Idiopathic neuropathy, prediabetes and the metabolic syndrome

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Abstract

Peripheral neuropathy is a common problem encountered by neurologists and primary care physicians. While there are many causes for peripheral neuropathy, none can be identified in a large percentage of patients (“idiopathic neuropathy”). Despite its high prevalence, idiopathic neuropathy is poorly studied and understood. There is evolving evidence that impaired glucose tolerance (prediabetes) is associated with idiopathic neuropathy. Preliminary data from a multicenter study of diet and exercise in prediabetes (the Impaired Glucose Tolerance Neuropathy Study) suggests a diet and exercise counseling regimen based on the Diabetes Prevention Program results in improved metabolic measures and small fiber function. Prediabetes is part of the Metabolic Syndrome, which also includes hypertension, hyperlipidemia and obesity. Individual aspects of the Metabolic Syndrome influence risk and progression of diabetic neuropathy and may play a causative role in neuropathy both for those with prediabetes, and those with otherwise idiopathic neuropathy. Thus, a multifactorial treatment approach to individual components of Metabolic Syndrome may slow prediabetic neuropathy progression or result in improvement.

Introduction

Peripheral neuropathy is one of the most common disorders seen in general neurology and neuromuscular specialty clinics, and foot numbness and pain is a frequent cause for referral for neurologic consultation. In our outpatient neuromuscular clinics, peripheral neuropathy is the most common diagnosis, accounting for over 20% of new patient visits. Despite its frequency, many neurologists approach the evaluation of peripheral neuropathy with ambivalence. While there are hundreds of causes for peripheral neuropathy, most patients present with symptoms of distal numbness and pain. Therefore, distinguishing one disorder from another can be challenging. Perhaps more discouraging is the mistaken perception that as many as two-thirds of neuropathy patients remain undiagnosed, relegated to the nebulous designation of “idiopathic” or “cryptogenic” neuropathy. Demonstration of familial, inflammatory, and toxic causes for neuropathy has chipped away at this large bloc of idiopathic patients, but in the past 25 years few novel causes of neuropathy have been recognized. However, recent work from our group and others suggests that impaired glucose tolerance (IGT or prediabetes) and other features of Metabolic Syndrome are important contributors to peripheral neuropathy [1], [2], [3], [4]. In this paper, we review the epidemiology of idiopathic neuropathy, discuss the evidence implicating prediabetes and Metabolic Syndrome, and suggest a unifying hypothesis and a means of testing it.

Section snippets

The problem of idiopathic neuropathy

Little population-based epidemiological data is available regarding the prevalence of idiopathic neuropathy. The Italian General Practitioner Study Group interviewed 4191 elderly subjects in northern Italy and demonstrated possible neuropathy in up to 8% [5]. The National Health and Nutrition Examination Survey (NHANES) demonstrated a 14% prevalence of peripheral neuropathy among 2873 individuals over 39 years of age. The risk among diabetics was approximately twice that of non-diabetic

Prediabetes and peripheral neuropathy

Diabetes is the most common cause of peripheral neuropathy worldwide. Diabetes affects over 14 million people in the United States alone and the number of diabetic patients is increasing by 5% each year. Half of diabetic patients develop peripheral neuropathy. Traditional view has held that diabetes only results in neuropathy after many years of sustained hyperglycemia. However, there is evidence that neuropathy occurs earlier in the course of hyperglycemia than other microvascular diabetic

Metabolic Syndrome as a contributor to neuropathy

Prediabetes is one component of an overall Metabolic Syndrome that also consists of obesity, elevated serum triglycerides, reduced serum high density lipoprotein levels, and hypertension. The Metabolic Syndrome is associated with an increased risk of large vessel atherosclerotic disease, but its relationship to microvascular outcomes (neuropathy, retinopathy, and nephropathy) outside of the setting of overt diabetes is unknown. In order to determine if other aspects of the Metabolic Syndrome

A unifying hypothesis and future directions

Epidemiologic data indicate peripheral neuropathy is a very common and clinically important entity. It often results in significant disability due to neuropathic pain. Patients with otherwise idiopathic neuropathy are more likely than the age matched general population to have prediabetes. There is evolving evidence that neuropathy is also associated with other features of the Metabolic Syndrome, and that treatment of hyperglycemia, hyperlipidemia, hypertension and smoking cessation may reduce

Acknowledgements

The authors would like to acknowledge Dr. Jack Petajan, who has been a role model during our tenure at the University of Utah. His intellectual curiosity and humanism have served as guiding principles. Dr. Petajan mentored Dr. Jasper Daube at the University of Wisconsin who subsequently trained Dr. James Albers at the Mayo Clinic. Dr. Albers in turn was our mentor at the University of Michigan. Therefore, all of our clinical and academic work, including that summarized in this paper, are a

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