Impaired blood flow and arterio-venous shunting in human diabetic neuropathy: a novel technique of nerve photography and fluorescein angiography

Summary New techniques of sural nerve photography and fluorescein angiography which are able to provide an index of nerve blood flow have been developed. Under local anaesthetic, 3 cm of sural nerve was exposed at the ankle using an operating microscope. Without disturbing the epineurium, vessels were identified and photographed at a standard magnification (× 30). These were independently graded by an ophthalmologist not otherwise involved with the study. Fluorescein angiography was then carried out on the exposed nerve. The fluorescein appearance time and intensity of fluorescence were quantified, using computer analysis of digitised images. Thirteen subjects with chronic sensory motor neuropathy, five non-neuropathic diabetic and nine normal control subjects were studied. The mean epineurial vessel pathology score of the neuropathic group was significantly higher than the combined normal control and non-neuropathic diabetic groups (p <0.01). Direct epineurial arteriovenous shunting was observed in six neuropathic and one non-neuropathic diabetic patients and not in any of the normal control subjects. The nerve fluorescein appearance time was significantly delayed in subjects with chronic sensory motor neuropathy (51.5 ± 12 s) compared to both normal (34.7 ± 9 s, p <0.01) and non-neuropathic diabetic subjects (33.4 ± 11 s, p <0.025). The mean intensity of fluorescence at 96, 252 and 576 s, was significantly lower in subjects with chronic sensory motor neuropathy compared with both of the other groups (p <0.05). The epineurial vessel pathology score was significantly related to reduced sural (p <0.01) and peroneal (p <0.001) nerve conduction velocities, elevated vibration (p <0.01) and thermal (p <0.001) perception and the severity of retinopathy (p <0.002). The fluorescein appearance time was significantly related to reduced sural sensory (p <0.02) conduction velocity, elevated vibration (p <0.01) perception and epineurial vessel (p <0.002) pathology score, but it failed to relate to peroneal motor (p = 0.06) conduction velocity, thermal (p = 0.1) perception and the severity of retinopathy (p = 0.3). Intensity of fluorescence was significantly related to fluorescein appearance time (at 96 s, p <0.001; at 576 s, p <0.05) but did not relate to measures of neuropathic severity. These techniques have enabled us to observe that epineurial vessel anatomy is abnormal and that nerve blood flow is impaired in subjects with chronic sensory motor neuropathy. In addition epineurial arterio-venous shunting may be a feature of diabetic neuropathy. These techniques may further be applied to study nerve blood flow in early diabetic neuropathy.     

Subclinical nerve dysfunction in children and adolescents with IDDM

Summary The purpose of this study was to investigate whether young insulin-dependent diabetic patients still develop peripheral nerve dysfunction when using modern multiple insulin injection therapy and to elucidate if this correlated with various disease parameters. Seventy-five patients, 7 to 20 years old with a duration of diabetes of more than 3 years, and 128 age-matched healthy control subjects underwent bilateral studies of median, peroneal, and sural nerves. Presence of diabetes lowered motor conduction velocity (p<0.0001), sensory conduction velocity (p<0.0001) and sensory nerve action potential (p<0.05) in all examined nerves. The mean change in conduction velocity induced by diabetes was –4.8 m/s in the peroneal nerve, –3.3 m/s in the median motor nerve, –2.6 m/s in the sural nerve and –2.4 m/s in the median sensory nerve. Fifty-seven percent of the patients had abnormal conduction (values outside 95% predictive interval) which was seen most often in the motor nerves, especially in the peroneal nerve (41%) followed by the median nerve (24%). In multiple regression analysis, long-term poor metabolic control and increased body length correlated with nerve dysfunction identified in most examined parameters. Three patients had signs or symptoms suggestive of neuropathy. It is concluded that despite modern multiple insulin injection therapy, with reasonably good metabolic control, nerve dysfunction is still common in children and adolescents with insulin-dependent diabetes mellitus. Risk factors are increased height and long-term poor metabolic control.Abbreviations IDDM Insulin-dependent diabetes mellitus - MIT multiple insulin injection therapy - MCV motor nerve conduction velocity - CMAP compound muscle action potential - DML distal motor latency - SCV sensory nerve conduction velocity - SNAP sensory nerve action potential     

