Sural nerve pathology in diabetic patients with minimal but progressive neuropathy.

AIMS/HYPOTHESIS: The early pathological features of human diabetic neuropathy are not clearly defined. Therefore we quantified nerve fibre and microvascular pathology in sural nerve biopsies from diabetic patients with minimal neuropathy. METHODS: Twelve diabetic patients underwent detailed assessment of neuropathy and fascicular sural nerve biopsy at baseline, with repeat assessment of neuropathy 8.7+/-0.6 years later. RESULTS: At baseline, neuropathic symptoms, neurological deficits, quantitative sensory testing, cardiac autonomic function and peripheral nerve electrophysiology showed minimal abnormality, which deteriorated at follow-up. Myelinated fibre density, fibre and axonal area, and g-ratio were normal but teased fibre studies showed paranodal abnormalities (p<0.001), segmental demyelination (p<0.01) and remyelination (p<0.01) without axonal degeneration. Unassociated Schwann cell profile density (p<0.04) and unmyelinated axon density (p<0.001) were increased and axon diameter was decreased (p<0.007). Endoneurial capillaries demonstrated basement membrane thickening (p<0.006), endothelial cell hyperplasia (p<0.004) and a reduction in luminal area (p<0.007). CONCLUSIONS/INTERPRETATION: The early pathological features of human diabetic neuropathy include an abnormality of the myelinated fibre Schwann cell and unmyelinated fibre degeneration with regeneration. These changes are accompanied by a significant endoneurial microangiopathy.

Prolonged remission of hypercalcaemia due to parathyroid carcinoma with pamidronate.

Parathyroid carcinoma is rare and the associated hypercalcaemia is often resistant to all treatment. A case is described in which prolonged control of hypercalcaemia has been achieved by infrequent infusions of pamidronate despite continuing hypersecretion of parathyroid hormone.

Evidence against a putative role for glucagon as a physiological splanchnic vasodilator in man.

1. Previous studies have suggested that glucagon in supraphysiological doses may mediate postprandial and hypoglycaemia-induced splanchnic vasodilatation in man and experimental animals. There are no reported studies investigating the role of glucagon in doses producing circulating concentrations within the physiological range. 2. Two separate studies were performed. In study 1, superior mesenteric artery blood flow was measured by Doppler ultrasound in six normal subjects during either saline or glucagon infusion at 1, 3 and 6 ng min-1kg-1, which resulted in circulating glucagon levels within the physiological range. Mean superior mesenteric artery blood flow fell during the 3 and 6 ng min-1kg-1 glucagon infusions (3 ng min-1kg-1: -31.8%, range -20 to -56% of baseline; 6 ng min-1kg-1: -20.7%, range -8 to -53% of baseline; P < 0.05). 3. In study 2, superior mesenteric artery blood flow was measured during hypoglycaemia induced by an insulin infusion in 12 normal subjects. In six of these subjects the effect of suppression of glucagon release during hypoglycaemia was assessed by pretreatment with the somatostatin analogue octreotide (0.8 microgram/kg subcutaneously) given 30 min before the insulin infusion. 4. The nadir in blood glucose concentration at the hypoglycaemic reaction was similar in both groups and glucose recovery was complete by 60 min after the hypoglycaemic reaction. Plasma catecholamine concentrations rose in both groups after the hypoglycaemic reaction. 5. Superior mesenteric artery blood flow rose at the hypoglycaemic reaction in both groups despite suppression of glucagon release with octreotide.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of lipolysis in normal man does not inhibit recovery from insulin-induced hypoglycaemia.

Pharmacological suppression of lipolysis is being increasingly used in the treatment of diabetic hyperlipidaemia. Although theoretical hazard of such treatment is that recovery from hypoglycaemia might be impaired. Seven normal subjects were therefore studied on two occasions, following treatment with a single dose of either acipimox 250 mg or placebo. Hypoglycaemic recovery was unaffected, despite effective suppression of plasma non-esterified fatty acid levels with acipimox. The results suggest that under these conditions activation of lipolysis may not be essential to recovery from hypoglycaemia.

