title: 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.
authors.affiliation: Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hidmark
authors.affiliation: Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Fleming
authors.affiliation: Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Vittas
authors.affiliation: Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Mendler
authors.affiliation: Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Deshpande
authors.affiliation: Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: J B
authors.initials: JB
authors.lastname: Groener
authors.affiliation: Department of Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: B P
authors.initials: BP
authors.lastname: Müller
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: P W
authors.initials: PW
authors.lastname: Reeh
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: S K
authors.initials: SK
authors.lastname: Sauer
authors.affiliation: Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pham
authors.affiliation: Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University of Heidelberg, Heidelberg, Germany.
authors.forename: M U
authors.initials: MU
authors.lastname: Muckenthaler
authors.affiliation: Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Bendszus
authors.affiliation: Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: P P
authors.initials: PP
authors.lastname: Nawroth
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism* / Q000628:therapy; D003929:Diabetic Neuropathies / Q000097:blood / Q000378:metabolism* / Q000628:therapy*; D017127:Glycation End Products, Advanced / Q000097:blood / Q000378:metabolism; D006037:Glyoxal / Q000097:blood / Q000378:metabolism; D006801:Humans; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D006037:Glyoxal