P.J. Watkins

Measurement of Markers of Osteoclast and Osteoblast Activity in Patients with Acute and Chronic Diabetic Charcot Neuroarthropathy

Excess osteoclast activity is believed to be responsible for the early bone changes associated with Charcot neuroarthropathy in diabetes mellitus. Markers of osteoclast and osteoblast activity were measured in four groups of patients: 16 with an acute Charcot foot, 16 with a chronic Charcot foot, 10 diabetic controls, and 10 non‐diabetic controls. Serum carboxyterminal telopeptide of type 1 collagen (1CTP), a marker of osteoclastic bone resorption, was significantly raised in the dorsal venous arch of the acute Charcot foot, 6.1 ± 1.5 μg l−1 (mean ± SD) compared with the chronic Charcot foot 4.1 ± 1.4, diabetic controls 3.3 ± 1.4, and non‐diabetic controls 2.8 ± 1.4, p < 0.0001. This local increase in 1CTP was also reflected systemically in a study subgroup of 6 patients with acute Charcot neuroarthropathy, in whom peripheral antecubital vein 1CTP was 9.2 ± 2.6 compared with 9.0 ± 3.1 in the foot. In 6 chronic Charcot neuroarthropathy patients, foot (3.8 ± 1.3) and systemic (4.0 ± 1.5) 1CTP values were similar. Serum procollagen carboxyterminal propeptide (P1CP), an indicator of osteoblastic bone formation, was not significantly different between the feet of patients with acute Charcot neuroarthropathy 112 ± 1.5 μg l−1, patients with chronic Charcot neuroarthropathy 109 ± 1.5 μg l−1, diabetic controls 93.5 ± 2.3 μg l−1, and non‐diabetic controls 90.1 ± 1.5 μg l−1. These results suggest that the acute Charcot foot demonstrates excess osteoclastic activity without concomitant increase in osteoblastic function. This may be important in its pathogenesis. © 1997 John Wiley & Sons, Ltd.

The Value of the Neurometer in Assessing Diabetic Neuropathy by Measurement of the Current Perception Threshold

The Neurometer is a relatively new device for assessing neuropathy by measuring current perception threshold (CPT). The study aim was to assess the ability of the Neurometer to distinguish between different types of nerve fibre damage by using different frequencies (2000 Hz, 250 Hz, and 5 Hz) of electric stimulus (high frequencies for large fibres and low frequencies for small fibres) and comparing the results with standard sensory tests of vibration perception threshold (VPT) and thermal perception threshold (TPT). CPT was determined on index finger and great toe of 51 patients with diabetic neuropathy and 28 non‐diabetic control subjects, age and sex matched. CPT in neuropathic patients could be distinguished from controls at all three frequencies in both feet and hands (p < 0.05). The best correlation was found between CPT at 2000 Hz and VPT (r = 0.48, p < 0.001) in the feet suggesting a degree of neuroselectivity. Internal correlations between CPT at the three frequencies showed the weakest correlation between CPT at 2000 Hz and 5 Hz (r = 0.27, p < 0.005), suggesting also that possibly different types of fibres were examined. CPT reproducibility was better in control (CV = 6.4–27.7%), than in neuropathic subjects (CV = 28.4–52.3%), although the coefficient of variation was comparable to that of standard tests of sensory function, VPT and TPT. The Neurometer is a simple instrument to use in clinical practice. It has a degree of neuroselectivity but like all subjective sensory tests has a large variability.

Direct measurement of capillary blood flow in the diabetic neuropathic foot

SummaryThe two major components of the microcirculation in the diabetic neuropathic foot have been examined in detail. Nutritive capillary blood flow was measured directly using the non-invasive technique of television microscopy, applied to the toe nailfold. Arteriovenous shunt flow was assessed using the technique of laser Doppler flowmetry, applied to the toe pulp. Fourteen diabetic patients with peripheral and autonomic neuropathy, 11 with no clinical evidence of neuropathy and 14 normal subjects were studied. Laser Doppler flowmetry (predominantly arteriovenous shunt flow) was increased more than three-fold (p<0.01) in the diabetic patients with neuropathy compared to control subjects, (median 3.57, interquartile range 2.00–5.32 volts vs median 0.93, interquartile range 0.47–2.36 volts respectively). There was no evidence of skin capillary closure. The calculated capillary blood flow (erythrocyte flux) was significantly increased in the diabetic neuropathic patients compared to control subjects (median 76.4, interquartile range 34.4–109.8 picolitres/s vs median 23.2, range 8.0–44.8 picolitres/s, p<0.01). This study demonstrates that foot skin capillary blood flow is increased in diabetic patients with neuropathy. There is, therefore, no evidence to support the supposition that capillary ischaemia, either secondary to a “capillary steal phenomenon” or “advanced microangiopathy”, is a feature of diabetic neuropathy under resting conditions.

