Hypertension Management and Microvascular Insulin Resistance in Diabetes

Abstract

Type 2 diabetes is in essence a vascular disease and is frequently associated with hypertension, macrovascular events, and microvascular complications. Microvascular dysfunction, including impaired recruitment and capillary rarefaction, has been implicated in the pathogenesis of diabetic complications. Microvascular insulin resistance and renin-angiotensin system upregulation are present in diabetes, and each contributes to the development of hypertension and microvascular dysfunction. In the insulin-sensitive state, insulin increases microvascular perfusion by increasing endothelial nitric oxide production, but this effect is abolished by insulin resistance. Angiotensin II, acting via the type 1 receptors, induces inflammation and oxidative stress, leading to impaired insulin signaling, reduced nitric oxide availability, and vasoconstriction. Conversely, it acts on the type 2 receptors to cause vasodilatation. Because substrate and hormonal exchanges occur in the microvasculature, antihypertensive agents targeted to improve microvascular insulin sensitivity and function may have beneficial effects beyond their capacity to lower blood pressure in patients with diabetes.

Cutaneous iontophoresis of treprostinil, a prostacyclin analog, increases microvascular blood flux in diabetic malleolus area

“…However, the area under the curve was smaller in diabetics, though this result should be taken with caution given that it was a post hoc analysis using two groups that were unmatched for sex and age. It could be explained by the decreased microvascular density or function in diabetes mellitus (Ko et al, 2010), but we did not quantify microvascular density in our study.…”

Exercise Training Reverses Structural Microvascular Rarefaction and Improves Endothelium-Dependent Microvascular Reactivity in Rats with Diabetes

“…36 This phenomenon, coupled with the activation of the inflammatory response and increased recruitment of leukocytes in postcapillary venules, may result in capillary obstruction and decreased capillary perfusion. These processes may result in the temporary obstruction of blood flow (functional capillary rarefaction), followed by disappearance of the capillaries (structural capillary rarefaction).…”

Protein kinase A mediates glucagon-like peptide 1-induced nitric oxide production and muscle microvascular recruitment

“…We have reported recently that GLP-1 acutely increases muscle glucose use via increased muscle microvascular recruitment and insulin delivery through a nitric oxide (NO)-dependent mechanism (8). We and others have shown in the past that factors increasing NO production are able to recruit muscle microvasculature, leading to increased endothelial exchange surface area and substrate and hormonal exchanges between plasma and muscle interstitium (4,5,12,24).Endothelial NO synthase (eNOS) is regulated by signaling pathways involving multiple sites of phosphorylation. The coordinated phosphorylation of eNOS at Ser 1177 and dephosphorylation at Thr 497 activate whereas Ser 1177 dephosphorylation and Thr 497 phosphorylation deactivate the enzyme.…”