Individuals with type 2 diabetes mellitus (T2DM) often exhibit microvascular dysfunction that may contribute to impaired thermoregulation, but potential mechanisms remain unclear. Our goals were to quantify skin blood flow responses and nitric oxide-mediated vasodilation during body heating in individuals with T2DM compared with nondiabetic control subjects of similar age. We measured skin blood flow (laser-Doppler flowmetry) in conjunction with intradermal microdialysis of N(G)-nitro-l-arginine methyl ester (l-NAME; nitric oxide synthase inhibitor) or vehicle during 45-60 min of whole body heating (WBH) in 10 individuals with T2DM and 14 control subjects. In six individuals from each group, we also measured forearm blood flow (FBF) by venous occlusion plethysmography on the contralateral forearm. FBF responses showed diminished absolute cutaneous vasodilation during WBH in the T2DM group (P(ANOVA) < 0.01; peak FBF in control 13.1 +/- 1.7 vs. T2DM 9.0 +/- 1.6 ml.100 ml(-1).min(-1)). However, the relative contribution of nitric oxide to the cutaneous vasodilator response (expressed as % of maximal cutaneous vascular conductance) was not different between groups (P > 0.05). We conclude that cutaneous vasodilator responses to WBH are decreased in individuals with T2DM, but the contribution of nitric oxide to this smaller vasodilation is similar between T2DM and control individuals. This decrease in cutaneous vasodilation is likely an important contributor to impaired thermoregulation in T2DM.

In humans, sympathetic vasoconstrictor nerves in the skin contribute to resting vascular tone and mediate reflex vasoconstrictor responses to body cooling. Although it is well recognized that type 2 diabetes mellitus (T2DM) is associated with peripheral neurovascular changes, it is unclear to what extent the thermal responsiveness of the cutaneous vasoconstrictor system is altered in individuals with relatively uncomplicated T2DM. We tested the hypothesis that skin sympathetic nerve activity (SSNA) is decreased at baseline and during body cooling in individuals with T2DM compared to healthy controls (C) of similar age and body size. We measured SSNA (microneurography) and skin blood flow (laser-Doppler flowmetry) in the innervated area in 8 T2DM and 12 C subjects at baseline and during 3-4 minutes of rapid whole body cooling via water-perfused suit. SSNA (total integrated activity) increased, and cutaneous vascular conductance decreased in both groups during body cooling (P < 0.01 for both). However, SSNA was not different between groups during either baseline or body cooling conditions (P = NS). The deltas in SSNA between baseline and body cooling were similar between groups: T2DM: 55 ± 27 and C: 57 ± 12 units (P = NS). We conclude that reflex cutaneous sympathetic and vascular responses to rapid whole body cooling are preserved in relatively healthy individuals with T2DM.

