Ectopic Lipids in the Pancreatic Alpha Cell Link Insulin Resistance to Hyperglycemia

胰腺α细胞中的异位脂质与胰岛素抵抗高血糖有关

• 批准号: 9412379
• 负责人: Roger Harold Unger
• 金额: --
• 依托单位: VA NORTH TEXAS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9412379
• 关键词: Ablation; Adipose tissue; Agonist; Alpha Cell; Anabolism; Antidiabetic Drugs; Apoptosis; Atherosclerosis; Attenuated; Catabolism; Cell physiology; Cells; Ceramidase; Ceramides; Data; Deposition; Development; Diabetes Mellitus; Diet; Disease; Enzymes; FGF21 gene; FOXO1A gene; Feasibility Studies; Food; Functional disorder; Glucagon; Glucagon Receptor; Gluconeogenesis; Glucose; Glucose Intolerance; Glucosylceramides; Hamsters; Health; Heart failure; Hepatic; Homeostasis; Hyperglycemia; Image; Impairment; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Lead; Leptin; Link; Lipids; Liver; Mass Spectrum Analysis; Mediating; Metabolic; Metabolism; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Palmitoyl Coenzyme A; Pancreas; Perfusion; Pharmacologic Substance; Pharmacology; Production; Protein Phosphatase 2A Regulatory Subunit PR53; Rattus; Receptor Activation; Receptor Cell; Recombinants; Regulation; Reporting; Role; Saturated Fatty Acids; Serum; Signal Transduction; Sphingolipids; Structure of alpha Cell of islet; Techniques; Testing; Therapeutic; Therapeutic Agents; Thinness; Time; Tissues; Veterans; adiponectin; analog; blood glucose regulation; desensitization; diabetic; fibroblast growth factor 21; galactosylgalactosylglucosylceramidase; gamma-Aminobutyric Acid; glucose metabolism; glucose production; hormone regulation; hyperglucagonemia; improved; in vivo; inhibitor/antagonist; insulin signaling; lipid mediator; mimetics; non-diabetic; novel; novel therapeutic intervention; overexpression; preproglucagons; prevent; receptor; small molecule

Ectopic Lipids in the Pancreatic Alpha Cells Link Insulin Resistance to Hyperglycemia Just as insulin insufficiency can lead to elevated glucagon secretion, preliminary data suggest that impaired insulin action within the -cell can also promote hyperglucagonemia, hyperglycemia, aberrant gluconeogenesis, and excess glucose efflux from the liver. Pancreatic perfusion with anti-insulin serum causes marked hyperglucagonemia, and ablation of insulin receptor from -cells prompts fed hyperglucagonemia and glucose intolerance. Sphingolipids, such as ceramides and glucosylceramides, are an important class of bioactive lipids which may impair insulin signal transduction in the -cell. Most recently, it has been demonstrated that ceramide is sufficient to impair insulin-induced suppression of glucagon from -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, -cell apoptosis and -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. We hypothesize that: 1) Preventing ceramide excess within -cells enhances suppression of glucagon by 3 of its endogenous attenuating signals (insulin, leptin, and GABA-all repress glucagon via Akt/FoxO1) A portion of adiponectin’s glucose-lowering effects are mediated by inhibiting glucagon secretion which is directly triggered by adiponectin receptor-driven lowering of sphingolipids in -cells; 3) The glucagon-suppressive effects of FGF21 are mediated by ceramide-lowering within the -cell in an adiponectin-dependent manner; and 4) Limiting glucagon secretion or glucagon receptor activation improves insulin signal transduction by preventing glucagon-induced activation of PP2A. In essence, we believe that the insulin-desensitizing effects heavily studied in muscle, liver and adipose can also occur in the -cell, triggering hyperglucagonemia, hyperglycemia, and metabolic sequelae of diabetes. As such, many potential therapeutic agents currently under development (including FGF21 analogs, adiponectin mimetics, and ceramide synthesis inhibitors) may function as glucagon suppressors via sphingolipid-mediated actions and may require glucagon-suppressive actions in order to achieve full anti-diabetic efficacy. Newly-available imaging mass spectrometry techniques make these studies feasible for the first time.

胰腺α细胞异位脂质与胰岛素抵抗和高血压的关系 正如胰岛素不足会导致胰高血糖素分泌增加一样，初步数据表明， 胰岛β细胞内受损的胰岛素作用也可促进高胰高血糖素血症，高血糖症， 异常造血和过量葡萄糖从肝脏流出。抗胰岛素胰腺灌注 血清引起明显的高胰高血糖素血症，β-细胞胰岛素受体的消融促使进食 高胰高血糖素血症和葡萄糖耐受不良。鞘脂，如神经酰胺和葡糖神经酰胺， 一类重要的生物活性脂质，可能损害胰岛细胞中的胰岛素信号转导。最 最近，已经证明神经酰胺足以削弱胰岛素诱导的胰高血糖素抑制 从细胞。这些脂质的水平作为脂肪组织质量和功能的函数而变化， 部分由棕榈酰辅酶A的细胞可用性驱动。鞘脂的异常积累 参与多种代谢过程，包括动脉粥样硬化、胰岛素抵抗、脂毒性心脏 细胞凋亡和细胞功能障碍。脂肪源性分泌因子脂联素促进 增加神经酰胺catenin，这是依赖于脂联素受体1和2（AdipoR 1/R2）。 相关的神经酰胺酶活性促进神经酰胺降解，并与神经酰胺酶抑制相关。 肝葡萄糖流出成纤维细胞生长因子21（FGF 21，一种已报道的胰高血糖素抑制剂）， 刺激脂联素分泌，通过利用脂联素降低神经酰胺来改善肥胖 潜力初步结果表明，脂联素的新型小分子模拟物（目前在 药物开发）可以提供脂联素相同的潜在治疗益处，以改善 通过减少神经酰胺过量和胰高血糖素分泌来维持葡萄糖稳态。 我们假设：1）防止β细胞内神经酰胺过量可增强胰高血糖素的抑制作用， 其内源性衰减信号（胰岛素、瘦素和GABA-均通过Akt/FoxO 1抑制胰高血糖素）A 脂联素的一部分降糖作用是通过抑制胰高血糖素分泌介导的， 由脂联素受体驱动的β-细胞中鞘脂的降低触发; 3）胰高血糖素抑制 FGF 21的作用是通过脂联素依赖性方式降低β细胞内的神经酰胺介导的; 和4）限制胰高血糖素分泌或胰高血糖素受体活化通过以下方式改善胰岛素信号转导： 阻止胰高血糖素诱导的PP 2A活化。本质上，我们认为胰岛素脱敏 在肌肉、肝脏和脂肪中大量研究的影响也可能发生在胰岛细胞中， 高胰高血糖素血症、高血糖症和糖尿病的代谢后遗症。因此，许多潜在的 目前正在开发的治疗剂（包括FGF 21类似物、脂联素模拟物和 神经酰胺合成抑制剂）可以通过鞘脂介导的作用作为胰高血糖素抑制剂 并且可能需要胰高血糖素抑制作用以达到完全的抗糖尿病功效。新推出 成像质谱技术首次使这些研究成为可能。