Longitudinal Association of Glycemia and Microalbuminuria

James B. Meigs, MD, MPH, Ralph B. D’Agostino, Sr., PHD, David M. Nathan, MD, Nader Rifai, PHD, Peter W.F. Wilson, MD

Disclosures

Diabetes Care. 2002;25(6) 

In This Article

Abstract and Introduction

Objective. To assess current and long-term associations of glycemia with microalbuminuria, a marker of generalized endothelial injury.
Research Design and Methods. 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.
Results. 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.
Conclusions. Long-term hyperglycemia and subdiabetic glycemia increase risk for microalbuminuria. Microalbuminuria, type 2 diabetes, and CVD seem to arise together over the course of decades, consistent with the hypothesis that they share a common antecedent.

Microalbuminuria, a mildly abnormal elevation in urinary albumin excretion, is a harbinger of progression to nephropathy in diabetes as well as a powerful predictor of cardiovascular disease (CVD) in both diabetic and nondiabetic subjects [1–3]. Microalbuminuria is usually absent at diagnosis of type 1 diabetes but may be present at diagnosis of type 2 diabetes [4,5], partly because diagnosis is often delayed. Risk for microalbuminuria is proportional to the level and duration of hyperglycemia, with rates increasing within ~5 years of onset of diabetes [6–8]. Aggressive glycemic control in diabetes prevents its onset and progression, demonstrating that hyperglycemia over the course of several years is a cause of microalbuminuria [9,10]. However, temporal associations between subdiabetic glycemia and risk for microalbuminuria are not as well established.

Microalbuminuria also reflects diffuse vasculopathy and endothelial dysfunction, which in large arterial beds hypothetically leads to atherosclerosis and, in the microcirculation, may precede or contribute to development of insulin resistance and type 2 diabetes [11]. The hypothesis that endothelial dysfunction is the "common soil" for the insulin resistance syndrome provides a plausible mechanism linking microalbuminuria, type 2 diabetes, and CVD [12,13]. Several different studies suggest that the development of microalbuminuria, type 2 diabetes, insulin resistance, or CVD may each precede the development of the others, providing support for a common etiology [3,14–21].

If microalbuminuria is primarily caused by relatively recent hyperglycemia, then its development should be related to the recent onset of diagnosed diabetes. However, if microalbuminuria is also a marker of some "common soil," then it should also be associated with subdiabetic levels of glycemia over many years before the development of type 2 diabetes or CVD. In this study, we examined the current and long-term associations of glycemia with risk for microalbuminuria, type 2 diabetes, and CVD among participants in a community-based cohort study.

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