Integrated analysis reveals that miR-548ab promotes the development of obesity and T2DM.

Abstract

Dysregulation of microRNA (miRNA) expression following the development of obesity is closely linked to the onset of type 2 diabetes mellitus (T2DM). Identifying differentially expressed miRNAs and their roles in regulating glucose metabolism will provide a theoretical foundation for the molecular mechanisms underlying obesity-induced T2DM. Here, we perform a genome-wide association study involving 5 glycolipid metabolism traits in 1783 Kazakh and 1198 Uyghur individuals to identify miRNAs associated with fasting plasma glucose (FPG) levels. A miR-548ab mimic and inhibitor are administered to hepatocytes and adipocytes, as well as obese and diabetic mice, to determine miR-548ab-related downstream signalling pathways. The effects of miR-548ab on glucose metabolism are validated using the glucose tolerance test and insulin tolerance test. Collectively, these results indicate that miR-548ab is significantly associated with FPG levels and obesity-related T2DM in both Kazakh and Uyghur populations. The miR-548ab-GULP1/SLC25A21-GLUT4 network exerts regulatory effects on glucose metabolism, obesity, and T2DM, positioning it as a candidate risk factor, potential diagnostic marker, and therapeutic target for obesity-induced T2DM. Additionally, through evolutionary analysis, the authentic variants or haplotypes of GULP1 and SLC25A21 are categorized according to their genetic susceptibility to T2DM. The miR-548ab inhibitor shows beneficial effects in obese and diabetic mice.