Kevin B Stansberry

Diabetes, peripheral neuropathy, and old age disability

The purpose of this study was to determine whether peripheral neuropathy explains the apparent association between diabetes and disability in old age, and to evaluate the utility of lower extremity function tests in older diabetic adults with and without neuropathy. We evaluated 39 adults, aged 70–79 years, for pressure sensation (log10g), vibration perception threshold (VPT; microns), and electrophysiologic function of the peroneal nerve. The subjects included patients with established diabetic neuropathy (DN; n = 14), diabetic controls without neuropathy (DC; n = 13), and nondiabetic controls (NDC; n = 12). Nonparametric statistical methods were used to relate neuropathy measures to performance in tests of walking speed, static and dynamic balance, coordination, and ankle strength (kilograms). Significant age‐adjusted correlations were observed between measures of sensory neuropathy and a variety of performance measures, and electrophysiologic measures were related to static balance. DN subjects had significantly higher pressure sensation than NDC (5.17 vs 3.38g, P < 0.05), higher VPT (62.5 vs 21.7 μm, P < 0.05), and lower peroneal motor response amplitudes at multiple sites. Pressure sensation and nerve conduction measures did not differ between DC and NDC. Compared with NDC, DN subjects performed significantly worse on tests of walking speed (0.99 vs 1.34 m/s; P < 0.05), static balance (4.9 vs 20.4 s; P < 0.05), dynamic balance (9.23 vs 25.52 s; P < 0.05), and coordination (6.73 vs 4.76 s; P < 0.05). No differences were observed in these measures between DC and NDC. Observed differences in physical abilities between older diabetic and nondiabetic adults may have been due to the subset of diabetic individuals with peripheral neuropathy. Quantitative measures of sensory and motor nerve function have distinct effects on physical performance. Interventions aimed at reducing the impact of diabetes‐associated disability in old age may have the greatest impact among people with peripheral neuropathy.

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.

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.

The natural progression of autonomic neuropathy and autonomic function tests in a cohort of people with IDDM

OBJECTIVE To test the natural progression of symptoms of autonomic neuropathy (AN) and function tests in subjects with IDDM. RESEARCH DESIGN AND METHODS Seventy-six subjects with IDDM of < 10 years duration had cardiovascular autonomic reflex tests and were evaluated for signs and symptoms of AN. RESULTS Fifty-seven subjects (66%) were available for restudy 9 years later (15 had died, 4 could not be located). Of the symptoms of AN, only gastroparesis increased in prevalence (P < 0.01). Of the five cardiovascular AN measures, only the R-R response to the Valsalva maneuver deteriorated (F[1,44] = 10.61, P < 0.01). CONCLUSIONS The progression of AN in IDDM is monitored best longitudinally by the Valsalva maneuver because of the small variance ratio in repeated measures. Prevalence rates can be monitored by expiration-to-inspiration R-R or Valsalva ratios. Most clinical signs and symptoms of AN do not progress, underscoring the need for objective and quantitative autonomic function tests to identify people at risk for premature death.

Chronic exercise is associated with enhanced cutaneous blood flow in Type 2 diabetes

Impaired blood flow to skin contributes to foot ulceration and amputation. The overall objective of this cross-sectional study was to examine the relationship between chronic physical activity and skin blood flow in Type 2 diabetes. To do so, diabetic and control subjects were separated into four groups based on a physical activity questionnaire: control exerciser (CE), control sedentary (CS), diabetic exerciser (DE), and diabetic sedentary (DS) subjects. After a physical exam and neuropathic testing, skin blood flow was measured noninvasively by continuous laser Doppler assessment of lower limb blood flow in response to various stimuli. Both groups of exercisers had enhanced baseline and ischemia reperfusion (IRP)-induced blood flow. Significant differences in maximal neurogenic dorsal foot skin perfusion were also present (P<.05): CE had greater perfusion than either diabetic group, but CS blood flow was higher than DS only. Since, nitric oxide (NO) is a potent vasodilator, concurrent real-time measurements of NO in cutaneous interstitial fluids were recorded. No significant differences in maximal levels of NO were found among the four groups during any flow condition. Fasting serum glucose levels and HbA(1c) were significantly inversely correlated with skin blood flow during heating. Chronic exercise is associated with enhanced skin blood under certain flow conditions in Type 2 diabetes compared with the sedentary state. As such, regular physical activity may be an invaluable tool in the prevention and reversal of defective skin vasodilation and resultant foot ulcers so common in diabetes.

