Elevated lactate aggravates insulin resistance by downregulating the PI3K/AKT/GLUT2 pathway in type 2 diabetes mellitus.

AIMS: Type 2 diabetes mellitus (T2DM), a hyperglycemic metabolic disorder, is driven by progressive insulin secretion deficiencies and insulin resistance (IR). Lactate, a product of glycolysis, has also been found to be involved in regulating insulin-linked signaling pathways via lactylation, a novel post-translational modification that couples metabolic flux to protein mediator expression. However, the association between lactate and lactylation with IR is still largely unknown.

MATERIALS AND

METHODS

Serum lactate and hepatic lactylation levels, as well as their effects on IR, were investigated among T2DM patients, in vitro HepG2 cell and in vivo diabetic animal (Chinese hamster, db/db mice) models. Rotenone (ROT) and dichloroacetate (DCA) were used to pharmacologically upregulate and downregulate lactate/lactylation levels, respectively.

KEY FINDINGS: T2DM patients had significantly higher serum lactate and hepatic lactylation levels than non-diabetics. Furthermore, increased lactate/lactyation corresponded to lowered HepG2 glucose uptake in vitro, as well as higher fasting blood glucose and Homeostatic Model Assessment of Insulin Resistance scores in Chinese hamsters and mice in vivo. Moreover, increasing lactate/lactylation levels with ROT was linked to downregulation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/Glucose Transporter 2 (GLUT2) signaling, which plays a key role in insulin-mediated glucose homeostasis. This downregulation, in turn, exacerbated IR. On the other hand, lowering lactate/lactylation levels with DCA upregulated PI3K/AKT/GLUT2 expression and alleviated IR.

SIGNIFICANCE: All these findings suggested that higher lactate and lactylation exacerbated IR via suppressing PI3K/AKT/GLUT2. Therefore, modulating lactate levels could serve as a potential approach for treating IR in T2DM.