Relationships between haemostatic factors and capillary morphology in human diabetic neuropathy.

We have examined haemostatic factors in 15 diabetic patients with peripheral neuropathy and 10 diabetic patients without clinical complications. Plasma and blood viscosity, fibrinogen, factor VIIIc, von Willebrand factor activity, spontaneous platelet aggregation and fibrinolytic activity were not significantly different between diabetic patients without clinical complications and diabetic patients with peripheral neuropathy. Platelet aggregation was enhanced in diabetic patients with neuropathy compared with those without complications. In the 15 patients with neuropathy and 3 without complications, who underwent biopsy of sural nerve, skin and muscle, associations were found between haemostatic variables and measures of nerve capillary pathology, notably: plasma fibrinogen and nerve capillary basement membrane thickness (r = 0.70, p < 0.001); thromboxane B2 production and nerve capillary basement membrane thickness (r = -0.61, p < 0.01); plasma fibrinolytic activity and endoneurial capillary lumen size (r = 0.60, p < 0.01) and endothelial cell outer perimeter (r = 0.65, p < 0.01). The main associations of skin and muscle capillary abnormalities were with measures of in vitro platelet aggregation, and the correlations found with nerve capillary measurements were not echoed in the overlying muscle and skin. The results are supportive of the involvement of haemostatic abnormalities in the pathogenesis of diabetic neuropathy.

Primary renal renin secretion responding to angiotensin converting enzyme inhibition.

A case of primary renal renin secretion of probable neoplastic origin is reported. Investigation demonstrated renin secretion to be incompletely autonomous with suboptimal suppression to posture and hypervolaemia. Easy control of the hypertension and hypokalaemia was achieved with an angiotensin converting enzyme inhibitor. Such treatment may prove to be a preferable option to surgery.

Studies of acquired sustained hypernatraemia occurring in a diabetic patient.

We describe studies undertaken in a diabetic patient with acquired sustained severe hypernatraemia. Arginine vasopressin levels and thirst scores were grossly subnormal in the presence of marked hypernatraemia but arginine vasopressin increased normally under the influence of negative pressure-induced hypovolaemia. Despite very low levels of arginine vasopressin, polyuria was not a feature suggesting acquired renal hyper-responsiveness. This patient is an additional case of acquired osmoregulatory dysfunction, whose features do not fall neatly into previously described categories.

Splanchnic haemodynamic changes during acute hypoglycaemia in man.

1. Splanchnic haemodynamic changes were studied in seven healthy subjects during hypoglycaemia induced by the intravenous infusion of insulin. Superior mesenteric artery blood flow and cardiac output were examined noninvasively by a Doppler ultrasound technique. 2. Blood glucose concentration fell from 4.5 (0.14) mmol/l basally to 1.5 (0.09) mmol/l [mean (SEM), P less than 0.003] at the hypoglycaemic reaction ('R') and recovered to baseline by 'R' + 60 min. There was an associated rise in plasma glucagon, adrenaline and noradrenaline levels. 3. Superior mesenteric artery blood flow rose at 'R' from a basal value of 532 (38) ml/min to a peak of 803 (73) ml/min at 'R' + 10 min [mean (SEM), P less than 0.005] and remained significantly elevated until 'R' + 40 min. Resistance in this vessel fell by 33% at 'R' + 10 min (P less than 0.005) and remained significantly low until 'R' + 40 min. 4. Cardiac output rose by 33% at 'R' (P less than 0.004) and returned to normal by 'R' + 20 min. This was associated with a 24% rise in pulse rate (P less than 0.03), but no change in stroke volume or mean arterial pressure. Total peripheral resistance fell by 21% at 'R' (P less than 0.005) and had returned to normal by 'R' + 20 min. 5. The sustained rise in splanchnic blood flow during hypoglycaemic recovery may be of homoeostatic importance by providing metabolic fuel to the liver for gluconeogenesis.

Do in-vivo suppression and stimulation of lipolysis influence thyroid hormone levels in man?

