A E Caballero 1, S Arora, R Saouaf, S C Lim, P Smakowski, J Y Park, G L King, F W LoGerfo, E S Horton, A Veves Affiliations expand
Abstract Abnormalities in vascular reactivity in the micro- and macrocirculation are well established in type 2 diabetes. However, little is known about changes in vascular reactivity in those at risk for developing type 2 diabetes. To address this situation, the vascular reactivity in both the micro- and macrocirculation was studied in four age and sex comparable groups: 30 healthy normoglycemic subjects with no history of type 2 diabetes in a first-degree relative (controls), 39 healthy normoglycemic subjects with a history of type 2 diabetes in one or both parents (relatives), 32 subjects with impaired glucose tolerance (IGT), and 42 patients with type 2 diabetes without vascular complications (diabetes). Laser Doppler perfusion imaging was used to measure vasodilation in the forearm skin in response to iontophoresis of 1% acetylcholine chloride (Ach) (endothelium-dependent) and 1% sodium nitroprusside (SNP) (endothelium-independent), whereas high-resolution ultrasound images were used to measure brachial artery diameter changes during reactive hyperemia. Plasma concentrations of endothelin-1 (ET-1), von Willebrand 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) compared 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 in 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 greater responses than men in both the micro- and macrovascular circulatory tests, but a similar progressive reduction was observed in both sexes with increasing degrees of glucose intolerance. A significant inverse correlation was found between microvascular reactivity and systolic blood pressure, fasting plasma glucose, HDL cholesterol, fasting plasma insulin, and homeostasis model assessment (HOMA) values, an index of insulin resistance. BMI and diastolic blood pressure had a significant inverse correlation only with endothelium-dependent vasodilation. In the macrocirculation, systolic blood pressure, HbA1c, HDL cholesterol, and HOMA had significant correlation with brachial artery diameter changes. Compared with control subjects, ET-1 was significantly higher in all groups, vWF was higher only in the diabetic group, 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, and BMI were the most important contributing factors to the variation of vascular reactivity. Addition of all clinical and biochemical measures explained only 32-37% of the variation in vascular reactivity. These results suggest that abnormalities in vascular reactivity and biochemical markers of endothelial cell activation are present early in individuals at risk of developing type 2 diabetes, even at a stage when normal glucose tolerance exists, and that factors in addition to insulin resistance may be operative.
Soluble intercellular adhesion molecule, vascular cell adhesion molecule, and impaired microvascular reactivity are early markers of vasculopathy in type 2 diabetic individuals without microalbuminuria.Lim SC, Caballero AE, Smakowski P, LoGerfo FW, Horton ES, Veves A.Diabetes Care. 1999 Nov;22(11):1865-70. doi: 10.2337/diacare.22.11.1865.PMID: 10546021
The effects of troglitazone, an insulin-sensitizing agent, on the endothelial function in early and late type 2 diabetes: a placebo-controlled randomized clinical trial.Caballero AE, Saouaf R, Lim SC, Hamdy O, Abou-Elenin K, O'Connor C, Logerfo FW, Horton ES, Veves A.Metabolism. 2003 Feb;52(2):173-80. doi: 10.1053/meta.2003.50023.PMID: 12601628 Clinical Trial.
Comparison of skin microvascular reactivity with hemostatic markers of endothelial dysfunction and damage in type 2 diabetes.Beer S, Feihl F, Ruiz J, Juhan-Vague I, Aillaud MF, Wetzel SG, Liaudet L, Gaillard RC, Waeber B.Vasc Health Risk Manag. 2008;4(6):1449-58. doi: 10.2147/vhrm.s4175.PMID: 19337558.
Kidney oxygenation during water diuresis and endothelial function in patients with type 2 diabetes and subjects at risk to develop diabetes.Economides PA, Caselli A, Zuo CS, Sparks C, Khaodhiar L, Katsilambros N, Horton ES, Veves A.Metabolism. 2004 Feb;53(2):222-7. doi: 10.1016/j.metabol.2003.09.019.PMID: 14767875 Clinical Trial.
[Microcirculation in diabetes: implications for chronic complications and treatment of the disease].Aguiar LG, Villela NR, Bouskela E.Arq Bras Endocrinol Metabol. 2007 Mar;51(2):204-11. doi: 10.1590/s0004-27302007000200009.PMID: 17505627 Review. Portuguese.