Lipid Sensing in Pancreatic Alpha Cells

胰腺α细胞中的脂质感应

基本信息

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
项目类别：
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

项目摘要

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

抽象的胰腺α细胞中鞘脂的积累与胰岛素抵抗和高血糖有关该资助评估了胰腺α细胞中脂质代谢物积累对胰肽胰高血糖素的异常产生和胰高血糖素随之而来的高血糖效应。胰岛以紧密并列的方式分泌胰岛素和胰高血糖素。胰高血糖素可促进肝脏葡萄糖的产生，但长期以来一直被低估为糖尿病是由于胰岛素分泌不足而导致的。这包括α细胞对胰岛素的需求，以减少胰高血糖素的产生和我们的初步数据表明，α细胞内胰岛素作用受损可以促进胰岛素分泌。高胰高血糖素血症，导致高血糖、糖异生异常和葡萄糖外流过多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质。这可能会损害α细胞中的胰岛素信号转导最近，我们证明神经酰胺是。足以削弱胰岛素诱导的α细胞胰高血糖素抑制。这些脂质的水平发生变化。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的异常积累与多种代谢有关。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细胞脂肪源性分泌因子脂联素促进神经酰胺分解代谢的增加，这取决于脂联素受体 1 和 2 (AdipoR1/R2) 相关的神经酰胺酶活性。促进神经酰胺降解并与抑制肝成纤维细胞相关。生长因子 21（FGF21，一种据报道的胰高血糖素抑制剂），迅速刺激脂联素分泌，通过利用脂联素的神经酰胺降低潜力来改善血糖。脂联素的新型小分子模拟物（目前正在药物开发中）可能提供相同的效果脂联素通过减少神经酰胺过量来改善葡萄糖稳态的潜在治疗益处在这里，我们将通过 3 个相互关联的目标来测试以下 3 个问题：1）α 是否存在？细胞以鞘脂依赖性方式产生胰岛素、瘦素或 GABA 抗性 2) 脂联素是否起到作用？通过脂联素受体诱导的神经酰胺酶活性和神经酰胺降低来抑制胰高血糖素 3) FGF21 对 α 细胞有直接作用还是依赖脂联素来钝化我们认为α细胞内的神经酰胺是胰岛素抵抗之间的关键联系和糖尿病，并作为血糖调节的关键生理节点，这将是一个主要目标；用于治疗和预防 2 型糖尿病的治疗干预