Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation

Abstract

AimNumerous reports have demonstrated the key importance of macrophage-elicited metabolic inflammation in insulin resistance (IR). Our previous studies confirmed that hyperuricemia or high uric acid (HUA) treatment induced an IR state in several peripheral tissues to promote the development of type 2 diabetes mellitus (T2DM). However, the effect of HUA on glucose uptake and the insulin sensitivity of macrophages and its mechanism is unclear.MethodsTo assess systemic IR, we generated hyperuricemic mice by urate oxidase knockout (UOX-KO). Then, glucose/insulin tolerance, the tissue uptake of 18F-fluorodeoxyglucose, body composition, and energy balance were assessed. Glucose uptake of circulating infiltrated macrophages in the liver was evaluated by glucose transporter type 4 (GLUT-4) staining. Insulin sensitivity and the insulin signaling pathway of macrophages were demonstrated using the 2-NBDG kit, immunoblotting, and immunofluorescence assays. The immunoprecipitation assay and LC-MS analysis were used to determine insulin receptor substrate 2 (IRS2) levels and its interacting protein enrichment under HUA conditions.ResultsCompared to WT mice (10 weeks old), serum uric acid levels were higher in UOX-KO mice (WT, 182.3 ± 5.091 μM versus KO, 421.9 ± 45.47 μM). Hyperuricemic mice with metabolic disorders and systemic IR showed inflammatory macrophage recruitment and increased levels of circulating proinflammatory cytokines. HUA inhibited the nuclear translocation of GLUT-4 in hepatic macrophages, restrained insulin-induced glucose uptake and glucose tolerance, and blocked insulin IRS2/PI3K/AKT signaling. Meanwhile, HUA mediated the IRS2 protein degradation pathway and activated AMPK/mTOR in macrophages. LC-MS analysis showed that ubiquitination degradation could be involved in IRS2 and its interacting proteins to contribute to IR under HUA conditions.ConclusionThe data suggest that HUA-induced glucose intolerance in hepatic macrophages contributed to insulin resistance and impaired the insulin signaling pathway via IRS2-proteasome degradation

The dysregulation of immune cells induced by uric acid: mechanisms of inflammation associated with hyperuricemia and its complications

“…Macrophages transporting these migrated MSU crystals may potentially contribute to the tissue’s widespread inflammatory response ( 57 ). Recent research also illustrates that curtailing macrophage migration to the MSU site effectively mitigates HUA’s inflammatory response and associated complications ( 58 ).…”

“…Increased glucose uptake and glycolysis are metabolic markers of pro-inflammatory activation of immune cells. MSU activates macrophage glycolysis to promote inflammatory factor expression ( 58 ). Glycolysis regulates NLRP3 inflammasome activation in macrophages ( 61 ).…”

“…MSU crystals increase glucose uptake in macrophages by upregulating glucose transporter protein 1 (GLUT1) and upregulating glycolysis. This triggers metabolic reprogramming, leading to NLRP3-dependent IL-1β production ( 58 ). Inhibition of both GLUT1 and glycolysis reduced MSU crystal-induced inflammation response.…”

“…Inhibition of both GLUT1 and glycolysis reduced MSU crystal-induced inflammation response. Notably, immune cells in tissues injured by HUA complications have higher GLUT1 expression than those in circulation ( 58 ). This suggests that targeting and inhibiting GLUT1 in macrophages is a promising and specific approach as a treatment for HUA and its complications.MSU crystals also induce inactivation of mitochondrial pyruvate carrier (MPC) in macrophages promoting NLRP3 inflammasome activation and gout development.…”

Association Between Triglyceride-Glucose Index and Serum Uric Acid Levels: A Biochemical Study on Anthropometry in Non-Obese Type 2 Diabetes Mellitus Patients

“… 19 SUA may influence insulin signaling and induce IR under the action of inflammatory factors. 20 On the other hand, IR can cause inflammation and indirectly promote HUA. Administration of anti-inflammatory intervention to insulin-resistant individuals reduces SUA levels.…”