Accelerated atrophy of lower leg and foot muscles—a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI)

Aims/hypothesis  The aim of the study was to determine the loss of muscle volume in the lower leg and foot in long-term diabetic patients in relation to the presence of neuropathy. Methods  We re-examined 26 type 1 diabetic patients who had participated in magnetic resonance imaging (MRI) studies on muscle volume in the lower leg and foot 9 to 12 years earlier. Re-examination involved MRI, isokinetic dynamometry, clinical examination, electrophysiological studies and quantitative sensory examinations. Results  Annual loss of muscle volume of ankle dorsal and plantar flexors was 4.5 (5.5–3.9)% (median [range]) and 5.0 (7.0–4.2)% in neuropathic patients, 1.9 (3.2–1.0)% and 1.8 (2.6–1.3)% in non-neuropathic patients, and 1.7 (2.8–0.8)% and 1.8 (2.4–0.8)% in controls, respectively (p < 0.01). Annual change of volume and strength correlated for ankle dorsal flexors (r _s = 0.73, p < 0.01) and for ankle plantar flexors (r _s = 0.63, p < 0.05) in diabetic patients. In addition, annual change of muscle volume for dorsal and plantar flexors was related to the combined score of all measures of neuropathy (r _s = −0.68, p < 0.02 and r _s = −0.73, p < 0.01, respectively). Foot muscle volume declined annually by 3.0 (3.4–1.0)% in neuropathic patients and by 1.1 (4.0–0.2)% in non-neuropathic patients, both values being significantly different from controls (0.2 [−2.5 to 2.4]%). Loss of foot muscle volume was related to severity of neuropathy assessed at clinical evaluation (r _s = −0.6, p < 0.05). Conclusions/interpretation  Muscular atrophy in long-term diabetic neuropathy occurs early in the feet, progresses steadily in the lower legs, relates to severity of neuropathy and leads to weakness at the ankle. An erratum to this article can be found at     

Impaired short-term blood pressure regulation and autonomic dysbalance in children with type 1 diabetes mellitus

Aims Because reduction in baroreceptor sensitivity (BRS) has been associated with hypertension in the normal population and with increased cardiovascular morbidity and mortality in patients with diabetes mellitus, we measured BRS in a patient cohort of children with type 1 diabetes mellitus. Methods Two hundred and eight children (150 patients with type 1 diabetes mellitus, mean age 13.9 ± 2.8 years, 70 boys, mean HbA_1c 7.8 ± 1.4%; and 58 healthy controls, mean age 14.1 ± 3.1 years, 32 boys) were studied. BRS and heart rate variability (HRV) were analysed from a short-time ECG and BP recording using the sequence method (BRS) and the frequency domain method (HRV). Results There were 111 of 150 patients (74%) and 5 of 58 controls (8.6%) that showed impaired BRS. Mean BRS differed significantly between patients and controls (18.4 ± 7.2 vs 25.8 ± 8.2 ms/mm, p < 0.001). BRS correlated inversely with systolic BP (r = −0.23, p = 0.009) and was related to diabetes duration (r = −0.194, p = 0.027). Analysis of HRV showed greater sympathetic and less parasympathetic influence in patients than in controls (low frequency/high frequency ratio 1.3 ± 0.8 vs 0.9 ± 0.6, p < 0.05); the low frequency/high frequency ratio was inversely correlated with BRS (r = −0.28, p = 0.001). Conclusions/interpretation Diabetic children show reduced BRS. In our patient group, the single risk factor for this finding was found to be the disease duration. The degree of BRS impairment was related to the degree of autonomic dysbalance. R. Dalla Pozza and S. Bechtold contributed equally to this study.     

The steel ball-bearing test: a new test for evaluating protective sensation in the diabetic foot

Aims/hypothesis The aim of the study was to assess a new steel ball-bearing test as a means of evaluating protective sensation in the diabetic foot. Methods Subjects were enrolled for this study as follows: (1) 39 patients (mean age 61.3±9.7 years) with neuropathy and prior neuropathic ulcer (Group A); (2) 36 patients (mean age 63.7±10.1 years) with neuropathy without neuropathic ulcer (Group B); (3) 34 patients (mean age 52.1±10.4 years) without neuropathy (Group C); and (4) 21 healthy volunteers (mean age 46.7±8.7 years) (Group D). Neuropathy was diagnosed by means of neuropathy disability score (NDS). The plantar area over the second metatarsal head of each foot was examined with steel ball-bearings of varying diameters. The smallest diameter that the patient could feel was used to define the ball-bearing score (range 1–6). Results A high ball-bearing score was significantly more frequent in patients with neuropathic ulceration than in neuropathic patients without ulceration and in diabetic patients without neuropathy (p<0.001). A high score was also more frequent in neuropathic patients without ulceration, than in patients without neuropathy (p<0.001). The ball-bearing score was significantly (p=0.01) correlated with the NDS, the monofilament test, the vibration perception threshold and the thermal perception threshold. The ball-bearing test had a sensitivity of 84% and a specificity of 100% for impaired protective sensation due to neuropathy, and a sensitivity of 84.6% and a specificity of 86.1% for detection of patients with prior neuropathic ulceration. Conclusions/interpretation The steel ball-bearing test has a high sensitivity and specificity both for the evaluation of protective sensation and for detection of patients with prior neuropathic ulceration.     

