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.

The prevalence and distribution of medial arterial calcification was assessed in the feet of four subject groups; 54 neuropathic diabetic patients with previous foot ulceration (U), median age 60.5 (50.5-67 interquartile range) years, duration of diabetes 19.5 (9.9-29.9) years; 40 neuropathic diabetic patients without a foot ulcer history (N), age 68 (62-73) years, duration of diabetes 14.0 (8.0-28.0) years; 43 non-neuropathic diabetic patients (NN), age 60.5 (52-68.5) years, duration of diabetes 14.0 (8.0-28.0) years and 50 non-diabetic control subjects, age 62.5 (53.7-70) years. A single radiologist graded medial arterial calcification as absent, mild or severe, at the ankle, hind-foot, mid-foot, metatarsals and toes on standardised plain lateral and antero-posterior foot radiographs taken by a single radiographer. Diabetes history, vibration perception threshold, ankle systolic pressure and serum creatinine were also assessed. Medial arterial calcification was significantly greater (total score 18 [3-31]) in neuropathic diabetic patients with previous ulceration (U vs N p < 0.01, U vs NN p < 0.001). Non-neuropathic diabetic patients did not have significantly higher arterial calcification scores than age-matched non-diabetic control subjects. Medial arterial calcification correlated with vibration perception threshold (r = 0.35), duration of diabetes (r = 0.32) and serum creatinine (r = 0.41), (all p < 0.01). Logistic regression models showed vibration perception and duration of diabetes to predict the probability of any calcification. Serum creatinine level was added to predict severe calcification.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral nerve oxygen tensions were assessed in vivo by using microelectrodes to measure endoneurial oxygen tension in exposed sural nerve. In 11 diabetic patients with chronic sensorimotor neuropathy the mean endoneurial oxygen tension was 39 7

No abstract

In diabetic foot ulcers (DFUs) the normal sequence of events in the healing process is disrupted. The condition is a major clinical concern, both in terms of cost ($500 million per year [1]), time and debility for the patient. It is the commonest cause of admission to hospital amongst diabetic patients [2] resulting in 50±70 % of all non-traumatic amputations [3] with a cost of at least £ 7000 per case in the United Kingdom [4]. Furthermore, with an increasingly aged population there is likely to be a rise in the incidence of these ulcers. It has therefore been the goal of clinicians for years to stimulate the normal reparative process in this debilitating disorder.The severe tissue destruction associated with DFUs suggests a number of candidate factors in their aetiology, in particular the metabolism of l-arginine is vital in the repair process. The metabolism of larginine by the enzyme nitric oxide synthase (NOS) Diabetologia (1999) AbstractAims/hypothesis. l-arginine, an amino acid involved in wound healing, is metabolised by one of two pathways; nitric oxide synthase and arginase. If metabolised by nitric oxide synthase, this can result in tissue destruction, or matrix deposition if metabolised by arginase. The aim therefore was to investigate the role of these enzymes in the pathogenesis of diabetic foot ulcers. Methods. The activity, proteins by Western blot analysis and cellular distribution (using immunocytochemistry) of these enzymes were measured in diabetic foot ulcers, diabetic skin and normal skin. Results. Total and inducible nitric oxide synthase (p < 0.001) and endothelial nitric oxide synthase were increased in diabetic ulcers compared with diabetic and normal skin and were associated with increased plasma nitrite concentrations in diabetic ulcers (p < 0.05). Inducible nitric oxide synthase was the major isoform, with the macrophage being the predominant cellular source. Similarly arginase activity was increased (p < 0.01) in diabetic ulcers. The protein levels corroborated with the activity data, with the fibroblast being the major cellular source. The spatial and cellular distribution of the two enzyme systems was distinct. Transforming growth factor-beta1 was decreased in diabetic ulcers in comparison with diabetic skin and normal skin. Conclusion/interpretation. Increased nitric oxide synthase activity in diabetic foot ulcers may be responsible for the impaired healing in this disease. Furthermore, the increased activity of arginase could account for the characteristic callus formation around these ulcers. In addition, the lower concentrations of transforming growth factor-beta1 in diabetic ulcers may explain the raised concentrations of nitric oxide in this condition. [Diabetologia (1999) 42: 748±757]

Insulin insensitivity is present in PHPT even in the absence of hypertension and obesity, and may be the cause of glucose intolerance and diabetes. PHPT subjects with reduced beta-cell function are more likely to develop glucose intolerance.