A new minimally invasive technique to show nerve ischaemia in diabetic neuropathy

Aims/hypothesis. Experimental studies have shown that abnormalities of nerve microcirculation are important factors in the pathogenesis of diabetic neuropathy but there have been few clinical studies. We have applied microlightguide spectrophotometry to measure intravascular oxygen saturation (HbO₂%) and blood flow in human sural nerve. Methods. We studied ten patients with mild-moderate sensory motor diabetic neuropathy, nine patients without neuropathy and nine control subjects. We took 300 measurements of oxygen saturation under direct visual control through a 1.9 mm rigid endoscope over three regions of the nerve. Spectrophotometric measurements of nerve fluorescence were taken after an intravenous injection of sodium fluorescein and the rate of increase in nerve fluorescence (rise time) was used as an indicator of nerve blood flow. Results. Nerve oxygen saturation was reduced in patients with neuropathy compared with control subjects (67.1 ± 2.2 % vs 76.7 ± 2.1 %, p = 0.006). Fluorescein rise time was prolonged in patients with neuropathy compared with the control group (48.5 ± 7.0 s vs 14.0 ± 3.1 s, p = 0.001) suggesting impaired nerve blood flow. There was a correlation between rise time, nerve oxygen saturation, glycaemic control and sural nerve sensory conduction velocity (p < 0.01). Conclusion/interpretation. The combination of microlight-guide spectrophotometry and micro-endoscopy provides a valuable minimally invasive technique for clinical investigation of nerve microcirculation. We have shown reduced nerve oxygenation and impaired blood flow in diabetic neuropathy and these findings strongly support a central role of microvascular disease in the pathogenesis of diabetic neuropathy. [Diabetologia (1999) 42: 737–742] Received: 8 October 1998 and in revised form: 7 January 1999     

Blood flow patterns in painful diabetic neuropathy

Summary Peripheral blood flow is known to be qualitatively increased in diabetic patients with neuropathy. We have measured the actual blood flow in the feet of diabetic patients with neuropathy using non-invasive mercury strain gauge plethysmography and Doppler sonogram techniques and shown that it is increased on average five times above normal at an ambient temperature of 20 °–22 °C. Moreover, reduction of this high flow by sympathetic arousal stimuli proved possible in those with severe painful neuropathy contrasting strongly with failure to reverse it in those with severe non-painful sensory neuropathy. Reduction of blood flow was associated with reduction in neuropathic pain. We studied 22 diabetic patients with severe sensory neuropathy and eight with painful neuropathy. High resting foot blood flows were demonstrated in both groups with neuropathy. The big toe flow in those with severe sensory neuropathy was 29.3±9.2 ml · min^–1 · 100 ml^–1 (mean±SD) and in the painful neuropathy group, 25.9±7.5, compared with 5.2±2.4ml · min^–1 · 100ml^–1 in the non-diabetic control subjects (p<0.001). High foot skin temperatures were also recorded in the groups with neuropathy, reflecting the high blood flow. The subjects with painful neuropathy retained the ability to constrict peripheral blood vessels in response to arousal stimuli, and reduce peripheral flow on average by 32% compared with the patients with sensory neuropathy who responded on average by only 10%. The demonstration of a peripheral sympathetic defect, responsible for the high blood flow and the potential reversal of such flow in painful neuropathy may be important in our further understanding of the aetiology of such pain and its treatment.     

Pattern of myelinated fibre loss in the sural nerve in neuropathy related to Type 1 (insulin-dependent) diabetes

Summary Sural nerve biopsies were obtained from 17 diabetic patients with neuropathy. All patients except three had both a symmetric distal sensory and autonomic polyneuropathy related to Type 1 (insulin-dependent) diabetes mellitus; 3 patients had a purely sensory polyneuropathy. Mean age was 34.5 years (range 18–53 years). The biopsies were compared with specimens from an age-matched control series. Myelinated fibre loss in the diabetic nerves was found to be nonuniform. Although patchy fibre loss has been considered to favour a vascular basis, an identical pattern of nonuniform loss was observed in a series of sural nerve biopsies from patients with Type I hereditary motor and sensory neuropathy, a subgroup within the spectrum of peroneal muscular atrophy, mainly of autosomal dominant inheritance, and a condition in which a vascular causation can be discounted. Possible reasons for nonuniform fibre loss other than vascular disease are discussed.     