SM, Charkoudian N. Local sensory nerve control of skin blood flow during local warming in type 2 diabetes mellitus. J Appl Physiol 108: 293-297, 2010. First published December 3, 2009 doi:10.1152/japplphysiol.01077.2009.-Cutaneous sensory nerve-mediated vasodilation is an important component of normal microvascular responsiveness to thermal and nonthermal stimuli. Since both neural and microvascular function can be impaired in type 2 diabetes mellitus (T2DM), we tested the hypothesis that local sensory nerve-mediated vasodilation during nonpainful local warming of the skin is less in T2DM compared with healthy controls (C) matched for age and body size. The rapid vasodilation during the first ϳ5 min of this local warming ("initial peak") was previously shown to rely primarily on local sensory nerves. We measured skin blood flow in T2DM and C subjects (n ϭ 7 in each group) at baseline and during 35 min of local warming of the skin to 42°C at two sites on the ventral forearm. One site was pretreated with 4% lidocaine (LIDO) to block local sensory innervation. During local warming, cutaneous vascular conductance (CVC) during the initial peak was not different between groups, either at the untreated site [T2DM 75 Ϯ 2 vs. C 81 Ϯ 6% of maximum CVC (%maxCVC); P Ͼ 0.05] or at the LIDO site (T2DM 63 Ϯ 7 vs. C 64 Ϯ 6%maxCVC; P Ͼ 0.05). The difference between untreated and LIDO sites (sensory nerve contribution) was also similar between groups (T2DM 13 Ϯ 5 vs. C 18 Ϯ 5%maxCVC; P Ͼ 0.05) and was smaller with LIDO than was previously shown with other local anesthetics. Our results suggest that relatively healthy individuals with T2DM do not exhibit impairments in local sensory nerve vasodilation during thermal stimulation compared with controls of similar age and body size. cutaneous circulation; vasodilation; temperature; metabolic syndrome IN HUMANS, nonpainful local warming of the skin elicits a biphasic vasodilation involving local sensory nerve mechanisms and nitric oxide (6, 8). Initial, rapid blood flow increases during the first 3-5 min (called the "initial peak" of the vasodilator response) are thought to be caused primarily by direct action of local sensory nerves, potentially through release of local vasodilators such as calcitonin gene-related peptide (CGRP) and substance P (5, 8). The second phase of the vasodilation is nitric oxide dependent and occurs over a longer period, typically 25-30 min, after which a plateau in blood flow is reached (6,8).Type 2 diabetes mellitus (T2DM) is strongly associated with neural and microvascular dysfunction. As the incidence and prevalence of T2DM are increasing, also increasing are the number of individuals who are otherwise relatively healthy and live with T2DM but manage it well so that the number of comorbid conditions is minimal. We have therefore focused our efforts on this growing population in our attempts to understand mechanisms of cutaneous microvascular dysfunction in T2DM (12)(13)(14). Recent studies in our laboratory have shown that relatively healthy individual...

Arterial blood pressure can often fall too low during dehydration, leading to an increased incidence of orthostatic hypotension and syncope. Systemic sympathoexcitation and increases in volume regulatory hormones such as angiotensin II (AngII) may help to maintain arterial pressure in the face of decreased plasma volume. Our goals in the present study were to quantify muscle sympathetic nerve activity (MSNA) during dehydration (DEH), and to test the hypothesis that endogenous increases in AngII in DEH have a mechanistic role in DEH-associated sympathoexcitation. We studied 17 subjects on two separate study days: DEH induced by 24 h fluid restriction and a euhydrated (EUH) control day. MSNA was measured by microneurography at the peroneal nerve, and arterial blood pressure, electrocardiogram, and central venous pressure were also recorded continuously. Sequential nitroprusside and phenylephrine (modified Oxford test) were used to evaluate baroreflex control of MSNA. Losartan (angiotensin type 1 receptor (AT1) antagonist) was then administered and measurements were repeated. MSNA was elevated during DEH (42 ± 5 vs. EUH: 32 ± 4 bursts per 100 heartbeats, P = 0.02). Blockade of AT1 receptors partially reversed this change in MSNA during DEH while having no effect in the control EUH condition. The sensitivity of baroreflex control of MSNA was unchanged during DEH compared to EUH. We conclude that endogenous increases in AngII during DEH contribute to DEH-associated sympathoexcitation.

This study examined the relationship between airway blood flow (Q̇a w ), ventilation (V̇E) and cardiac output (Q̇t ot ) during exercise in healthy humans (n = 12, mean age 34 ± 11 yr). Q̇a w was estimated from the uptake of the soluble gas dimethyl ether while V̇E and Q̇t ot were measured using open circuit spirometry. Measurements were made prior to and during exercise at 34 ± 5W (Load 1) and 68 ± 10 W (Load 2) and following the cessation of exercise (recovery). Q̇a w increased in a stepwise fashion (P < 0.05) from rest (52.8 ± 19.5 µl min −1 ml −1 ) to exercise at Load 1 (67.0 ± 20.3 µl min −1 ml −1 ) and Load 2 (84.0 ± 22.9 µl min −1 ml −1 ) before returning to pre-exercise levels in recovery (51.7 ± 13.2 µl min −1 ml −1 ). Qȧ w was positively correlated with both Q̇t ot (r = 0.58, P < 0.01) and V̇E (r = 0.50, P < 0.01). These results demonstrate that the increase in Qȧ w is linked to an exercise related increase in both Q̇t ot and V̇E and may be necessary to prevent excessive airway cooling and drying.