Klein, Christopher J.

OBJECTIVE—The objective of this study was to test whether monotone worsening of nerve function, attributable to diabetes, can be demonstrated before criteria for diabetic sensorimotor polyneuropathy (DSPN) have been met. Which nerve tests are best? RESEARCH DESIGN AND METHODS—From a prevalence cohort of 504 individuals in the Rochester Diabetic Neuropathy study (RDNS), we identified 238 individuals (group 1) who at first examination were without polyneuropathy (DSPN) by a sum score of the normal deviates (from percentiles) of five attributes of nerve conduction of the legs (i.e., their five nerve conduction normal deviate values were <97.5th percentile) and were followed longitudinally two or more times. Of these 238, 90 (group 2) were followed six or more times at yearly or biyearly intervals. We compared different nerve tests for the ones most sensitive and reliable in showing latent nerve dysfunction and monotone (the extent to which a variable measured repeatedly over time reveals a significant trend of worsening or improvement). RESULTS—In group 1 patients, the mean sum score of five attributes of nerve conduction (Σ 5 NC nds) at baseline was 1.08 and at the last examination (only patients with Σ 5 NC nds <97.5th percentile) was 3.63, markedly higher than that in healthy subjects (only of individuals with Σ 5 NC nds <97.5th percentile) (−0.12), indicating a subtle latent shift of nerve conduction tests toward abnormality. Serial evaluations of many individual and especially sum scores of nerve conduction tests in group 2 patients showed statistically significant worsening with time, even when nerve conduction tests were still well within normal limits. Neurologic signs also worsened but barely to significant levels; however, symptoms and quantitative sensation tests did not. Considering the composite score Σ 5 NC nds, 42 (of 90 group 2 patients) showed significant worsening, 22 were still without DSPN by nerve conduction test criteria, and some were even below the 50th percentile at the last evaluation. CONCLUSIONS—Subtle and latent functional worsening of nerve conduction can be demonstrated even before nerve conduction test criteria for DSPN have been met. For demonstrating monotone worsening, the order (from best to worst) of tests was: some composite scores of nerve conduction and individual attributes of nerve conduction. We did not show monotone worsening of symptoms or of quantitative sensation test results. In multivariate analysis of risk factors and their association with worsening Σ 5 NC nds, 24-h microalbuminuria (a marker of microvessel disease) was found to be a significant covariate, an indication that the asymptomatic alterations of nerve conduction are meaningful.

OBJECTIVE—The degree to which chronic glycemic exposure (CGE) (fasting plasma glucose [FPG], HbA1c [A1C], duration of diabetes, age at onset of diabetes, or combinations of these) is associated with or predicts the severity of microvessel complications is unsettled. Specifically, we test whether combinations of components correlate and predict complications better than individual components. RESEARCH DESIGN AND METHODS—Correlations and predictions of CGE and complications were assessed in the Rochester Diabetic Neuropathy Study, a population-based, cross-sectional, and longitudinal epidemiologic survey of 504 patients with diabetes followed for up to 20 years. RESULTS—In multivariate analysis, A1C and duration of diabetes (and to a lesser degree age at onset of diabetes but not FPG) were the main significant CGE risk covariates for complications. A derived glycemic exposure index (GEi) correlated with and predicted complications better than did individual components. Composite or staged measures of polyneuropathy provided higher correlations and better predictions than did dichotomous measures of whether polyneuropathy was present or not. Generally, the mean GEi was significantly higher with increasing stages of severity of complications. CONCLUSIONS—A combination of A1C, duration of diabetes, and age at onset of diabetes (a mathematical index, GEi) correlates significantly with complications and predicts later complications better than single components of CGE. Serial measures of A1C improved the correlations and predictions. For polyneuropathy, continuous or staged measurements performed better than dichotomous judgments. Even with intensive assessment of CGE and complications over long times, only about one-third of the variability of the severity of complications is explained, emphasizing the role of other putative risk covariates.