The effect of 8 years of strict glycaemic control on peripheral nerve function in IDDM patients: the Oslo study

Summary We have investigated the effect of long-term strict glycaemic control on peripheral and autonomic nerve function in 45 IDDM patients (age 18–42 years, diabetes duration 7–23 years) without clinical signs of neuropathy or other neurological disease. They were randomly assigned to treatment either with continuous insulin infusion, multiple injections (4–6 times daily), or conventional treatment (twice daily) for 4 years and followed prospectively for 8 years. Motor and sensory nerve conduction velocities were measured at the start and after 8 years. Autonomic nerve function tests were performed only once, after 8 years. A significant reduction of nerve conduction velocity was observed during 8 years in patients with mean HbA₁ more than 10% (n=12, group mean 10.9%, range 10.1–13.2%) compared to patients with HbA₁ less than 10% (n=33, group mean 9.0%, range 7.5–9.9%). Change of motor nerve conduction velocity in the peroneal nerve was: –4.8±4.9 (SD) vs –2.2±5.3 m/s (p<0.01). Change of motor nerve conduction velocity in the posterior tibial nerve was: –6.8±5.7 vs –3.9±5.1 m/s (p<0.05). No significant changes were observed in the ulnar nerve. Change of sensoric nerve conduction velocity in the sural nerve was: –8.9±8.0 vs –4.6±5.3 m/s (p<0.05). Multiple regression analysis showed that a change in HbA₁ of 1% resulted in a 1.3 m/s change in nerve conduction velocity during 8 years. A significantly lowered heart-rate variation during deep breathing (p<0.05) and heart-rate response to standing (p<0.01) was found in patients with HbA₁ more than 10% compared to patients with HbA₁ less than 10%. This study confirms that the long-term lowering of blood glucose retards the deterioration in nerve conduction velocity observed in the diabetic nerve.Abbreviations IDDM Insulin-dependent diabetes mellitus     

Current perception thresholds: a new,quick, and reproducible method for the assessment of peripheral neuropathy in diabetes mellitus

Summary The Neurometer is a variable constant current sine wave stimulator, and has recently been proposed as a simple non-invasive and quantitative measure of peripheral nerve function. The device is portable and battery operated; assessment of upper and lower extremities takes only a few min, in contrast to conventional assessment techniques. In order to assess its potential in the quantification of diabetic neuropathy, detection thresholds for constant current electric sine wave stimulation were measured at three different frequencies in different sites in 31 healthy control subjects and 90 diabetic patients with and without neuropathy. The device provides good discrimination between neuropathic and non-neuropathic groups (p<0.001) and is quick and easy to use. Comparisons with results of conventional tests of nerve function show that high frequency detection thresholds correlate best with tests of large fibre function (r= 0.42–0.69, p<0.001), and low frequency detection thresholds correlate with tests of small fibre function (r=0.34–0.46, p<0.005). It is concluded that the device may be a simple and comprehensive way of assessing peripheral nerve function.     

The activity of the renin-angiotensin-aldosterone system before and during submaximal bicycle exercise in relation to circulatory catecholamines in patients with Type 1 (insulin-dependent) diabetes mellitus

