For those who suffer from painful diabetes-related nerve pain, there’s new research that shows promise in alleviating diabetic neuropathy. How’d they do it?
The researchers studied worms.
More specifically, they studied the nematode C. elegans and found a sensor for the reactive molecules linked to diabetic complications, which provides a pathway to study diabetic neuropathy – a disease that is a dysfunction of the peripheral nerves, which can cause numbness, weakness, and pain, and affects 29 million people in the United States.
The scientists identified two natural compounds which prevent nerve damage in worms experiencing a similar hypersensitivity to touch as do humans who suffer from diabetic neuropathy. The researchers said that “the compounds essentially cured the nematodes of the condition.”
“We realize that it is a huge leap between humans and C. elegans, but it’s important to note that the pathway involved in neuropathy is conserved among species,” said Buck Institute professor Pankaj Kapahi, PhD, senior scientist on the study. “We now have a good model and a novel pathway that allows us to study many of the complications of diabetes. We also have novel compounds that slow the accumulation of these toxic molecules and show real promise in alleviating a very painful condition.”
This research, which was detailed in Current Biology, focused on identifying the root cause for diabetic neuropathy. It focused on a compound called Methylglyoxal (MGO), which is formed from glucose in the body. MGO is extremely toxic and reacts with essential proteins, DNA, and lipids to form AGEs- advanced glycation end products. These AGEs have been implicated as the cause of many diabetic complications, such as neuropathy.
Kapahi says that damage from accumulated AGEs becomes irreversible. “Our goal is to stop them from forming in the first place,” he stated.
In the lab, the researchers identified a critical sensor for MGO. It’s a protein called TRPA1 that responds to high levels of MGO and detoxifies them.
“TRP (Transient Receptor Potential) ion channels are evolutionarily conserved proteins that function in sensing many stimuli,” said Jyotiska Chaudhuri, PhD, a post-doctoral fellow at the Buck Institute.
“Of them, TRPA1 is a well-known mechanosensory receptor that responds to many noxious stimuli – including pain. Because our model exhibited mechanosensory phenotypes we examined if it played a role in diabetic neuropathy,” Chaudhuri added.
When the activity of TRPA1 was boosted by feeding the worms alpha-lipoic acid and podocarpic acid, they saw dramatic results.
“The worms were no longer hypersensitive to touch, they moved normally, they exhibited no neuronal damage and lived a long healthy life. Our work demonstrates that TRPA1 activity is critical in limiting diabetic complications,” Chaudhuri exclaimed.
Alpha-lipoic acid is an antioxidant naturally found in organ meats such as liver and kidney as well as in yeast, spinach and broccoli. It’s also available as a supplement. Several human studies suggest that alpha-lipoic acid helps lower blood sugar levels.
Kapahi added that the short-lived worm provides a way to get to the root cause of diabetic complications, and also facilitates rapid drug discovery. “It can take decades for symptoms to develop in humans – in the worm we see problems within two weeks.”
He also thinks the findings could help hone in on research on substances that are known to activate TRPA-1, such as cinnamon, garlic, and wasabi. “There is some evidence that people who eat spicy food are protected against diabetes,” said Kapahi. “Maybe it’s because of TRPA-1.”