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Aims/hypothesis: Emerging evidence suggests that in addition to hyperglycaemia, dyslipidaemia could represent a contributing pathogenetic factor to diabetic neuropathy, while obesity and insulin resistance play a role in the development of diabetic cardiac autonomic neuropathy (CAN) characterised by reduced heart rate variability (HRV), particularly in type 2 diabetes. We hypothesised that distinct lipid metabolites are associated with diminished HRV in recent-onset type 2 diabetes rather than type 1 diabetes., Methods: We analysed 127 plasma lipid metabolites (11 acylcarnitines, 39 NEFA, 12 sphingomyelins (SMs), 56 phosphatidylcholines and nine lysophosphatidylcholines) using MS in participants from the German Diabetes Study baseline cohort recently diagnosed with type 1 (n = 100) and type 2 diabetes (n = 206). Four time-domain HRV indices (number of normal-to-normal (NN) intervals >50 ms divided by the number of all NN intervals [pNN50]; root mean square of successive differences [RMSSD]; SD of NN intervals [SDNN]; and SD of differences between adjacent NN intervals) and three frequency-domain HRV indices (very-low-frequency [VLF], low-frequency [LF] and high-frequency [HF] power spectrum) were computed from NN intervals recorded during a 3 h hyperinsulinaemic-euglycaemic clamp at baseline and in subsets of participants with type 1 (n = 60) and type 2 diabetes (n = 95) after 5 years., Results: In participants with type 2 diabetes, after Bonferroni correction and rigorous adjustment, SDNN was inversely associated with higher levels of diacyl-phosphatidylcholine (PCaa) C32:0, PCaa C34:1, acyl-alkyl-phosphatidylcholine (PCae) C36:0, SM C16:0 and SM C16:1. SD of differences between NN intervals was inversely associated with PCaa C32:0, PCaa C34:1, PCaa C34:2, PCae C36:0 and SM C16:1, and RMSSD with PCae C36:0. For VLF power, inverse associations were found with PCaa C30:0, PCaa C32:0, PCaa C32:1, PCaa C34:2 and SM C16:1, and for LF power inverse associations were found with PCaa C32:0 and SM C16:1 (r = -0.242 to r = -0.349; p ≤ 0.0005 for all correlations). In contrast, no associations of lipid metabolites with measures of cardiac autonomic function were noted in participants recently diagnosed with type 1 diabetes. After 5 years, HRV declined due to ageing rather than diabetes, whereby prediction analyses for lipid metabolites were hampered., Conclusions/interpretation: Higher plasma levels of specific lipid metabolites are closely linked to cardiac autonomic dysfunction in recent-onset type 2 diabetes but not type 1 diabetes, suggesting a role for perturbed lipid metabolism in the early development of CAN in type 2 diabetes. Graphical abstract.

Aims/hypothesis: Few studies examine the association between age at diagnosis and subsequent complications from type 2 diabetes. This paper aims to summarise the risk of mortality, macrovascular complications and microvascular complications associated with age at diagnosis of type 2 diabetes., Methods: Data were sourced from MEDLINE and All EBM (Evidence Based Medicine) databases from inception to July 2018. Observational studies, investigating the effect of age at diabetes diagnosis on macrovascular and microvascular diabetes complications in adults with type 2 diabetes were selected according to pre-specified criteria. Two investigators independently extracted data and evaluated all studies. If data were not reported in a comparable format, data were obtained from authors, presented as minimally adjusted ORs (and 95% CIs) per 1 year increase in age at diabetes diagnosis, adjusted for current age for each outcome of interest. The study protocol was recorded with PROSPERO International Prospective Register of Systematic Reviews (CRD42016043593)., Results: Data from 26 observational studies comprising 1,325,493 individuals from 30 countries were included. Random-effects meta-analyses with inverse variance weighting were used to obtain the pooled ORs. Age at diabetes diagnosis was inversely associated with risk of all-cause mortality and macrovascular and microvascular disease (all p < 0.001). Each 1 year increase in age at diabetes diagnosis was associated with a 4%, 3% and 5% decreased risk of all-cause mortality, macrovascular disease and microvascular disease, respectively, adjusted for current age. The effects were consistent for the individual components of the composite outcomes (all p < 0.001)., Conclusions/interpretation: Younger, rather than older, age at diabetes diagnosis was associated with higher risk of mortality and vascular disease. Early and sustained interventions to delay type 2 diabetes onset and improve blood glucose levels and cardiovascular risk profiles of those already diagnosed are essential to reduce morbidity and mortality. Graphical abstract.

