Dermal Neurovascular Dysfunction in Type 2 Diabetes

Abstract

OBJECTIVE -To review evidence for a relationship between dermal neurovascular dysfunction and other components of the metabolic syndrome of type 2 diabetes.RESEARCH DESIGN AND METHODS -We review and present data supporting concepts relating dermal neurovascular function to prediabetes and the metabolic syndrome. Skin blood flow can be easily measured by laser Doppler techniques.RESULTS -Heat and gravity have been shown to have specific neural, nitrergic, and independent mediators to regulate skin blood flow. We describe data showing that this new tool identifies dermal neurovascular dysfunction in the majority of type 2 diabetic patients. The defect in skin vasodilation is detectable before the development of diabetes and is partially correctable with insulin sensitizers. This defect is associated with C-fiber dysfunction (i.e., the dermal neurovascular unit) and coexists with variables of the insulin resistance syndrome. The defect most likely results from an imbalance among the endogenous vasodilator compound nitric oxide, the vasodilator neuropeptides substance P and calcitonin gene-related peptide, and the vasoconstrictors angiotensin II and endothelin. Hypertension per se increases skin vasodilation and does not impair the responses to gravity, which is opposite to that of diabetes, suggesting that the effects of diabetes override and counteract those of hypertension.CONCLUSIONS -These observations suggest that dermal neurovascular function is largely regulated by peripheral C-fiber neurons and that dysregulation may be a component of the metabolic syndrome associated with type 2 diabetes. Diabetes Care 24:1468 -1475, 2001A number of functional disturbances are found in the dermal microvasculature of diabetic subjects. These include decreased microvascular blood flow (1), increased vascular resistance (2), decreased tissue PO 2 (3), and altered vascular permeability characteristics, such as loss of the anionic charge barrier and decreased charge selectivity. Decreased microvascular blood flow and increased vascular resistance in diabetes could result from alterations in dermal neurovascular function, such as impaired dilator responses to substance P, calcitonin gene-related peptide (CGRP), and reactivity to nociceptive stimulation. Diabetes also disrupts vasomotion-the rhythmic contraction exhibited by arterioles and small arteries (4,5). Unmyelinated C-fibers, which constitute the central reflex pathway, are assumed to be damaged in diabetic neuropathy, contributing to abnormalities in cutaneous blood flow (6). Warm thermal sensation is a functional measure of C-fibers in the periphery, and the impairment of this function was paralleled by a reduction of vasomotion. These findings support an interaction between small unmyelinated C-fiber function and vasomotion, although it is not clear whether the neurological deficit precedes or follows the loss of baseline vascular response. A clear relationship between skin microvascular insufficiency and neuropathy has not yet been established. It is possible that ski...

Neurovascular microcirculatory vasodilation mediated by C-fibers and Transient receptor potential vanilloid-type-1 channels (TRPV 1) is impaired in type 1 diabetes

“…Heat-induced vasodilation is due to nerve fibers for the early peak and to the NO-dependent pathway and the EDHF-dependent pathway for the late plateau2452.…”

Prospects of Laser Doppler flowmetry application in assessment of skin microcirculation in diabetes

“…Важно отметить то, что изменения вазомоций в коже могут наблюдаться у лиц с инсулинорезистентностью еще до манифестации СД 2 типа [44]. Это связано с на-рушениями нейрогенного вазодилататорного механизма, реализуемого посредством ноцицептивных немиелини-зированных С-волокон (поражение этих волокон также отражается в снижении вазодилататорной реакции на на-грев) [45].…”

NRP-1 Receptor Expression Mismatch in Skin of Subjects with Experimental and Diabetic Small Fiber Neuropathy

“…Though the precise mechanism of this process is poorly understood, it is proposed that interplay among endothelial dysfunction, impaired nerve axon reflex activities, and microvascular regulation due to hyperglycemia in diabetes may play a significant role [31]. Hyperglycemia leads to reduced supply of oxygen to nerves and tissues; hypoxia impedes the viability of tissues and the wound healing process [32,33] and induces the expression of several angiogenic genes, most notably vascular endothelial growth factor (VEGF) through the HIF-1 pathway [34–36]. The HIF-1-mediated transactivation and subsequent angiogenic abilities are functionally inhibited in diabetes, resulting in an impairment to restore blood flow to ischemic regions [35,37,38] and leading to vascular complications [39].…”