QT Interval Length and Diabetic Autonomic Neuropathy

QT interval length was measured in ECG recordings from three groups of age-matched male subjects: 36 normal subjects, 41 diabetic patients without (DAN-ve), and 34 with (DAN+ve) autonomic neuropathy. ECG samples were selected from previously recorded 24-h ECGs on the basis of a clearly defined T wave and a steady RR interval over 2 min of around 750 ms (80 beats min^?1). There were no significant differences in RR interval between the groups. The two diabetic groups had slightly longer QT measurements (normal 365 ± 14 (±SD) ms, DAN-ve 373 ± 18 ms, DAN+ve 375 ± 23 ms, p = 0.05), and corrected QT (QTc) values (normal 423 ± 15 ms, DAN-ve 430 ± 20 ms, DAN+ve 435 ± 24 ms, p = 0.05). Ten diabetic patients fell above our defined upper limit of normal for QTc (>mean + 2SD). There was a significant correlation in the DAN-ve group between the QT indices and 24-h RR counts (QT r = ?0.38, p < 0.01; QTc r = ?0.40, p < 0.01). We conclude that there are some small alterations in QT interval length in the steady state in diabetic autonomic neuropathy. The changes appear to be due to autonomic impairment, rather than diabetes per se.     

Erectile and endothelial dysfunction in Type II diabetes: a possible link

Aims/hypothesis: The aim of this study was to evaluate the relation between erectile dysfunction and endothelial functions, coagulation activation, peripheral and autonomic neuropathy in men with Type II (non-insulin-dependent) diabetes mellitus. Methods: We studied 30 Type II diabetic patients with symptomatic erectile dysfunction and 30 potent diabetic patients matched for age and disease. Endothelial functions were assessed with the l-arginine test, plasma thrombomodulin and cell adhesion molecules circulating concentrations. Haemostasis was evaluated with markers of thrombin activation and fibrinolysis. Quantitative sensory testing (vibratory, warming, and heat-pain thresholds), cardiovascular reflex tests and 24-h blood pressure monitoring were used to assess peripheral or autonomic neuropathy. Results: Mean erectile score and HbA_{1 c} were 10.5 ± 5.8 and 8.3 ± 1.6 % in patients with erectile dysfunction, and 24.0 ± 0.7 and 6.8 ± 1.4 % in those without erectile dysfunction, respectively (p < 0.001); there was a significant relation between HbA_{1 c} and erectile function score in patients with erectile dysfunction (r = –0.45, p = 0.02). The decrease in blood pressure and platelet aggregation in response to l-arginine was lower (p < 0.05–0.02) in patients with erectile dysfunction, whereas soluble thrombomodulin, P-selectin and intercellular cell ahhesion molecule-1 concentrations were higher (p < 0.05–0.02). Indices of coagulation activation (F1 + 2 and d-dimers) and reduced fibrinolysis (PAI-1) were also found to be higher in erectile dysfunction patients. Heat-pain and warm perception thresholds, as well as cardiovascular reflex tests, were most commonly abnormal in patients with erectile dysfunction (p < 0.05). In multivariate analysis, HbA_{1 c}, MBP response to l-arginine, P-selectin, indices of coagulation, and quantitative sensory testing were independent predictors of erectile function score. Conclusion/interpretation: Erectile dysfunction in diabetic men correlates with endothelial dysfunction. A reduced nitric oxide activity might provide a unifying explanation. [Diabetologia (2001) 44: 1155–1160] Received: 18 April 2001 and in revised form: 21 April 2001     

Relationship between glyco-oxidation, antioxidant status and microalbuminuria in type 2 diabetic patients