Summary To evaluate the renin-angiotensin-aldosterone system in relation to circulatory catecholamines, we determined renin activity, angiotensin II, aldosterone, adrenaline, and noradrenaline in plasma before and during a submaximal bicycle exercise test in 23 Type 1 (insulin-dependent) diabetic patients (aged 19–57 years, mean 37; duration of diabetes 2–32 years, mean 16), 17 with signs of cardiac autonomic neuropathy, and in 18 healthy non-diabetic subjects (aged 24–41 years, mean 29). At rest, Type 1 diabetic patients showed significantly lower aldosterone values than control subjects (0.14±0.02 nmol/l and 0.22±0.02 nmol/l; p<0.01) while renin activity (1.0±0.1 nmol·l^–1·h^–1 and 0.9±0.1 nmol·l^–1·h^–1) and angiotensin II (14±1 nmol/l and 18±2 nmol/l) did not differ significantly between patients and control subjects. During exercise, increments (increase from the resting value to the value at 80% of maximal working capacity) in renin (1.5±0.4 nmol·l^–1·h^–1 and 3.7±0.5 nmol·l^–1 ·h^–1; p<0.001), angiotensin II (28±8 nmol/l and 60±8 nmol/l; p<0.01), aldosterone (0.16±0.04 nmol/l and 0.25±0.05 nmol/l; p<0.05), adrenaline (1.96±0.49 nmol/l and 2.92±0.51 nmol/l; ps<0.05), and noradrenaline (12.01±1.25 nmol/l and 18.74±1.45 nmol/l; p<0.01) were significantly lower in the patients than in control subjects. There was no difference in the renin-angiotensin-aldosterone response to exercise between patients with and without cardiac autonomic neuropathy but the impaired catecholamine reaction was confined to patients with cardiac autonomic neuropathy. In conclusion, Type 1 diabetic patients demonstrated low resting plasma aldosterone and reduced increments in renin activity, angiotensin II, aldosterone, and catecholamines during exercise. The low aldosterone values might be related to dysfunction of adrenal zona glomerulosa cells while it is unlikely that the reduced response to exercise of the renin-angiotensin-aldosterone system simply reflects sympathetic nerve failure.     

The effect of the calcium antagonist nifedipine on peripheral nerve function in streptozotocin-diabetic rats

Summary Recent data suggests that reduced nerve blood flow is implicated in the aetiology of experimental diabetic neuropathy, which may be prevented by manipulations that reduce receptor-mediated vasoconstrictor activity. This investigation examines the effects of nifedipine, a voltage-sensitive calcium channel antagonist which has a direct vasodilatory effect on vessels, on nerve conduction, hypoxic resistance and capillary density in streptozotocin-induced diabetic rats. Treated and non-treated non-diabetic and diabetic groups were employed. Diabetes duration was 2 months. Treatment was preventive, groups received a nifedipine dietary supplement (40 mg · kg^–1 · day^–1) for 2 months from the start of the study. Conduction was measured in sciatic motor branches supplying tibialis anterior and gastrocnemius muscles, and sensory saphenous nerve. Diabetes resulted in a 23–28 % reduction in motor conduction velocity (p<0.001), and a 15% deficit for sensory saphenous nerve (p<0.001). In the nifedipine-treated diabetic group, motor and sensory conduction deficits were minimal compared with non-treated diabetes (p<0.001). Nifedipine treatment had no significant effect on conduction velocity in nondiabetic rats. In vitro measurement of sciatic nerve hypoxic resistance revealed a 60 % increase in the time taken for compound action potential amplitude to reach half its initial value with diabetes (p<0.001). This was not significantly affected by nifedipine treatment. Experimental diabetes or nifedipine treatment did not significantly alter sciatic nerve endoneurial capillary density. We conclude that nifedipine, a vasodilator which acts directly on vascular smooth muscle, prevents nerve conduction deficits in experimental diabetes.     

Increased accumulation of skin advanced glycation end-products precedes and correlates with clinical manifestation of diabetic neuropathy

