A muscarinic receptor antagonist reverses multiple indices of diabetic peripheral neuropathy: preclinical and clinical studies using oxybutynin.

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

Utilizing a quality of life tool to examine the presence of fatigue in subjects with diabetes mellitus.

Introduction: The prevalence of fatigue in patients with diabetes mellitus (DM) can be as high as 50 %. Physical, mental, and psychosocial components of fatigue negatively impact quality of life (QOL), morbidity and mortality. Several tools have been developed to address fatigue, but none specifically for measuring fatigue in DM. The aim of this study was to assess the impact of diabetes and neuropathy on fatigue using the Norfolk QOL-Fatigue (QOL-F) survey. Methods: 605 adult participants from [Anonymous] were recruited (400 subjects with type 1 or type 2 DM and 205 subjects without diabetes (controls)). All subjects completed the Norfolk QOL-F. Demographics, weight, BMI, and duration of diabetes were obtained. The Norfolk QOL-F, a 35-item validated questionnaire, assesses five domains: subjective fatigue, physical and cognitive fatigue, reduced activities, impaired activities of daily living, and depression. Results: Subjects with DM reported significantly higher fatigue total scores (52.63vs33.89, p < 0.0001) and in all five domains when compared to controls. Patients with DM with neuropathy were significantly more fatigued than those without (59.72vs27.83, p < 0.0001). Fatigue scores in patients with DM without neuropathy were similar to controls (27.83vs33.89, p = NS). In multivariate analysis, age, gender, and presence of neuropathy significantly impacted fatigue scores. Conclusions: The Norfolk QOL-F questionnaire can potentially identify the impact of chronic diseases such as diabetes on fatigue. Assessing the different components of fatigue is important for clinicians in improving disease management and outcomes. Further investigations are needed to confirm these observations in specific cohorts with other comorbidities.

Cardiac and Sudomotor Autonomic Function in Subjects with Psoriasis With and Without Metabolic Syndrome.

Purpose: Studies have shown that subjects with psoriasis (PsO) are associated with an increased risk of developing metabolic syndrome (MetS), diabetes, and cardiovascular disease. In addition, MetS and diabetes are associated with autonomic dysfunction (AD). The aim of this study was to investigate cardiac and sudomotor autonomic function in subjects with PsO and without diabetes. Methods: A cross-sectional study was performed in 20 subjects with PsO, compared with age- and sex-matched 21 healthy controls, and 20 subjects with MetS. Subjects underwent skin evaluation by dermatologist, glycated hemoglobin (HbA1c), insulin, glucose, and lipid levels, sudomotor function testing with Sudoscan™ device (Impeto Medical, Paris, France), and cardiac autonomic function testing with ANSAR device (ANX 3.0; ANSAR Group, Inc., Philadelphia, PA). Quality of Life (QOL) and peripheral neurologic function were also assessed. Results: Participants with PsO were significantly more obese, had higher levels of fasting insulin and triglycerides, and were more insulin resistant when compared to controls. Subjects with PsO showed significantly worse cardiac autonomic function when compared to control and MetS groups. Sudomotor function and QOL scores were similar between the groups. Subgroup analysis of PsO subjects without MetS criteria (n = 15) showed persistent significantly deteriorated cardiac autonomic function when compared to the other two groups. Conclusion: This study suggests an association between PsO and cardiac AD, independent of the presence of overt dysglycemia and MetS. Additional larger studies are needed to clarify the significance of these findings and the relationship between PsO, AD, and metabolic disease.

Development and Validation of the Norfolk Quality of Life Fatigue Tool (QOL-F): A New Measure of Perception of Fatigue.

