The IDNC will address three fundamental and critical areas related to diabetic neuropathy where our present knowledge is insufficient and where unsolved problems block the development of new therapies:
- Pathophysiology of diabetic neuropathy. The cause of diabetic neuropathy remains unknown, but studies have mainly focused on two main hypotheses for the development of diabetic neuropathy: a) a metabolic hypothesis where hyperglycaemia leads to a feed-forward cascade of cellular impairment(s) including oxidative stress, mitochondrial dysfunction, and eventually neuronal damage and b) a vascular hypothesis where microangiopathy impairs the vascular supply of nerve fibres resulting in nerve damage. We have proposed an alternative mechanism by which the development of diabetic neuropathy is linked to capillary dysfunction, which reduces the amount of oxygen and glucose that can be extracted by the tissue, leading to nerve damage and the signs and symptoms of diabetic neuropathy.
- Epidemiology and risk factors of diabetic neuropathy. Suggested risk factors for diabetic neuropathy in type 1 diabetes include increased age, longer diabetes duration, poor glycaemic control, hypertension, obesity, and cigarette smoking, whereas less is known about risk factors for diabetic neuropathy in type 2 diabetes. Up to 50% of all type 2 diabetes patients develop diabetic neuropathy. It remains unclear why some patients with type 2 diabetes develop diabetic neuropathy and others do not. Similarly, it is not known why only a proportion of patients with diabetic neuropathy develop pain. While the metabolic syndrome has been shown to be associated with diabetic neuropathy, studies investigating the role of specific components of the metabolic syndrome have yielded inconsistent results. In type 1 diabetes, enhanced glycaemic control substantially reduces the incidence of diabetic neuropathy, while a recent meta-analysis of glycaemic control in type 2 diabetes failed to show a reduction in diabetic neuropathy despite large trials. To improve the diagnosis, prevention, and treatment of diabetic neuropathy, large-scaled population-based studies are needed to quantify the exact incidence of diabetic neuropathy and to clarify the determinants of diabetic neuropathy development and prognosis in type 2 diabetes, including lifestyle factors, biomarkers, metabolic factors, drug use, and comorbidities. By using high-quality nationwide healthcare databases and well-established cohorts, such as the Danish National T2 Cohort (DD2), the Anglo-Danish-Dutch Study of Intensive Treatment and Complication Prevention in Type 2 Diabetic Patients (ADDITION), it is possible to study the burden of diabetic neuropathy, to distinguish between patients with and without diabetic neuropathy pain, and to identify risk and prognostic factors at the population level.
- Clinical phenotype of diabetic neuropathy. There is an urgent need to establish valid reproducible methods to determine the development and course of diabetic neuropathy. More than 50% of the patients will develop diabetic neuropathy as part of their diabetes, and up to 50% of these, corresponding to 25% of all diabetic patients, will experience disabling pain. The underlying mechanisms and what separates painful from non-painful diabetic neuropathy both in type 1 diabetes and type 2 diabetes are still unclear and require additional research, including careful clinical phenotyping of affected patients.