Aims/hypothesis The accumulation of AGE is related to the progression of the renal, retinal and vascular complications of diabetes. However, the relationship with diabetic neuropathy remains unclear. We recently showed that skin autofluorescence, measured non-invasively with an AutoFluorescence Reader (AFR), could be used to assess skin AGE accumulation. We evaluated the relationship between skin autofluorescence and the severity of diabetic neuropathy.Materials and methods Skin autofluorescence in arbitrary units (AU) was assessed in 24 diabetic patients with a history of neuropathic foot ulceration (NP⁺), 23 diabetic patients without clinical neuropathy (NP^–) and 21 control subjects, using the AFR. Arterial occlusive disease was excluded in all. The severity of foot ulceration was assessed by the Wagner score. Peripheral nerve function was assessed by neurography, measuring motor and sensory nerve conduction velocity and amplitude of the median, peroneal and sural nerves. Heart rate variability (HRV) and baroreflex sensitivity (BRS) were measured by Finapres to assess autonomic nervous function.Results Autofluorescence was increased in NP^– compared with control subjects. In NP⁺ patients, autofluorescence was further increased and correlated with the Wagner score. Autofluorescence correlated negatively with nerve conduction velocity and amplitude, HRV and BRS in both NP⁺ and NP^– groups. Autofluorescence correlated with age, diabetes duration, mean HbA₁c of the previous year, serum creatinine level, presence of microalbuminuria and severity of diabetic retinopathy.Conclusions/interpretation Skin autofluorescence correlates with the severity of peripheral and autonomic nerve abnormalities in diabetes, even before being clinically manifest. The AFR may be a convenient and rapid clinical tool for assessing risk of progression of long-term diabetic complications.     

The relationship between sural nerve morphometric findings and measures of peripheral nerve function in mild diabetic neuropathy.

The morphological findings in sural nerve biopsy specimens from 15 diabetic patients with mild neuropathy were compared with control biopsies from eight non-neuropathic, non-diabetic subjects, and correlations were sought with electrophysiological studies and quantitative sensory tests for vibration, thermal, and current perception thresholds. Myelinated fibre density was reduced compared with control biopsies (4042 +/- 2090 (+/- SD) vs 6800 +/- 1100 mm-2; p less than 0.01). A strong correlation existed between myelinated fibre density and sural sensory conduction velocity (r = 0.84, p less than 0.001), sural action potential amplitude (r = 0.74, p less than 0.001), peroneal motor conduction velocity (r = 0.58, p less than 0.02), and median sensory amplitude (r = 0.64, p less than 0.01) but there was no correlation between myelinated fibre density and any quantitative sensory test. We conclude that conventional electrophysiological tests in the lower limb are reliable surrogate measures for structural abnormalities in early diabetic neuropathy.     

Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy

Summary Clinical, electrophysiological and ultrastractural morphometric observations were made in 5 diabetic non-neuropathic patients, 5 diabetic patients with mild neuropathy and 11 diabetic patients with severe neuropathy. Capillary abnormalities were assessed in simultaneous nerve, muscle and skin biopsies and compared with results from 6 age-matched, non-diabetic control subjects.Nerve capillaries demonstrated markedly greater pathology than skin and muscle capillaries. Endoneurial capillary density was significantly reduced in severely neuropathic diabetic patients (p<0.01) when compared with control subjects. Capillary basement membrane (p<0.002), endothelial cell (p<0.003) and total diffusion barrier (endothelial cell, pericyte, basement membrane) (p<0.001) thickness were significantly increased, and oxygen diffusing capacity was significantly reduced (p<0.001) in the nerves of patients with severe diabetic neuropathy when compared to control subjects. Endothelial cell profile number and luminal perimeter were significantly increased in asymptomatic (p<0.01), (p<0.05) and severely neuropathic (p<0.001), (p<0.05) diabetic patients respectively. However, endothelial cell outer perimeter, a measure of capillary size, showed no significant increase in diabetic patients when compared with control subjects. An association was observed between neurophysiological and neuropathological measures of neuropathic severity. There was no significant correlation between the duration of diabetes and HbA₁ levels with capillary pathology or with neuropathic severity. Very few abnormalities of muscle and skin correlated with neuropathic severity. However, all measures of nerve capillary pathology correlated significantly with neurophysiological and neuropathological measures of neuropathic severity.     