OBJECTIVES: To design a questionnaire to evaluate and distinguish between cognitive and physical aspects of fatigue in different age groups of "nondiseased" people and guide appropriate prevention and interventions for the impact of frailty occurring in normative aging. STUDY DESIGN AND PARTICIPANTS: The Norfolk QOL-Fatigue (QOL-F) with items of cognitive and physical fatigue, anxiety, and depression from validated questionnaires including items from the Patient-Reported Outcomes Measure Information System (PROMIS) databank was developed. The preliminary QOL-F was administered to 409 healthy multiethnic local participants (30-80 years old) in 5 age groups. METHODS: The authors distilled the item pool using exploratory (EFA) and confirmatory factor analysis (CFA). EFA identified 5 latent groups as possible factors related to problems due to fatigue, subjective fatigue, reduced activities, impaired activities of daily living (ADL), and depression. RESULTS: CFA demonstrated good overall fit [χ2(172) = 1094.23, P < .001; Tucker-Lewis index = 0.978; root mean square error of approximation = 0.049] with factor loadings >0.617 and strong interfactor correlations (0.69-0.83), suggesting that fatigue in each domain is closely related to other domains and to the overall scale except for ADL. The 5-factor solution displayed good internal consistency (Cronbach α = 0.78-0.94). Total and domain scores were fairly equivalent in all age groups except for the 40 to 49-year-old group with better overall scores. In addition, 70 to 79-year-olds had better ADL scores. In item response analysis, factor scores in different age groups were similar, so age may not be a significant driver of fatigue scores. Fatigue scores were significantly higher in females than in males (P < .05). CONCLUSIONS AND CLINICAL IMPLICATIONS: The developed Norfolk QOL-F tool demonstrated fatigue as a perceived cognitive phenomenon rather than an objective physical measure, suggesting mandatory inclusion of cognitive as well as physical measures in the evaluation of people as they age. QOL-F is able to distinguish QOL-F domain scores unique to different age groups, proposing clinical benefits from physical, balance, and cognitive interventions tailored to impact frailty occurring in normative aging.

Exercise status affects skin perfusion via prostaglandin, nitric oxide, and EDHF pathways in diabetes.

Participation in regular exercise training improves dorsal skin perfusion, while type 2 diabetes mellitus (T2 DM) often limits it via reductions in the action or release of vasodilatory compounds. This study was undertaken to investigate the relative contributions of prostaglandins (PG), nitric oxide (NO), and endothelial-derived hyperpolarizing factor (EDHF) in dorsal foot skin perfusion in individuals with and without T2 DM and a sedentary lifestyle. Participants included 24 individuals with T2 DM and 28 nondiabetic controls whose exercise status was determined via questionnaire. Their dorsal foot skin perfusion was measured at rest using laser Doppler assessment during localized heating to 44 degrees C with oral aspirin (ASA, 325 mg) treatment. In addition, they received an infusion via a subcutaneous microdialysis probe of either saline (left foot) or L-NAME, a NOS-inhibitor (right foot). Compared to normative data without ASA, heat-stimulated perfusion in regular exercisers (n=22) was significantly more suppressed by ASA and by ASA/L-NAME than in sedentary individuals (n=30). Chronic exercisers exhibit a greater reliance on PG and lesser involvement of EDHF with unchanged NO compared to sedentary individuals, who rely more on EDHF and less on PG release. One possible exception may be diabetic, sedentary individuals, who may rely somewhat more on NO than EDHF. These results suggest that regular exercise may exhibit the greatest effect on the normal functioning of these vasodilatory pathways, although diabetes and a sedentary state together may somewhat alter their relative importance.

Supervised Balance Training and Wii Fit-Based Exercises Lower Falls Risk in Older Adults With Type 2 Diabetes.

