Oxidative stress in families of type 1 diabetic patients

OBJECTIVE - The link between hyperglycemia and the complications of diabete s is unknown. It is still discussed whether oxidative stress precedes or me rely reflects diabetic complications. To search for a familial predispositi on to oxidative stress, we investigated indexes of glucose and lipid metabo lism, markers of plasma and cell lipid oxidation, a marker of oxidant-induc ed protein damage, and the effects of oxygen radicals on erythrocytes (or r ed blood cells [RBCs]) of patients with type 1 diabetes and their relatives . RESEARCH DESIGN AND METHODS - We recruited 30 type 1 diabetic subjects (10 without diabetic complications, 10 with retinopathy, and 10 with nephropath y), 36 nondiabetic siblings, 37 nondiabetic parents of type 1 diabetic subj ects, and 3 control groups of healthy subjects without a family history of diabetes. Levels of blood creatinine, glucose, HbA(1c), cholesterol, trigly cerides, lipoprotein(a) (Lp [a]), fibrinogen, malondialdehyde (MDA), and ad vanced oxidation protein products were determined. The RBC response to oxid ative stress (3-h incubation at 37 degrees C with or without a radical gene rating system) was evaluated by measuring RBC glutathione (GSH), RBC-MDA, a nd hemolysis. RESULTS - Diabetic patients had higher levels of blood glucose (P < 0.001), HbA(1c) (P < 0.001), Lp(a) (P < 0.01), and fibrinogen (P < 0.05) than cont rol subjects. Siblings of diabetic patients had higher Lp(a) levels (P < 0. 001). Parents had higher levels of plasma glucose (P < 0.05) and Lp(a) (P < 0.01). Plasma and RBC-MDA were significantly elevated in diabetic subjects and relatives compared with control subjects. Basal RBC-GSH was lower in d iabetic subjects (P < 0.01). In diabetic subjects, incubations of cells cau sed a decrease in RBC-GSH of a lesser degree than that in control subjects, but they caused a significant increase in hemolysis. Among relatives, hemo lysis was increased both at baseline and after incubation. Plasma MDA level s were associated with blood glucose, creatinine, and fibrinogen levels (mu ltiple r = 0.5, P < 0.001), and basal RBC-MDA levels were associated with p lasma Lp(a), fibrinogen, and plasma MDA levels (r = 0.6, P < 0.001). Basal RBC-GSH content correlated with serum glucose and RBC-MDA production (r = 0 .3, P < 0.01). CONCLUSIONS - Our study is the first to present evidence that markers of li poprotein metabolism (Lp[a]), oxidative stress (plasma and RBC-MDA), and ce llular fragility (hemolysis) are abnormal in nondiabetic relatives of type 1 diabetic subjects, thereby supporting the view that familial elements of diabetes even precede the onset of diabetes. It seems reasonable that the s ame biological markers considered major predictors of cardiovascular diseas e can also trace familial susceptibility to type 1 diabetes, just as they h ave been associated with the development of type 2 diabetes.