Simon E.M Eaton

Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy

Abstract. Diabetes mellitus is a major cause of peripheral neuropathy, commonly manifested as distal symmetrical polyneuropathy. This review examines evidence for the importance of vascular factors and their metabolic substrate from human and animal studies. Diabetic neuropathy is associated with risk factors for macrovascular disease and with other microvascular complications such as poor metabolic control, dyslipidaemia, body mass index, smoking, microalbuminuria and retinopathy. Studies in human and animal models have shown reduced nerve perfusion and endoneurial hypoxia. Investigations on biopsy material from patients with mild to severe neuropathy show graded structural changes in nerve microvasculature including basement membrane thickening, pericyte degeneration and endothelial cell hyperplasia. Arterio-venous shunting also contributes to reduced endoneurial perfusion. These vascular changes strongly correlate with clinical defects and nerve pathology. Vasodilator treatment in patients and animals improves nerve function. Early vasa nervorum functional changes are caused by the metabolic insults of diabetes, the balance between vasodilation and vasoconstriction is altered. Vascular endothelium is particularly vulnerable, with deficits in the major endothelial vasodilators, nitric oxide, endothelium-derived hyperpolarising factor and prostacyclin. Hyperglycaemia and dyslipidaemia driven oxidative stress is a major contributor, enhanced by advanced glycation end product formation and polyol pathway activation. These are coupled to protein kinase C activation and ω-6 essential fatty acid dysmetabolism. Together, this complex of interacting metabolic factors accounts for endothelial dysfunction, reduced nerve perfusion and function. Thus, the evidence emphasises the importance of vascular dysfunction, driven by metabolic change, as a cause of diabetic neuropathy, and highlights potential therapeutic approaches. [Diabetologia (2001) 44: 1973–1988]

Risk factors for cardiac autonomic neuropathy in type 1 diabetes mellitus

Aims/hypothesisCardiac autonomic neuropathy (CAN) is associated with increased morbidity and mortality in type 1 diabetes. Apart from glycaemic control, risk factors for CAN have not been extensively studied.MethodsAs part of the EURODIAB Prospective Complications Study, CAN—defined as either a loss of heart rate variability or postural hypotension on standing—was assessed at baseline and follow-up (7.3±0.6 years from baseline) in patients with type 1 diabetes.ResultsFollow-up measurements were available for 956 participants without CAN at baseline (age at baseline 31.3±8.9 years, duration of diabetes 13.5±8.3 years). During follow-up, 163 (17%) subjects developed CAN, yielding an incidence of 23.4 per 1,000 person-years. Blood pressure, weight, the presence of cardiovascular disease, albuminuria, distal symmetrical polyneuropathy (DSP) and retinopathy at baseline were associated with the incidence of CAN after adjustment for sex, duration of diabetes and HbA1c. In a multivariate regression model, baseline factors associated with an increased risk of developing CAN were age [odds ratio (OR)=1.3 per decade, 95% CI 1.1–1.7], HbA1c (OR=1.2 per percentage point, 95% CI 1.1–1.4), systolic blood pressure (OR=1.1 per 10xa0mmHg, 95% CI 1.0–1.3), feeling faint on standing (OR=2.0, 95% CI 1.2–3.2), DSP (OR=1.9, 95% CI 1.2–3.0) and retinopathy (OR=1.7, 95% CI 1.1–2.6).Conclusion/interpretationThis study confirms the importance of exposure to hyperglycaemia as a risk factor for CAN. A small set of variables, including HbA1c, hypertension, DSP and retinopathy, predict the risk of CAN. Clinical trials are needed to address the impact of intensive antihypertensive treatment on CAN in type 1 diabetes.

