A New Paradigm to Understand and Treat Diabetic Neuropathy

Abstract

The clinical symptoms of diabetic neuropathy (DN) manifest in a time dependent manner as a positive symptoms (i. e. pain, hypersensitivity, tingling, cramps, cold feet etc.) during its early stages and by a loss of function (i. e. loss of sensory perception, delayed wound healing etc.) predominating in the later stages. Elevated blood glucose alone cannot explain the development and progression of DN and the lowering of blood glucose is insufficient in preventing and/or reversing neuropathy in patients with type 2 diabetes. Recently it has been shown that the endogenous reactive metabolite methylglyoxal (MG) can contribute to the gain of function via post-translational modification in DN of neuronal ion channels involved in chemosensing and action potential generation in nociceptive nerve endings. Dicarbonyls, such as MG, that are elevated in diabetic patients, modify DNA as well as extra- and intracellular proteins, leading to the formation of advanced glycation endproducts (AGEs). Increased formation of AGEs leads to increased cellular stress, dysfunction and ultimately cell death. The interaction of AGE-modified proteins through cell surface receptors, such as RAGE, can lead to increased cellular activation and sustained inflammatory responses, which are the molecular hallmarks of the later, degenerative, stages of DN. The direct and indirect effects of dicarbonyls on nerves or neuronal microvascular network provides a unifying mechanism for the development and progression of DN. Targeting the accumulation of MG and/or prevention of RAGE interactions may therefore provide new, more effective, therapeutic approaches for the treatment of DN.

Soluble urokinase receptor (suPAR) predicts microalbuminuria in patients at risk for type 2 diabetes mellitus

“…Renal involvement in diabetes has been shown prior to manifest disease in patients with prediabetes25 and in normoglycemic individuals with insulin resistance26. Furthermore, triggering factors other than glycemia have been discussed for end-organ manifestations in diabetes2728. In our carefully phenoptyped cohort, glycated hemoglobin levels were significantly higher and more subjects showed prediabetes among those developing microalbuminuria than in subjects not reaching the endpoint.…”

Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

“…Alternatively, non-PPARγ mechanisms can be proposed for the antihyperalgesic effects of pioglitazone in PDN. Pioglitazone inhibits HMGB1-RAGE signaling in spinal neurons 104 and reduces plasma RAGE 34 , both of which are implicated in the pathogenesis of neuropathic pain in models of traumatic nerve injury 24 and PDN 33, 77 . Whether pioglitazone reduces the contribution of spinal gliosis and/or HMGB1-RAGE signaling to PDN remains an important direction of future studies.…”

Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond

“…Nawroth and colleagues and Thornalley and colleagues [52,53] proposed that the role of the AGE precursor methylglyoxal is of profound interest since its formation depends not on hyperglycaemia but on the balance between formation and enzymatic detoxification through the glyoxalase 1 and 2 system. In addition, increased dicarbonyl stress not only arises from hyperglycaemia but also occurs in conditions that promote accelerated ageing and metabolic and vascular complications.…”