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Reversing Neuropathic Pain in Diabetes

Mechanism for diabetic neuropathy may be….

Diabetic neuropathies are disorders that are associated with diabetes, which are thought to be due to damage to the blood vessels that supply nerves. Patients can suffer from painful symptoms as a result of uncontrolled diabetes. Allodynia (pain to a stimulus that doesn’t normally cause pain) and hyperalgesia (increased sensitivity to pain) are examples of symptoms as a result of diabetic neuropathy. Previous studies have established that the T-type voltage gated calcium channels play a role in the sensitized state of nociceptive sensory neurons that are in response to hyperglycemia. Unfortunately, there has been a lack of pharmacologic therapy that specifically target these channels. Moreover, current treatments for diabetic neuropathy have also been limited due to their significant adverse effects and potential for abuse. This study hopes to better understand the underlying mechanism for the calcium channel activity and to develop specific pharmacologic therapy for peripheral diabetic neuropathy.

Tests were done on leptin deficient, obese mouse models. Researchers hypothesized that exposure to specific types of enzymes would alter the currents of these T-type calcium channels. They then exposed the mice to two types of enzymes that deglycoslyates proteins. The experiment showed that exposure to these two enzymes, when used in combination, slowed the current activation in the channels, thereby desensitizing them to a certain extent and pulling it out of a hyperexcitable state. These results strongly suggest that manipulating the glycosylation states of the calcium channels can relieve them from their hyperexcitable state that they are in during conditions of hyperglycemia. By relieving them from their hyperexcitable state, pain can then be reduced and theoretically eliminated.

In conclusion, there is evidence from this study that shows that developing drugs that can target and manipulate the glycosylation state of the calcium T-channels may show promise in how we treat painful diabetic neuropathy. If successful, treatments for diabetic neuropathy can be achieved without causing significant adverse effects and creating the potential for drug abuse that current drug therapy cause.

Practice Pearls:
  • Current treatment for painful diabetic neuropathy has been restricted due to drugs that are nonspecific for diabetic neuropathy, have significant adverse effects, and a potential for abuse
  • The manipulation of glycosylation states of these nociceptors may be key in developing effective therapies for diabetic neuropathy. 

Diabetes/Metabolism Research & Reviews 2014; Orestes, P. et al. "Reversal of Neuropathic Pain in Diabetes by Targeting Glycosylation of Cav3.2 T-Type Calcium Channels." Diabetes. 2013; 62(11):3828-3838