The vanilloid capsaicin has long been known to desensitize pain pathways leading to long-term analgesia through selectively binding to small unmyelinated sensory afferent nerves. However the pungency and systemic toxicity of capsaicin has largely precluded its therapeutic utility. Recent data published by Dorte X. Gram from Novo Nordisk A/S are now emerging to suggest that sensory afferents might also be implicated in the development of glucose intolerance. The present study reports that sensory nerve desensitization by resiniferatoxin, a capsaicin analogue with reduced relative pungency compared to capsaicin is able to improve glucose tolerance, increase glucose-induced insulin release and inhibit DPPIV (dipeptidyl peptidase IV) activity. Hence, either resiniferatoxin, its synthetic analogues or other compounds that can downregulate sensory nerve activity could offer a novel approach to metabolic control as well as neuropathic pain that develops in response to prolonged metabolic imbalance.

The vanilloid, capsaicin has long been known to acutely stimulate pain pathways through the release of a variety of sensory afferent neurotransmitters. High doses of capsaicin or resiniferatoxin induces a desensitized state in which nerve endings are unresponsive to stimuli and neurotransmitters are not released.

The present study has investigated the desensitized state in diabetic rats. Since desensitization involves a general downregulation of sensory nerve activity, many components (eg the tachykinins, CGRP etc) of the nerves could be speculated to be affected and thus co-responsible for the metabolic improvements reported.

It is estimated that there are more than 38 million people in the seven major markets with diabetes and this figure is set to rise to 50 million in 2012 (for an in depth evaluation of the diabetes market size and value, plus an analysis of emerging therapeutics see our recent feature Non-insulin Antidiabetics - Three New Classes Compete for Market Control). Most individuals with diabetes have type 2 diabetes, a condition that is strongly related to the development of obesity. Indeed a recent report suggests that a body mass index (BMI) in excess of 30 increases the risk of developing diabetes 10-fold; this rises to 80-fold with a BMI of over 35 compared to 22. Despite this well established correlation the mechanism of the deterioration of glucose metabolism in obese subjects developing type 2 diabetes has not been established. Although it is probably multifactorial, two earlier abstracts describing studies conducted by Dorte Gram et al suggest involvement of the sensory nerves, since capsaicin desensitization improves glucose tolerance and the glucose stimulated insulin response in the Zucker Diabetic Fatty rat, which is a spontaneous model of type 2 diabetes.

Therapeutic regulation of sensory nerve activity has involved the use of desensitizing agonists; most commonly capsaicin. Such ligands produce continuous stimulation of the receptor followed by a prolonged period of desensitization. Unfortunately the transient pain that accompanies stimulation as well as its systemic toxicity has limited therapeutic use of capsaicin to topical application, for example cream for the treatment of arthritis pain. To overcome this limitation researchers have sought to develop molecules that can produce desensitization with reduced pungency such as resiniferatoxin and analogues thereof.

Resiniferatoxin is a natural compound found in the Mexican hat cactus. With a considerably improved pungency:desensitization ratio resiniferatoxin and its synthetic analogues have greater potential than capsaicin as therapeutic agents. In the present EJP study, Dorte X. Gram from Novo Nordisk A/S, Denmark and colleagues evaluate the effect of resiniferatoxin in Zucker Diabetic Fatty rats.

Gram et al report that a single subcutaneous administration of resiniferatoxin produces a prolonged improvement in the glucose tolerance of Zucker Diabetic Fatty rats, with efficacy demonstrated for up to 7 weeks. Resiniferatoxin was also found to increase glucose stimulation of insulin release from islet cells resulting in increased plasma insulin levels following glucose loading.

A wave of non-insulin antidiabetic drugs are currently in development (see Non-insulin Antidiabetics - Three New Classes Compete for Market Control) and one of the most exciting new classes of agents includes a number of glucagon like peptide-1 (GLP-1) agonists. The naturally occurring incretin hormone, GLP-1 stimulates the body’s ability to produce insulin in response to elevated levels of blood glucose, inhibits the release of glucagon following meals and slows the rate at which nutrients are absorbed into the bloodstream. In animal studies administration of GLP-1 agonists resulted in preservation and formation of new beta cells which fail as type 2 diabetes progresses. This class aims to address two of the main unmet needs in diabetes treatment, prolonged efficacy and the potential to act on the underlying cause of the disease rather than on its symptoms. As an alternative to GLP-1 analogs, companies are also developing inhibitors of the enzyme DPPIV which is responsible for the metabolism of GLP-1.

One of the key findings of the present study is that resiniferatoxin is associated with a reduction in plasma DPPIV activity. This did not correspond to an increase in plasma levels of GLP-1 and could reflect the broad substrate specificity of DPPIV or that the underlying mechanism is not reflected in changes in the plasma concentration of GLP-1. A recent study has demonstrated that the insulin response to GIP, PACAP38, and GRP are all increased following DPPIV inhibition (Ahren & Hughes, 2005) and one or more of these hormones, rather than GLP-1 may mediate the insulinotrophic effect of resiniferatoxin.

The current study therefore clearly demonstrates that downregulation of sensory nerve activity has the potential to improve metabolic parameters in diabetes associated with obesity. Therefore, compounds that might specifically target the sensory nerves might prove beneficial as novel anti-diabetics. Of further interest, one of the results of chronic metabolic imbalance is the development of diabetic neuropathy. Nearly half of the 18 million Americans with diabetes will develop some form of diabetic neuropathy over the course of their disease and about one in six diabetes patients will experience painful diabetic neuropathy (see Diabetic Neuropathic Pain - Market Success is Not Limited to Pregabalin). Up until recently there have been no drugs specifically approved for diabetic pain however over the past year both European authorities and the FDA have approved Lyrica (pregabalin) for the treatment of this condition. In addition to Lyrica, topical capsaicin has been shown to be effective for reducing pain in patients with painful diabetic neuropathy. On the basis of these data resiniferatoxin or its analogues could therefore offer a dual advantage of improving glucose homeostasis and decreasing neuropathic pain in diabetes.

Entry date Thursday, May 19, 2005

Eur J Pharmacol. 2005 Feb 21;509(2-3):211-7.