In parallel with the growing diabetes pandemic, there is an increasing burden of micro- and macrovascular complications, occurring in the majority of patients. The identification of a number of synergistic accelerators of disease, providing therapeutic pathways, has stabilised the incidence of complications in most western nations. However, the primary instigators of diabetic complications and, thus, prevention strategies, remain elusive. This has necessitated a refocus on natural history studies, where tissue and plasma samples are sequentially taken to determine when and how disease initiates. In addition, recent Phase III trials, wherein the pleiotropic effects of compounds were arguably as beneficial as their glucose-lowering capacity in slowing the progression of complications, have identified knowledge gaps. Recently the influence of other widely recognised pathological pathways, such as mitochondrial production of reactive oxygen species, has been challenged, highlighting the need for a diverse and robust global research effort to ascertain viable therapeutic targets. Technological advances, such as -omics, high-resolution imaging and computational modelling, are providing opportunities for strengthening and re-evaluating research findings. Newer areas such as epigenetics, energetics and the increasing scrutiny of our synergistic inhabitants, the microbiota, also offer novel targets as biomarkers. Ultimately, however, this field requires concerted lobbying to support all facets of diabetes research.

Aims/hypothesis: The purpose of the study was to evaluate the association between retinal vascular calibre and micro- and macrovascular complications in a population-based cohort of Danish type 1 diabetic patients., Methods: This was a cross-sectional study of 208 long-surviving type 1 diabetic patients from a population-based Danish cohort. Retinal photographs were obtained at a clinical examination attended by each participant in 2007-2008, and retinal vascular calibre was measured and summarised as the central retinal artery or vein equivalent (CRAE or CRVE) using a computer-based program and a standardised protocol. Associations between retinal vascular calibre and micro- and macrovascular complications were examined after adjusting for confounding clinical characteristics., Results: Retinal photographs were gradable for 188 of 208 patients (90.3%). The median age and duration of diabetes for patients with gradable photos were 57.9 and 42 years, respectively. After multivariate adjustments, individuals with narrower retinal arterioles were more likely to have nephropathy (OR 2.17, 95% CI 1.29-3.68, per SD decrease in CRAE) and macrovascular disease (OR 3.17, 95% CI 1.59-6.34, per SD decrease in CRAE), but not neuropathy (OR 1.10, 95% CI 0.70-1.71, per SD decrease in CRAE). Retinal venular calibre was not associated with any micro- or macrovascular complications., Conclusions/interpretation: In type 1 diabetic patients, retinal arteriolar narrowing is associated with nephropathy and macrovascular disease independently of other clinical characteristics. If supported by further prospective studies, measurement of retinal vessel diameter may allow a non-invasive evaluation of the risk of diabetes-related complications.

There is concern that antipsychotic drugs cause diabetes. Although there has been an explosion in the quantity of literature about this subject, it remains confusing and inconsistent. To assess whether the association between antipsychotic drugs and diabetes is causative, we applied the Austin Bradford Hill criteria to the available evidence. In support of a causative relationship, there is temporality for some cases of diabetes, and there is a biologically plausible explanation. The causative link between antipsychotic drugs and diabetes is coherent with our understanding of diabetes and there are other analogies. However the strength of association is weak, there is lack of consistency or specificity, and there is little evidence to support a biological gradient. We should therefore conclude that the evidence surrounding a causative link between antipsychotic drugs and diabetes is inconclusive. Moreover, the risk is probably low and the attributable risk of developing diabetes is greater for traditional risk factors such as family history, ethnicity, obesity and ageing than it is for receiving an antipsychotic drug. Consequently, the majority of patients receiving second-generation antipsychotics will not develop diabetes as a result of their medication.

