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: 10420857
• 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/10420857
• 关键词: 4-Aminobutyrate aminotransferase; Acute; Affect; Beta Cell; Cell membrane; Ceramides; Chronic; Clinical; Clinical Trials; Data; Data Set; Diglycerides; Disease; Dose; Enzymes; Equilibrium; Failure; GABA transporter; Glucose; Glucose Clamp; Glutamate Decarboxylase; Hepatic; Hepatocyte; Human; Human body; Hyperinsulinism; In Vitro; Incidence; Insulin; Insulin Resistance; Knock-out; Link; Lipids; Liver; Mediating; Modeling; Mus; NADH; Nerve; Neuraxis; 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; Translations; 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; mRNA Expression; new therapeutic target; non-alcoholic fatty liver disease; novel; overexpression; response; translational impact; uptake

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的严重程度和发生率与肝脂质浓度直接相关。甚至在β-之前 随之而来的细胞衰竭，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。急性消除肝脏传递信号传导 刺激胰岛素释放并减少骨骼肌葡萄糖间隙，同时导致 高胰岛素血症和胰岛素抵抗。相反，急性刺激肝脏传入神经抑制胰岛素 释放并改善葡萄糖清除率。直到最近，还没有证据表明与 迷走神经紧张改变葡萄糖稳态。我们已经确定肝脂质积累剂量 - 依赖性地增加肝氨基丁酸（GABA）的肝产生和释放，一种抑制 神经递质。我们的数据提出肝细胞产生GABA会刺激胰岛素释放和下降 骨骼肌葡萄糖清除率通过改变肝素迷走神经的活性。建立治疗 潜力，我们已经表明肝脏GABA转氨酶敲低可减少肝脏GABA释放，恢复 饮食诱导的肥胖小鼠中的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GABA - 转氨酶mRNA表达与血清胰岛素和HOMA-IR呈正相关。在 这些相同的临床样品，我们已经表明，在高胰岛素高血糖夹中的葡萄糖处置 与GABA再摄取转运蛋白的mRNA表达呈正相关，并与 GABA出口商的mRNA表达。我们提出3个目标，重点是我们的中心假设，即GABA是一个 可以帮助解释肝脂质积累与高胰岛素血症和胰岛素之间的联系的肝素 肥胖症的抗性。 目标1：评估肥胖，脂质，二酰基甘油，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在质膜上的运输。 目标2：评估对瘦小鼠的加剧肝GABA产生的葡萄糖调节反应或 限制肥胖小鼠的肝癌产量。 AIM 3：评估对敲除（损失）和腺病毒诱导的过表达的葡萄糖调节反应 （增益）瘦肉和饮食引起的肥胖小鼠中的肝脏GABA转运蛋白。 影响：将GABA作为一种新型肝素的验证，影响肥胖症血清胰岛素和胰岛素敏感性 将为治疗这种疾病提供新的治疗靶标。