Samovski Dmitri, Smith Gordon I, Palacios Hector, Pietka Terri, Fuchs Anja, Patti Gary J, Nawaz Allah, Kahn C Ronald, Klein Samuel
Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
Department of Chemistry, Washington University School of Medicine, St. Louis, MO.
Diabetes Care. 2025 Aug 1;48(8):1342-1351. doi: 10.2337/dc24-2739.
Weight loss improves insulin sensitivity in people with obesity and type 2 diabetes. However, the mechanisms responsible for this effect are unclear. We hypothesized that alterations in adipose tissue biology and adipose tissue-related factors in plasma are involved in mediating the systemic metabolic benefits of weight loss.
We evaluated blood and adipose tissue samples obtained from 10 adults with obesity and type 2 diabetes before and after marked (16-20%) weight loss and >50% increase in whole-body insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp procedure.
Weight loss 1) decreased adipose tissue expression of genes related to extracellular matrix remodeling; 2) decreased adipose tissue expression of SERPINE 1, which encodes plasminogen activator inhibitor 1 (PAI-1); 3) did not decrease adipose tissue immune cell content or expression of genes involved in inflammation; 4) decreased adipose tissue ceramide content; 5) decreased plasma PAI-1 and leptin concentrations and increased plasma high-molecular weight (HMW) adiponectin; and 6) decreased plasma small extracellular vesicle (sEV) concentration and the sEV content of microRNAs proposed to inhibit insulin action, and completely reversed the inhibitory effect of plasma sEVs on insulin signaling in myotubes.
These findings suggest that weight loss increases insulin sensitivity in people with obesity and type 2 diabetes by modifying adipose tissue biology, with concomitant alterations in circulating PAI-1, leptin, HMW adiponectin, and sEV microRNAs.
体重减轻可改善肥胖和2型糖尿病患者的胰岛素敏感性。然而，导致这种效应的机制尚不清楚。我们推测，脂肪组织生物学的改变以及血浆中与脂肪组织相关的因子参与介导体重减轻带来的全身代谢益处。
我们评估了10名肥胖和2型糖尿病成年人在体重显著减轻（16 - 20%）且全身胰岛素敏感性增加>50%前后采集的血液和脂肪组织样本，胰岛素敏感性通过高胰岛素-正常血糖钳钳钳钳夹术进行评估。
体重减轻1）降低了与细胞外基质重塑相关基因的脂肪组织表达；2）降低了编码纤溶酶原激活物抑制剂1（PAI - 1）的SERPINE 1的脂肪组织表达；3）未降低脂肪组织免疫细胞含量或参与炎症的基因表达；4）降低了脂肪组织神经酰胺含量；5）降低了血浆PAI - 1和瘦素浓度，并增加了血浆高分子量（HMW）脂联素；6）降低了血浆小细胞外囊泡（sEV）浓度以及被认为抑制胰岛素作用的微小RNA的sEV含量，并完全逆转了血浆sEV对肌管胰岛素信号传导的抑制作用。
这些发现表明，体重减轻通过改变脂肪组织生物学特性，同时伴随循环中的PAI - 1、瘦素、HMW脂联素和sEV微小RNA的变化，增加了肥胖和2型糖尿病患者的胰岛素敏感性。
