Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA; Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA.
Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA.
Biochem Pharmacol. 2019 Feb;160:46-61. doi: 10.1016/j.bcp.2018.12.005. Epub 2018 Dec 7.
Alcoholic ketoacidosis and diabetic ketoacidosis are life-threatening complications that share the characteristic features of high anion gap metabolic acidosis. Ketoacidosis is attributed in part to the massive release of ketone bodies (e.g., β-hydroxybutyrate; βOHB) from the liver into the systemic circulation. To date, the impact of ethanol consumption on systemic ketone concentration, glycemic control, and hepatic gluconeogenesis and glycogenesis remains largely unknown, especially in the context of type 2 diabetes. In the present study, ethanol intake (36% ethanol- and 36% fat-derived calories) by type 2 diabetic db/db mice for 9 days resulted in significant decreases in weight gain (∼19.5% ↓) and caloric intake (∼30% ↓). This was accompanied by a transition from macrovesicular-to-microvesicular hepatic steatosis with a modest increase in hepatic TG (∼37% ↑). Importantly, ethanol increased systemic βOHB concentration (∼8-fold ↑) with significant decreases in blood glucose (∼4-fold ↓) and plasma insulin and HOMA-IR index (∼3-fold ↓). In addition, ethanol enhanced hepatic βOHB content (∼5-fold ↑) and hmgcs2 mRNA expression (∼3.7-fold ↑), downregulated key gluconeogenic mRNAs (e.g., Pcx, Pck1, and G6pc), and depleted hepatic glycogen (∼4-fold ↓). Furthermore, ethanol intake led to significant decreases in the mRNA/protein expression and allosteric activation of glycogen synthase (GS) in liver tissues regardless of changes in the phosphorylation of GS, GSK-3β, or Akt. Together, our findings suggest that ethanol-induced ketonemia may occur in concomitance with significant lowering of blood glucose concentration, which may be attributed to suppression of gluconeogenesis in the setting of glycogen depletion in type 2 diabetes.
酒精性酮症酸中毒和糖尿病酮症酸中毒是危及生命的并发症，它们具有高阴离子间隙代谢性酸中毒的共同特征。酮症酸中毒部分归因于大量酮体（如β-羟丁酸；βOHB）从肝脏释放到全身循环中。迄今为止，乙醇摄入对全身酮浓度、血糖控制以及肝糖异生和糖生成的影响在很大程度上仍不清楚，特别是在 2 型糖尿病的背景下。在本研究中，2 型糖尿病 db/db 小鼠连续 9 天摄入乙醇（36%乙醇和 36%脂肪衍生热量），导致体重增加（19.5%↓）和热量摄入（30%↓）显著减少。随之而来的是从大泡性到微泡性肝脂肪变性的转变，肝甘油三酯（TG）适度增加（37%↑）。重要的是，乙醇增加了全身βOHB 浓度（8 倍↑），同时显著降低了血糖（4 倍↓）和血浆胰岛素以及 HOMA-IR 指数（3 倍↓）。此外，乙醇增强了肝βOHB 含量（5 倍↑）和 hmgcs2 mRNA 表达（3.7 倍↑），下调了关键的糖异生 mRNA（如 Pcx、Pck1 和 G6pc），并耗尽了肝糖原（~4 倍↓）。此外，无论 GS 的磷酸化、GSK-3β 或 Akt 是否发生变化，乙醇摄入都会导致肝组织中 GS 的 mRNA/蛋白表达和变构激活显著降低。总之，我们的研究结果表明，在 2 型糖尿病糖原耗竭的情况下，乙醇诱导的酮血症可能伴随着血糖浓度的显著降低。
