Relationship between proinsulin-to-insulin ratio and advanced glycation endproducts in Japanese type 2 diabetic subjects

Objective: Type 2 diabetes (T2DM) is characterized by increased proinsulin-to-insulin ratio (P/I ratio), increased glycation and oxidative stress, and β-cell dysfunction. Previous reports implicated that increased P/I ratio, glycation and oxidative stress constitute markers of β-cell dysfunction in T2DM. However, its clinical relevance remains to be elucidated. Therefore, in the present study we investigated the relationship between the P/I ratio, glycation and oxidative stress markers in patients with T2DM, using newly developed intact chemiluminescent immunoassay for proinsulin. Methods: Fasting intact proinsulin, insulin, advanced glycation endproducts (AGEs), pentosidine, lipid peroxide and urine 8-isoprostane as well as other metabolic parameters were measured in 64 T2DM subjects. Results: Using univariate analysis, P/I ratio showed significant positive correlations with plasma glucose (r = 0.465), HbA1c (r = 0.434) and AGEs (r = 0.282), and significant negative correlations with insulin (r = -0.330) and HOMA-β (r = -0.520) even after adjustment for age, sex, duration of diabetes, family history of diabetes, use of sulfonylureas, smoking and body mass index. Additionally, stepwise multiple regression analysis revealed that HOMA-β, HbA1c and AGEs were independently and significantly correlated with P/I ratio. Conclusion: These findings suggest that not only hyperglycemia per se but also glycation is involved in β-cell dysfunction in T2DM subjects.