Primary nociceptive afferents mediate the blood flow dysfunction in non-glabrous (hairy) skin of type 2 diabetes: a new model for the pathogenesis of microvascular dysfunction.

OBJECTIVE: To test the independent contributions of vascular endothelium, sympathetic activation and inhibition, vessel distensibility, and nociceptor-mediated vasodilation in both glabrous and hairy skin circulations. RESEARCH DESIGN AND METHODS: We measured blood flow using laser Doppler techniques in 10 people with type 2 diabetes and 10 age- and BMI-matched healthy control subjects at the pulp of the index finger (glabrous skin) and the dorsum of the hand (hairy skin). A 5-min ischemic block of the arm was used to test vascular endothelium. Warming of the probe site to 45 degrees C tested neurogenic vasodilation in hairy skin only. Vessel distensibility was tested by gravitational pressure. RESULTS: Basal blood flow and reactive hyperemia did not differ between groups at either skin site. The vasodilative response to local warming (P < 0.01) and limb lowering (P < 0.05) were significantly different between groups in hairy skin but not in glabrous skin in the absence of objective measured neuropathy. Nociceptor-mediated flow correlated significantly with the warm thermal threshold (r = -0.50, P < 0.05). Endothelial-mediated blood flow correlated with systolic blood pressure (r = -0.76, P < 0.01), LDL cholesterol (r = -0.62, P < 0.001), C-peptide (r = 0.65, P < 0.05), and triglycerides (r = 0.47, P < 0.05). CONCLUSIONS: These data suggest that neurogenic nociceptor-mediated vasodilation is impaired in subjects with type 2 diabetes when endothelial and sympathetic function are relatively intact. Heat-induced vasodilation may be a specific test of small heat-sensitive C-fiber peripheral neurons and may be an integral part of the metabolic syndrome.

Normal blood flow response and vasomotion in the diabetic Charcot foot.

Vasomotion, the spontaneous rhythmic contraction exhibited by small arteries and arterioles is dysregulated in patients with diabetic neuropathy. We examined the relationship between Charcot arthropathy and vasomotion at the dorsum of the foot. We studied nine diabetic patients with clinically diagnosed neuropathy and Charcot arthropathy in 13 feet (n=13), twelve subjects with diabetic neuropathy and no Charcot deformity (n=12), and 11 healthy controls (n=11). Following neuropathy assessment, blood flow was measured by laser Doppler flowmetry with local skin warming. Fast Fourier transformation was performed to provide an index of vasomotion. Subjects with Charcot osteoarthropathy had more severe somatic neuropathy and higher circulating levels of serum calcium (9.8+/-0.1 versus 9.3+/-0.1 mg/dL). Raising local temperature increased skin blood flow and vasomotion in both control subjects and Charcot subjects, but not in diabetic patients with neuropathy alone (p < 0.05 for blood flow, p < 0.02 for vasomotion). Patterns of peripheral vasomotion and blood flow which are clearly disordered in diabetic neuropathy are intact in patients with a Charcot osteoarthropathy, despite a more severe sensory nerve impairment. These findings suggest that the loss of peripheral blood flow and vasomotion often seen in diabetic neuropathy may actually be protective against Charcot arthropathy by preventing bone resorption. It remains unclear then whether the Charcot arthropathy is a direct result of a failure to decrease blood flow to bone, or is the manifestation of some other pathology.

Impairment of peripheral blood flow responses in diabetes resembles an enhanced aging effect.

OBJECTIVE: To test the hypothesis that skin blood flow responses in the fingertip of diabetic patients are impaired and to examine the role of aging in both healthy control subjects and diabetic patients. RESEARCH DESIGN AND METHODS: We measured cutaneous blood flow using laser Doppler techniques in 40 people with diabetes and in 20 age- and sex-matched healthy control subjects. To induce vasoconstriction, subjects were asked to perform three 1-min stressor tasks: mental arithmetic, contralateral hand grip, and immersion of the contralateral hand in ice water. To induce vasodilatation, a local heat stimulus of 45 degrees C was applied for 5 min. RESULTS: Basal blood flow did not differ between groups, but vasoconstrictive responses induced by arithmetic or immersion of the contralateral hand in ice-cold water and vasodilatation induced by local heating were severely impaired in diabetic subjects, compared with healthy control subjects (P < 0.01). These responses correlated with autonomic nerve function and deteriorated significantly with advancing age in control subjects, but not in diabetic subjects. Blood flow in younger diabetic subjects resembled that of older control subjects. CONCLUSIONS: These data demonstrate that diabetes has effects on precapillaries that may by direct or mediated via autonomic nerves, which result in a deficit that resembles premature aging.

Impaired peripheral vasomotion in diabetes.

OBJECTIVE: To test the hypothesis that vasomotion, the rhythmic contraction exhibited by small arteries and arterioles, is impaired in diabetic subjects compared with healthy control subjects. RESEARCH DESIGN AND METHODS: We mathematically modeled the oscillations in laser Doppler microvascular measurements taken from the pulpar surface of the index finger in 20 healthy control subjects and 20 age-matched diabetic subjects (8 with type I and 12 with type II diabetes). The mean duration of diabetes was 17.1 +/- 2.3 years, and mean HbA1c was 9.1 +/- 0.4%. Blood flow was measured for 5 min as subjects rested quietly in a closed room. Fast Fourier transformation was performed to provide the frequency power spectrum of each recording. Amplitude of vasomotion was correlated with six quantitative measurements of neuropathy. RESULTS: Diabetic subjects had impaired low-frequency oscillation vasomotion in 75% of age-matched patients (15 of 20 patients), with mean amplitudes of 24.9 +/- 6.4 vs. 129.0 +/- 33.2 (P < 0.0039). Of six somatic and autonomic neuropathy variables, only the warm thermal sensory threshold correlated significantly with the mean amplitude of vasomotion (r = -0.75, P < 0.0009). CONCLUSIONS: Patterns of peripheral vasomotion are clearly disordered in diabetes. The loss of low-frequency oscillations observed here suggests a peripheral vascular abnormality that extends past the capillary network to arterial vessels. It is uncertain whether the accompanying small unmyelinated nerve C-fiber dysfunction is a cause or consequence of the impaired microvascular function. Measurement of vasomotion may prove useful as a novel test for peripheral neurovascular function.

Quantitative measurement of cutaneous perception in diabetic neuropathy.

To determine the diagnostic value of various cutaneous sensory modalities in diabetic neuropathy, we studied cutaneous perception at the dominant hallux of 113 subjects (32 normal healthy controls and 81 diabetic subjects). The cutaneous sensory perception tests included warm and cold thermal perception, vibration, touch-pressure sensation, and current perception testing (CPT). The sensitivity of each modality when specificity is held greater than 90% was as follows: warm = 78%, cold = 77%, vibration = 88%, tactile-pressure = 77%, 5-Hz CPT = 52%, 250-Hz CPT = 48%, and 2000-Hz CPT = 56%. Combination thermal and vibratory gave optimum sensitivity (92-95%) and specificity (77-86%). We conclude that vibratory and thermal testing should be the primary screening tests for diabetic peripheral neuropathy. Other modalities may be of use only in specific situations.