OBJECTIVES: This study examined the benefits of and differences between 12 weeks of thrice-weekly supervised balance training and an unsupervised at-home balance activity (using the Nintendo Wii Fit) for improving balance and reaction time and lowering falls risk in older individuals with type 2 diabetes mellitus (T2DM). DESIGN: Before-after trial. SETTING: University research laboratory, home environment. PARTICIPANTS: Sixty-five older adults with type 2 diabetes were recruited for this study. Participants were randomly allocated to either supervised balance training (mean age 67.8 ± 5.2) or unsupervised training using the Nintendo Wii Fit balance board (mean age 66.1 ± 5.6). INTERVENTION: The training period for both groups lasted for 12 weeks. Individuals were required to complete three 40-minute sessions per week for a total of 36 sessions. MEASUREMENT: The primary outcome measure was falls risk, which was as derived from the physiological profile assessment. In addition, measures of simple reaction time, lower limb proprioception, postural sway, knee flexion, and knee extension strength were also collected. Persons also self-reported any falls in the previous 6 months. RESULTS: Both training programs resulted in a significant lowering of falls risk (P < .05). The reduced risk was attributable to significant changes in reaction times for the hand (P < .05), foot (P < .01), lower-limb proprioception (P < .01), and postural sway (P < .05). CONCLUSIONS: Overall, training led to a decrease in falls risk, which was driven by improvements in reaction times, lower limb proprioception, and general balance ability. Interestingly, the reduced falls risk occurred without significant changes in leg strength, suggesting that interventions to reduce falls risk that target intrinsic risk factors related to balance control (over muscle strength) may have positive benefits for the older adult with T2DM at risk for falls.

Cardiac Autonomic Neuropathy in Diabetes: A Predictor of Cardiometabolic Events.

Autonomic nervous system (ANS) imbalance manifesting as cardiac autonomic neuropathy in the diabetic population is an important predictor of cardiovascular events. Symptoms and signs of ANS dysfunction, such as resting heart rate elevations, diminished blood pressure responses to standing, and altered time and frequency domain measures of heart rate variability in response to deep breathing, standing, and the Valsalva maneuver, should be elicited from all patients with diabetes and prediabetes. With the recognition of the presence of ANS imbalance or for its prevention, a rigorous regime should be implemented with lifestyle modification, physical activity, and cautious use of medications that lower blood glucose. Rather than intensifying diabetes control, a regimen tailored to the individual risk of autonomic imbalance should be implemented. New agents that may improve autonomic function, such as SGLT2 inhibitors, should be considered and the use of incretins monitored. One of the central mechanisms of dysfunction is disturbance of the hypothalamic cardiac clock, a consequence of dopamine deficiency that leads to sympathetic dominance, insulin resistance, and features of the metabolic syndrome. An improvement in ANS balance may be critical to reducing cardiovascular events, cardiac failure, and early mortality in the diabetic population.

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.

Bariatric Surgery Restores Cardiac and Sudomotor Autonomic C-Fiber Dysfunction towards Normal in Obese Subjects with Type 2 Diabetes.

OBJECTIVE: The aim was to evaluate the impact of bariatric surgery on cardiac and sudomotor autonomic C-fiber function in obese subjects with and without Type 2 diabetes mellitus (T2DM), using sudorimetry and heart rate variability (HRV) analysis. METHOD: Patients were evaluated at baseline, 4, 12 and 24 weeks after vertical sleeve gastrectomy or Roux-en-Y gastric bypass. All subjects were assessed using SudoscanTM to measure electrochemical skin conductance (ESC) of hands and feet, time and frequency domain analysis of HRV, Neurologic Impairment Scores of lower legs (NIS-LL), quantitative sensory tests (QST) and sural nerve conduction studies. RESULTS: Seventy subjects completed up to 24-weeks of follow-up (24 non-T2DM, 29 pre-DM and 17 T2DM). ESC of feet improved significantly towards normal in T2DM subjects (Baseline = 56.71±3.98 vs 12-weeks = 62.69±3.71 vs 24-weeks = 70.13±2.88, p<0.005). HRV improved significantly in T2DM subjects (Baseline sdNN (sample difference of the beat to beat (NN) variability) = 32.53±4.28 vs 12-weeks = 44.94±4.18 vs 24-weeks = 49.71±5.19, p<0,001 and baseline rmsSD (root mean square of the difference of successive R-R intervals) = 23.88±4.67 vs 12-weeks = 38.06±5.39 vs 24-weeks = 43.0±6.25, p<0.0005). Basal heart rate (HR) improved significantly in all groups, as did weight, body mass index (BMI), percent body fat, waist circumference and high-density lipoprotein (HDL). Glycated hemoglobin (HbA1C), insulin and HOMA2-IR (homeostatic model assessment) levels improved significantly in pre-DM and T2DM subjects. On multiple linear regression analysis, feet ESC improvement was independently associated with A1C, insulin and HOMA2-IR levels at baseline, and improvement in A1C at 24 weeks, after adjusting for age, gender and ethnicity. Sudomotor function improvement was not associated with baseline weight, BMI, % body fat or lipid levels. Improvement in basal HR was also independently associated with A1C, insulin and HOMA2-IR levels at baseline. CONCLUSION: This study shows that bariatric surgery can restore both cardiac and sudomotor autonomic C-fiber dysfunction in subjects with diabetes, potentially impacting morbidity and mortality.