Aims/hypothesis: We have previously shown that in diabetes nitrergic neurones innervating the urogenital and gastrointestinal organs undergo a selective degenerative process. This comprises an initial insulin-reversible decrease in neuronal nitric oxide synthase (nNOS) in the axons, followed by apoptosis of the nitrergic neurones, a process that is not reversible by insulin. Since apoptosis was independent of serum glucose concentrations, and advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of diabetic complications, we have now measured AGEs in the serum and penis, pyloric sphincter and pelvic ganglia of diabetic animals at different times after streptozotocin treatment. Furthermore, we have studied their effect in vitro on human neuroblastoma (SH-SY5Y) cells in the presence or absence of nNOS expression., Methods: Serum AGEs were measured using fluorometry and ELISA. Accumulation of AGEs in the tissues was evaluated with immunohistochemistry. The viability, apoptosis and oxidative stress in SH-SY5Y cells were measured upon exposure to AGEs or high concentrations of glucose., Results: AGEs increased gradually in the serum and tissues of streptozotocin-induced diabetic rats; this process was not affected by delayed insulin treatment. In SH-SY5Y cells, AGEs, but not high glucose concentrations, increased the reactive oxygen species and caspase-3-dependent apoptosis in a synergistic fashion with endogenous nitric oxide (NO). Apoptosis was prevented by treatment with a NOS inhibitor, a pan-caspase inhibitor, a soluble receptor of AGEs or an anti-oxidant, but not an inhibitor of soluble guanylate cyclase., Conclusions/interpretation: The synergistic actions of NO and AGEs account for the irreversible nitrergic degeneration in diabetes.

Aims/hypothesis: A loss of sympathetic function could lead to changes in capillary fluid filtration in diabetic patients. We investigated whether a decreased sympathetically mediated vasomotion in the skin in diabetic patients with peripheral neuropathy is associated with an abnormal capillary leakage., Methods: Three matched groups were studied: 18 diabetic patients with documented peripheral neuropathy (DN), 18 diabetic patients without peripheral neuropathy (D), and 18 healthy control subjects (C). Sensory and motor nerve function of the distal extremities were assessed by standard neurography, and expressed in a sensory-motor nerve function score. Sympathetic vasomotion of the skin microcirculation was assessed by determining the power of blood flow variability in the low-frequency (0.02-0.14 Hz) band by spectral analysis of laser Doppler flowmetry at the median ankle. Skin capillary leakage was evaluated by sodium fluorescein videodensitometry at the same site of the foot., Results: Sympathetically mediated vasomotion of the foot skin microcirculation was lower in diabetic patients with documented peripheral neuropathy compared with diabetic patients without peripheral neuropathy and control subjects (p<0.001). Capillary sodium fluorescein leakage was larger in 18 diabetic patients with documented peripheral neuropathy than in diabetic patients without peripheral neuropathy (p<0.02) and C (p<0.005). Multiple regression analysis disclosed that a reduced sympathetically mediated vasomotion, together with a lower sensory-motor nerve function score, independently contributed to the variance in sodium fluorescein leakage, for 30% (p<0.001) and 17% (p<0.01), respectively., Conclusions: A loss of sympathetic tone, apart from sensory-motor nerve dysfunction, seems to be a major determinant of an increased capillary permeability in diabetic patients with neuropathy.

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 omega-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.

