Abstract : Type 2 diabetes mellitus (T2DM) is the major type of diabetes around the world with a diabetic nephropathy (DN) is the most common complication of this illness. Several pathways involving pro-inflammatory and polyol are activated through the course of T2DM. The current study aims to evaluate the role of sorbitol dehydrogenase (SDH), zinc, fructose and glycosyl phosphatidyl inositol high density lipoprotein binding protein 1 (GPIHBP1) in development of DN in T2DM Iraqi patients. This is a nested case control study, involved 122 patients with DN (72 patients with microalbuminuria (MA) and 50 patients with normoalbuminuria (NA)) and other age- and gender-matched 58 apparently healthy subjects. The SDH activity, fructose and Zn+2 concentration were determined using spectrophotometric assays, while enzyme linked immunosorbent assay (ELISA) was used to measure serum level of GPIHBP1. Other parameters including lipid profile, fasting blood sugar (FBS), glycated hemoglobin (HbA1c) and renal function tests were measured with standard biochemical methods. The mean serum level of SDH activity in MA and NA was 22.26±9.91U/L and 26.39±10.58 U/L, respectively with no significant difference. However, both groups differed significantly from controls (48.39±24.43 U/L). Similarly, fructose level was comparable between MA and NA groups (6.1±1.5 mg/dl and 6.75±1.54 mg/dl, respectively) and significantly lower than that of controls (10.0±2.0 mg/dl). The median level of GPIHBP1 in MA patients was (878.2 pg/ml) which was higher than that of NA group (1014.05pg/ml) and controls (1189.5 pg/ml) with significant differences. In the context of discrimination between MA and healthy control, the area under the curve (AUC) for SDH and fructose was 0.904, 95%CI= 0.853-0.954, p <0.00 and 0.931, 95%CI= 0.886-0.976, p <0.001, respectively, while in the context of discrimination between NA and healthy controls, it was 0.841, 95%CI= 0.767-0.915, p <0.001, and 0.903, 95%CI= 0.848-0.958, p <0.001, respectively. For GPIHBP1, the AUC in the context of discrimination between MA and healthy controls 0.846, 95%CI= 0.776-0.916, p <0.001; between MA and NA controls 0.773, 95%CI= 0.688-0.857, p <0.001, and between NA and healthy controls 0.762, 95%CI= 0.616-0.837, p <0.001. Diabetic nephropathy (whether normo- or microalbuminuria) is associated with elevated serum levels of TG and vLDL compared with healthy subjects. Serum level of GPIHBP1 is not only decreased in patients with DN, but also inversely associated with the severity of the disease, and can differentiate between normo- and microalbuminuria with a good sensitivity and specificity.