神经酰胺等鞘脂是一类重要的生物活性脂类 这可能损害α细胞中的胰岛素信号转导。最近，我们证明了神经酰胺是 足以削弱胰岛素诱导的对来自α细胞的胰高血糖素的抑制。这些脂质的水平变化 作为脂肪组织质量和功能的函数，并且部分由细胞可用性驱动， 棕榈酰辅酶A鞘脂的异常积累与多种代谢紊乱有关。 过程，包括动脉粥样硬化、胰岛素抵抗、脂毒性心力衰竭、β细胞凋亡和β细胞凋亡。 功能障碍脂肪源性分泌因子脂联素促进神经酰胺catenin的增加， 其依赖于脂联素受体1和2（AdipoR 1/R2）。相关神经酰胺酶活性 促进神经酰胺降解并与肝葡萄糖流出抑制相关。成纤维 生长因子21（FGF 21，一种已报道的胰高血糖素抑制剂）迅速刺激脂联素分泌， 通过利用脂联素的降低神经酰胺的潜力来改善糖尿病。初步结果表明 脂联素的新的小分子模拟物（目前在药物开发中）可以提供相同的 脂联素通过减少神经酰胺过量改善葡萄糖稳态的潜在治疗益处 和胰高血糖素分泌。在这里，我们将通过3个相互关联的目标来测试以下3个问题：1）alpha是否 细胞以鞘脂依赖的方式成为胰岛素、瘦素或GABA抗性？2)脂联素是否作为 通过脂联素受体诱导的神经酰胺酶活性和神经酰胺降低的胰高血糖素抑制剂 阿尔法细胞3)FGF 21是否对α细胞有直接影响，或者它是否依赖于脂联素来钝化 胰高血糖素分泌我们认为α细胞内的神经酰胺是胰岛素抵抗与胰岛素抵抗之间的关键联系。 和糖尿病，并作为调节血糖的关键生理节点;这将是主要目标 用于治疗和预防2型糖尿病的治疗性干预