Association of Glycemia and Microalbuminuria Effecting Endothelial Function

Long-term hyperglycemia and subdiabetic glycemia increase risk for microalbuminuria. 

The object of the study was to assess current and long-term associations of glycemia with microalbuminuria, a marker of generalized endothelial injury.

We measured clinical characteristics, fasting plasma glucose, and the urinary albumin-to-creatinine ratio (UACR) in 1,311 men and 1,518 women attending the sixth examination cycle (1995–1998) of the Framingham Offspring Study. After excluding participants with diabetes or cardiovascular disease (CVD) at the baseline examination (1971–1974), we used fasting glucose measured at baseline, examination 6, and at least two additional examinations from 1974 to 1995 in regression models to predict risk for microalbuminuria (UACR >/=30 mg/g) associated with baseline, current, and 24-year time-integrated glycemia.

The results showed that Microalbuminuria was present in 9.5% of men and 13.4% of women. Among men, age-adjusted odds ratios (95% CI) for microalbuminuria associated with each 0.28 mmol/l (5 mg/dl) increase in baseline, current, and time-integrated glucose levels were 1.12 (1.00–1.16), 1.08 (1.05–1.10), and 1.16 (1.11–1.21), respectively. These effects persisted after adjustment for systolic blood pressure and other confounders. Higher glucose levels also predicted incident diabetes and CVD. Mean time-integrated glucose levels were highest among men who developed both CVD and microalbuminuria (SE 6.82 ± 0.16 mmol/l), intermediate among men with either condition (6.03 ± 0.65 mmol/l), and lowest among men with neither condition (5.49 ± 0.02 mmol/l; P < 0.001 for all pairwise comparisons). We observed similar associations in women.

In conclusion the results showed that hyperglycemia in the diabetic range can cause microalbuminuria. The study confirms that current and antecedent elevations in fasting plasma glucose are strongly associated with abnormal urinary albumin excretion. Controlled trials demonstrate that intensive lowering of blood glucose toward normal levels in patients with diabetes prevents the onset and progression of microalbuminuria, with a continuous graded relationship between level of glycemia and risk of abnormal urinary albumin excretion ^[6,9,10]. Mechanisms of glucose-related albuminuria include glycation of basement membrane proteins with loss of charge selectivity and glomerular hyperperfusion and hyperfiltration ^[28–30]. The clinical course of abnormal urinary albumin excretion in patients with diabetes is quite heterogeneous; 11–67% of patients progress to overt proteinuria over 5–15 years of follow-up ^[1,31,32]. An important novel finding of our study is that risk for microalbuminuria associated with hyperglycemia was detectable up to at least 24 years before assessment of urinary albumin excretion.  Long-term associations between metabolic risk factors strongly suggest that interventions to reduce insulin resistance and risk for diabetes and CVD should begin in childhood and extend well into adult life. Diabetes Care 25(6):977-983, 2002