Walking-Induced Fatigue Leads to Increased Falls Risk in Older Adults.

BACKGROUND: For older adults, falls are a serious health problem, with more than 30% of people older than 65 suffering a fall at least once a year. One element often overlooked in the assessment of falls is whether a person's balance, walking ability, and overall falls risk is affected by performing activities of daily living such as walking. OBJECTIVE: This study assessed the immediate impact of incline walking at a moderate pace on falls risk, leg strength, reaction time, gait, and balance in 75 healthy adults from 30 to 79 years of age. Subjects were subdivided into 5 equal groups based on their age (group 1, 30-39 years; group 2, 40-49 years; group 3, 50-59 years; group 4, 60-69 years; group 5, 70-79 years). METHODS: Each person's falls risk (using the Physiological Profile Assessment), simple reaction time, leg strength, walking ability, and standing balance were assessed before and after a period of incline walking on an automated treadmill. The walking task consisted of three 5-minute trials at a faster than preferred pace. Fatigue during walking was elicited by increasing the treadmill incline in increments of 2° (from level) every minute to a maximum of 8°. RESULTS: As predicted, significant age-related differences were observed before the walking activity. In general, increasing age was associated with declines in gait speed, lower limb strength, slower reaction times, and increases in overall falls risk. Following the treadmill task, older adults exhibited increased sway (path length 60-69 years; 10.2 ± 0.7 to 12.1 ± 0.7 cm: 70-79 years; 12.8 ± 1.1 to 15.1 ± 0.8 cm), slower reaction times (70-79 years; 256 ± 6 to 287 ± 8 ms), and declines in lower limb strength (60-69 years; 36 ± 2 to 31 ± 1 kg: 70-79 years; 32.3 ± 2 to 27 ± 1 kg). However, a significant increase in overall falls risk (pre; 0.51 ± 0.17: post; 1.01 ± 0.18) was only seen in the oldest group (70-79 years). For all other persons (30-69 years), changes resulting from the treadmill-walking task did not lead to a significant increase in falls risk. CONCLUSIONS: As most falls occur when an individual is moving and/or fatigued, assessing functional properties related to balance, gait, strength, and falls risk in older adults both at rest and following activity may provide additional insight.

Change in cutaneous perfusion following 10 weeks of aerobic training in Type 2 diabetes.

