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.

L-糖尿病中的半胱氨酸、PIP3和胰岛素信号转导 糖尿病已经成为一种流行病，仍然是世界范围内的一个主要公共卫生问题。本应用的主要目的是发现补充L半胱氨酸(LC)改善糖尿病患者血糖稳态的机制。糖尿病患者血中L-半胱氨酸(LC)、硫化氢(H2S)和谷胱甘肽(GSH)水平较低。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-乳白蛋白)、LC或N-乙酰半胱氨酸(NAC)已被证明可以降低血糖。然而，LC增加葡萄糖利用率和降低血糖的分子机制尚不清楚。我们的研究表明，在2型糖尿病大鼠模型中，补肾益气汤能激活肝脏中的PI3K，抑制肝脏中的核因子-κB，降低血糖。利用脂肪细胞模型的进一步研究表明，在高糖(HG)处理的细胞中，LC导致PI3K激活，PTEN抑制，PIP3(三磷酸磷脂酰肌醇)和葡萄糖利用率增加。LC对PIP3和葡萄糖利用的影响可被催化LC生成H_2S的胱硫醚-γ-裂解酶(CSE)的抑制剂丙叉甘氨酸所阻止。在HG处理的细胞中，经LC、H_2S或PIP3处理后，IRS1、AKT和PKCζ/λ的磷酸化以及GLUT4的活化和葡萄糖的利用均增加。这些研究为LC增加PIP3和上调胰岛素的代谢作用从而改善糖代谢的新的分子机制提供了证据。这一建议将检验LC上调胰岛素依赖(PI3K/AKT/PKCζ/λ)和胰岛素非依赖(SIRT1，AMPK)信号通路的假说。数据将进行统计分析。对补充LC改善血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(包含硫化物和半胱氨酸部分)来改善糖尿病患者的葡萄糖代谢和预防胰岛素抵抗(IR)的临床干预设计。长期目标是发现一种相对低成本的膳食补充剂，可以作为预防T2D中IR的辅助疗法。