Choice and availability of takeaway and restaurant food is not related to the prevalence of adult obesity in rural communities in Australia

OBJECTIVES:To establish whether choice and availability of takeaway and restaurant food consumption are associated with increased obesity.DESIGN:Crossroads Undiagnosed Disease Study: a cross-sectional study undertaken between June 2001 and March 2003.SETTING:A regional centre and six shire capitals of variables size in rural Victoria, Australia.PARTICIPANTS:In total, 1454 residents of randomly selected households.MEASUREMENTS:Obesity (by body mass index (BMI) or waist circumference), weekly recreational activity, self-reported frequency of takeaway consumption, number of local takeaway and restaurant food outlets in the area.RESULTS:The prevalence of obesity ranged from 25.5–30.8% and was higher than the general Australian population among both men and women. Those in the regional centre were less likely than those in large and small shire capitals to participate in recreational activity of 150u2009min or more (39.7 vs 48.4%, 46.0% respectively, P=0.023) and yet reported better access to facilities and amenities for physical activity. Recreational activity of ≥150u2009min/week was associated with 0.75 (0.58–0.97) fold less risk of obesity. BMI was unrelated to takeaway consumption. Waist circumference was significantly lower among those eating no takeaways, but similar whether takeaways were consumed <1/month or ≥1/week. Increased takeaway consumption was associated with increased consumption of higher fat preparations of dairy and meat products. Availability of takeaway outlets and restaurants was unrelated to obesity.CONCLUSION:The obesity epidemic exists among those without significant consumption of or availability to takeaway foods. In a setting of easy availability of food, the obesity epidemic relates strongly to reduced physical activity, but not to consumption of takeaway food.

Spinal-cord involvement in diabetic peripheral neuropathy

The pathogenesis of diabetic distal symmetrical polyneuropathy (DSP) is poorly understood but there is some evidence that the disease process might extend beyond peripheral nerves. We used magnetic-resonance imaging to measure spinal-cord cross-sectional area in diabetic patients with and without DSP and in healthy controls. There were significant differences in cord area between the groups at C4/5 and T3/4 (p=0.004 and p=0.033, respectively), with a smaller cord area in those with DSP compared with controls (p=0.001 and p=0.016 for C4/5 and T3/4, respectively). These results indicate that DSP is not simply a disease of the peripheral nerve and that there is substantial involvement of the spinal cord.

Increased sural nerve epineurial blood flow in human subjects with painful diabetic neuropathy

Aims/hypothesisThe pathogenesis of painful diabetic neuropathy remains unknown. As a consequence we still do not have any effective, rational treatments and a greater understanding of the mechanisms is urgently required. Previous studies have shown no consistent morphological differences in the nerves of patients with and without painful neuropathy. The aim of this study was to compare epineurial haemodynamics in patients with chronic painful and painless neuropathy.MethodsThe techniques of microlightguide spectrophotometry and fluorescein angiography were used to measure epineurial intravascular oxygen saturation and blood flow respectively. Eleven patients with painful and eight with painless neuropathy were studied, with the groups matched carefully in terms of severity of neuropathy and diabetes control.ResultsIntravascular oxygen saturation was higher in the painful neuropathy group compared to those without pain (median 73.8% vs 67.7%, respectively; p=0.021). Fluorescein rise time was also faster in those with painful symptoms (median 18.3xa0s vs 53.6xa0s; p=0.046) indicating higher epineurial blood flow in these subjects.Conclusion/interpretationThese results indicate that there are distinct differences in haemodynamics within the epineurium of the sural nerve in subjects with painful and painless neuropathy. Haemodynamic factors could therefore have an important role in the pathogenesis of neuropathic pain and might offer further insight into potential treatments for this distressing condition.

Digital imaging: an accurate and easy method of measuring foot ulcers.

Aims A progressive reduction in the area of foot ulcer on serial measurement is traditionally done by tracing the margin of the ulcer on a transparent film and counting the number of squares on a graph paper underneath. We set out to use and validate the measurement of foot ulcers using a digital imaging technique and compare this with the traditional method.