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.

Rosiglitazone treatment increases nitric oxide production in human peripheral skin: A controlled clinical trial in patients with type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of micro- and macrovascular complications, causing considerable morbidity and mortality. Endothelial dysfunction and insulin resistance have been strongly associated with reduced vascular reactivity in T2DM. We investigated the effect of the insulin-sensitizing antidiabetic agent rosiglitazone at a dose level of 8 mg/day on in vivo skin nitric oxide (NO) production and blood flow in the foot in a 16-week, randomized, double-blind, placebo-controlled crossover to open-label, single-blind study in patients with T2DM. NO production was assessed using an amperometric meter inserted directly into the skin. Skin perfusion was studied using laser Doppler techniques in response to local warming. Ten patients completed the study. NO production was significantly increased by rosiglitazone compared with baseline after 8-16 weeks of treatment (from 61.6+/-13.5 to 85.3+/-6.4 nM, P<.05 in response to warming). Fasting serum C-peptide levels were significantly reduced (P<.05) compared with baseline following rosiglitazone (4.78+/-1.19 ng/dl at Week 2 compared with 3.63+/-0.72 ng/dl after rosiglitazone treatment at Week 16), correlating inversely (r=-.65, P=.08) with the increase in NO production. Skin perfusion increased after 16 weeks of rosiglitazone treatment (P=ns). This is the first study to show that rosiglitazone attenuates the effects of T2DM on NO production, a marker of endothelial function, in vivo. This provides further evidence for the beneficial effects of rosiglitazone on nontraditional cardiovascular risk factors associated with T2DM.

Phospholipid and Glutamic Acid Decarboxylase Autoantibodies in Diabetic Neuropathy

OBJECTIVE To determine the prevalence and significance of phospholipid autoantibodies (PLAs) and glutamic acid decarboxylase (GAD) autoantibodies in the circulation of normal patients and diabetic patients with and without neuropathy. RESEARCH DESIGN AND METHODS We measured PLAs in a total of 78 patients (a diabetic group with somatic or autonomic neuropathy [n = 40] another group without neuropathy [n = 38]), and GAD autoantibodies in a subset of 22 patients. RESULTS PLAs are found in 2% of the general population. We found PLAs in 32% of the diabetic population without neuropathy, in 88% of those with neuropathy, in 55% of those with retinopathy, and in 25% of those with established nephropathy. The frequencies of immunoglobulins in the neuropathic group were: IgG = 78%, IgM = 33%, and IgA = 23%. There was no correlation between PLAs and microalbuminuria, macrovascular disease, fibrinogen, duration of diabetes, or neuropathy, but there was a strong correlation with total neuropathy score. Sera with high PLA IgG titers bound to the surface of neuroblastoma cells and inhibited cell growth. Antibodies to GAD65 were present in 32% and to GAD67 in 0% of patients. No titers of GAD65, GAD67, or the GAD65 ratio were associated with the degree of neuropathy of the presence of PLAs. CONCLUSIONS PLAs occur frequently in the sera of patients with diabetes and correlate with the extent of neuropathy, suggesting a role for PLAs in the etiology thereof. The measurement of PLAs may constitute a marker for ongoing damage to nerves.

Neurotrophic role of interleukin-6 and soluble interleukin-6 receptors in N1E-115 neuroblastoma cells.

Interleukin 6 (IL-6) plays a role in physiological and pathophysiological processes in neuronal cells. We studied whether IL-6 plays a role in neuroblastoma cells in culture. These studies demonstrate that N1E-115 cells constitutively express IL-6 but not IL-6R. Exogenous IL-6 stimulated neuronal proliferation in a dose-dependent manner. Under serum-free conditions soluble IL-6 receptors (sIL-6R) alone or in combination with IL-6 exerted significant proliferative effects, while IL-6 alone failed to promote cell proliferation. Neutralizing anti-IL-6 antibody caused a 30-40% reduction in IL-6 mediated proliferation. Our results suggest the importance of IL-6/sIL-6R for proliferation and survival of N1E-115 adrenergic neuroblastoma cells.