Many patients with diabetes mellitus complain of early satiety and postprandial gastric fullness. In 1945, these symptoms were first found to result from a gastric motor dysfunction which makes the delivery of ingesta into the small intestine, the time of their absorption and the related blood-glucose rise unpredictable. Consequently, insulin or hypoglycaemic agents are administered at inappropriate time points and poor glycaemic control ensues. About 50% of patients with Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus are affected. Hyperglycaemia may play an important role in the disorder: gastric emptying was found to be slower in states of induced hyperglycaemia than in euglycaemia. However, significantly reduced blood-glucose concentrations after therapy readjustment were not associated with an increase in emptying rate. Prolonged hyperglycaemia could alter nerve metabolism and contribute to the development of neuropathy. Severity of cardiovascular autonomic neuropathy, but not actual blood-glucose and glycated haemoglobin level, has been found to correlate with the degree of emptying impairment. Drugs enhancing gastric emptying could improve the coordination between insulin administration and the onset of nutrient absorption and thus glycaemic control. Disappointingly, trials to study the long-term effects of such drugs are scarce and their results predominantly negative. In conclusion, many diabetic patients have impaired gastric motor function which could contribute to poor glycaemic control. Evidence suggests that autonomic neuropathy is the main underlying factor. This review aims to offer a critical survey of all the data available at present on these topics.

Cross-sectional studies have shown plasma cell adhesion molecules (CAMs) to be increased in patients with diabetes-related complications. In the first prospective study of CAMs, we have shown that plasma CAMs may be a predictor of the development of diabetic neuropathy. We followed up 28 diabetic patients (13 neuropathic) over a 5 year period, starting from 1991. All patients had peroneal nerve conduction velocity (PNCV), vibration perception threshold and plasma CAMs measured at baseline and follow-up. We found P-selectin and intercellular adhesion molecule-1 (ICAM-1) to be increased at baseline in patients with neuropathy compared to non-neuropathic patients. P-selectin and E-selectin were also found to be significantly higher at baseline in patients who at follow-up showed deterioration in PNCV of more than 3 m/s (p<0.05; p=0.01; respectively). P-selectin and ICAM-1 strongly correlated with PNCV. Univariate and multivariate regression analyses showed a significant inverse association between increasing log P-selectin, log E-selectin and log ICAM-1 with decreasing PNCV, and remained significant even after adjustment for glycaemic control. P-selectin and E-selectin, odds ratios of 8.8 (95% CI: 1.1-68.8; p=0.038) and 12.5 (95% CI: 1.2-132.1; p=0.036), respectively, were significantly associated with the risk of deterioration of PNCV after 5 years. This study suggests that plasma cell adhesion molecules may play an important role in the development and progression of peripheral neuropathy in diabetes mellitus.

There is no information on the mutual occurrence and the development of autonomic and peripheral somatic neuropathies based on long-term follow-up of patients with non-insulin-dependent diabetes mellitus (NIDDM). We investigated the relation between the changes in autonomic function values and electrodiagnostic values, and the relation between the occurrence of autonomic neuropathy and peripheral somatic polyneuropathy in a group of patients with newly diagnosed NIDDM (n = 133, aged 45-65 years) at baseline and 5 and 10 years later. Parasympathetic autonomic neuropathy was diagnosed on the basis of heart rate variability during deep-breathing and sympathetic autonomic neuropathy on the basis of fall in systolic blood pressure while changing from supine to standing. Polyneuropathy was diagnosed on the basis of both clinical criteria and electrodiagnostic studies (nerve conduction velocity and response-amplitude values). In 10 years 36 patients died, mainly from cardiovascular causes. Altogether 78 patients completed the study. At 10 years, parasympathetic autonomic neuropathy was diagnosed in 61.3% of those with polyneuropathy and 66.7% of those without. Likewise, the frequency of sympathetic autonomic neuropathy was similar in those with polyneuropathy (21.9%) and those without (26.5%). The respective figures for combined (both parasympathetic and sympathetic) autonomic neuropathy were 10.0% and 18.8%. The worsening of parasympathetic and sympathetic autonomic function values was not related to the worsening in electrodiagnostic results with time. In conclusion, the development of autonomic and peripheral somatic neuropathies was divergent in patients with NIDDM suggesting different pathophysiological processes for these neuropathies.

