Department of Pharmacology and Toxicology, Wright State University, School of Medicine Dayton, Fairborn, Ohio, United States of America.
Institut für Humangenetik, Universitätsklinikum Jena, Jena, Germany.
PLoS One. 2022 Dec 29;17(12):e0279560. doi: 10.1371/journal.pone.0279560. eCollection 2022.
The risk of type-2 diabetes and cardiovascular disease is higher in subjects with metabolic syndrome, a cluster of clinical conditions characterized by obesity, impaired glucose metabolism, hyperinsulinemia, hyperlipidemia and hypertension. Diuretics are frequently used to treat hypertension in these patients, however, their use has long been associated with poor metabolic outcomes which cannot be fully explained by their diuretic effects. Here, we show that mice lacking the diuretic-sensitive Na+K+2Cl-cotransporter-1 Nkcc1 (Slc12a2) in insulin-secreting β-cells of the pancreatic islet (Nkcc1βKO) have reduced in vitro insulin responses to glucose. This is associated with islet hypoplasia at the expense of fewer and smaller β-cells. Remarkably, Nkcc1βKO mice excessively gain weight and progressive metabolic syndrome when fed a standard chow diet ad libitum. This is characterized by impaired hepatic insulin receptor activation and altered lipid metabolism. Indeed, overweight Nkcc1βKO but not lean mice had fasting and fed hyperglycemia, hypertriglyceridemia and non-alcoholic steatohepatitis. Notably, fasting hyperinsulinemia was detected earlier than hyperglycemia, insulin resistance, glucose intolerance and increased hepatic de novo gluconeogenesis. Therefore, our data provide evidence supporting the novel hypothesis that primary β-cell defects related to Nkcc1-regulated intracellular Cl-homeostasis and β-cell growth can result in the development of metabolic syndrome shedding light into additional potential mechanisms whereby chronic diuretic use may have adverse effects on metabolic homeostasis in susceptible individuals.
代谢综合征是一组以肥胖、葡萄糖代谢受损、高胰岛素血症、血脂异常和高血压为特征的临床病症，患有该病症的患者发生 2 型糖尿病和心血管疾病的风险更高。在这些患者中，利尿剂常被用于治疗高血压，但长期以来，它们的使用与代谢不良结局相关联，而这些不良结局不能仅用其利尿作用来解释。在这里，我们发现，在胰岛胰岛素分泌β细胞中缺乏利尿剂敏感的 Na+K+2Cl 共转运蛋白-1（Nkcc1）的小鼠（Nkcc1βKO），其体外对葡萄糖的胰岛素反应降低。这与胰岛发育不良有关，表现为β细胞数量减少和体积减小。值得注意的是，Nkcc1βKO 小鼠在自由摄取标准食物时会过度增加体重并逐渐出现代谢综合征。其特征为肝胰岛素受体激活受损和脂质代谢改变。事实上，超重的 Nkcc1βKO 但非消瘦的小鼠出现了空腹和进食后高血糖、高甘油三酯血症和非酒精性脂肪性肝炎。值得注意的是，空腹高胰岛素血症比高血糖、胰岛素抵抗、葡萄糖耐量受损和肝内新生葡萄糖生成增加更早出现。因此，我们的数据提供了证据支持一种新假说，即与 Nkcc1 调节的细胞内 Cl 稳态和β细胞生长相关的原发性β细胞缺陷可导致代谢综合征的发生，这为慢性使用利尿剂可能对易感个体的代谢稳态产生不良影响提供了额外的潜在机制。
