Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13–18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.

Other than glycemic control, there are no treatments for diabetic neuropathy. Thus, identifying potentially modifiable risk factors for neuropathy is crucial. We studied risk factors for the development of distal symmetric neuropathy in 1172 patients with type 1 diabetes mellitus from 31 centers participating in the European Diabetes (EURODIAB) Prospective Complications Study. Neuropathy was assessed at baseline (1989 to 1991) and at follow-up (1997 to 1999), with a mean (±SD) follow-up of 7.3±0.6 years. A standardized protocol included clinical evaluation, quantitative sensory testing, and autonomic-function tests. Serum lipids and lipoproteins, glycosylated hemoglobin, and the urinary albumin excretion rate were measured in a central laboratory. At follow-up, neuropathy had developed in 276 of 1172 patients without neuropathy at baseline (23.5 percent). The cumulative incidence of neuropathy was related to the glycosylated hemoglobin value and the duration of diabetes. After adjustment for these factors, we found that higher levels of total and low-density lipoprotein cholesterol and triglycerides, a higher body-mass index, higher von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking were all significantly associated with the cumulative incidence of neuropathy. After adjustment for other risk factors and diabetic complications, we found that duration of diabetes, current glycosylated hemoglobin value, change in glycosylated hemoglobin value during the follow-up period, body-mass index, and smoking remained independently associated with the incidence of neuropathy. Cardiovascular disease at baseline was associated with double the risk of neuropathy, independent of cardiovascular risk factors. This prospective study indicates that, apart from glycemic control, the incidence of neuropathy is associated with potentially modifiable cardiovascular risk factors, including a raised triglyceride level, body-mass index, smoking, and hypertension.

The Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of the Toronto Consensus Panel on Diabetic Neuropathy worked to update CAN guidelines, with regard to epidemiology, clinical impact, diagnosis, usefulness of CAN testing, and management. CAN is the impairment of cardiovascular autonomic control in the setting of diabetes after exclusion of other causes. The prevalence of confirmed CAN is around 20%, and increases up to 65% with age and diabetes duration. Established risk factors for CAN are glycaemic control in type 1 and a combination of hypertension, dyslipidaemia, obesity, and glycaemic control in type 2 diabetes. CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy. Criteria for CAN diagnosis and staging are: (1) one abnormal cardiovagal test result identifies possible or early CAN; (2) at least two abnormal cardiovagal test results are required for definite or confirmed CAN; and (3) the presence of orthostatic hypotension in addition to abnormal heart rate test results identifies severe or advanced CAN. Progressive stages of CAN are associated with increasingly worse prognosis. CAN assessment is relevant in clinical practice for (1) diagnosis of CAN clinical forms, (2) detection and tailored treatment of CAN clinical correlates (e.g. tachycardia, orthostatic hypotension, non‐dipping, QT interval prolongation), (3) risk stratification for diabetic complications and cardiovascular morbidity and mortality, and (4) modulation of targets of diabetes therapy. Evidence on the cost‐effectiveness of CAN testing is lacking. Apart from the preventive role of intensive glycaemic control in type 1 diabetes, recommendations cannot be made for most therapeutic approaches to CAN. Copyright © 2011 John Wiley & Sons, Ltd.

Diabetic peripheral neuropathy (DPN) is a common complication of both type 1 and 2 diabetes. It is a leading cause of lower-limb amputation and disabling neuropathic pain. Amputations in patients with diabetes have a devastating effect on quality of life and are associated with an alarmingly low life expectancy (on average only 2 years from the amputation). Amputation also places a substantial financial burden on health-care systems and society in general. With the introduction of national diabetes eye screening programmes, the prevalence of blindness in working-age adults is falling. This is not the case, however, with diabetes related amputations. In this Review, we appraise innovative point-of-care devices that enable the early diagnosis of DPN and assess the evidence for early risk factor-based management strategies to reduce the incidence and slow the progression of DPN. We also propose a framework for screening and early multifactorial interventions as the best prospect for preventing or halting DPN and its devastating sequelae.

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]