Aims/hypothesis  This study examined the relationship, if any, between glucose-induced oxidative stress, antioxidant status and microalbuminuria in patients with type 2 diabetes. Methods  The study involved 99 consecutive type 2 diabetic patients (57 men, 42 women). Patients with persistent microalbuminuria were identified and the following variables evaluated: fasting plasma glucose, HbA_1c, malonyldialdehyde (MDA), pentosidine, AGE, the total radical-trapping antioxidant parameter (TRAP), vitamin E, creatinine, estimated GFR and lipid profile. Results  Patients were divided into two groups, i.e. 37 individuals without microalbuminuria (AER <20 μg/min) and 62 with microalbuminuria (AER ≥20 μg/min). The following variables were significantly higher in patients with microalbuminuria than in those without microalbuminuria (mean ± SD): fasting plasma glucose 9.41 ± 2.88 vs 8.19 ± 1.93 mmol/l, p < 0.05; HbA_1c 7.97 ± 1.51 vs 7.39 ± 1.03%, p < 0.05; MDA 1.18 ± 0.35 vs 1.02 ± 0.29 μmol/l, p < 0.05; pentosidine 98.5 ± 24.6 vs 82.9 ± 20.9 pmol/ml, p < 0.005; and AGE 13.2 ± 4.8 vs 10.6 ± 3.8 μg/mg protein, p < 0.01. However, vitamin E and TRAP did not differ between the two groups. Serum creatinine values and estimated GFR were similar in the two groups. Only in patients with microalbuminuria were significant linear correlations seen between AER and both oxidation (HbA_1c r = 0.33, p < 0.01; MDA r = 0.59, p < 0.001; pentosidine r = 0.48, p < 0.001; and AGE r = 0.44, p < 0.001) and antioxidation variables (vitamin E r = −0.55, p < 0.001; TRAP r = −0.49, p < 0.001). Considering all variables together, multiple regression revealed a correlation between microalbuminuria and vitamin E, TRAP, HbA_1c and MDA, but not pentosidine or AGE. Conclusions/interpretation  Our data suggest that microalbuminuria in type 2 diabetic patients might be promoted by an insufficient counter-regulation of the antioxidant system in the event of increased glyco-oxidation/glycation.     

New squatting test indices are useful for assessing baroreflex sensitivity in diabetes mellitus

Aims The heart rate (HR) responses after performance of the squatting and standing manoeuvre are thought to be a useful tool to assess autonomic neuropathy in diabetics. Our aim was to develop new simple squatting test indices and to analyse their applicability to the assessment of baroreflex sensitivity (BRS) in patients with diabetes. Methods Twenty healthy volunteers (mean age 23.2 ± 3.8 years) and 51 patients with diabetes (mean age 55.9 ± 10.6 years) were enrolled in study 1 and study 2, respectively. Each subject stood for 3 min (basal period), then squatted down for 1 min (Sq) and stood up again for 1 min (St). In study 1, the squatting test was performed before and after pharmacological autonomic blockade. In study 2, we measured HR in each period and calculated the difference between basal HR and HRSq (ΔHRSq) and between HRSt and HRSq (ΔHRSt). BRS was also measured using the phenylephrine method in diabetic patients. Results In healthy individuals during autonomic blockade, HR changes were mainly controlled by the vagal tone during squatting and by the sympathetic tone during standing. In diabetic patients, ΔHRSq and ΔHRSt positively correlated (r = 0.86, P < 0.0001) and both ΔHRSq and ΔHRSt significantly correlated with BRS (r = 0.66, P < 0.0001 and r = 0.61, P < 0.0001, respectively). Conclusions The new squatting test indices provide useful information for assessing autonomic neuropathy and for identifying diabetic patients at high risk of cardiovascular events.     

