Role of the hepatic GABA shunt in insulin resistance and hyperinsulinemia

摘要：T2 DM的严重程度和发病率与肝脂浓度有直接关系。甚至在β之前- 细胞衰竭随之而来，非酒精性脂肪性肝病(NAFLD)的严重程度与 高胰岛素血症和胰岛素抵抗。肝迷走神经在血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，减少骨骼肌葡萄糖清除，同时导致 高胰岛素血症和胰岛素抵抗。相反，剧烈刺激肝脏传入神经会抑制胰岛素。 释放和改善葡萄糖清除。直到最近，还没有证据表明肝细胞因子会发出信号 迷走神经来改变血糖的稳态。我们已经确定了肝脏脂肪蓄积量- 依赖性地增加肝脏产生和释放γ-氨基丁酸(一种抑制性物质 神经递质。我们的数据表明，肝细胞产生的GABA刺激胰岛素的释放和减少 通过改变肝脏迷走神经的活动来清除骨骼肌的葡萄糖。为了建立治疗方法 潜在的，我们已经表明，肝脏GABA转氨酶基因敲除会减少肝脏GABA的释放，恢复 饮食诱导肥胖小鼠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 潜在靶向肝脏GABA信号的翻译影响。在临床样本中，我们已经表明 肝脏GABA转氨酶基因表达与血清胰岛素、HOMA-IR呈正相关。在……里面 同样的临床样本，我们已经证明了在高胰岛素正血糖钳夹期间葡萄糖的处置 与GABA重摄取转运体的mRNA表达呈正相关，与 γ-氨基丁酸输出子的基因表达。我们提出了三个目标，重点是我们的核心假设，即GABA是一种 有助于解释肝脏脂肪堆积与高胰岛素血症和胰岛素之间联系的肝细胞因子 肥胖的抵抗力。 目标1：评估肥胖、血脂、二酰甘油、神经酰胺和下游信号如何影响方向 通过GABA分流的通量和跨质膜的GABA运输。 目的2：评估瘦小鼠肝脏GABA生成加剧时的糖调节反应 限制肥胖小鼠肝脏GABA的产生。 目的3：评估基因敲除(丢失)和腺病毒诱导的过表达对糖调节的反应 瘦身和饮食诱导的肥胖小鼠肝脏GABA转运体的(增益)。 影响：验证GABA作为一种新的肝素影响肥胖患者的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点。

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.