Diabetes mellitus is very common, with Type II (noninsulin-dependent) diabetes mellitus accounting for 90 % to 95 % of the diagnosed patients [1]. A frequent complication of diabetes is erectile dysfunction (ED), with an estimated prevalence of 20 % to 85 % (ranging from mild to complete ED) [2], which occurs at an earlier age than in non-diabetic men. In the Massachusetts Male Aging study [3], men with treated diabetes had an age-adjusted prevalence of complete ED (no erections) of 28 %, which was approximately three times higher than the prevalence of complete ED observed in the entire sample of men (10 %).Although ED in patients with diabetes is often complex and can be caused by several mechanisms Diabetologia (2001) Abstract Aims/hypothesis. Ninety percent of all men with diabetes have Type II (non-insulin-dependent) diabetes mellitus, and erectile dysfunction (ED) is common in this patient group. This study evaluated the effects of sildenafil on men with erectile dysfunction and Type II diabetes and compared the results with glycated haemoglobin concentrations and chronic diabetic complications. Methods. Patients (mean age, 59 years) in this double-blind, placebo-controlled trial were randomised to sildenafil (25±100 mg; n = 110) or matching placebo (n = 109) for 12 weeks. Primary criteria for efficacy included questions 3 (achieving an erection) and 4 (maintaining an erection) from the International Index of Erectile Function (IIEF, score range, 0±5). Secondary outcome measures included a global efficacy question (GEQ), patient event logs, a life satisfaction checklist, and the remaining IIEF questions. Results. After 12 weeks, the mean scores for questions 3 and 4 had improved significantly in patients receiving sildenafil (3.42 0.23 and 3.35 0.24) compared with placebo (1.86 0.22 and 1.84 0.23; p < 0.0001). Similarly, the GEQ score was higher in the sildenafil (64.6 %) than the placebo group (10.5 %). Even when correlating efficacy with glycated haemoglobin concentrations ( £ 8.3 % or > 8.3 %, the median concentration found in this study) or the number of diabetic complications (0 or ³ 1), the mean scores for the GEQ and questions 3 and 4 from the IIEF remained higher for all the sildenafil groups compared with the placebo groups (p < 0.0001). Conclusion/interpretation. Sildenafil was well-tolerated and effective in improving erectile dysfunction in men with Type II diabetes, even in patients with poor glycaemic control and chronic complications. [Diabetologia (2001

The effects of troglitazone, a novel thiazolidinedione, in non-insulin-dependent diabetic (NIDDM) patients were studied in a double-blind, parallel-group, placebo-controlled, dose-ranging trial. A total of 330 patients (63% male), mean age 57 years (range 39-72), with two fasting capillary blood glucose values > or = 7 and < or = 15 mmol/l (within 2.5 mmol/l of each other) were randomised to treatment with placebo or troglitazone at doses of 200, 400, 600 or 800 mg once daily, or 200 or 400 mg twice daily, for 12 weeks. Prior to the study, treatment had been with diet alone (38% patients) or with oral hypoglycaemic agents which were stopped 3-4 weeks before study treatment started. During treatment, HbA1c tended to rise in patients taking placebo (7.2-8.0%), but remained unchanged with all doses of troglitazone. After 12 weeks of treatment, HbA1c was significantly lower in the troglitazone-treated (mean 7.0-7.4%) compared to the placebo-treated (8.0%) patients (p = 0.055 to < 0.001), as was fasting serum glucose concentration (troglitazone, 9.3-11.0 mmol/l vs placebo, 12.9 mmol/l, p < 0.001). All doses of troglitazone were equally effective. Troglitazone also lowered fasting plasma insulin concentration, by 12-26% compared to placebo (p = 0.074 to < 0.001). Insulin sensitivity assessed by homeostasis model assessment (HOMA) was greater after 12 weeks of treatment in troglitazone-treated patients (troglitazone, 34.3-42.8% vs placebo, 29.9%, p < 0.05). In addition, serum triglyceride and non-esterified fatty acid concentrations were significantly lower and HDL cholesterol higher at troglitazone doses of 600 and 800 mg/day. LDL cholesterol increased at 400 and 600 mg doses only (from 4.3 and 3.9 mmol/l at baseline to 4.8 and 4.5 mmol/l, respectively at 12 weeks, p < 0.05), but not at doses of 800 mg once daily or 400 mg twice daily. LDL/HDL ratio did not change during treatment. All doses were well tolerated; incidence of adverse events in troglitazone-treated patients was no higher than in those treated with placebo. However, a tendency to reduced neutrophil counts was observed in patients taking the highest doses of troglitazone. We conclude that troglitazone is effective and well-tolerated and shows potential as a new therapeutic agent for the treatment of NIDDM.