To investigate the presence of autoantibodies against sympathetic nervous tissue and their correlation with cardiac sympathetic dysinnervation in insulin-dependent diabetes mellitus (IDDM), 20 newly diagnosed (age 26 +/- 6 years) and 48 long-term IDDM patients (age 40 +/- 13 years, duration of diabetes 22 +/- 12 years) without myocardial perfusion abnormalities (normal 99mTC-methoxyisobutylisonitrile uptake) were assessed for myocardial 123I-metaiodo benzylguanidine (123I-MIBG) uptake and complement-fixing sympathetic ganglia (CF-SG) autoantibodies. Both groups of patients were also studied for islet cell antibodies (ICA) and ECG-based cardiac autonomic neuropathy. Eighty control subjects (age 18-49 years) were investigated for CF-SG autoantibodies. Eight newly diagnosed (40%) and 12 long-term (25%) IDDM patients exhibited CF-SG autoantibodies, compared to 4 control subjects (5%; p < 0.01, p < 0.05). In long-term diabetic patients, the reduction of global but not of regional myocardial 123I-MIBG uptake correlated with CF-SG autoantibodies (r = 0.34, p = 0.02). Newly diagnosed diabetic patients did not show an association between CF-SG autoantibodies and global or regional myocardial 123I-MIBG uptake. ECG-based cardiac autonomic neuropathy (> or = two of five cardiac reflex tests abnormal) was present in 22 and absent in 26 long-term IDDM patients, of whom 9 (41%) and 3 (12%), respectively were positive for CF-SG autoantibodies (p = 0.02). Only 1 newly diagnosed IDDM patient demonstrated ECG-based cardiac autonomic neuropathy and was also positive for CF-SG autoantibodies. Although they are somewhat suggestive, results concerning autoantibodies against sympathetic nervous tissue and cardiac sympathetic dysinnervation do not strongly support the view that autoimmune mechanisms play a major role in the pathogenesis of cardiac sympathetic neuropathy in IDDM.

Insulin neuritis, or painful neuropathy following rapid improvement in glycaemic control, is well recognised but its aetiology is unclear. An understanding of the processes involved in the genesis of acute painful neuropathy of rapid glycaemic control may give an insight into the early pathogenetic factors leading to diabetic nerve damage in general. We have identified five subjects with insulin neuritis including one who developed severe autonomic neuropathy following treatment with insulin. Subjects underwent: 1) assessment of neuropathic symptom and deficit scores; 2) quantitative sensory and electrophysiological studies and 3) sural nerve epineurial vessel photography and fluorescein angiography in vivo. The sural nerve photographs were independently graded by an ophthalmologist. All subjects with insulin neuritis presented with severe sensory symptoms but clinical examination and electrophysiological tests were normal except in the subject with the severe autonomic neuropathy in whom all the tests were abnormal. On nerve photography, there was an abundance of epineurial nutrient vessels although these showed severe abnormalities including arteriolar attenuation, tortuosity and arterio-venous shunting in all subjects. Proliferating neural 'new vessels' which bear striking similarities to those found in the retina and that were more leaky to fluorescein than normal vessels, were observed in three subjects. Venous distension and/or tortuosity was also observed in three subjects and this was most marked in the subject with severe autonomic neuropathy. This study shows that epineurial nutrient vessel anatomy is abnormal in subjects with acute painful neuropathy of rapid glycaemic control, a condition previously thought to be purely metabolic in origin. The presence of epineurial arterio-venous shunting and a fine network of vessels resembling the new vessels of the retina, may lead to a 'steal' effect rendering the endoneurium ischaemic. This process may be important in the genesis of neuropathic pain, and further supports the importance of vascular factors in the pathogenesis of diabetic neuropathy.

In this study we report a randomized double-blind, placebo-controlled trial to evaluate the effect of ORG 2766 in IDDM patients with peripheral neuropathy. Sixty-two patients were selected based on the following criteria: abnormal vibration perception threshold above the 95th-percentile adjusted for age and/or abnormal warm temperature threshold, both measured in the right hand. The patients were randomized into two treatment groups after baseline studies: Group 1 was treated with placebo and Group 2 was treated with 3 mg of the ACTH4-9 analogue ORG 2766 every 24 h. The total study period was 1 year. After 1 year of treatment there was a significant improvement in vibration threshold in Group 1 compared to Group 2. No other parameters improved in the study period. The number of patients selected may have been too small to detect a more important treatment effect. We conclude from this study that ORG 2766 can improve vibration threshold, indicating large myelinated fibre function, but does not affect any of the other neurophysiological function tests.

