Hyperhomocysteinemia and Increased Risk of Retinopathy: A cross-sectional, case-control study in patients with type 2 diabetes

Increased total plasma homocysteine (tHcy) level—secondary to excessive alcohol intake, cigarette smoking, or deficiency of methylene-tetrahydrofolate reductase—is one new identified risk factor for atherosclerotic cardiovascular diseases and for macrovascular complications of diabetes (1,2). Homocysteine (Hcy)-induced vascular damage is probably initiated by reactive oxygen species formed during Hcy auto-oxidation in plasma and results in decreased nitric oxide production, platelet activation, impaired arterial vasodilatation, and isolated systolic hypertension (1).

To assess whether hyperhomocysteinemia is also an independent risk factor for microvascular complications, we cross-sectionally studied the relations among tHcy levels, diabetic retinopathy (diagnosed by indirect ophtalmoscopy and retinal photography), insulin sensitivity and glomerular filtration rate (measured by euglycemic-hyperinsulinemic clamp and unlabeled iohexol plasma clearance, respectively), lipid profile, overnight urinary albumin excretion rate, and other clinical and laboratory parameters in 11 consecutive type 2 diabetic subjects with retinopathy (case subjects) and 26 age- and sex-matched type 2 diabetic subjects without retinopathy (control subjects). To limit the confounding effect of decreased tHcy clearance associated with advanced renal insufficiency, only subjects with serum creatinine ≤2.0 mg/dl were considered. Patients gave written informed consent. The Ethical Committee of the Clinical Research Center, “Aldo & Cele Daccò,” Mario Negri Institute, Italy, approved the protocol.

Altogether, 1 case subject had proliferative and 10 subjects had nonproliferative diabetic retinopathy. Prevalence of hyperhomocysteinemia (54.5 vs. 26.9%) and tHcy levels (17.2 ± 6.6 vs. 12.3 ± 4.1 μmol/l, P < 0.05) were higher in case than in control subjects. Case subjects also had longer diabetes duration (171 ± 96 vs. 73 ± 75 months), lower BMI (27 ± 5 vs. 31 ± 5 kg/m²), higher systolic blood pressure (155 ± 15 vs. 145 ± 12 mmHg) and albumin excretion rate (412 ± 600 vs. 212 ± 385 μg/min), and were more frequently micro- or macroalbuminuric (P < 0.05 for all comparisons). Age, sex distribution (with a male prevalence in both groups), smoking habit, HbA_1c level, diastolic blood pressure, insulin sensitivity, lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides), serum creatinine, glomerular filtration rate, and antidiabetic and antihypertensive treatments were comparable in both groups. At univariate logistic regression analysis, only longer duration of diabetes, higher systolic blood pressure, and increased tHcy levels were associated with diabetic retinopathy. Glomerular filtration rate was not related to diabetic retinopathy (P > 0.05). At multivariate forward stepwise logistic regression, tHcy (β = 4.47, P = 0.019), diabetes duration (β = 2.10, P = 0.009), and systolic blood pressure (β = 0.09, P = 0.020) were independent markers of diabetic retinopathy. Altogether, they predicted the disease with 86.5% accuracy (model χ² = 23.19, P = 0.0001).

Thus, hyperhomocysteinemia is associated with an increased risk of diabetic retinopathy and clusters with longer diabetes duration and systolic hypertension as an independent marker. The finding that case subjects had higher albumin excretion rates than control subjects and were more frequently micro- or macroalbuminuric suggests that hyperhomocysteinemia is also an indicator of overall microvascular damage in type 2 diabetes.

Hcy evaluation may serve to identify diabetic patients predisposed to sight-threatening complications who may benefit from intensified screening and treatment strategies, including folic acid and vitamin B₆ and B₁₂ supplements, aimed to limit or prevent the incidence and progression of micro- and macrovascular complications.