A small, but positive, association between aerobic training status or prior maximal exercise and enhanced dorsal foot skin perfusion in active individuals with Type 2 diabetes has been shown. This study, therefore, was designed to examine whether an aerobic training intervention would positively affect cutaneous perfusion in sedentary Type 2 diabetic individuals as well. Nine sedentary participants with Type 2 diabetes (DS) and 10 obese nondiabetic controls (CS) were studied. Prior to the initiation of aerobic training, dorsal foot cutaneous perfusion was measured noninvasively by continuous laser Doppler assessment at baseline and during localized heating to 44 degrees C. These measurements were repeated 48-72 h following 10 weeks of moderate aerobic training performed 3 days per week. Interstitial nitric oxide (NO) levels were measured concurrently in the contralateral foot dorsum. Aerobic training did not significantly enhance baseline skin perfusion, nor were interstitial NO levels different under any condition. At baseline, groups differed only in glycated hemoglobin (HbA1c), fasting serum glucose, HDL-cholesterol, and insulin resistance. At rest, cutaneous perfusion during local heating to 44 degrees C was significantly lower in DS before training, but did not differ significantly from CS afterward. Neither group, however, experienced significant increases in dorsal foot perfusion during local responsiveness to heating to 44 degrees C following 10 weeks of moderate aerobic training, despite slightly lower perfusion in DS before training; these findings were independent of interstitial NO levels. Thus, moderate aerobic training for only 10 weeks does not appear to reverse the impairment in cutaneous perfusion of the foot dorsum in response local heating in a Type 2 diabetic population.

Cutaneous blood flow in type 2 diabetic individuals after an acute bout of maximal exercise.

OBJECTIVE: We previously demonstrated a positive association between chronic aerobic exercise and dorsal foot skin blood flow during local heating in type 2 diabetic individuals. Thus, we hypothesized that a prior acute bout of maximal exercise would also have positive effects on postexercise blood flow. RESEARCH DESIGN AND METHODS: Subjects consisted of 32 individuals with type 2 diabetes and 26 nondiabetic control subjects further subdivided based on their physical activity status: diabetic exerciser (DE), diabetic sedentary (DS), control exerciser (CE), or control sedentary. Dorsal foot cutaneous blood flow was measured noninvasively by continuous laser-Doppler assessment at baseline and during local heating to 44 degrees C before and after a maximal bout of cycle exercise. Interstitial nitric oxide (NO) levels were measured concurrently in the foot dorsum. RESULTS: Increases in blood flow and its responsiveness to local heating to 44 degrees C were significantly lower in both diabetic groups compared with CE before maximal exercise, but perfusion responsiveness remained lower in DS subjects only after exercise (P < 0.05). Baseline skin blood flow was not different among groups preexercise, but it was significantly increased postexercise in DE subjects only. Interstitial NO levels were not significantly different at either time. At baseline, groups differed only in HbA(1c), fasting serum glucose, HDL cholesterol, and insulin resistance (homeostasis model assessment method). CONCLUSIONS: All diabetic individuals exhibit a blunted responsiveness of cutaneous blood flow with local heating to 44 degrees C before maximal exercise compared with active nondiabetic individuals, but after an exercise bout, it remains significantly blunted only in diabetic individuals who are sedentary. These findings occur independently of changes in interstitial NO levels.

The effect of an aerobic exercise training program on quality of life in type 2 diabetes.

PURPOSE: The purpose of this study was to determine the effect of 10 weeks of moderate aerobic exercise training on quality of life (QOL) and selected physiological parameters in previously sedentary persons with diabetes. METHODS: A quality-of-life survey (SF36v2 health survey) and measurement of physiological parameters were completed before and after 10 weeks of supervised aerobic exercise training 3 days a week for 20 to 45 minutes by subjects with diabetes (n = 9) and control subjects (n = 10). Nontraining subjects with diabetes (n = 12) and control subjects (n = 10) also completed the QOL survey at equivalent times. RESULTS: Participants in all groups had similar characteristics. A training effect was evident in exercisers, with an increase in lactate threshold and a decrease in percent body fat for both groups. Training did not affect body mass index or interstitial nitric oxide levels. Physical and mental component scores on the QOL survey in the training and nontraining groups did not differ significantly before or after the training, and diabetes status had no significant effect on these scores. CONCLUSIONS: No physiological changes were significantly associated with scores on the SF36v2 health survey. In addition, neither training nor the presence of type 2 diabetes significantly affected the physical or mental component scores on the QOL survey.

Exercise improves gait, reaction time and postural stability in older adults with type 2 diabetes and neuropathy.

