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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：糖尿病中的 L-半胱氨酸、PIP3 和胰岛素信号传导摘要：糖尿病已成为一种流行病，并且仍然是世界范围内的一个主要公共卫生问题，该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。 L-半胱氨酸（LC）、硫化氢（H2S）和谷胱甘肽（GSH）。补充富含半胱氨酸的蛋白质（乳清蛋白和α-乳清蛋白），在糖尿病动物研究中，LC 或 N-乙酰半胱氨酸 (NAC) 已被证明可以降低血糖，但是，LC 增加葡萄糖利用率和降低血糖的分子机制尚不清楚。补充 LC 的 ZDF 大鼠（2 型糖尿病模型）中的肝脏中的 NF-κB 和血糖降低使用脂肪细胞模型进行的进一步研究表明，LC 引起 PI3K 激活、PTEN 抑制和高葡萄糖 (HG) 处理的细胞中 PIP3（磷脂酰肌醇-3,4,5 三磷酸）和葡萄糖利用率增加。PAG（炔丙基甘氨酸）是一种胱硫醚-γ 抑制剂，可防止 LC 对 PIP3 和葡萄糖利用率的影响。 -裂合酶 (CSE)，催化 LC 形成 H2S，用 LC、H2S 或 PIP3 处理可增加 LC 的磷酸化。这些研究为 HG 处理的细胞中的 IRS1、AKT 和 PKC z/λ 以及 GLUT4 激活和葡萄糖利用提供了证据，证明 LC 可以增加 PIP3 并上调胰岛素的代谢作用，从而改善葡萄糖代谢。该提案将检验 LC 上调胰岛素依赖性 (PI3K/AKT/PKCz/λ) 和胰岛素非依赖性 (SIRT1、AMPK) 葡萄糖代谢信号级联的假设。对 LC 补充剂改善葡萄糖稳态和降低血糖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）来改善血糖的临床干预措施的设计。长期目标是发现一种相对低成本的膳食补充剂，可用作预防 T2D IR 的辅助疗法。