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World J Gastroenterol. Jan 14, 2007; 13(2): 175-191
Published online Jan 14, 2007. doi: 10.3748/wjg.v13.i2.175
Early diabetic neuropathy: Triggers and mechanisms
Maxim Dobretsov, Dmitry Romanovsky, Joseph R Stimers
Maxim Dobretsov, Departments of Anesthesiology, Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, United States
Dmitry Romanovsky, Department of Anesthesiology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, United States
Joseph R Stimers, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, United States
Author contributions: All authors contributed equally to the work.
Supported by NIH National Institute of Diabetes and Digestive and Kidney Diseases, No. DK067248
Correspondence to: Maxim Dobretsov, Department of Anesthesiology, Slot 515, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, United States. dobretsovmaxim@uams.edu
Telephone: +1-501-6031936 Fax: +1-501-6031951
Received: August 17, 2006
Revised: September 2, 2006
Accepted: September 26, 2006
Published online: January 14, 2007
Abstract

Peripheral neuropathy, and specifically distal peripheral neuropathy (DPN), is one of the most frequent and troublesome complications of diabetes mellitus. It is the major reason for morbidity and mortality among diabetic patients. It is also frequently associated with debilitating pain. Unfortunately, our knowledge of the natural history and pathogenesis of this disease remains limited. For a long time hyperglycemia was viewed as a major, if not the sole factor, responsible for all symptomatic presentations of DPN. Multiple clinical observations and animal studies supported this view. The control of blood glucose as an obligatory step of therapy to delay or reverse DPN is no longer an arguable issue. However, while supporting evidence for the glycemic hypothesis has accumulated, multiple controversies accumulated as well. It is obvious now that DPN cannot be fully understood without considering factors besides hyperglycemia. Some symptoms of DPN may develop with little, if any, correlation with the glycemic status of a patient. It is also clear that identification of these putative non-glycemic mechanisms of DPN is of utmost importance for our understanding of failures with existing treatments and for the development of new approaches for diagnosis and therapy of DPN. In this work we will review the strengths and weaknesses of the glycemic hypothesis, focusing on clinical and animal data and on the pathogenesis of early stages and triggers of DPN other than hyperglycemia.

Keywords: Diabetes; Pre-diabetes; Neuropathy; Impaired glucose tolerance; Hyperglycemia; Insulinopenia; Insulin-resistance