Structure-function relationships within peripheral nerves in diabetic neuropathy: the hydration hypothesis

Summary To define the quantitative relationship between peripheral nerve structure and function imposed by endoneurial oedema in the diabetic state, we determined values for sural nerve hydration structure as measured by magnetic resonance spectroscopy, and for neurological function with scores for nerve conduction properties (NCV-score), neuropathic symptoms (NS-score), and examination signs (NE-score). The coefficient of sural nerve hydration was elevated to 30±6% (p<0.05) in 79 symptomatic neuropathic diabetic subjects with an average of 15 years of diabetes mellitus, compared to a value of 25±3% in 72 non-diabetic control subjects. In contrast, in 75 asymptomatic diabetic subjects with an average of 6 additional years of diabetes, the mean hydration coefficient was only 28±5% (p<0.05). A nerve hyperhydration state was identified with a prevalence of 25% within the asymptomatic group characterized by nerve hydration greater than the 95th percentile, early changes in nerve electrophysiology and neurological examination, but with no symptomatology of neuropathy. Stratification of the symptomatic neuropathic group by worsening nerve electrophysiology, demonstrates a coincident deterioration in neurological examination (RR=5.39 at maximum NCV-score), and neuropathy symptomatology (RR=4.80 at maximum NE-score). The present data are consistent with the hypothesis that endoneurial oedema initiates deterioration sequentially in nerve electrophysiology, followed by abnormal findings on neurological examination, preceding the patient's final perception of symptomatic stocking-glove peripheral diabetic neuropathy.Abbreviations MRS Magnetic resonance spectroscopy - NCV nerve conduction velocity - NE neurological examination - NS neurological symptoms - IDDM insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus     

Hemorheologic and hemostatic changes in long-standing insulin-dependent (type I) diabetic patients with peripheral and autonomic cardiovascular neuropathy

Summary Diabetic microangiopathy may be associated with the pathogenesis and progression of autonomic and peripheral neuropathy. In 17 long-standing type I diabetic patients with peripheral and autonomic cardiovascular neuropathy, several hemorheological and hemostatic alterations were found compared to 13 matched type I patients without neuropathy. In particular, increased plasma von Willebrand factor antigen (p<0.001), fibronectin (p<0.001) and fibrinogen (p<0.001) levels were demonstrated in neuropathic in comparison with non-neuropathic diabetic patients. Moreover negative correlations between these parameters and both motor and sensitive conduction velocity of median, sural and peroneal nerves were observed in diabetic patients with neuropathy. Higher blood viscosity (p<0.05 at shear-rate of 450 and 225 s⁻¹; p<0.01 at 90 s⁻¹; p<0.001 at 4.5 and 2.25 s⁻¹), plasma viscosity (p<0.001) and lower erythrocyte filtrability (p<0.001) were also found in neuropathic compared to non-neuropathic diabetics. Increased prevalence of retinopathy (p<0.01) and nephropathy (p<0.001) was finally reported in patients with autonomic and peripheral neuropathy. Microvascular disease may be involved in the development of neuropathy in long-term type I diabetes mellitus. This study was presented in part at the 23rd Annual Meeting of the European Association for the Study of Diabetes, Leipzig (GDR), 15–19 September 1987.     

Parotid salivary secretion in diabetic autonomic neuropathy

Parotid salivary flow rates and amylase concentrations were measured in three groups of eight subjects each (normal control, non-neuropathic diabetic, and neuropathic diabetic). Flow rates were significantly reduced in neuropathic diabetic patients as compared with normal controls (p < 0.001) and non-neuropathic diabetic patients (p < 0.02). Amylase concentrations were similar. These data are consistent with parasympathetic denervation of the parotid gland in diabetic neuropathy and provide evidence for a widespread distribution of autonomic denervation in diabetes.     

Elevated plasma insulin-like growth factor binding protein-1 levels in Type 1 (insulin-dependent) diabetic patients with peripheral neuropathy