Transcutaneous oxygen, laser Doppler flowmetry, peroneal nerve motor conduction velocity and skin temperature were assessed in both legs of 34 diabetic patients, who had a mean age of 41 (range 29-77) years, and diabetes duration of 21 (3-34) years. Transcutaneous oxygen significantly correlated with peroneal nerve motor conduction velocity (r = 0.59 p < 0.001) and laser Doppler flowmetry (r = 0.7 p < 0.001). Laser Doppler flowmetry correlated weakly with peroneal motor conduction velocity, (r = 0.34 p < 0.05). In each patient the leg with the higher transcutaneous oxygen (mean 70.2 +/- 9.3 (SD) mmHg) had a significantly higher peroneal motor conduction velocity (45.3 +/- 7.1 vs 41.5 +/- 6.3 m/s, p < 0.01), than the leg with the lower transcutaneous oxygen (61.0 +/- 11.9 mmHg), though no difference in skin temperature was observed, 31.4 +/- 0.4 vs 31.1 +/- 0.5 degrees C. We then assessed the potential for reversibility of conduction velocity deficits in ten non-diabetic patients, aged 59 (52-77) years, undergoing unilateral femoro-popliteal bypass, measuring transcutaneous oxygen, peroneal nerve motor conduction velocity and skin temperature pre- and 6 weeks post-surgery. In the control leg (unoperated) there was no significant change in transcutaneous oxygen (63.2 +/- 8.8 vs 63.0 +/- 4.6 mm Hg), peroneal nerve motor conduction velocity (45.1 +/- 7.8 vs 43.4 +/- 7.2 m/s) or skin temperature (30.8 +/- 1.3 vs 30.2 +/- 1.2 degrees C) after surgery (all NS).(ABSTRACT TRUNCATED AT 250 WORDS)

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 micrograms/l-169 micrograms/l. In contrast, mean plasma IGFBP-1 levels declined steadily from a high level of 1.99 micrograms/l at 08.00 hours to approximately one half (0.86 microgram/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.(ABSTRACT TRUNCATED AT 250 WORDS)

It has been shown that parameters of oxidative stress are increased in experimental diabetic neuropathy. The glutathione redox system is one of the intracellular scavenger systems for neutralizing free oxygen radicals. In this investigation we studied the effect of glutathione-treatment on the development of diabetic neuropathy in streptozotocin-induced diabetic rats by measuring sensory and motor nerve conduction velocities. The total study period was 10 weeks. Four groups of rats were studied: Group 1 consisted of non-diabetic, age-matched control rats; Group 2, of diabetic rats treated with placebo from week 0 to 10; Group 3, of diabetic rats treated with 200 mg glutathione/kg body weight i.v. two times per week from weeks 0 to 10; and Group 4, of diabetic rats treated with placebo from weeks 0 to 4 and as Group 3 from weeks 4 to 10. The sensory and motor nerve conduction velocity of rats treated prophylactically with glutathione (Group 3) were significantly different from those of rats treated with placebo (Group 2) or with glutathione administered at a later time point (Group 4). Complete restoration of sensory and motor nerve conduction velocity was not reached. There was a significant improvement in motor nerve conduction velocity from weeks 4 to 6 (p less than 0.005), but not in sensory nerve conduction velocity in the delayed treatment group (Group 4). In conclusion, treatment with glutathione, a free radical scavenger, is partially effective in the prevention of diabetic neuropathy in streptozotocin-induced diabetic rats, but is of limited value when the neuropathy is already present.

