Risk Factors for the Development of Diabetic Neuropathy

Abstract & Commentary

Commentary by Michael Rubin, MD, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, Assistant Editor, Neurology Alert.

Synopsis: Cardiovascular risk factors are significantly associated with the development of diabetic neuropathy and modification of these parameters should be aggressively encouraged as part of the management of diabetic neuropathy.

Source: Tesfaye S, et al. Vascular Risk Factors and Diabetic Neuropathy. N Engl J Med. 2005;352;341-350.

What, apart from tight glycemic control, might a diabetic undertake to reduce the risk of developing diabetic neuropathy? Among diabetics participating in the 31 center European Diabetes Prospective Complications Trial (EURODIAB, which ran from 1989-99), neuropathy and its possible risk factors were assessed at baseline and at follow-up, a mean 7.3 years later. All patients underwent clinical examination, quantitative sensory, autonomic function testing (change in heart rate and systolic blood pressure on standing after a 5-minute rest), measurement of serum lipid, lipoprotein, and glycosylated hemoglobin, and assessment of urinary albumin excretion rate from a single 24-hour urine collection. Cardiovascular disease was defined on the basis of previous myocardial infarction, angina, bypass surgery, stroke, or ischemic changes on electrocardiogram. Symptoms of neuropathy were present for 6 months, and patients with alternative causes of neuropathy, besides diabetes, were excluded. Diagnosis of neuropathy was based on the presence of 2 or more neuropathic symptoms, absent ankle or knee deep tendon reflexes, abnormal vibration perception threshold, and abnormal autonomic function (postural hypotension or loss of heart rate variability). Student’s t-test, the Mann-Whitney U test, and logistic-regression models provided statistical analysis.

Of 3250 patients enrolled in the trial (1668 men and 1582 women, mean age 32.7 years, mean disease duration 14.7 years), 1819 were without neuropathy at baseline. Of these, 647 were lost to follow-up and, of the remaining 1172, 276 (23.5%) developed neuropathy by study completion. After adjusting for duration of diabetes and glycosylated hemoglobin levels, risk factors significantly associated with development of diabetic neuropathy included total cholesterol (P = 0.001), LDL cholesterol (P = 0.02), triglycerides body-mass index, hypertension, smoking history (P < 0.001 for all 4 factors), as well as retinopathy, albuminuria, von Willebrand factor level, and history of cardiovascular disease. Cardiovascular risk factors are significantly associated with the development of diabetic neuropathy, and modification of these parameters, should be aggressively encouraged as part of the management of diabetic neuropathy.

Commentary

In the United States, diabetes affects more than 6% of the population and, as a result of its complications, accounts for the most common cause of adult blindness (diabetic retinopathy) and renal failure. More than 50% of diabetics will develop neuropathy and, in turn, the most common cause of non-traumatic amputations (Feldman E. J Clin Invest. 2003;111;431-433). Four pathways of glucose metabolism have been implicated in the pathogenesis of diabetic neuropathy. Increased polyol pathway activity results in over-production of sorbitol and fructose, depletes cellular anti-oxidant capacity and, ultimately, alters signal transduction. Glucose may become oxidized, forming advanced glycation end-products, which activate receptors and interfere with intracellular protein function. Glycolytic intermediates may activate PKC and result in oxidative stress, inflammation, and increased vascular disease, which may also result from enhanced hexosamine pathway activity, escape of fructose-6-phosphate, and reactive oxygen species generation, which impairs axonal transport and gene expression. Despite the pathway diversity, commonality exists as each is perturbed by glucose excess and consequent superoxide surplus generated by the mitochondrial transport chain. Neuronal and Schwann cell apoptosis, depressed levels of nerve growth factor, neurotrophin-3, ciliary neurotrophic factors, and insulin growth factor are the end result, and these findings correlate with the development of neuropathy.