Blood Pressure Response to Standing in the Diagnosis of Autonomic Neuropathy: The EURODIAB IDDM Complications Study

Autonomic neuropathy is associated with poor prognosis. Cardiovascular reflexes are essential for the diagnosis of autonomic nerve dysfunction. Blood pressure response to standing is the most simple test for the evaluation of sympathetic integrity, however it is still discussed which diagnostic criteria of abnormal response should be considered as optimal. The EURODIAB IDDM Complications Study involved the examination of randomly selected Type 1 diabetic patients from 31 centres in 16 European counties. Data from 3007 patients were available for the present evaluation. Two tests of autonomic function (response of heart rate /R-R ratio/ and blood pressure from lying to standing) just as the frequency of feeling faint on standing up were assessed. R–R ratio was abnormal in 24% of patients. According to different diagnostic criteria of abnormal BP response to standing (>30 mmHg, >20 mmHg, and >10 mmHg fall in systolic BP), the frequency of abnormal results was 5.9%, 18% and 32%, respectively (p < 0.001). The frequency of feeling faint on standing was 18%, thus, it was identical with the prevalence of abnormal blood pressure response to standing when >20 mmHg fall in systolic blood pressure was considered as abnormal. Feeling faint on standing correlated significantly with both autonomic test results (p < 0.001). A fall >20 mmHg in systolic blood pressure after standing up seems to be the most reliable criterion for the assessment of orthostatic hypotension in the diagnosis of autonomic neuropathy in patients with Type 1 diabetes mellitus.

Is grand multiparity associated with an increased risk of dysglycaemia

Aims/hypothesisWe sought to determine the risk of diabetes and IGT/IFG with grand multiparity.Subjects, materials and methodsWomen, aged ≥25xa0years, from the Australian Diabetes, Obesity and Lifestyle Study and the Crossroads Undiagnosed Disease Study (a rural study in Victoria, Australia), participated in a household census (response 67 and 70%, respectively), subsequently attending a biomedical examination that included an oral glucose tolerance test (58% [6198] and 69% [819]).ResultsAfter adjusting for age, obesity and socio-economic status, diabetes, but not IGT/IFG, was less common among women with a parity of 1 to 2 (odds ratio [OR]=0.64 [0.48–0.84]) and 3 to 4 (OR=0.72 [0.53–0.96]) than in grand multiparous women. This relationship was unrelated to past hysterectomy, use of the oral contraceptive pill or menopausal status.Conclusions/interpretationGrand multiparity is associated with an increased risk of diabetes but not of IGT/IFG. We postulate that parity accelerates transition from IGT/IFG to diabetes, more than it does transition from normal glucose tolerance to IGT/IFG.

Combined microlightguide spectrophotometry and microendoscopy for measurement of oxygen saturation in peripheral nerves

Microlightguide measurements of the spectral composition of backscattered light may be used to determine local tissue oxygen saturation and monitor tissue perfusion using intravenous injection of fluorescein dye as a contrast agent. We have used a combination of microlightguide spectrophotometry and microendoscopy to measure intravascular oxygen saturation (HbSaO2%) and monitor blood flow in the sciatic nerve of 12 healthy male Sprague-Dawley rats. The microlightguide and endoscope combination is a relatively new measurement technique. The aims of this study were to determine whether microlightguide spectrophotometry and microendoscopy could be used to measure HbO2 and blood flow in peripheral nerves and to compare the measurements made using the flexible lightguide with the endoscope-lightguide combination. We found no significant difference between the two types of measurement over similar regions of the nerve. mean SaO2% values 77.1% (95% CI = 75.4-78.8) and 78.8% (95% CI = 77.5-80.1) respectively. During a period of hypoxia there was a similar fall in both arterial and nerve oxygen saturation. Following injection of fluorescein, the rate of increase in nerve fluorescence was used as a measure of perfusion. The combination of microlightguide spectrophotometry and microendoscopy allows the exact site of measurement to be directly visualized. The minimally invasive nature of this technique may allow its application to the study of peripheral nerves in human subjects in conditions such as diabetic neuropathy where vascular factors are thought to have an important role in aetiology.