Abnormal Digital Pressure Measurements in Diabetic Neuropathic Foot Ulceration

The diabetic neuropathic ulcer is typically slow to heal and recurrent. Macrovascular insufficiency is usually excluded as foot pulses are present and ankle:brachial pressure ratios are not decreased. These assessments cannot however exclude more distal vascular disease. Digital pressure measurements enable a reliable assessment of the distal peripheral vascular status to be made. The aim of this study was therefore to use toe pressures to assess the contribution of distal ischaemia in the pathogenesis of the neuropathic ulcer. Sixteen diabetic patients with recurrent neuropathic foot ulceration had their toe pressures compared to 10 neuropathic patients without a history of foot ulceration, 10 diabetic control subjects, and 11 normal subjects. Four non-diabetic patients with neuropathy and foot ulceration were also assessed. All subjects had ankle:brachial pressure indices ≧ 1. Toe pressure was assessed using laser Doppler flowmetry to record the return of skin blood flow. The toe:brachial pressure index (TBI) was then calculated. The diabetic patients with a history of recurrent neuropathic ulceration, had the lowest mean TBI, 0.63 ± 0.14 (SD), compared to the non-ulcerated diabetic neuropathy patients, the diabetic control subjects, and the normal subjects. 0.84 ± 0.11, 0.82 ± 0.1, and 0.81 ± 0.07, p < 0.01, respectively. Three of the four non-diabetic patients with neuropathic foot ulceration also had an abnormally low TBI. Reduced toe pressure measurements are thus found to be associated with neuropathic foot ulceration. The contribution of distal ischaemia in the pathogenesis of the diabetic neuropathic foot ulcer needs to be evaluated. One hundred and eight non-insulin-dependent diabetic patients who had been tested for autonomic dysfunction in 1984/85 were re-evaluated 5 years later. Autonomic function was assessed by means of four cardiovascular tests (heart rate variation during deep breathing and standing, and blood pressure variation after standing and sustained handgrip). Eighteen subjects were lost to follow-up; in the 90 patients who completed the study, both the deep breathing and the handgrip test significantly worsened (respectively from 13.7 ± 7.8 to 11.6 ± 6.3 beats min^?1 p < 0.01, and from 16.9 ± 8.2 to 12.7 ± 7.1 mmHg, p < 0.001), whereas both the 30:15 ratio and the variation of blood pressure on standing did not change. The impairment of a comprehensive evaluation score (from 2.5 ± 1.7 to 3.0 ± 1.5; p < 0.05) also confirmed the gradual deterioration of autonomic function over the study period.     

Factors Related to the Electric Taste Threshold in Type 1 Diabetic Patients

To specify the factors related to taste function in Type 1 diabetes mellitus, 50 diabetic out-patients and 50 control subjects paired for age and sex were screened for taste disorders. None of them consumed significant amounts of alcohol, smoked, or had disease or took drugs capable of altering taste. Taste was studied with electrogustometry, retinopathy was detected by fluorescein angiography, nephropathy by measurement of albuminuria and microalbuminuria, peripheral neuropathy by electroneurography and electromyography, and autonomic neuropathy by cardiovascular function tests. The electrogustometric threshold was, on average, significantly higher in the diabetic group (133 ± 30 μA) than in the control group (29 ± 9 μA; p < 0.001). Electric hypogeusia (electrogustometric threshold > 100 μA) was found among 54% of the diabetic patients vs 2% of the control subjects (p < 0.001). In the diabetic group, the electrogustometric threshold was associated with complications of diabetes, especially with peripheral neuropathy (210 ± 24 vs 90 ± 22 μA; p < 0.001) and microalbuminuria (185 ± 25 vs 86 ± 21 μA; p < 0.01). It was correlated with age (r = 0.37; p < 0.01) and duration of diabetes (r = 0.52; p < 0.001) but not with HbA_1c (r = ?0.04). Using multivariate analysis, duration of diabetes and peripheral neuropathy had the strongest association with taste impairment. These results support previous findings, suggesting that taste impairment is a degenerative complication of diabetes mellitus.     

Does Abnormal QT Interval Prolongation Reflect Autonomic Dysfunction in Diabetic Patients? QTc Interval Measure Versus Standardized Tests in Diabetic Autonomic Neuropathy

The question as to whether the QTc interval correlates with five cardiovascular tests (deep breathing test, 30/15 ratio test, lying to standing test, cough test, and postural blood pressure test) for the diagnosis of diabetic autonomic neuropathy (DAN) was investigated in 168 (38 Type 1, 130 Type 2) consecutive outpatients (mean age 54.9 ± 11.2 years). QT interval was measured on an ECG recorded at rest and QTc calculated according to Bazett's formula. The percentage of patients with a QTc greater than 0.440 s was: absent DAN = 11% (n = 7), probable DAN = 7% (n = 4), definite DAN = 23% (n = 12) (p < 0.05), and the mean (± SD) QTc values were 0.403 ± 0.028 s, 0.405 ± 0.023 s, and 0.421 ± 0.026 s, respectively. A significant correlation between QTc duration and DAN score of autonomic cardiovascular test results (r = 0.34, p < 0.0001) was observed. The calculated specificity, sensitivity, positive and negative predictive values were 89%, 15%, 70% and 37%, respectively. In conclusion, QTc can be considered as an additional specific test in the assessment of diabetic autonomic neuropathy, but cannot replace the standard battery of cardiovascular tests.     

Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle

Aims/hypothesis Insulin resistance and type 2 diabetes are associated with mitochondrial dysfunction. The aim of the present study was to test the hypothesis that oxidative phosphorylation and electron transport capacity are diminished in the skeletal muscle of type 2 diabetic subjects, as a result of a reduction in the mitochondrial content. Materials and methods The O₂ flux capacity of permeabilised muscle fibres from biopsies of the quadriceps in healthy subjects (n = 8; age 58 ± 2 years [mean±SEM]; BMI 28 ± 1 kg/m²; fasting plasma glucose 5.4 ± 0.2 mmol/l) and patients with type 2 diabetes (n = 11; age 62 ± 2 years; BMI 32 ± 2 kg/m²; fasting plasma glucose 9.0 ± 0.8 mmol/l) was measured by high-resolution respirometry. Results O₂ flux expressed per mg of muscle (fresh weight) during ADP-stimulated state 3 respiration was lower (p < 0.05) in patients with type 2 diabetes in the presence of complex I substrate (glutamate) (31 ± 2 vs 43 ± 3 pmol O₂ s⁻¹ mg⁻¹) and in response to glutamate + succinate (parallel electron input from complexes I and II) (63 ± 3 vs 85 ± 6 pmol s⁻¹ mg⁻¹). Further increases in O₂ flux capacity were observed in response to uncoupling by FCCP, but were again lower (p < 0.05) in type 2 diabetic patients than in healthy control subjects (86 ± 4 vs 109 ± 8 pmol s⁻¹ mg⁻¹). However, when O₂ flux was normalised for mitochondrial DNA content or citrate synthase activity, there were no differences in oxidative phosphorylation or electron transport capacity between patients with type 2 diabetes and healthy control subjects. Conclusions/interpretation Mitochondrial function is normal in type 2 diabetes. Blunting of coupled and uncoupled respiration in type 2 diabetic patients can be attributed to lower mitochondrial content.     

Prospective Study of Autonomic Nerve Function in Type 1 and Type 2 Diabetic Patients: 24 Hour Heart Rate Variation and Plasma Motilin Levels Disturbed in Parasympathetic Neuropathy

To clarify the impact of autonomic neuropathy in diabetic patients, we have conducted a prospective study of 58 Type 1 and 51 Type 2 diabetic patients (investigated at baseline, after 4, and after 7 years). In Type 1 diabetic patients, the sympathetic nerve function (orthostatic acceleration and brake indices) and in Type 2 patients, parasympathetic nerve function (R-R interval variation; E/I ratio) deteriorated during 7 years of prospective observation. Symptoms of autonomic neuropathy were associated with signs of autonomic neuropathy (low brake indices) in Type 1 but not in Type 2 diabetic patients. In the latest assessment 24 h ECG recording was performed and blood samples assayed for neuropeptide Y (NPY) and motilin were obtained. Type 1 diabetic patients with parasympathetic neuropathy (abnormal E/I ratio) showed significantly lower SD value (less variation in the R-R intervals; 29 [17] vs 50 [16], [mean {interquartile range}]; p = 0.001) and higher postprandial plasma motilin values (70 [20] pmol I^?1 vs 50 [15] pmol I^?1; p< 0.01) than patients with normal parasympathetic nerve function. In Type 2 diabetic patients, sympathetic neuropathy (low brake indices) was associated with an increased frequency of ventricular extra systolic beats during 24 h ECG recording (r_s = 0.65; p<0.01). Postprandial plasma NPY levels were not associated with disturbed autonomic nerve function.     

Autonomic neuropathy and transcutaneous oxymetry in diabetic lower extremities

Summary Transcutaneous oxygen tension is a useful method with which to assess the functional status of skin blood flow. The reduced values observed in diabetic patients have been interpreted as a consequence of peripheral vascular disease. However, diabetic patients show lower transcutaneous oxygen tension values than control subjects with equivalent degrees of peripheral vascular disease, suggesting that additional factors are involved. Since the autonomic nervous system influences peripheral circulation, we studied the relationship between autonomic neuropathy and foot transcutaneous oxymetry in non-insulin-dependent diabetic (NIDDM) patients without peripheral vascular disease. The following age-matched patients were selected and evaluated: control subjects, C, (n=20), NIDDM patients without autonomic neuropathy, D, (n=16) and with autonomic neuropathy, DN, (n=20). All diabetic patients showed lower transcutaneous oxygen tension values than control subjects, while no differences were observed between the diabetic patients with and without autonomic neuropathy. In addition the saturation index that increases in the presence of autonomic neuropathy does not correlate with foot TcPO₂. In conclusion autonomic neuropathy does not influence foot TcPO₂ and therefore it is unlikely that it contributes to development of foot lesions during induction of foot skin ischaemia.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - TcPO₂ transcutaneous oxymetry - A-V arterio-venous shunts - PVD peripheral vascular disease - HbA_1c glycated haemoglobin - SI saturation index     

