Effect of SGLT2 Inhibitors on Hepatic Glucose Metabolism: Role of Autonomic Nervous System

SGLT2 抑制剂对肝葡萄糖代谢的影响：自主神经系统的作用

• 批准号: 10218140
• 负责人: Muhammad Abdul-Ghani
• 金额: $ 60.44万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218140
• 关键词: Adverse event; Affect; Aftercare; Antidiabetic Drugs; Applications Grants; Area; Autonomic nervous system; Body fat; Consumption; Data; Development; Diabetes Mellitus; Equilibrium; FDA approved; Fasting; Fatty acid glycerol esters; Glucagon; Glucose; Glucose Plasma Concentration; Hepatic; Hepatocyte; Hormonal Change; Impaired fasting glycaemia; In Vitro; Indirect Calorimetry; Individual; Infusion procedures; Insulin; Ketones; Kidney; Liver; Measures; Metabolic; Methods; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Oral; Patients; Pharmaceutical Preparations; Plasma; Production; Pyruvate; Role; Signal Transduction; Skeletal Muscle; Sodium; Sympathetic Nervous System; Testing; Tracer; Type 2 diabetic; base; clinically relevant; clinically significant; diabetic; diabetic patient; fasting plasma glucose; glucose disposal; glucose metabolism; glucose production; glucose tolerance; glucose uptake; heart rate variability; inhibitor/antagonist; member; non-diabetic; novel; novel drug class; oxidation; reuptake

Sodium-Glucose cotransport inhibitors (SGLT2i) are a novel class of antidiabetic agents which lower the plasma glucose concentration by inhibiting renal glucose reuptake and producing glucosuria. In addition to lowering the plasma glucose concentration, members of this class exert multiple metabolic actions in T2DM all of which have significant clinical relevance and include: (1) stimulation of hepatic glucose production; (2) reduce fasting plasma insulin concentration and stimulate glucagon secretion, these hormonal changes were suggested to cause the increase in HGP; (3) inhibition of glucose oxidation; and (4) increase in fat oxidation and ketone production. Our preliminary data demonstrate that, in normal glucose tolerant individuals, SGLT2 inhibitors, stimulate glucose production, and cause significant increase in fat oxidation without a change in plasma glucose, insulin, glucagon and ketone concentrations. Further, SGLT2 inhibitors inhibited pyruvate oxidation in hepatocytes in culture. Based upon these novel findings, we hypothesize that, signals (likely neuronal) other than change in plasma insulin to glucagon ratio are activated by glucosuria and stimulate the increase in HGP in non-diabetic and likely in diabetic individuals as well. Further, we hypothesize that the increase in fat oxidation by SGLT2 inhibitors will depletes liver fat content in IFG and T2DM patients, increase hepatic glucose uptake and decrease the fasting plasma glucose concentration. To test these hypotheses, we will (1) Measure autonomic balance (with heart rate variability) and sympathetic nervous system activity (3H-norepinephrine turnover) in IFG, NGT and T2DM subjects (drug naïve with FPG <160 mg/dl) at baseline and at day 1 and 12 weeks of treatment with SGLT2 inhibitors, and (2) Measure FPG, bHGP (3H-glucose infusion), HGU (with Oral-IV double tracer infusion), whole body fat oxidation (indirect calorimetry), plasma insulin, glucagon, FFA, ketone and lactate concentrations, and hepatic fat content (1H-MRS) in IFG, NGT and T2DM patients (drug naïve with FPG <160 mg/dl) at baseline and at day 1 and 12 weeks after treatment with SGLT2 inhibitor

钠-葡萄糖协同转运抑制剂（SGLT 2 i）是一类新型抗糖尿病药物 其通过抑制肾葡萄糖再摄取来降低血浆葡萄糖浓度， 产生糖尿。除了降低血浆葡萄糖浓度外， 该类成员在T2 DM中发挥多种代谢作用， 显著临床相关性，包括：（1）刺激肝葡萄糖产生; (2)降低空腹血浆胰岛素浓度并刺激胰高血糖素分泌，这些 提示激素变化可引起HGP的增加;（3）抑制HGP， 葡萄糖氧化;和（4）增加脂肪氧化和酮产生。我们 初步数据表明，在正常葡萄糖耐受个体中，SGLT 2 抑制剂，刺激葡萄糖产生，并导致脂肪氧化显着增加 而血浆葡萄糖、胰岛素、胰高血糖素和酮浓度无变化。 此外，SGLT 2抑制剂可抑制培养肝细胞中的丙酮酸氧化。基于 根据这些新的发现，我们假设，信号（可能是神经元），而不是 血浆胰岛素与胰高血糖素比率的变化被糖尿激活，并刺激 非糖尿病患者和糖尿病患者中HGP增加。我们还 假设SGLT 2抑制剂引起的脂肪氧化增加将消耗肝脏脂肪 IFG和T2 DM患者中的葡萄糖含量，增加肝脏葡萄糖摄取， 空腹血糖浓度。为了验证这些假设，我们将（1）测量 自主平衡（心率变异性）和交感神经系统活动 IFG、NGT和T2 DM受试者（FPG初治受试者）中的3 H-去甲肾上腺素转换率 <160 mg/dl）， （2）测定FPG、bHGP（~ 3 H-葡萄糖输注）、HGU（口服-IV双示踪剂 输注）、全身脂肪氧化（间接量热法）、血浆胰岛素、胰高血糖素、FFA， IFG、NGT和 基线、第1天和第12周时的T2 DM患者（FPG <160 mg/dl的药物初治患者） SGLT 2抑制剂治疗后