To determine whether increases in non-esterified fatty acids alter free thyroid hormone and TSH levels, the effect of endogenous activation of lipolysis by insulin-induced hypoglycaemia was examined in seven healthy volunteers pretreated with placebo or acipimox. Whilst levels of non-esterified fatty acid were very different in the two groups, levels of free thyroxine, tri-iodothyronine and TSH were unchanged. Thus, within the range of non-esterified fatty acid levels likely to be seen in clinical practice, any effect on thyroid hormone measurements can be safely ignored.

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 less than 0.001) and non-neuropathic diabetic patients (p less than 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.

Autonomic denervation may be a prerequisite of diabetic neuropathic foot ulceration.

Studies using visceral (cardiovascular) autonomic function testing have left doubt as to the importance of autonomic neuropathy in the development of diabetic neuropathic foot ulceration. A test for peripheral autonomic denervation has been developed (acetylcholine sweatspot test), dependent on intradermal acetylcholine causing secretion by innervated sweat glands, detected by starch/iodine discoloration. The response is photographed and quantified using a grid (normal score = 0 or 1; abnormal = 5 to 60). The sweatspot test was applied to the feet of 19 diabetic patients with a history of foot ulceration, 17 with neuropathic pain, 8 complaining of numbness, and to 15 diabetic control patients. The sweatspot test score of the foot ulcer patients (median 54) was very much greater than that of the other groups (pain group, 4, p less than 0.005; numbness group, 2, p less than 0.01; diabetic control group, 2, p less than 0.0001). All the patients with neuropathic foot ulceration had peripheral autonomic denervation. The results suggest that autonomic denervation in the feet is always present in patients with diabetic neuropathic foot ulceration. Tests of peripheral autonomic denervation such as the acetylcholine sweatspot test may be useful to identify patients at risk of neuropathic foot ulceration.

Relationship between longevity and lifeline: a manual study of 100 patients.

The relationship between length of lifeline and age at death has been evaluated in 100 consecutive autopsies. A highly significant association between the two was discovered which was strengthened further when hand size was controlled for. We feel that a powerful new prognostic sign may thus be within grasp.

Self-management of adrenal insufficiency by rectal hydrocortisone.

An alternative to intramuscular hydrocortisone self-injection was evaluated in healthy controls and in patients with adrenal insufficiency. Plasma cortisol concentrations were assayed after administration of 200 mg hydrocortisone by intramuscular injection (10 healthy subjects) or after insertion of an identical dose by rectal suppository (12 healthy subjects, 3 patients with adrenal failure). Plasma cortisol concentrations peaked at 1 hour (about 4000 nmol/l) following intramuscular injection and declined thereafter. After rectal administration, levels peaked at between 1 and 2 hours and persisted for 8 or more hours. Similar levels were achieved at 4 hours (about 1000 nmol/l) by both methods of administration. Self-treatment by rectal suppository may be useful in the prevention of Addisonian crises.

Impaired sweating in the diabetic neuropathic foot and its influence on skin flora.

Three groups each of 10 subjects, were defined by clinical and neurophysiological studies: diabetic with neuropathy (Group A), diabetic without neuropathy (Group B) and normal control (Group C). Sweating on the foot was quantified and the bacterial flora on the dorsum of the foot and deltoid area were examined. There were no significant differences in type of density of bacterial species found on either foot or deltoid regions between any of the three groups. Diabetics free of clinical infection have a similar skin microbial flora to non-diabetics even when sweating is seriously impaired. It is therefore unlikely that a change in the resident microbial flora is involved in the propensity of diabetic neuropathic patients to foot ulceration and infection.

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

Clinical, electrophysiological and ultrastructural 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 less than 0.01) when compared with control subjects. Capillary basement membrane (p less than 0.002), endothelial cell (p less than 0.003) and total diffusion barrier (endothelial cell, pericyte, basement membrane) (p less than 0.001) thickness were significantly increased, and oxygen diffusing capacity was significantly reduced (p less than 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 less than 0.01), (p less than 0.05) and severely neuropathic (p less than 0.001), (p less than 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.

Reduced hyperaemic response under the diabetic neuropathic foot.