Diabetic polyneuropathy is associated with respiratory muscle impairment in type 2 diabetes

Aims/hypothesis Diabetes has a major negative effect on intensive care unit outcome. This has been partly attributed to impaired respiratory neuromuscular function. However, data on respiratory neuromuscular involvement in diabetes are lacking. This study therefore aimed to assess respiratory neuromuscular function related to diabetic polyneuropathy in patients with type 2 diabetes. Methods Respiratory neuromuscular function was assessed by the use of volitional tests and twitch mouth (TwPmo) and twitch transdiaphragmatic (TwPdi) pressures during non-volitional bilateral anterior magnetic phrenic nerve stimulation in 21 male type 2 diabetic patients without pulmonary disease and in 23 healthy, well-matched controls (forced expiratory volume in 1 s 103 ± 11 vs 103 ± 12% predicted; p = 0.9). Results Both volitionally assessed maximal inspiratory and expiratory mouth pressures, and sniff nasal and transdiaphragmatic pressures were comparable between diabetic patients and controls (p > 0.1 for all). TwPmo was reduced in diabetic patients compared with controls (1.3 ± 0.5 vs 1.0 ± 0.4 kPa; p = 0.04), while TwPdi was comparable (1.7 ± 0.5 vs 1.6 ± 0.7 kPa; p = 0.6). Following subgroup analysis, patients with no or mild polyneuropathy (n = 10) as assessed by neurological disability scoring had normal respiratory neuromuscular function, whereas patients with moderate or severe polyneuropathy (n = 11) presented with markedly impaired respiratory neuromuscular function as indicated by TwPmo (1.3 ± 0.4 vs 0.8 ± 0.3 kPa; p = 0.01) and TwPdi (1.9 ± 0.6 vs 1.1 ± 0.4 kPa; p < 0.01). Conclusions/interpretation With regard to volitional tests, diabetes does not affect respiratory neuromuscular function. In contrast, the application of non-volitional phrenic nerve stimulation provides strong evidence that diabetic polyneuropathy, as simply assessed by neurological disability scoring, is associated with substantially impaired respiratory neuromuscular function in type 2 diabetic patients.     

Relationships between dyspeptic symptoms and gastrointestinal motility in patients with Type 1 (insulin-dependent) diabetes mellitus

Summary Reports on motor abnormalities in Type 1 (insulin-dependent) diabetes mellitus are inconsistent. In 20 Type 1 diabetic patients and in 11 control subjects antroduodenojejunal manometry was performed under euglycaemic conditions in order to examine the prevalence of gastric and small intestinal motor abnormalities in relation to dyspeptic symptoms and the degree of cardiac autonomic neuropathy. In diabetic patients compared to control subjects phase III (regular, high-amplitude contractile activity at maximal frequency) involved the gastric antrum less often (12 vs 35%,p<0.05), the duration of phase I (motor quiescence) was shorter (6±1 vs 21±4 min,p<0.002) and in phase II (irregular motor activity) the frequency of duodenal and jejunal contractions was higher. After a meal the duration of the fed state was shorter in diabetic patients with symptoms during the study than in diabetic patients without symptoms and than in control subjects (57±27 vs 157±11 and 140±13 min,p<0.02). Postprandial antral hypomotility was seen in diabetic patients with symptoms only in the first 30 min after the meal. One hour after the meal the frequency of duodenal and jejunal contractions was again higher in diabetic patients. In diabetic patients compared to control subjects more burst activity (clusters of non-propagated high-amplitude contractile activity at maximal frequency) was seen (7.9±1.6 vs 0.8±0.5% of the total time of study,p<0.002). No correlation was found between manometric parameters and the degree of cardiac autonomic neuropathy. In conclusion, in Type 1 diabetic patients with cardiac autonomic neuropathy a variety of gastric and small intestinal motor abnormalities can be found. The most important of these is hyperactivity in the interdigestive state. These abnormalities correlate with symptoms, but are not related to the severity of cardiac autonomic neuropathy.     

