U.S. Department of Health and Human Services

Newly Discovered Pathway for Nerve Pain in Diabetes

A factor produced during glucose metabolism may be responsible for painful peripheral neuropathy in diabetes. Many people with diabetes suffer from peripheral neuropathy, nerve damage that starts in the feet and can cause either pain or loss of feeling in the toes and then feet, legs, and hands. While scientists have suspected that elevated blood glucose levels play a role in painful peripheral neuropathy, the exact mechanism(s) has been unclear. In a recent study, researchers found that, compared to people without diabetes, people with type 2 diabetes have higher circulating levels of methylglyoxal, a small molecule that is produced during glucose metabolism. Intriguingly, people with diabetes and foot pain had significantly higher levels of this molecule than either people without diabetes or people with diabetes but no pain. Methylglyoxal is metabolized by a cellular enzyme called glyoxylase 1, or GLO1. Peripheral nerves, such as those detecting sensations in the hands and feet, have low GLO1 activity; because there may be insufficient GLO1 to metabolize excess methylglyoxal, these nerves may be particularly vulnerable to accumulating high levels of the molecule. To determine whether methylglyoxal exacerbates pain responses, the researchers used a variety of approaches to experimentally raise the levels of this molecule in mice, including chemically inducing diabetes in some and inhibiting the GLO1 enzyme activity in others. They found that, compared to untreated animals, these mice became hypersensitive to both heat and mechanical stimuli. In contrast, the scientists were able to “rescue” diabetic mice from hypersensitivity to heat either by increasing GLO1 enzyme levels in peripheral nerves, or by injecting the mice with a molecule that gets rid of excess amounts of methylglyoxal. Through additional experiments, the researchers uncovered evidence for a molecular mechanism that could explain how exposure to excess methylglyoxal increases the excitability of pain-signaling peripheral nerve cells and enhances activation of brain regions involved in pain processing. 
At this time, few effective treatments exist for painful diabetic neuropathy. The novel discovery of a metabolically driven mechanism that increases sensitivity to potentially painful stimuli not only opens up a new line of study, but could potentially lead to new therapeutic approaches for this pain condition in people with diabetes. 
Bierhaus A, Fleming T, Stoyanov S, et al. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med 18: 926-933, 2012.