Summary Previous studies have suggested that nerve regeneration may be defective in patients with diabetic polyneuropathy. Since insulin-like growth factor I (IGF-I) has been shown to stimulate nerve regeneration, and IGF binding protein-1 is acutely regulated by plasma insulin we have investigated the relationships between plasma IGF-I, IGFBP-1, glucose and insulin in Type 1 (insulin-dependent) diabetic patients with peripheral polyneuropathy. Plasma samples were taken at hourly intervals over an 11-h period (08.00–19.00 hours) in order to characterise secretory profiles for 15 Type 1 diabetic patients (eight neuropathic and seven non-neuropathic) and eight non-diabetic control subjects. In the non-diabetic subjects, mean plasma IGF-I levels were stable throughout the 11-h period with a range of 97 g/l–169 g/l. In contrast, mean plasma IGFBP-1 levels declined steadily from a high level of 1.99 g/l at 08.00 hours to approximately one half (0.86 g/l) at 15.00 hours. Comparison of areas under the curves revealed significant negative correlations between IGFBP-1 and glucose (–0.88, p=0.01), IGFBP-1 and insulin (–0.75, p=0.016), and IGFBP-1 and IGF-I (–0.68, p=0.03). A significant positive correlation was found between insulin and IGF-I (+ 0.89, p=0.001). The diabetic patients had markedly elevated plasma IGFBP-1 levels (area under curve, p=0.01) and lower plasma IGF-I levels (p=0.033) even though these patients were hyperinsulinaemic throughout the study period. The neuropathic diabetic patients had grossly elevated IGFBP-1 levels (–X=40 g/l at 08.00 hours) which were significantly higher (area under curve, p=0.05) than in patients without neuropathy (¯X=15 g/l at 08.00 hours). However, plasma levels of insulin and IGF-I in neuropathic and non-neuropathic subjects were similar, suggesting that the regulation of IGFBP-1 is more resistant to insulin in the neuropathic patients. In contrast to the non-diabetic subjects comparison of area under curve values revealed no positive correlation between insulin and IGF-I or negative correlations between IGF-I and IGFBP-1, and IGFBP-1 and glucose. We conclude that in Type 1 diabetes the relationships between plasma glucose, insulin, IGF-I and IGFBP-1 are clearly abnormal, and these abnormalities are more pronounced in patients with peripheral neuropathy.     

Sorbitol and myo-inositol levels and morphology of sural nerve in relation to peripheral nerve function and clinical neuropathy in men with diabetic, impaired, and normal glucose tolerance.

AIMS: Sorbitol and myo-inositol levels and morphology of sural nerve were compared with nerve function and clinical neuropathy in men with diabetic, impaired (IGT), and normal glucose tolerance. METHODS: After neurography of sural nerve and determinations of sensory thresholds for vibration, warm and cold on the foot, whole nerve sural nerve biopsy was performed in 10 men with Type 1 diabetes mellitus, 10 with IGT, and 10 with normal glucose tolerance. Polyol levels were assessed by gas-liquid chromatography/mass spectrometry. RESULTS: Sural nerve amplitudes were significantly lower and sorbitol levels significantly higher in diabetic patients (median (interquartile range)) (3.7 (3.5) microV and 643 (412) pmol/mg protein, respectively) both compared with IGT (11.3 (10.6)microV; P = 0.04 and 286 (83) pmol/mg protein; P = 0.0032, respectively) and normally glucose tolerant (10.0 (11.6); P = 0.0142 and 296 (250) pmol/mg protein; P = 0.0191, respectively) subjects. There were no differences in nerve morphology between the three groups. Nerve myo-inositol levels correlated, however, positively with cluster density (rs = 0.56; P = 0.0054). In diabetic and IGT subjects, sural nerve amplitudes (2.6 (3.8) vs. 12.1 (10.6) microV; P = 0.0246) and myelinated nerve fibre density (MNFD; 4,076 (1091) vs. 5,219 (668) nerve fibres/mm2; P = 0.0021) were significantly lower in nine subjects with clinical neuropathy than in 10 without. CONCLUSIONS: Nerve degeneration (i.e. MNFD) correlated with clinical neuropathy but not with glucose tolerance status whereas nerve myo-inositol levels positively correlated with signs of nerve regeneration (i.e. increased cluster density).     