The influence of local capsaicin treatment on small nerve fibre function and neurovascular control in symptomatic diabetic neuropathy

Topical treatment wit capsaicin cream has been shown to be successful in the treatment of different symptomatic nerve disorders like diabetic neuropathy. Conflicting data exist on the effect of capsaicin on nerve function and neurovascular control especially in patients with diabetic neuropathy. The aim of this pilot study was to investigate the impact of topical capsaicin application on small nerve fibre function and neurovascular control. Capsaicin cream was applied to the feet of 13 patients with symptomatc diabetic neuropathy over a period of 8 weeks. Before and during the treatment period, we investigated the total symptoms score, the vibration, thermal (heat and cold) and pain perception thresholds, and the neurovascular responses to heat and acetylcholine stimuli. In addition, the serum plasma levels of substance P, a neurotransmitter of nociceptor C-fibres, were measured. A significant improvement in total symptoms score was observed during topical capsaicin treament (18.3±3.2 vs. 14.3±3.3; p<0.05). An improvement in the heat perception threshold was also found (12.7±0.4°C vs. 11.4±0.7°C; p<0.05), while other sensory nerve fibre functions remained unchanged. No significant change in neurovascular control was observed, neither after mild thermal injury nor after stimulation with acetylcholine. Serum substance P levels increased after initiation of topical capsaicin treatment (72.9±5.8 pg/ml vs. 81.7±5.0 pg/ml; p<0.05), but returned to baseline levels during further treatment (77.4±8.3 pg/ml; n. s.). In conclusion, topical treatment with capsaicin cream over a period of 8 weeks in patients with symptomatic diabetic neuropathy is effective without adverse effects on nerve fibre function or neurovascular control. Received: July 2000 / Accepted in revised form: May 2001     

Plasma pancreatic polypeptide levels are associated with differences in body fat distribution in human subjects

Aims/hypothesis Pancreatic polypeptide (PP) is produced by the F-cells of the pancreas, and its plasma concentration has been used as a marker of parasympathetic activity. Recent work in rodents suggests that there is both sympathetic and parasympathetic innervation of white adipose tissue and that parasympathetic activity is anabolic resulting in lipid accumulation. We have examined whether in humans increased PP levels are associated with increased intra-abdominal fat (IAF), and thereby insulin resistance. Materials and methods We measured PP levels in 177 non-diabetic subjects (75 male/102 female; age 32–75 years) 3 min after an i.v. glucose bolus during a frequently sampled intravenous glucose tolerance test. IAF and s.c. fat (SCF) areas were measured by CT scan. The insulin sensitivity index (S _I) was quantified using Bergman’s minimal model. Results PP levels were higher in men than in women (96.2 ± 72.2 vs 76.1 ± 55.0 pg/ml, mean ± SD, p = 0.037), as was IAF area (124.7 ± 67.4 vs 83.0 ± 57.7 cm², p < 0.001). While PP levels were significantly associated with IAF (r = 0.16, p = 0.031), WHR (r = 0.30, p < 0.001) and age (r = 0.37, p < 0.01), they were not associated with SCF (r = 0.02, p = 0.829). The association between PP and IAF was not independent of age and/or sex. S _I was negatively associated with PP levels (r = −0.17, p = 0.026) and IAF area (r = −0.65, p < 0.001). The association between S _I and PP disappeared after adjusting for IAF area, indicating that S _I was not a major determinant of PP levels. Conclusions/interpretation In humans, age and sex may modulate the association between plasma PP level and IAF area, suggesting that they may be determinants of parasympathetic activity and thus IAF accumulation.     

N-terminal pro-B-type natriuretic peptide and functional capacity in patients with obstructive sleep apnea

The obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular abnormalities including left ventricular hypertrophy, left ventricular diastolic dysfunction, and endothelial dysfunction. The present study evaluated whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) and peak oxygen consumption (peak VO₂), both integral markers of cardiovascular function, are related to OSAS severity. In addition, we tested whether NT-proBNP levels depend on body composition in OSAS patients, similar to what has been reported in patients without OSAS. Eighty-nine patients with untreated OSAS underwent NT-proBNP measurement, dual X-ray absorptiometry, and cardiopulmonary exercise testing. In a representative subgroup (n = 32), transthoracic echocardiography was performed. The severity of OSAS was classified based on apnea–hypopnea index (AHI) values as mild (AHI 5–15 h⁻¹), moderate (AHI 15–30 h⁻¹), and severe (AHI >30 h⁻¹). OSAS was mild in 19 (21%), moderate in 21 (24%), and severe in 49 (55%) patients. NT-proBNP levels did not differ among patients with mild [30 (10–57)], moderate [37 (14–55)], and severe [24 (13–49) pg/ml; p = 0.8] OSAS and were not related to body mass index (r = 0.07; p = 0.5), percent lean body mass (r = −0.17; p = 0.1), and percent fat mass (r = 0.18; p = 0.1). Percent predicted peak VO₂ was on average normal and did not differ among patients with mild (115 ± 26), moderate (112 ± 23), and severe OSAS (106 ± 29%; p = 0.4). Body weight-indexed peak VO₂ did not differ among patients with mild (31.9 ± 10.3), moderate (32.1 ± 7.9), and severe OSAS (30.0 ± 9.9 ml kg⁻¹ min⁻¹; p = 0.6) either. Lower NT-proBNP (β = −0.2; p = 0.02) was independently but weakly associated with higher body weight-indexed peak VO₂. In the echocardiography subgroup, NT-proBNP was not significantly related to left ventricular mass index (r = 0.26; p = 0.2). In conclusion, NT-proBNP and peak VO₂ are not related to OSAS severity, and NT-proBNP poorly reflects left ventricular hypertrophy in OSAS. The lack of a relationship between NT-proBNP and OSAS severity is not due to a significant influence of body composition on NT-proBNP. There is an association between higher NT-proBNP and lower peak VO₂, indicating that NT-proBNP is a marker of cardiorespiratory fitness in patients with OSAS. However, the association is too weak to be clinically useful.     

