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OBJECTIVE: Albuminuria is thought to be a biomarker of microvascular and macrovascular endothelial dysfunction. However, direct evidence for an association of microvascular endothelial dysfunction with albuminuria is limited. In addition, experimental data suggest a stronger association of microvascular endothelial dysfunction with albuminuria in individuals with than in those without diabetes.METHODS: We examined cross-sectional associations of flicker light-induced retinal arteriolar dilation (n = 2095) and heat-induced skin hyperemia (n = 1508) with 24-h albuminuria in the population-based, diabetes-enriched Maastricht Study. We used linear regression analyses to adjust for age, sex, type 2 diabetes, and cardiovascular disease risk factors. In addition, we tested for statistical interaction with type 2 diabetes.RESULTS: Median [interquartile range] albuminuria was 6.5 [3.9-11.6] mg/24 h and 8.2% had albuminuria at least 30 mg/24 h. After adjustment, albuminuria was 1.168 (95% confidence interval, 1.046-1.303) times greater in participants in the quartile with the smallest flicker light-induced retinal arteriolar dilation relative to those with the greatest dilation, and this association was stronger in participants with type 2 diabetes (Pinteraction < 0.10). Further, each 100 percentage points lower heat-induced skin hyperemia was associated with a 1.022 (1.010-1.035) times greater albuminuria in participants with type 2 diabetes, whereas it was not associated with albuminuria in nondiabetic participants (Pinteraction < 0.10).CONCLUSION: This is the first population-based study that provides direct evidence that microvascular endothelial dysfunction is associated with albuminuria, and that this association is stronger in individuals with than in those without type 2 diabetes.

OBJECTIVE: Albuminuria is thought to be a biomarker of microvascular and macrovascular endothelial dysfunction. However, direct evidence for an association of microvascular endothelial dysfunction with albuminuria is limited. In addition, experimental data suggest a stronger association of microvascular endothelial dysfunction with albuminuria in individuals with than in those without diabetes.METHODS: We examined cross-sectional associations of flicker light-induced retinal arteriolar dilation (n = 2095) and heat-induced skin hyperemia (n = 1508) with 24-h albuminuria in the population-based, diabetes-enriched Maastricht Study. We used linear regression analyses to adjust for age, sex, type 2 diabetes, and cardiovascular disease risk factors. In addition, we tested for statistical interaction with type 2 diabetes.RESULTS: Median [interquartile range] albuminuria was 6.5 [3.9-11.6] mg/24 h and 8.2% had albuminuria at least 30 mg/24 h. After adjustment, albuminuria was 1.168 (95% confidence interval, 1.046-1.303) times greater in participants in the quartile with the smallest flicker light-induced retinal arteriolar dilation relative to those with the greatest dilation, and this association was stronger in participants with type 2 diabetes (Pinteraction < 0.10). Further, each 100 percentage points lower heat-induced skin hyperemia was associated with a 1.022 (1.010-1.035) times greater albuminuria in participants with type 2 diabetes, whereas it was not associated with albuminuria in nondiabetic participants (Pinteraction < 0.10).CONCLUSION: This is the first population-based study that provides direct evidence that microvascular endothelial dysfunction is associated with albuminuria, and that this association is stronger in individuals with than in those without type 2 diabetes.

Poor growth before birth is associated with impaired insulin sensitivity later in life, increasing the risk of type 2 diabetes. The tissue sites at which insulin resistance first develops after intrauterine growth restriction (IUGR), and its molecular basis, are unclear. We have therefore characterized the effects of placental restriction (PR), a major cause of IUGR, on whole-body insulin sensitivity and expression of molecular determinants of insulin signaling and glucose uptake in skeletal muscle and liver of young lambs. Whole-body insulin sensitivity was measured at 30 d by hyperinsulinaemic euglycaemic clamp and expression of insulin signaling genes (receptors, pathways, and targets) at 43 d in muscle and liver of control (n = 15) and PR (n = 13) lambs. PR reduced size at birth and increased postnatal growth, fasting plasma glucose (+15%, P = 0.004), and insulin (+115%, P = 0.009). PR reduced whole-body insulin sensitivity (-43%, P < 0.001) and skeletal muscle expression of INSR (-36%), IRS1 (-28%), AKT2 (-44%), GLUT4 (-88%), GSK3α (-35%), and GYS1 (-31%) overall (each P < 0.05) and decreased AMPKγ3 expression in females (P = 0.030). PR did not alter hepatic expression of insulin signaling and related genes but increased GLUT2 expression (P = 0.047) in males. Whole-body insulin sensitivity correlated positively with skeletal muscle expression of IRS1, AKT2, HK, AMPKγ2, and AMPKγ3 in PR lambs only (each P < 0.05) but not with hepatic gene expression in control or PR lambs. Onset of insulin resistance after PR and IUGR is accompanied by, and can be accounted for by, reduced expression of insulin signaling and metabolic genes in skeletal muscle but not liver.