Role of the hepatic GABA shunt in insulin resistance and hyperinsulinemia

肝 GABA 分流在胰岛素抵抗和高胰岛素血症中的作用

• 批准号: 10597227
• 负责人: Benjamin Jennings Renquist
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597227
• 关键词: 4-Aminobutyrate aminotransferase; Acute; Affect; Beta Cell; Cell membrane; Central Nervous System; Ceramides; Chronic; Clinical; Clinical Data; Clinical Trials; Communication; Data; Data Set; Diglycerides; Disease; Dose; Enzymes; Equilibrium; Failure; GABA transporter; Glucose; Glucose Clamp; Glutamate Decarboxylase; Hepatic; Hepatocyte; Human; Hyperinsulinism; In Vitro; Incidence; Insulin; Insulin Resistance; Knock-out; Link; Lipids; Liver; Mediating; Modeling; Mus; NADH; Nerve; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Oxidoreductase; Pancreas; Play; Preparation; Production; Reaction; Research; Research Personnel; Role; Sampling; Serum; Severities; Shunt Device; Signal Transduction; Signaling Molecule; Skeletal Muscle; Slice; Succinates; Therapeutic; Thinness; Validation; afferent nerve; blood glucose regulation; diet-induced obesity; gain of function; gamma-Aminobutyric Acid; glucose disposal; glycemic control; improved; in vivo; insulin sensitivity; knock-down; loss of function; mRNA Expression; new therapeutic target; non-alcoholic fatty liver disease; novel; overexpression; response; reuptake; translational impact; translational potential

Abstract: The severity and incidence of T2DM is directly related to hepatic lipid concentration. Even before β- cell failure ensues, the severity of non-alcoholic fatty liver disease (NAFLD) is positively associated with hyperinsulinemia and insulin resistance. The hepatic vagal nerve plays a key role in glucose homeostasis affecting both pancreatic insulin release and insulin sensitivity. Acutely eliminating hepatic afferent signaling stimulates insulin release and decreases skeletal muscle glucose clearance, simultaneously resulting in hyperinsulinemia and insulin resistance. Conversely, acutely stimulating the hepatic afferent nerve inhibits insulin release and improves glucose clearance. Until recently there was no evidence for a hepatokine that signaled to the vagal nerve to alter glucose homeostasis. We have established that hepatic lipid accumulation dose- dependently increases hepatic production and release of γ-aminobutyric acid (GABA), an inhibitory neurotransmitter. Our data proposes that hepatocyte produced GABA stimulates insulin release and decrease skeletal muscle glucose clearance by altering activity of the hepatic vagal nerve. To establish therapeutic potential, we have shown that liver GABA transaminase knockdown decreases liver GABA release, restoring insulin sensitivity and normo-insulinemia in diet-induced obese mice. Through clinical trials, we have highlighted the translational impact of potentially targeting hepatic GABA signaling. In clinical samples, we have shown that hepatic GABA-transaminase mRNA expression is positively correlated with serum insulin and HOMA-IR. In these same clinical samples, we have shown that glucose disposal during a hyperinsulinemic euglycemic clamp is positively associated with mRNA expression of GABA re-uptake transporters and negatively associated with mRNA expression of GABA exporters. We propose 3 Aims focused on our central hypothesis that GABA is a hepatokine that can help explain the link between hepatic lipid accumulation and hyperinsulinemia and insulin resistance in obesity. Aim 1: Assess how obesity, lipids, diacylglycerol, ceramides, and downstream signaling affect direction of flux through the GABA shunt and transport of GABA across the plasma membrane. Aim 2: Assess the glucoregulatory response to exacerbating hepatic GABA production in lean mice or limiting hepatic GABA production in obese mice. Aim 3: Assess the glucoregulatory response to knockout (loss) and adenoviral induced overexpression (gain) of hepatic GABA transporters in lean and diet-induced obese mice. Impact: Validation of GABA as a novel hepatokine that affects serum insulin and insulin sensitivity in obesity will provide new therapeutic targets to treat this disease.

翻译后摘要：T2 DM的严重程度和发病率是直接相关的肝脏脂质浓度。甚至在β- 非酒精性脂肪性肝病（NAFLD）的严重程度与细胞衰竭呈正相关， 高胰岛素血症和胰岛素抵抗。肝迷走神经在葡萄糖稳态中起关键作用 影响胰腺胰岛素释放和胰岛素敏感性。急性消除肝传入信号 刺激胰岛素释放并降低骨骼肌葡萄糖清除率，同时导致 高胰岛素血症和胰岛素抵抗。相反，急性刺激肝传入神经抑制胰岛素 释放并改善葡萄糖清除。直到最近，还没有证据表明肝细胞因子可以发出信号， 迷走神经改变葡萄糖稳态我们已经确定肝脏脂质蓄积剂量- 依赖性地增加肝脏产生和释放γ-氨基丁酸（GABA），一种抑制性 神经传递素我们的数据表明，肝细胞产生的GABA刺激胰岛素释放， 通过改变肝迷走神经的活性来影响骨骼肌葡萄糖清除。为了建立治疗 潜在的，我们已经表明，肝脏GABA转氨酶敲低减少肝脏GABA的释放，恢复 胰岛素敏感性和正常胰岛素血症。通过临床试验，我们强调了 潜在靶向肝GABA信号传导的翻译影响。在临床样本中，我们已经表明， 肝脏GABA-转氨酶mRNA表达与血清胰岛素、HOMA-IR呈正相关。 这些相同的临床样本，我们已经表明，在高胰岛素正葡萄糖钳夹过程中， 与GABA再摄取转运蛋白的mRNA表达呈正相关， GABA输出体的mRNA表达。我们提出了3个目标集中在我们的中心假设，GABA是一个 肝细胞因子可以帮助解释肝脏脂质积聚和高胰岛素血症之间的联系， 肥胖的抵抗力。 目的1：评估肥胖、脂质、甘油二酯、神经酰胺和下游信号传导如何影响方向 通过GABA分流的流量和GABA跨质膜的运输。 目的2：评估瘦小鼠对肝脏GABA产生加剧的葡萄糖调节反应， 限制肥胖小鼠肝脏GABA的产生。 目的3：评估对基因敲除（缺失）和腺病毒诱导的过表达的葡萄糖调节反应 在瘦小鼠和饮食诱导的肥胖小鼠中肝脏GABA转运蛋白的增加。 影响：GABA作为一种新型肝细胞因子影响肥胖患者血清胰岛素和胰岛素敏感性的验证 将为该病的治疗提供新的靶点。