Objective

Hyperinsulinemia can be both a cause and consequence of obesity and insulin resistance. Hyperinsulinemia can result from increased insulin secretion and/or reduced insulin clearance. While many studies have focused on mechanisms triggering insulin secretion during obesity, the triggers for changes in insulin clearance during obesity are less defined. In this study, we investigated the role of the microbiota in regulating insulin clearance during diet-induced obesity.

Methods

Blood glucose and insulin clearance were tested in conventional male mice treated with antibiotics and germ-free mice colonized with microbes from mice that were fed a control (chow) diet or an obesogenic high-fat diet (HFD). The composition of the fecal microbiota was analyzed using 16S rRNA sequencing.

Results

Short-term HFD feeding and aging did not alter insulin clearance in the mice. Oral antibiotics mitigated impaired blood insulin clearance in the mice fed an HFD for 12 weeks or longer. Germ-free mice colonized with microbes from HFD-fed donor mice had impaired insulin but not C-peptide clearance. Microbe-transmissible insulin clearance impairment was only observed in germ-free mice after more than 6 weeks post-colonization upon HFD feeding. Five bacterial taxa predicted >90% of the variance in insulin clearance. Mechanistically, impaired insulin clearance was associated with lower levels of hepatic Ceacam-1 but increased liver and skeletal muscle insulin-degrading enzyme (IDE) activity.

Conclusions

Gut microbes regulate insulin clearance during diet-induced obesity. A small cluster of microbes or their metabolites may be targeted for mitigating defects in insulin clearance and hyperinsulinemia during the progression of obesity and type 2 diabetes.

中文翻译：

---

肠道微生物群会损害肥胖小鼠的胰岛素清除。

客观的

高胰岛素血症可能是肥胖和胰岛素抵抗的原因和结果。高胰岛素血症可由胰岛素分泌增加和/或胰岛素清除减少引起。虽然许多研究都集中在肥胖期间触发胰岛素分泌的机制上，但肥胖期间胰岛素清除率变化的触发因素尚不清楚。在这项研究中，我们研究了微生物群在饮食诱导肥胖期间调节胰岛素清除的作用。

方法

在用抗生素治疗的常规雄性小鼠和用来自小鼠的微生物定植的无菌小鼠中测试血糖和胰岛素清除率，这些小鼠喂食对照（食物）饮食或致肥高脂肪饮食（HFD）。使用 16S rRNA 测序分析粪便微生物群的组成。

结果

短期 HFD 喂养和衰老并未改变小鼠的胰岛素清除率。口服抗生素减轻了喂食 HFD 12 周或更长时间的小鼠的血液胰岛素清除受损。来自喂食 HFD 的供体小鼠的微生物定植的无菌小鼠的胰岛素受损，但 C 肽清除没有受损。仅在 HFD 喂养定植后 6 周以上的无菌小鼠中才观察到微生物传播的胰岛素清除障碍。五种细菌分类群预测了>90% 的胰岛素清除变异。从机制上讲，胰岛素清除受损与肝脏 Ceacam-1 水平降低有关，但肝脏和骨骼肌胰岛素降解酶 (IDE) 活性增加。

结论

肠道微生物在饮食引起的肥胖期间调节胰岛素清除。在肥胖和 2 型糖尿病的发展过程中，一小群微生物或其代谢物可能被用于减轻胰岛素清除和高胰岛素血症的缺陷。