Interaction between the GCKR rs1260326 variant and serum HDL cholesterol contributes to HOMA-β and ISI Matusda in the middle-aged T2D individuals

This study aims to investigate the correlations between islet function/ insulin resistance and serum lipid levels, as well as to assess whether the strength of such correlations is affected by the GCKR rs1260326 variant in healthy and T2D individuals. We performed an oral glucose tolerance test (OGTT) on 4889 middle-aged adults, including 3135 healthy and 1754 T2D individuals from the REACTION population study in the Nanjing region. We also measured their serum lipid levels and genotyped for rs1260326. We found that serum high-density lipoprotein (HDL) cholesterol and triglyceride (TG) levels were independently correlated with indexes of islet function (HOMA-β and IGI [insulinogenic index]) and insulin resistance (HOMO-IR and ISI Matsuda ) in both healthy and T2D individuals. The correlations were significantly decreased in T2D individuals, with significant heterogeneities compared to healthy controls ( I 2 > 75%, P het < 0.05). Although no correlation was observed between serum total cholesterol (TC) level and islet function/ insulin resistance in healthy controls, significant correlations were found in T2D individuals, with significant heterogeneity to healthy controls in the correlation with ISI Matsuda ( I 2 = 85.3%, P het = 0.009). Furthermore, we found significant interactions of the GCKR rs1260326 variant for the correlations between serum HDL cholesterol and HOMA-β/ISI Matsuda in T2D subjects ( P = 0.015 and 0.038, respectively). These findings illustrate that distinct correlations between serum lipid levels and islet function/ insulin resistance occurred in T2D subjects compared to healthy individuals. Common gene variants, such as rs1260326, might interact substantially when studied in specific populations, especially T2D disease status.