Objective: The increased cardiovascular risk in subjects with NIDDM is partly explained by an association with established risk factors like hypertension, dyslipidemia, and obesity. Mild hyperhomocysteinemia has emerged as a new risk factor for cardiovascular disease. The purpose of this study was to assess its role in NIDDM.
Research design and methods: We studied predictors of homocysteine levels and correlations between homocysteine and (micro-)albuminuria, retinopathy, and history of cardiovascular disease in normotensive NIDDM subjects under stable metabolic control. This was done in 85 NIDDM subjects by measuring fasting and post-methionine-loading homocysteine levels together with blood pressure, BMI, serum cholesterol, triglyceride, HDL cholesterol, folate, vitamin B12, pyridoxal-5-phosphate, HbA1c, and (micro-)albuminuria and creatinine clearance in triplicate 24-h urine samples. The relationship between micro- and macrovascular complications and fasting homocysteine only was studied in an additional 65 subjects, giving a total of 150 subjects.
Results: In multiple regression analysis, significant (P < 0.05) predictors of fasting homocysteine were low-normal values of creatinine clearance (threshold effect at < 80 ml.min-1 .1.73 m-2), folate (< 20 nmol/l), and vitamin B12 (< 350 pmol/l), and postmenopausal status in women. Determinants of post-methionine homocysteine were pyridoxal-5-phosphate levels < 80 nmol/l, creatinine clearance, and sex (higher levels in women). Hyperhomocysteinemia did not cluster with other cardiovascular risk factors, like hypertension, obesity, or dyslipidemia. Regarding cardiovascular complications, fasting homocysteine, but not post-methionine homocysteine, was higher in subjects with a history of cardiovascular disease. There was a stepwise increase in the prevalence of subjects with cardiovascular disease with increasing fasting homocysteine. The prevalence of cardiovascular disease was 19.4% in the bottom quartile of fasting homocysteine, versus 55.0% in the top quartile (P for trend < 0.01). Neither fasting homocysteine nor post-methionine homocysteine correlated with (micro-)albuminuria or with retinopathy.
Conclusions: The findings suggest that homocysteine levels in NIDDM rise even with modest deterioration of renal function and when vitamin status is in the low to low-normal range. Fasting homocysteine correlates with macrovascular disease, but we found no evidence of a correlation with retinopathy or (micro-)albuminuria. Post-methionine homocysteine levels do not show a correlation with micro- or macrovascular complications.