In 10 patients with Type 1 (insulin-dependent) diabetes mellitus gastric emptying of a digestible solid and liquid meal was measured during euglycaemia (blood glucose concentration 4-8 mmol/l) and during hyperglycaemia (blood glucose concentration 16-20 mmol/l). Gastric emptying was studied with a scintigraphic technique and blood glucose concentrations were stabilised using a modified glucose clamp. Patients were also evaluated for gastrointestinal symptoms, autonomic nerve function and glycaemic control. When compared to euglycaemia, the duration of the lag phase before any of the solid meal emptied from the stomach (p = 0.032), the percentage of the solid meal remaining in the stomach at 100 min (p = 0.032) and the 50% emptying time for the solid meal (p = 0.032) increased during hyperglycaemia. The 50% emptying time for the liquid meal (p = 0.042) was also prolonged during the period of hyperglycaemia. These results demonstrate that the rate of gastric emptying in Type 1 diabetes is affected by the blood glucose concentration.

The accumulation of 3H-fucose labelled glycoprotein and 35S-methionine labelled protein carried by the retrograde axonal transport in the sensory fibres of the sciatic nerve was examined on the day after injection of streptozotocin in rats. The accumulation of fucose-label was reduced (2.8 +/- 0.4 (SD) versus 2.1 +/- 0.5 (arbitrary units), 2p = 0.0044) indicating a decreased retrograde flux of glycoproteins. This early transport abnormality could have a key role in the development of peripheral neuropathy in diabetes.

The progression of subclinical polyneuropathy over 2.5 years has been studied in a representative group of 75 young patients with Type 1 (insulin-dependent) diabetes (initial age 16-19 years). The relationships between changes in nerve function, glycaemic control and concurrently developing microvascular complications (retinopathy, microproteinuria) were investigated. Deterioration of motor, sensory and autonomic nerve function, retinopathy and microproteinuria was related to poor glycaemic control. In addition, there was an association between developing neural and microvascular complications which was not diminished when their common relationship to hyperglycaemia was taken into account. These findings suggest that, although poor glycaemic control is an essential permissive factor in the early development of diabetic polyneuropathy, other influences, shared with microvascular complications, must also be important.

One thousand, two hundred and eighteen diabetic subjects living in and around country towns of Western Australia were screened for complications of diabetes. This population included 134 subjects of Aboriginal descent, who were compared with the Caucasoids taking part. In the Aboriginal group there was a greater proportion of Type 2 (non-insulin-dependent) diabetic patients, a relative female preponderance (69% compared with 51%) and a tendency to present at an earlier age of onset than their Caucasoid counterparts. Diabetic complications were at least as common in the Aboriginal group as in the Caucasoid patients. Indeed, retinopathy within 10 years of onset of diabetes was more common in the Aborigines. Peripheral neuropathy was more prevalent in Aborigines treated by diet alone or oral hypoglycaemic agents than in Caucasoids. A much greater prevalence of proteinuria was an additional feature of the Aboriginal subgroup (29% versus 4%).

Streptozotocin-diabetic rats were maintained on a 72% fructose diet for 4 weeks and some were treated with an aldose reductase inhibitor (either alrestatin: 0.9 g . kg-1 . day-1 or ONO-2235: 50 mg . kg-1 . day-1). Fructose feeding significantly influenced the development of impaired motor nerve conduction velocity in the diabetic rats and this effect was positively correlated with sorbitol accumulation in the sciatic nerve of diabetic rats maintained on a fructose-rich diet. Treatment with ONO-2235, a new aldose reductase inhibitor, prevented both slowing of motor nerve conduction velocity and elevation of nerve sorbitol concentration. On the other hand, erythrocyte sorbitol levels were significantly correlated to those of the sciatic nerve (r = 0.86, p less than 0.001) and the retina (r = 0.91, p less than 0.001) in these animals. Thus, our findings suggest that increased polyol pathway activity may be related to the pathogenesis of diabetic neuropathy and erythrocyte sorbitol concentrations may prove a useful indicator for the presence of diabetic complications.