Reduction of Gangrene and Amputations in Diabetic Renal Transplant Patients: the Role of a Special Foot Clinic

This 4‐year prospective study investigated the reasons for high levels of gangrene and major amputation in diabetic renal transplant patients and whether regular mutli‐disciplinary foot care could reduce morbidity. All foot lesions were documented and investigated in 50 diabetic patients, mean age 49.2 ± 11.0 (SD) years, duration of diabetes 25.3 ± 9.0 years, time since renal transplantation 60.2 ± 35.1 months, who attended a special foot clinic monthly for education, vascular and neurological assessment, podiatry and footwear. Foot lesions included: neuropathic ulcers, ischaemic ulcers, traumatic lesions, Charcots arthropathy, pathological fracture. Treatment included antibiotics, podiatry, footwear, and angioplasty or distal bypass where appropriate. Only 13 patients were deemed ischaemic but peripheral neuropathy was a very common finding (mean VPT 24.8 ± 12.9 V). Gangrene and major amputations showed a decrease on previous years and healing times for lesions were similar to those previously reported in diabetic patients without renal transplants. The majority of foot lesions, both in soft tissue and bone, were related to neuropathy and trauma and responded well to optimal foot care within the renal unit. Gangrene and major amputations were usually preventable.

NO-dependent smooth muscle vasodilatation is reduced in NIDDM patients with peripheral sensory neuropathy.

In order to determine the involvement of denervation in endothelium‐independent, nitric oxide (NO)‐dependent smooth muscle vasodilatation, we have measured vascular endothelial and smooth muscle function in three groups of age‐ and sex‐matched patients: 8 patients with non‐insulin‐dependent (Type 2) diabetes mellitus (NIDDM) with neuropathy; 7 NIDDM patients without neuropathy; and 10 non‐diabetic control subjects. Laser Doppler probes were used to measure blood flow in the dorsum of the left foot. Vascular endothelial response was assessed by measuring vasodilatory responses to iontophoretic application of acetylcholine to the dorsum of the foot. Vascular smooth muscle activity was assessed by the response to iontophoresis of sodium nitroprusside (SNP)—a NO donor and direct vasodilator. The vasodilator response to acetylcholine, expressed as the ratio of peak to basal blood flow, was significantly reduced in both diabetic groups when compared to non‐diabetic controls (geometric mean ×/÷ anti‐logged SD 9.81 ×/÷ 1.65 versus patients with neuropathy 3.50 ×/÷ 2.03, p < 0.005 and diabetic non‐neuropathic subjects 3.49 ×/÷ 1.67, p < 0.005). The difference between the two groups of diabetic patients was not significant. In contrast, the vasodilatation to nitroprusside was significantly reduced only in the diabetic neuropathic patients, significantly lower than in either the non‐neuropathic diabetic controls or the non‐diabetic controls (2.1 ×/÷ 2.0 versus 6.42 ×/÷ 1.56 and 7.02 ×/÷ 2.05, p < 0.005). This indicates that neuropathy is important in abnormalities of endothelium‐independent vasodilatation.

Morphometry of endoneurial capillaries in diabetic sensory and autonomic neuropathy

SummaryNerve biopsies were obtained from 27 patients with diabetic neuropathy. All had a symmetric distal sensory and autonomic neuropathy or a purely sensory neuropathy. Mean age was 39.8 years (range 23–57 years). Two patients had Type 2 (non-insulin-dependent) diabetes mellitus and the remainder Type 1 (insulin-dependent) diabetes. Morphometric observations on endoneurial capillaries were compared with results from organ donor control cases and from patients with type 1 hereditary motor and sensory neuropathy. The area of the lumen of the capillaries did not differ between the three groups. The area occupied by the capillary endothelial cells in transverse section and the number of endothelial cell nuclei were increased both in the patients with diabetic neuropathy and hereditary motor and sensory neuropathy, as was the thickness of the surrounding basal laminal zone. ‘Closure’ of endoneurial capillaries in diabetic neuropathy, reported in another study, was not confirmed. Capillary density and nearest-neighbour distances were similar in the diabetic and organ donor control cases. Capillary density was reduced in the patients with hereditary motor and sensory neuropathy, this being related to increased fascicular area consequent upon the presence of hypertrophic changes. The presence of thickening of the pericapillary basal laminal zone and endothelial cell hyperplasia both in diabetic and hereditary motor and sensory neuropathy, the latter being a neuropathy in which a vascular basis can be discounted, makes it difficult to use such changes as an argument favouring a vascular cause for diabetic neuropathy. There were differences in the basal laminal zone between the diabetic and hereditary motor and sensory neuropathy cases suggesting that the reduplicated basal lamina was more persistent in the diabetic patients.

