Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes

Abnormalities in vascular reactivity in the micro- and macrocirculation are well established in type 2 diabetes. However, little is known about change s in vascular reactivity in those at risk for developing type 2 diabetes. T o address this situation the vascular reactivity in both the micro- and mac rocirculation was studied in four age and sex comparable groups: 30 healthy normoglycemic subjects with no history of type 2 diabetes in a first-degre e relative (controls), 39 healthy normoglycemic subjects with a history of type 2 diabetes in one or both parents (relatives), 32 subjects with impair ed glucose tolerance (IGT), and 42 patients with type 2 diabetes without va scular complications (diabetes). Laser Doppler perfusion imaging was used t o measure vasodilation in the forearm skin in response to ioatophoresis of 1% acetylcholine chloride (Ach) (endothelium-dependent) and 1% sodium nitro prusside (SNP) (endothelium-independent), whereas high-resolution ultrasoun d images were used to measure brachial artery diameter changes during react ive hyperemia. Plasma concentrations of endothelin-1 (ET-1), vonWillebrand factor (vWF), soluble intercellular adhesion molecule (sICAM), and soluble vascular cell adhesion molecule (sVCAM) were also measured as indicators of endothelial cell activation. The vasodilatory responses to Ach, expressed as percent increase of blood flow over baseline, were reduced in relatives (98 +/- 48, mean +/- SD), IGT (94 +/- 52), and diabetes (74 +/- 45) compare d with controls (126 +/- 67) (P < 0.001 controls versus relatives, IGT, and diabetes). The responses to SNP were similarly reduced: controls (123 +/- 46), relatives (85 +/- 46), IGT (83 +/- 48), and diabetes (65 +/- 31) (P < 0.001 controls versus relatives, IGT, and diabetes) as were the responses i n the brachial artery diameter during reactive hyperemia: controls (13.7 +/ - 6.1), relatives (10.5 +/- 6.7), IGT (9.8 +/- 4.5), and diabetes (8.4 +/- 5.0) (P < 0.01 controls versus relatives, IGT, and diabetes). Women had gre ater responses than men in both the micro- and macrovascular circulatory te sts, but a similar progressive reduction was observed in both sexes with in creasing degrees of glucose intolerance. A significant inverse correlation was found between microvascular reactivity and systolic blood pressure fast ing plasma glucose, HDL cholesterol, fasting plasma insulin, and homeostasi s model assessment (HOMA) values, an index of insulin resistance. BMI and d iastolic blood pressure had a significant inverse correlation only with end othelium-dependent; vasodilation. In the macrocirculation, systolic blood p ressure, HbA(1c), HDL cholesterol, and HOMA had significant correlation wit h brachial artery diameter changes. Compared with control subjects, ET-1 wa s significantly higher in all groups, vWF was higher only in the diabetic g roup, sICAM levels were higher in the IGT and diabetic groups, while sVCAM concentrations were higher in the relatives and those with diabetes (P < 0. 05). On stepwise multivariate analysis, age, sex, fasting plasma glucose an d BMI were the most important; contributing factors to the variation of vas cular reactivity. Addition of all clinical and biochemical measures explain ed only 32-37% of the variation in vascular reactivity. These results sugge st that abnormalities in vascular reactivity and biochemical markers of end othelial cell activation are present early in individuals at risk of develo ping type 2 diabetes, even at; a stage when normal glucose tolerance exists , and that factors in addition to insulin resistance may be operative.