L-cysteine, PIP3 and Insulin Signaling in Diabetes

糖尿病中的 L-半胱氨酸、PIP3 和胰岛素信号传导

• 批准号: 8629232
• 负责人: Sushil K Jain
• 金额: $ 32.63万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629232
• 关键词: Acetylcysteine; Adipocytes; Adipose tissue; Adjuvant Therapy; Animals; Antioxidants; Attenuated; Biochemical; Blood; Blood Glucose; Body Weight; CCL2 gene; Cell Culture Techniques; Cell model; Cells; Clinical; Cystathionine; Cysteine; Data; Development; Diabetes Mellitus; Diabetic mouse; Diet; Eating; Enzymes; Epidemic; Fasting; GCLC gene; GCLM gene; GLUT4 gene; Glucose; Glucose tolerance test; Glutathione; Glycine; Goals; Health; Homeostasis; Hydrogen Sulfide; Hypoglycemic Agents; IRS1 gene; Inflammatory; Insulin; Insulin Resistance; Insulin Signaling Pathway; Intervention; Knockout Mice; Lead; Ligase; Liver; Liver Function Tests; Lyase; Mediating; Metabolic; Modeling; Molecular; Mus; Muscle; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Oral; Oxidative Stress; PI3K/AKT; PTEN gene; Pathway interactions; Patients; Phosphatidylinositols; Phosphorylation; Placebo Effect; Play; Prevention; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Publishing; Rattus; Regimen; Renal function; Research Personnel; Role; Safety; Signal Transduction; Signaling Molecule; Small Interfering RNA; Sulfides; Supplementation; Testing; Transfection; Tumor Necrosis Factor-alpha; Up-Regulation; Validation; Whey Protein; abstracting; blood glucose regulation; cost; cysteine rich protein; cytokine; design; diabetes control; diabetic; diabetic patient; dietary supplements; glucose metabolism; improved; in vivo; inflammatory marker; inhibitor/antagonist; insight; insulin signaling; monocyte; mouse model; novel; oxidation; patient population; prevent

DESCRIPTION (provided by applicant): L-cysteine, PIP3 and Insulin Signaling in Diabetes Abstract: Diabetes has become an epidemic and remains a major public health issue worldwide. The primary purpose of this application is to discover the mechanisms by which L-cysteine (LC) supplementation improves glucose homeostasis in diabetic patients. Diabetic patients have lower blood levels of L-cysteine (LC), hydrogen sulfide (H2S), and glutathione (GSH). Supplementation with cysteine-rich proteins (whey protein and α-lactoalbumin), LC, or N-acetyl cysteine (NAC) has been shown to lower glycemia in diabetic animal studies. However, the molecular mechanism by which LC increases glucose utilization and lowers glycemia is not known. Our study demonstrated activation of PI3K and inhibition of NF-κB in the liver and reduction in blood glucose in LC supplemented ZDF rats, a model of type 2 diabetes. Further studies using an adipocyte cell model showed that LC caused PI3K activation, PTEN inhibition, and an increase in PIP3 (phosphatidylinositol-3,4,5 trisphosphate) and glucose utilization in high glucose (HG)-treated cells. The effect of LC on PIP3 and glucose utilization was prevented by PAG (propargylglycine), an inhibitor of cystathionine-γ-lyase (CSE), which catalyzes H2S formation from LC. Treatment with LC, H2S, or PIP3 increased the phosphorylation of IRS1, AKT, and PKCζ/λ, as well as GLUT4 activation and glucose utilization in HG-treated cells. These studies provide evidence for a novel molecular mechanism by which LC can increase PIP3 and upregulate the metabolic actions of insulin, thus improving glucose metabolism. This proposal will test the hypothesis that LC upregulates both the insulin dependent (PI3K/AKT/PKCζ/λ) and insulin independent (SIRT1, AMPK) signaling cascades of glucose metabolism mediated by PIP3 upregulation. Data will be analyzed statistically. The understanding and validation of the mechanisms by which LC supplementation improves glucose homeostasis and lowers glycemia should support the design of clinical interventions using novel molecules (containing sulfide and cysteine moieties) to improve glucose metabolism and prevent insulin resistance (IR) in diabetes. The long-term goal is to discover a relatively low-cost dietary supplement that could be used as an adjuvant therapy for IR prevention in T2D.

描述（应用程序提供）：糖尿病中的L-结合症，PIP3和胰岛素信号传导摘要： 糖尿病已成为一种流行病，并且仍然是全球主要的公共卫生问题。该应用的主要目的是发现L-结晶石（LC）补充可改善糖尿病患者葡萄糖稳态的机制。糖尿病患者的血液水平较低，L-cysteine（LC），硫化氢（H2S）和谷胱甘肽（GSH）。在糖尿病动物研究中，补充富含半胱氨酸的蛋白（乳清蛋白和α-乳糖蛋白），LC或N-乙酰半半胱氨酸（NAC）可降低血糖。然而，LC通过增加葡萄糖利用并降低血糖的分子机制尚不清楚。我们的研究表明，肝脏中PI3K的激活和NF-κB的抑制作用，以及LC补充ZDF大鼠的血糖降低，这是一种2型糖尿病的模型。使用脂肪细胞模型的进一步研究表明，LC在高葡萄糖（HG）处理的细胞中引起PI3K激活，PTEN抑制和PIP3（磷脂酰肌醇-3,4,5三磷酸）和葡萄糖利用率的增加。 LC对PIP3和葡萄糖利用的影响通过PAG（propargylglycine）（一种胱淀粉 - γ-乙酰酶（CSE）的抑制剂（CSE）促进H2S形成H2S的抑制剂。用LC，H2S或PIP3处理增加了IRS1，AKT和PKCζ/λ的磷酸化，以及hg处理的细胞中GLUT4激活和葡萄糖利用率。这些研究提供了一种新型分子机制的证据，通过该机制可以通过该机制增加PIP3并上调胰岛素的代谢作用，从而改善了葡萄糖代谢。该提案将检验以下假设：LC更新胰岛素依赖蛋白（PI3K/AKT/PKCζ/λ）和胰岛素独立性（SIRT1，AMPK）信号级联的葡萄糖代谢级联由PIP3上调介导的葡萄糖代谢。数据将进行统计分析。对LC补充改善葡萄糖稳态和降低血糖的机制的理解和验证应支持使用新型分子（含有硫化物和半胱氨酸部分的含有硫化物和半胱氨酸部分）的临床干预设计，以改善糖尿病患者的葡萄糖代谢并预防胰岛素抵抗（IR）。长期目标是发现一种相对低成本的饮食补充剂，该补充剂可以用作T2D中IR预防的可调节疗法。