A quantitative ultrastructural analysis was made of the terminal innervation of epineurial arterioles in the sural nerve of 6 diabetic and 6 non-diabetic patients of comparable age (mean +/- SD: 68 +/- 9 non-diabetic, 65 +/- 16 diabetic) with end stage peripheral vascular disease. The results demonstrated specific differences, identifiable morphometrically, in the pattern of innervation of epineurial vessels of diabetics compared with non-diabetics. The differences were: 1) in the diabetic group the proportion of perivascular axons found less than 7 microns from the nearest smooth muscle cell was significantly less than in the non-diabetic group (p less than 0.001); 2) the mean distance of the axons from their effector sites, the vascular smooth muscle cells, was nearly twice as far in the diabetic group compared with the non-diabetic group (p less than 0.05); and 3) the mean absolute number of axons less than 7 microns from the arteriole in the diabetic group was significantly less than in the non-diabetic group (p less than 0.01). These results demonstrate that the neuropathy associated with diabetes mellitus also involves the autonomic terminal innervation of some blood vessels. In addition, this neuropathy selectively affects the vasomotor nerves closer than 7 microns to the media.

The natural history of erectile impotence in diabetic men has been defined in a 5-year prospective study of 466 patients initially aged 20-59 years. Of the 275 who were originally potent, 78 (28%) have become impotent. Five features present at first interview were found to be independently predictive of the subsequent development of impotence; age (p less than 0.0001), alcohol intake (p less than 0.0001), initial glycaemic control (p = 0.03), intermittent claudication (p = 0.04) and retinopathy (p = 0.05). The development of impotence was also significantly associated with the appearance of neuropathic symptoms (p = 0.003) and poor glycaemic control in the intervening 5 years (p = 0.01). Only 11 out of 128 (9%) of those originally impotent regained potency; they were young, had short duration of diabetes, and often features of psychogenic impotence. Those with impotence originally but no clinically apparent micro/macrovascular or neuropathic diabetic complications developed retinopathy (p = 0.001) and neuropathy (p = 0.01) more frequently than their comparable potent counterparts. It is concluded that diabetic impotence rarely reverses, that it is strongly associated with neuropathic and vascular complications of diabetes, and that moderation of alcohol consumption and improvement of glycaemic control are possible preventative factors.

The hypothesis that nerves in diabetes mellitus exhibit an increased susceptibility to compression was experimentally tested. Inhibition of fast axonal transport was induced by local compression in sciatic nerves of rats with streptozotocin-induced diabetes mellitus. Fast anterograde axonal transport was measured after application of 3H-leucine to the motor neurone cell bodies in the spinal cord. The sciatic nerve was subjected to local, graded compression in vivo by a small compression chamber. The amount of accumulation of proteins was quantified by calculation of a transport block ratio. Compression at 30 mm Hg for 3 h induced a significantly greater (p less than 0.05) accumulation of axonally transported proteins at the site of compression in nerves of diabetic animals (transport block ratio: 1.01 +/- 0.35; n = 7) than in nerves of controls (0.67 +/- 0.16; n = 7). Accumulation was significantly higher in ligature experiments of both control (1.34 +/- 0.44; n = 8; p less than 0.01) and diabetic animals (1.45 +/- 0.30; n = 8; p less than 0.05), indicating that the block of transport in compressed nerves was incomplete. Neither sham compressed diabetic (0.50 +/- 0.09; n = 6) nor control (0.49 +/- 0.11; n = 6) nerves showed any block of axonal transport. The possible causes of the increased inhibition of fast axonal transport in diabetic rats are discussed. The results indicate that diabetes may lead to an increased susceptibility of peripheral nerves to compression.

Brainstem auditory evoked potentials and pattern shift visual evoked potentials were measured in 34 Type 1 (insulin-dependent) diabetic patients with long-standing disease and in 43 control subjects. Thirty-two percent of diabetic patients had abnormal brainstem auditory evoked potentials and 15% had abnormal visual evoked potentials. These abnormalities were not related to duration of diabetes, diabetic control or individual diabetic complications (retinopathy, nephropathy, peripheral or autonomic neuropathy). The aetiology of the abnormalities must remain a subject for speculation. The findings of this study are consistent with a central diabetic neuropathy involving the brainstem in long-standing diabetic patients.