High uric acid promotes dysfunction in pancreatic β cells by blocking IRS2/AKT signalling

Area of Science:

• Metabolic disorders
• Endocrinology
• Cellular biology

Background:

• Hyperuricemia, characterized by elevated serum uric acid, is linked to metabolic diseases like insulin resistance.
• Previous research demonstrated high uric acid (HUA) induces insulin resistance in peripheral organs.
• The direct impact of HUA on pancreatic beta cells, crucial for insulin production, remained unclear.

Purpose of the Study:

• To investigate whether high uric acid (HUA) directly induces insulin resistance in pancreatic beta cells.
• To elucidate the molecular mechanisms underlying HUA-induced dysfunction in pancreatic beta cells.

Main Methods:

• Pancreatic beta cells (INS-1 cells) were pretreated with HUA.
• RNA sequencing (RNA-seq) was employed to analyze global gene expression changes.
• Cellular functions including insulin secretion, glucose uptake, and mitochondrial potential were assessed.
• Specific interventions like probenecid, N-acetyl-L-cysteine (NAC), and insulin-like growth factor 1 (IGF-1) were used.

Main Results:

• HUA exposure impaired insulin expression/secretion, glucose uptake, and the glycolytic pathway in INS-1 cells.
• RNA-seq identified HUA's broad effects on metabolic processes, including oxidoreduction and pyruvate metabolism.
• HUA reduced mitochondrial membrane potential and increased reactive oxygen species (ROS) production.
• Probenecid, NAC, and IGF-1 treatments partially or fully reversed HUA-induced impairments.

Conclusions:

• High uric acid directly induces insulin resistance and impairs the glycolytic pathway in pancreatic beta cells.
• HUA-induced beta cell dysfunction involves reduced mitochondrial function and increased oxidative stress.
• The IRS2/AKT pathway is implicated in mediating HUA's detrimental effects on pancreatic beta cells.