Relationships among pancreatic beta cell function, the Nrf2 pathway, and IRS2: a cross-sectional study

Area of Science:

• Endocrinology and Metabolism
• Molecular Biology
• Pathophysiology

Background:

• Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose regulation, oxidative stress (OS), and inflammation.
• The Nrf2 pathway and insulin receptor substrate 2 (IRS2) play critical roles in cellular defense against OS and in insulin signaling.

Purpose of the Study:

• To investigate the interplay between islet function, the Nrf2 pathway, and IRS2 in normal glucose tolerance (NGT), impaired glucose regulation (IGR), and T2DM.
• To elucidate the role of OS and inflammation in the progression of glucose dysregulation.

Main Methods:

• Cross-sectional study involving 300 participants each in NGT, IGR, and T2DM groups.
• Evaluation of glycemic control (FBG, 2hPG, HbA1c), lipid profiles (TG, TC, HDL-C, LDL-C), and serum levels of Nrf2, IRS2, TNF-α, and HO-1.

Main Results:

• T2DM patients exhibited significantly lower islet β-cell function and insulin sensitivity compared to NGT and IGR groups.
• Nrf2, IRS2, and HO-1 levels decreased progressively from NGT to IGR to T2DM, while TNF-α levels increased.
• Prediabetic individuals showed moderate increases in TNF-α, Nrf2, and HO-1, with marginal IRS2 inhibition, suggesting Nrf2 pathway activation under mild OS.

Conclusions:

• Impaired glucose regulation is associated with increased TNF-α, indicating heightened OS and inflammation.
• In IGR, the Nrf2 pathway is activated to resist OS and inflammation, maintaining islet function.
• In T2DM, significant OS and inflammation lead to suppressed Nrf2 pathway activation, reduced antioxidant capacity, increased IRS2 degradation, and impaired islet function.