Clinical observations and experiments in diabetic neuropathy

SummaryDiabetic neuropathies form a group of diverse conditions, which can be distinguished between those which recover (acute painful neuropathies, radiculopathies, mononeuropathies) and those which progress (sensory and autonomic neuropathies). These two main groups can be distinguished in several ways: sensory and autonomic neuropathies are classic diabetic complications progressing gradually in patients with long-standing diabetes who often have other specific complications, while the reversible neuropathies do not have these features. The latter are characterised by their occurrence at any stage of diabetes, often at diagnosis, they may be precipitated on starting insulin treatment, and they are more common in men; they can occur at any age, though more often in older patients, and are unrelated to other diabetic complications. The two groups of neuropathies also show differences in nerve structural abnormalities and with regard to distinctive blood flow responses. The underlying mechanisms responsible for these very different forms of neuropathy remain speculative, but evidence for an immunological basis for the development of severe symptomatic autonomic neuropathy is presented.

Diabetic neuropathy in the upper limb and the effect of twelve months sorbinil treatment

SummaryClinical and neurophysiological studies were undertaken, with particular reference to the arms, in 39 patients with diabetic neuropathy. The effects of an aldose reductase inhibitor, sorbinil, on neuropathy in these patients were studied in a 12 month double blind placebo controlled trial. Neurophysiological measurements, particularly of sensory amplitude, were considerably more sensitive than measurements of temperature and vibration sensation and remain of fundamental importance in measuring diabetic neuropathy at an early and potentially reversible stage. There was no significantly beneficial effect of sorbinil on clinical or neurophysiological measurements of nerve function in patients with established diabetic neuropathy. These results indicate that neurophysiological techniques are necessary, in conjunction with clinical measurements, for the assessment of ‘early’ diabetic neuropathy and that aldose reductase inhibitors are not effective in the treatment of established diabetic neuropathy.

Autoantibodies to nervous tissue structures are associated with autonomic neuropathy in Type 1 (insulin-dependent) diabetes mellitus

SummaryThere is evidence that the immune system may play a role in the pathogenesis of autonomic neuropathy in Type 1 (insulin-dependent) diabetes mellitus. In the present study, we investigated the presence of autoantibodies to sympathetic and parasympathetic nervous structures and their correlation with other conventional autoantibodies in well-characterised diabetic populations, with or without diabetic neuropathy, and normal subjects. An indirect immunofluorescent complement-fixation technique was used, with monkey adrenal gland, rabbit cervical ganglia and vagus nerve as substrates. Of the patients with symptomatic autonomic neuropathy 33% were positive for at least one autoantibody (20% anti-sympathetic ganglia, 10% anti-vagus nerve and 13% anti-adrenal medulla). The frequency of having one or more antibodies to nervous tissues and the prevalence of anti-cervical ganglia antibodies were significantly higher in the neuropathic patients than in the diabetic control subjects with disease of similar duration and in the normal subjects (p<0.05). Of the patients without complications with diabetes of shorter duration 33% were also positive for at least one autoantibody (13% anti-ganglia, 13% anti-vagus nerve and 13% anti-adrenal medulla). No correlation was found with other tissue autoantibodies, including islet cell antibodies. Our data indicate that nervous tissue autoantibodies are associated with symptomatic autonomic neuropathy. Anti-sympathetic ganglia and anti-vagus nerve antibodies seem to be more disease-specific. Patients with diabetes of shorter duration who were positive for these autoantibodies may represent pre-neuropathic patients.

Prevalence of autoantibodies to autonomic nervous tissue structures in Type 1 diabetes mellitus

Aims The pathogenesis of diabetic autonomic neuropathy is multifactorial, but recent studies have suggested a link between the presence of autoantibodies to nervous tissue structures and severe, symptomatic autonomic neuropathy. The present study was designed to examine the true prevalence of these autoantibodies in a large clinic‐based population of Type 1 diabetic patients compared to nondiabetic controls.