Topiramate improves neurovascular function, epidermal nerve fiber morphology, and metabolism in patients with type 2 diabetes mellitus.

PURPOSE: To assess the effects of topiramate on C-fiber function, nerve fiber morphology, and metabolism (including insulin sensitivity, obesity, and dyslipidemia) in type 2 diabetes. PATIENTS AND METHODS: We conducted an 18-week, open-label trial treating patients with topiramate. Twenty subjects with type 2 diabetes and neuropathy (61.5 ± 1.29 years; 15 male, 5 female) were enrolled and completed the trial. Neuropathy was evaluated by total neuropathy scores, nerve conduction studies, quantitative sensory tests, laser Doppler skin blood flow, and intraepidermal nerve fibers in skin biopsies. RESULTS: Topiramate treatment improved symptoms compatible with C-fiber dysfunction. Weight, blood pressure, and hemoglobin A(1c) also improved. Laser Doppler skin blood flow improved significantly after 12 weeks of treatment, but returned to baseline at 18 weeks. After 18 weeks of treatment there was a significant increase in intraepidermal nerve fiber length at the forearm, thigh, and proximal leg. Intraepidermal nerve fiber density was significantly increased by topiramate in the proximal leg. CONCLUSION: This study is the first to demonstrate that it is possible to induce skin intraepidermal nerve fiber regeneration accompanied by enhancement of neurovascular function, translating into improved symptoms as well as sensory nerve function. The simultaneous improvement of selective metabolic indices may play a role in this effect, but this remains to be determined.

A 6-month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-beta inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy.

OBJECTIVE: Diabetes leads to protein kinase C (PKC)-beta overactivation and microvascular dysfunction, possibly resulting in disordered skin microvascular blood flow (SkBF) and other changes observed in diabetic peripheral neuropathy (DPN) patients. We investigate the effects of the isoform-selective PKC-beta inhibitor ruboxistaurin mesylate on neurovascular function and other measures of DPN. RESEARCH DESIGN AND METHODS: Endothelium-dependent and C fiber-mediated SkBF, sensory symptoms, neurological deficits, nerve fiber morphometry, quantitative sensory and autonomic function testing, nerve conduction studies, quality of life (using the Norfolk Quality-of-Life Questionnaire for Diabetic Neuropathy [QOL-DN]), and adverse events were evaluated for 20 placebo- and 20 ruboxistaurin-treated (32 mg/day) DPN patients (aged > or =18 years; with type 1 or type 2 diabetes and A1C < or =11%) during a randomized, double-masked, single-site, 6-month study. RESULTS: Endothelium-dependent (+78.2%, P < 0.03) and C fiber-mediated (+56.4%, P < 0.03) SkBF at the distal calf increased from baseline to end point. Significant improvements from baseline within the ruboxistaurin group were also observed for the Neuropathy Total Symptom Score-6 (NTSS-6) (3 months -48.3%, P = 0.01; end point -66.0%, P < 0.0006) and the Norfolk QOL-DN symptom subscore and total score (end point -41.2%, P = 0.01, and -41.0, P = 0.04, respectively). Between-group differences in baseline-to-end point change were observed for NTSS-6 total score (placebo -13.1%; ruboxistaurin -66.0%, P < 0.03) and the Norfolk QOL-DN symptom subscore (placebo -4.0%; ruboxistaurin -41.2%, P = 0.041). No significant ruboxistaurin effects were demonstrated for the remaining efficacy measures. Adverse events were consistent with those observed in previous ruboxistaurin studies. CONCLUSIONS: In this cohort of DPN patients, ruboxistaurin enhanced SkBF at the distal calf, reduced sensory symptoms (NTSS-6), improved measures of Norfolk QOL-DN, and was well tolerated.

Pioglitazone treatment improves nitrosative stress in type 2 diabetes.

OBJECTIVE: The purpose of this study was to determine the effect of 24 weeks of treatment with 45 mg/day pioglitazone on peripheral skin blood flow (SkBF) and skin nitric oxide (NO) production in vivo in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a randomized, parallel, cross-over, double-blind, within- and between-subject study designed to compare vascular responses before and after treatment. We studied 12 subjects with type 2 diabetes (average age 58.6 +/- 30.8 years, HbA(1c) 7.9 +/- 00.4%, BMI 31.3 +/- 1.2 kg/m(2)). SkBF was measured using laser Doppler techniques in response to ischemia reperfusion and local skin warming, and NO production was assessed in vivo using an amperometric NO meter inserted directly into the skin. These measurements were performed before treatment and at 6 and 24 weeks. RESULTS: The SkBF response was not significantly improved after 24 weeks in either of the groups. NO production was significantly decreased in the pioglitazone-treated group in the basal condition (area under the curve 6.4 +/- 1.0 vs. 2.8 +/- 0.8, P < 0.01), after local heat stimulation at 40 degrees C (12.9 +/- 2.2 vs. 5.7 +/- 1.7, P < 0.01), and after nociceptor stimulated flow with local heating at 44 degrees C (36.4 +/- 6.3 vs. 16.6 +/- 3.4). Differences were not significant in the placebo-treated group. CONCLUSIONS: Treatment of patients with type 2 diabetes with pioglitazone for 24 weeks reduced skin NO production, thus probably reducing nitrosative stress without a demonstrable effect on SkBF. Because nitrosative stress is considered to be a factor in the pathogenesis of neurovascular dysfunction, these findings warrant further investigation.

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.