Diabetic neuropathic ulcers typically occur at high pressure sites. Microvascular blood flow has been assessed on the plantar surface of the foot in three matched groups each of 12 subjects free from macrovascular disease: (a) patients with diabetic neuropathy with abnormal foot pressures and previous neuropathic ulceration; (b) non-neuropathic diabetic patients; (c) non-diabetic control subjects. Resting flow was measured at the highest pressure point under the metatarsal heads (defined by pedobarograph) using laser doppler flowmetry, and the hyperaemic response was assessed at the same site following 3 min standing. Peak flow was significantly reduced in neuropathic patients (2.3 +/- 1.4 (SD) volts) compared with control subjects (4.0 +/- 2.0 volts; p less than 0.03). The time for blood flow return to baseline was significantly prolonged in neuropaths (159 +/- 72 s) compared with normal subjects (93 +/- 18 s; p less than 0.01), with a significant delay also seen in non-neuropaths (151 +/- 38 s; p less than 0.0001 compared with normal).

Nerve ischaemia-resistance: an early abnormality in diabetes.

Vibration perception threshold (VPT) has been measured before and 30 min after limb ischaemia in 17 newly diagnosed non-insulin-dependent diabetic patients and matched controls. Mean baseline VPT was higher in the diabetics than in controls (14 vs 11, p less than 0.01) while VPT at 30 min was lower (25 vs 30, p less than 0.05). The ischaemic index (VPT at 30 min/baseline VPT), calculated as a measure of nerve ischaemia-resistance, was lower in the diabetics compared with controls (p less than 0.01), and correlated with blood glucose (r = -0.53, p less than 0.03) but not glycosylated haemoglobin at the time of testing. The difference in ischaemic index persisted even when baseline VPT measurements, rather than patients, were matched. Ischaemic index was re-tested in 15 patients after a median interval of 17 months (range 6-19), at which time mean +/- SD glycosylated haemoglobin had improved significantly (12.2% +/- 0.4 versus 9.5% +/- 0.05, p less than 0.001), but this bore no relation to changes in ischaemic index. Peripheral nerve ischaemia-resistance is present at the time of diagnosis of non-insulin-dependent diabetes, even in the absence of other neurophysiological abnormalities, and is not explicable by glycaemic control alone.

Abnormalities of foot pressure in early diabetic neuropathy.

Dynamic foot pressure has been studied in 44 diabetic subjects of mean age 52 years with no clinical evidence of neuropathy and in an age and sex matched non-diabetic control group. Vibration perception threshold (VPT), sensory (SCV), and motor conduction velocities (MCV) were also measured in the diabetic subjects. Sixteen diabetic subjects (Group A) had abnormally high pressures under the metatarsal heads (greater than 10 kg/cm2), whereas the remaining 28 diabetic subjects had normal results (Group B). The ratio of toe to metatarsal head loading (normal 0.112) was significantly reduced in Group A (0.077) compared to Group B (0.127: p less than 0.05). VPT and sural nerve SCV were also significantly abnormal in Group A subjects compared with Group B (p less than 0.005 and p less than 0.02, respectively), though there were no differences in MCV. A significant inverse correlation was obtained between toe loading and VPT. It is concluded that abnormalities of foot pressure occur in early sensory neuropathy and may precede clinical abnormalities. Assessment of the toe-loading ratio may provide a sensitive measure of motor dysfunction in early diabetic neuropathy.

Benoxaprofen--adverse reactions and monitoring in general practice.

We report on the pattern of use of benoxaprofen (Opren) in a single group practice for a period which included the complete clinical life of the drug. One hundred and seventy-two patients of the 6495 practice patients had been prescribed benoxaprofen, but 55% had only a small exposure (less than 20 g). Recorded adverse reactions, of which none was serious, appeared in 25 patients. Most were taking benoxaprofen for osteoarthritis (53%) or non-specific musculoskeletal pain (39.9%). The issue of a prescription was not recorded in 19.6% of cases and 88% were on additional drugs. Greater precision in record-keeping is required to avoid problems similar to the experience with benoxaprofen.