Diabetic nerve damage linked to metabolic factors

Targeting the various aspects of the metabolic syndrome may provide a means for preventing the development of diabetic neuropathy, authors of a review suggested. The prevalence of neuropathy in patients with diabetes is about 30%, and up to 50% of patients will eventually develop it during the course of their disease. Current investigations support the concept that metabolic factors beyond hyperglycemia may be contributing components, according to Brian C. Callaghan, MD, and colleagues from the University of Michigan in Ann Arbor, writes  Nancy Walsh, MedPage Today. "In terms of the mechanisms linking the metabolic syndrome and type 2 diabetes to neuropathy, these pathways might be more accurately described as a network in which hyperglycemia, insulin resistance, dyslipidemia, systemic inflammation, and activation of the renin-angiotensin system all feed into a self-perpetuating cycle of oxidative stress, inflammatory signals, and disruption of normal cellular function," they explained in the June issue of Lancet Neurology. Because many of the risk factors that make up this network are modifiable -- and most current treatments are off-label and less than ideal -- establishing causality could dramatically help improve patients' quality of life and reduce the annual associated costs in this country that have been estimated at $4.6 to $13.7 billion. The only current disease-modifying approach to preventing diabetes-related neuropathy is glucose control, and that has had only modest effects for type 2 diabetes. Pain management remains a principal strategy. Even so, fewer than half of affected patients receive treatment for the pain, the authors noted. In reviewing the current options for pain control, Callaghan's group noted that first-line agents include tricyclic antidepressants, gabapentin, pregabalin, venlafaxine, and duloxetine. Treatment algorithms have been developed by the European Federation of Neurological Societies and the American Academy of Neurology. "The choice of agent is largely dependent on the comorbidities of the patient and side-effect profiles of the drugs," the authors noted. If first-line treatment options are inadequate, other agents include opioids and tramadol, but long-term use can be hampered by factors such as addictive potential and gradual loss of efficacy. The most common manifestation of diabetic neuropathy is distal symmetrical polyneuropathy, typically following a "stocking and glove" pattern of involvement. But clinicians also should be aware of other types of neuropathy, the authors wrote, including autonomic neuropathy, which can be associated with gastrointestinal and genitourinary symptoms, radiculopathy, and mononeuritis multiplex. Hyperglycemia is a recognized contributor to these various forms of neuropathy, possibly through effects on mitochondrial function, oxidative stress, and inflammation. Another contributor is dyslipidemia, which may have injurious effects through the presence of free fatty acids and secretion of cytokines from adipocytes. Modified lipoproteins also can add to oxidative stress, while cholesterol itself can lead to neuronal cell death. Abnormalities of insulin signaling also appears to play a role, as neuronal growth is encouraged by insulin. "Reduction of this neurotrophic signaling due to insulin deficiency (type 1 diabetes) or insulin resistance (type 2 diabetes) is thought to contribute to the pathogenesis of diabetic neuropathy," Callaghan and colleagues observed. Other aspects of the metabolic syndrome that may be involved include visceral adiposity, which can act through increased concentrations of free fatty acids in the plasma and inflammation, as well as hypertension and upregulation of the renin-angiotensin system. "One of the main challenges for researchers is to determine which aspects of this network of mechanisms can be blocked at which times to effectively limit or prevent progression of the neuropathy," the authors wrote. Identification of the specific mechanisms and metabolic factors involved will be crucial, they explained, because all the individual components of the metabolic syndrome can be treated. "These lines of enquiry will have direct implications for the development of new treatments for diabetic neuropathy," they concluded. from MedPageToday