Lipid-lowering therapy and peripheral sensory neuropathy in type 2 diabetes: the Fremantle Diabetes Study

Aims/hypothesis The aim of this study was to assess the relationships between lipid-lowering therapy and the prevalence and incidence of peripheral sensory neuropathy in type 2 diabetes mellitus. Methods We analysed data from an observational cohort study, the Fremantle Diabetes Study (FDS), specifically, (1) a cross-sectional sample comprising 1,237 FDS participants with type 2 diabetes mellitus, and (2) a longitudinal subgroup of 531 individuals who had attended six consecutive annual assessments. Neuropathy was identified using the clinical portion of the Michigan Neuropathy Screening Instrument. Results At entry, the cross-sectional sample had a mean ± SD age of 63.8 ± 11.3 years, 48.7% were men, median (interquartile range) diabetes duration was 4.0 (1.0–9.0) years, and 30.9% had peripheral neuropathy. Fibrates and statins were used by 3.5 and 6.8%, respectively. Multiple logistic regression analysis showed that older age, longer diabetes duration, central adiposity, increased height, higher fasting serum glucose, albuminuria and aboriginality were significant independent positive predictors of prevalent neuropathy, while systolic blood pressure and fibrate use (odds ratio 0.30, 95% CI 0.10–0.86; p = 0.025) were negatively associated. In the longitudinal subgroup, fibrate and statin use increased to 10.4 and 36.5%, respectively, over 5 years. In time-dependent Cox proportional hazards modelling, fibrate use [hazard ratio (HR) 0.52, 95% CI 0.27–0.98] and statin use (HR 0.65, 95% CI 0.46–0.93) were significant determinants of incident neuropathy (p ≤ 0.042). Conclusions/interpretation These preliminary observational data suggest that therapy with a statin or a fibrate may protect against the development of diabetic peripheral sensory neuropathy, but there is a need for additional confirmatory evidence, preferably from randomised clinical trials. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects

Aims/hypothesis Mitochondrial dysfunction and increased intramyocellular lipid (IMCL) content have both been implicated in the development of insulin resistance and type 2 diabetes mellitus, but the relative contributions of these two factors in the aetiology of diabetes are unknown. As obesity is an independent determinant of IMCL content, we examined mitochondrial function and IMCL content in overweight type 2 diabetes patients and BMI-matched normoglycaemic controls. Methods In 12 overweight type 2 diabetes patients and nine controls with similar BMI (29.4 ± 1 and 29.3 ± 0.9 kg/m² respectively) in vivo mitochondrial function was determined by measuring phosphocreatine recovery half-time (PCr half-time) immediately after exercise, using phosphorus-31 magnetic resonance spectroscopy. IMCL content was determined by proton magnetic resonance spectroscopic imaging and insulin sensitivity was measured with a hyperinsulinaemic–euglycaemic clamp. Results The PCr half-time was 45% longer in diabetic patients compared with controls (27.3 ± 3.5 vs 18.7 ± 0.9 s, p < 0.05), whereas IMCL content was similar (1.37 ± 0.30 vs 1.25 ± 0.22% of the water resonance), and insulin sensitivity was reduced in type 2 diabetes patients (26.0 ± 2.2 vs 18.9 ± 2.3 μmol min⁻¹ kg⁻¹, p < 0.05 [all mean ± SEM]). PCr half-time correlated positively with fasting plasma glucose (r ² = 0.42, p < 0.01) and HbA_1c (r ² = 0.48, p < 0.05) in diabetic patients. Conclusions/interpretation The finding that in vivo mitochondrial function is decreased in type 2 diabetes patients compared with controls whereas IMCL content is similar suggests that low mitochondrial function is more strongly associated with insulin resistance and type 2 diabetes than a high IMCL content per se. Whether low mitochondrial function is a cause or consequence of the disease remains to be investigated.