AIMS: For older adults with type 2 diabetes (T2DM), declines in balance and walking ability are risk factors for falls, and peripheral neuropathy magnifies this risk. Exercise training may improve balance, gait and reduce the risk of falling. This study investigated the effects of 12weeks of aerobic exercise training on walking, balance, reaction time and falls risk metrics in older T2DM individuals with/without peripheral neuropathy. METHODS: Adults with T2DM, 21 without (DM; age 58.7±1.7years) and 16 with neuropathy (DM-PN; age 58.9±1.9years), engaged in either moderate or intense supervised exercise training thrice-weekly for 12weeks. Pre/post-training assessments included falls risk (using the physiological profile assessment), standing balance, walking ability and hand/foot simple reaction time. RESULTS: Pre-training, the DM-PN group had higher falls risk, slower (hand) reaction times (232 vs. 219ms), walked at a slower speed (108 vs. 113cm/s) with shorter strides compared to the DM group. Following training, improvements in hand/foot reaction times and faster walking speed were seen for both groups. CONCLUSIONS: While falls risk was not significantly reduced, the observed changes in gait, reaction time and balance metrics suggest that aerobic exercise of varying intensities is beneficial for improving dynamic postural control in older T2DM adults with/without neuropathy.

Role of prostaglandin D2 and the autonomic nervous system in niacin-induced flushing.

BACKGROUND: Although niacin often has beneficial effects on the lipoprotein profile, flushing is an untoward effect associated with its use. Aspirin can only reduce the flushing response by 30-40%. Thus, the aim of the present study was to investigate the mechanisms of niacin-induced flushing, with and without aspirin, in normal, healthy individuals. METHODS: Niacin-induced flushing was evaluated in 30 healthy individuals after oral administration of 1000 mg niacin alone or with 325 mg aspirin. Neurological, autonomic nervous system, and skin blood flow measurements (using laser Doppler on the glabrous and hairy skin of each participant) were made at various times after drug administration. In addition, the systemic release of 9α,11ß-prostaglandin (PG) F(2) was determined. Flushing symptoms of redness, warmth, tingling, itching, and intensity were recorded using the modified Flushing ASsessment Tool (FAST). RESULTS: After aspirin, the mean flushing scores for all symptoms decreased significantly; however, 36-53% of participants still had some degree of symptoms, even though aspirin completely blocked 11ß-PGF(2) synthesis. Maximum skin blood flow (MaxSkBF) in both the glabrous and hairy forearm increased significantly after niacin, but decreased significantly after aspirin only in hairy skin. Regression analysis showed that, in glabrous skin, both PGF(2) and parasympathetic activity were significant predictors of MaxSkBF after niacin, contributing 26% and 14%, respectively (total R(2) = 40%). CONCLUSIONS: The present study indicates, for the first time, that the parasympathetic nervous system, in addition to PGD(2) , may play an important role in niacin-induced flushing. Changing the sympathetic/parasympathetic balance in favor of parasympathetic activation may be a good therapeutic target to reduce niacin-induced flushing.

Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction.

OBJECTIVE: Sudomotor dysfunction may be an early detectable abnormality in diabetic small fiber neuropathy. The aim of this study was to evaluate the efficacy of Sudoscan™ (Impeto Medical, Paris, France) in detecting diabetic neuropathy (DN), in comparison with other standardized tests, in patients with diabetes mellitus (DM). SUBJECTS AND METHODS: Sudoscan measures electrochemical skin conductance (ESC) of hands and feet through reverse iontophoresis. We evaluated 83 DM patients with and without DN and 210 healthy controls (HCs). Neuropathy Impairment Score-Lower Legs (NIS-LL), quantitative autonomic function testing (QAFT), and quantitative sensory testing (QST) were performed. Symptomatic pain was recorded using a visual analog scale. Receiver-operator characteristic (ROC) curves were calculated to evaluate the efficacy of Sudoscan in detecting DN compared with traditional modalities. RESULTS: Diabetes patients with DN had significantly worse ESCs of feet and hands than DM patients without DN and HCs (respectively, 56.3±3 vs. 75.9±5.5 and 84.4±0.9 [P<0.0001] for feet and 51.9±2.4 vs. 67.5±4.3 and 73.1±0.8 [P<0.0001] for hands). Increasing NIS-LL scores were associated with decreasing ESC values. ESCs correlated significantly with clinical (NIS-LL), somatic (QST), and autonomic (QAFT) measures of neuropathy and with pain scores. ROC curve analysis showed significant results for both hands and feet ESC (area under the curve of 0.86 and 0.88, respectively; P<0.0001) with sensitivity of 78% and specificity of 92% for feet to detect DN. CONCLUSIONS: Sudoscan is a promising, sensitive tool to detect neuropathy in patients with DM. This is a very simple, easy-to-perform test that can be done in the clinical setting in 3-5 min.

