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

基本信息

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
项目类别：
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

项目摘要

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.

摘要：T2DM 的严重程度和发病率与肝脂质浓度直接相关，甚至在 β- 之前也是如此。随着细胞衰竭的发生，非酒精性脂肪肝病 (NAFLD) 的严重程度与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着关键作用。影响胰腺胰岛素释放和胰岛素敏感性。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在线，急性刺激肝传入神经抑制胰岛素。释放并改善葡萄糖清除率，直到最近还没有证据表明肝因子可以发出信号。我们已经确定肝脏脂质积累剂量-迷走神经改变葡萄糖稳态。依赖性地增加肝脏产生和释放γ-氨基丁酸（GABA），γ-氨基丁酸是一种抑制性物质我们的数据表明，肝细胞产生的 GABA 会刺激胰岛素释放并减少胰岛素分泌。通过改变肝迷走神经的活动来降低骨骼肌葡萄糖清除率以建立治疗方法。潜力，我们已经证明肝脏 GABA 转氨酶敲低会减少肝脏 GABA 的释放，恢复通过临床试验，我们强调了饮食诱导的肥胖小鼠的胰岛素敏感性和正常胰岛素血症。在临床样本中，我们已经证明了潜在靶向肝脏 GABA 信号传导的翻译影响。肝脏GABA转氨酶mRNA表达与血清胰岛素和HOMA-IR呈正相关。这些相同的临床样本，我们已经表明，高胰岛素正常血糖钳夹期间的葡萄糖处理与 GABA 再摄取转运蛋白的 mRNA 表达呈正相关，与 GABA 输出蛋白的 mRNA 表达我们提出了 3 个目标，重点关注我们的中心假设，即 GABA 是一种肝因子有助于解释肝脏脂质积累与高胰岛素血症和胰岛素之间的联系肥胖的抵抗力。目标 1：评估肥胖、脂质、二酰甘油、神经酰胺和下游信号如何影响方向通过 GABA 分流的通量和 GABA 跨质膜的运输。目标 2：评估瘦小鼠或小鼠中肝脏 GABA 生成加剧的葡萄糖调节反应。限制肥胖小鼠肝脏 GABA 的产生。目标 3：评估对基因敲除（丢失）和腺病毒诱导的过度表达的葡萄糖调节反应瘦小鼠和饮食诱导的肥胖小鼠中肝脏 GABA 转运蛋白的（增益）。影响：验证 GABA 作为一种影响肥胖患者血清胰岛素和胰岛素敏感性的新型肝因子将为治疗该疾病提供新的治疗靶点。