Restoring lower limb blood flow improves conduction velocity in diabetic patients

Summary Human diabetic peripheral neuropathy is believed to have, at least in part, a microvascular basis. This study was designed to examine the effects of restoration of arterial blood supply on peripheral nerve function in six non-insulin-dependent diabetic patients with peripheral occlusive vascular disease. In the revascularised legs, transcutaneous oxygen increased from a median 37.5 (28.5–45.7 interquartile range) mmHg to 55.5 (53.5–62.5) mmHg, p=0.036, mean increase 20.2 (14.8–25.6, 95% confidence intervals(CI)) mmHg. This was accompanied by a significant improvement in peroneal motor nerve conduction velocity from 31.7 (26.5–36.3) m/s to 33.5 (32.9–39.4) m/s, p=0.04, mean increase 4.7 (1.7–7.7, 95% CI) m/s. There was no significant change in transcutaneous oxygen or peroneal nerve motor conduction velocity in the contralateral control limbs. This improvement in conduction velocity with improved tissue oxygenation suggests that studies of agents which might indirectly bring about improvements in microvascular blood flow should be urgently considered.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - MCV motor conduction velocity - TcPO₂ transcutaneous oxygen     

Persistent Postoperative Complaints After Whole Sural Nerve Biopsies in Diabetic and Non-diabetic Subjects

The postoperative effects of a whole sural nerve biopsy in diabetic (11) and non-diabetic (10 healthy controls, 10 patients with impaired glucose tolerance and 2 patients with polyneuropathy) subjects were investigated by a mailed questionnaire 20–44 months after the surgical procedure (10/11 vs 21/22 answers received). Pain in the biopsy area at follow-up was reported in 4/10 of the diabetic patients (p = 0.01) but in none of the non-diabetic subjects (0/21). An increased number (p = 0.01) of diabetic patients (5/10 vs 1/21) had cold intolerance in their foot or leg whereas 11/31 of all patients had dysaesthesia in the affected skin. Overall 6/31 patients described serious problems at the time of the questionnaire, and 4 of this 6 having diabetes. Loss of sensation was reported in almost all subjects irrespective of diabetes or not; however, a decrease in the area of loss of sensation was reported most often in diabetic patients (8/10 vs 8/21, p = 0.02). It is concluded that whole surval nerve biopsies give rise to persistent problems both in diabetic and non-diabetic subjects. The reason for a sural nerve biopsy has always to be carefully considered before being conducted. © 1997 by John Wiley & Sons, Ltd.     

Elevated von Willebrand factor antigen predicts deterioration in diabetic peripheral nerve function

Summary We have studied the temporal relationship of plasma von Willebrand Factor (vWF), a marker of endothelial damage, with the development of complications in 63 young diabetic patients (56 of whom were insulin-dependent) who took part in a prospective study. Results are presented from baseline to follow-up. In the group as a whole, no significant changes were found in any autonomic function tests, temperature discrimination threshold or nerve conduction velocities. Median motor and peroneal latency were significantly increased, while median motor, peroneal motor and sural sensory potentials were significantly decreased at follow-up compared with baseline (p<0.001). There was a significant fall in mean plasma vWF antigen and ristocetin co-factor activity in the entire group. Within the group, we identified eight patients whose peroneal motor and sural sensory conduction velocities had decreased by over 2 ms^–1. In these patients (Group A), baseline vWF antigen and activity were significantly higher than in the rest of the patients (Group B), (p=0.04) and vWF antigen was still significantly higher after 3 years (p=0.02). There were no differences between the groups in incidence of retinopathy, urinary albumin excretion rate or macrovascular disease. To assess the influence of glycaemic control on vWF, we first compared a matched group (C) of diabetic patients with similar HbA₁ to that of group A, but with normal nerve conduction velocities: vWF was still significantly higher in group A compared with group C (p=0.02). Furthermore, hierarchical regression showed that vWF predicted deteriorating nerve function independently of glycaemic control or the type of diabetes. Endothelial dysfunction may be associated with development of peripheral neuropathy in young diabetic patients.Abbreviations Standardized regression coefficient - B unstandardized regression coefficient - IQR inter-quartile ranges - MMCV median motor nerve conduction velocity - MSCV median sensory nerve conduction velocity - PMCV peroneal motor nerve conduction velocity - SSCV sural sensory nerve conduction velocity - UAER urinary albumin excretion rate - vWF von Willebrand factor - vWFact von Willebrand factor activity - vWFag von Willebrand factor antigen - IDDM insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus