By Russell L. Chin, MD

Associate Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Chin reports no financial relationships relevant to this field of study.

SYNOPSIS: Microstructural nerve damage in distal symmetric diabetic neuropathy differs between subjects with type 1 diabetes (T1D) and type 2 diabetes (T2D). The predominant nerve lesions in T1D correlated with hyperglycemia and nerve conduction impairment, while the predominant lesions in T2D correlated with dyslipidemia.

SOURCE: Jende JME, Groener JB, Oikonomou D, et al. Diabetic neuropathy differs between type 1 and type 2 diabetes: Insights from magnetic resonance neurography. Ann Neurol 2018;83:588-598.

Diabetes mellitus, specifically type 2 diabetes (T2D), is the most common cause of neuropathy in the United States and Europe. Approximately half of all diabetic patients will develop some form of neuropathy during their lifetime. More than 20 million Americans currently have neuropathy secondary to either prediabetes, type 1 diabetes (T1D), or T2D, and the worldwide prevalence is expected to increase, particularly in countries adopting a more Western diet.1 Distal symmetric diabetic neuropathy (DPN) accounts for about 75% of diabetic neuropathies and is characterized by bilateral, symmetric damage to nerves of the feet in a “stocking” distribution with later involvement of hands and mild distal motor weakness. Neuropathic pain is a disabling consequence of DPN, affecting 25-50% of patients. Sensory symptoms include positive symptoms of pain, tingling, prickling sensations, altered sensation (such as allodynia or hyperalgesia), and negative symptoms of numbness.

The pathogenesis of DPN remains elusive, and, consequently, there are no approved disease-modifying therapies that unequivocally prevent or reverse the neuropathy. Vigilance about foot care and neuropathy development, lifestyle changes, and strict glycemic control are counseled. Symptoms are managed, often suboptimally, with pregabalin, duloxetine, and gabapentin. Medications that target ion channels that are more selectively expressed in nociceptors (e.g., Nav 1.7, 1.8, and 1.9) are under investigation.1

Research into the pathophysiology of DPN has evolved from a “glucocentric” viewpoint to a broader understanding that the DPN is a complex disorder secondary to multiple linked and cascading reactions. Inflammation, endothelial dysfunction, deposition of advanced glycation end products (AGE), microvascular-induced ischemia, increased aldose reductase activity, and oxidative stress are implicated in nerve damage. Research into whole nerve metabolism and insulin sensitivity and resistance (potentially at the level of the nervous system) also provide clues about the mechanism behind DPN in T2D.2 Rigorous glycemic control, while reducing the incidence of DPN in T1D, has little to no effect in the more common T2D, indicating different mechanisms underlying the DPN in each disorder. It is likely that components of the metabolic syndrome promote the onset and progression of DPN in T2D, as evidenced by the higher rates of dyslipidemia and obesity in T2D compared with T1D.3,4

In this study, 120 patients (35 with T1D and 85 with T2D), of whom 84 had DPN, were evaluated. Detailed medical history, clinical and electrodiagnostic findings, blood studies, and objective and subjective scoring data were obtained. High-resolution MR neurography of the right leg in a 3.0T magnetic resonance scanner was obtained. The earliest and most prominent nerve lesions in DPN have been reported to occur at the level of the distal sciatic nerve, so calculation of the T2-weighted hyperintense and hypointense lesions was performed for the sciatic nerve at the mid-thigh level. Both kinds of lesions were found more commonly in DPN and associated with an increased severity of clinical symptoms.

T2-weighted hypointense lesions appeared hyperintense on T1-weighted images, strongly suggesting a high lipid content. The lipid volume in these lesions was higher in T2D compared to T1D patients with and without DPN, and there was a positive correlation with neuropathy symptoms and triglyceride levels and a negative correlation with serum HDL levels. The authors hypothesized that these lesions might represent an imaging correlate of intraneural aggregates of lipids or microvascular lipid deposits inside the wall of perineural blood vessels. However, T2-weighted hyperintense lesion load was higher in T1D compared with T2D, and there was a positive correlation with hemoglobin A1c level and impairment of nerve conductions. The authors hypothesized that these lesions represent an imaging correlate of AGEs in the extracellular matrix of myelinating cells.


MR neurography allows unprecedented in vivo evaluation of DPN, offsetting the limitations of human nerve accessibility and rodent models of DPN. The differing patterns of nerve damage described in this article provide additional evidence of the unique pathophysiologic mechanisms behind the two types of DPN and help explain the limited benefit of glycemic control in T2D DPN. An improved basic understanding of the disease process is crucial to clinical trials, which have been disappointing to date. Mechanism-based treatments are desperately needed for this global epidemic.


  1. Feldman El, Nave KA, Jensen TS, Bennett DLH. New horizons in diabetic neuropathy: Mechanisms, bioenergetics, and pain. Neuron 2017;93:1296-1313.
  2. Kobayashi M, Zochodne DW. Diabetic neuropathy and the sensory neuron: New aspects of pathogenesis and their treatment implications. J Diabetes Investig 2018;13: doi: 10.1111/jdi.12833.
  3. Callaghan BC, Little AA, Feldman EL, Hughes RAC. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev 2012;(6):CD007543.
  4. Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic neuropathy: A position statement by the American Diabetes Association. Diabetes Care 2017;40:136-154.