Contact heat-evoked potential stimulation for the evaluation of small nerve fiber function.

BACKGROUND: Small fiber peripheral neuropathy (SFN) is emerging as a common complication in diabetes. Currently there are few, not easily available methods of determining the integrity of small nerve fibers. This study was designed to determine the utility of a noninvasive technique, contact heat-evoked potential stimulation (CHEPS), on the identification of SFN and compare it with standardized measures of diabetic peripheral neuropathy (DPN). SUBJECTS AND METHODS: We evaluated 31 healthy controls and 30 participants with type 2 diabetes and DPN using neurologic examination, nerve conduction studies (NCS), autonomic function tests, quantitative sensory tests (QSTs), and CHEPS. Contact heat was administered to the thenar eminence, volar and dorsal forearms, lower back, and distal lower limb. Evoked potentials were recorded from the skull vertex. Latencies and amplitudes were determined. RESULTS: Intrapeak amplitude (IA) values were significantly reduced in the DPN group at the lower back (44.93±6.5 vs. 23.87±3.36 µV; P<0.01), lower leg (15.87±1.99 vs. 11.68±1.21 µV; P<0.05), and dorsal forearm (29.89±8.86 vs. 14.96±1.61 µV; P<0.05). Pooled data from both groups showed that IA values at different sites significantly correlated with clinical neurologic scores, NCS, QSTs, and autonomic function. Receiver operator characteristic curve analysis, used to evaluate the performance of CHEPS in detecting nerve dysfunction, was most significant for IA at the lower back (area under the curve, 0.778;±SE, 0.06; 95% confidence interval, 0.654-0.875; P<0.0001). CONCLUSIONS: This study suggests that CHEPS is a novel, noninvasive technique able to detect impairment of small nerve fiber function from skin to cerebral cortex, providing an objective measure of C and Aδ nerve dysfunction.

Cardiac autonomic imbalance in newly diagnosed and established diabetes is associated with markers of adipose tissue inflammation.

INTRODUCTION: Diabetics die from cardiovascular disease at a much greater rate than nondiabetics. Cardiac autonomic imbalance predicts increased cardiovascular risk and mortality. We studied the relationship between cardiac autonomic imbalance and adipose tissue-derived inflammation in newly diagnosed and established type 2 diabetes. MATERIALS AND METHODS: Non-diabetics, newly diagnosed diabetics, and established diabetics were included. Anthropomorphic and biochemical measurements were obtained, and insulin resistance was approximated. Cardiac autonomic function was assessed using conventional measures and with power spectral analysis of heart rate. RESULTS AND DISCUSSION: Heart rate variability was reduced in all diabetics. Interleukin-6 was higher in diabetics, as was the high molecular weight adiponectin-to-leptin ratio. Interleukin-6 correlated negatively with measures of autonomic balance. Ratios of adiponectin to leptin correlated positively with measures of autonomic balance. Cardiac autonomic imbalance and inflammation occur early in diabetes and are interrelated. CONCLUSIONS: Cardiac autonomic imbalance correlates with the adipose tissue-derived inflammation seen early in type 2 diabetes.