Trends in Pharmacological Sciences
OpinionThe emerging role of TRPV1 in diabetes and obesity
Introduction
In the USA, the prevalence of diabetes has reached epidemic proportions. Almost 21 million Americans (7% of the population) have diabetes and the prevalence of type 2 diabetes mellitus (T2DM) exceeds 20% in the elderly – National Institute of Diabetes and Digestive and Kidney Diseases (www.diabetes.niddk.nih.gov/dm). Furthermore, an estimated 65% of US adults are overweight or obese – Centers for Disease Control and Prevention (www.cdc.gov/nchs/products/pubs/pubd/hestats/obese). It has been suggested that this rampant obesity bears at least partial responsibility for the rapidly increasing prevalence of T2DM as well as of heart disease and possibly cancer. The combined cost of obesity and diabetes is staggering. In 2002, the US spent an estimated $130 billion on diabetes- and obesity-linked illnesses, accounting for 7% of the $1.9 trillion healthcare expenditure – Centers for Disease Control (www.cdc.gov/nccdphp/dnpa/obesity/economic_consequences.htm); USA Today (www.usatoday.com/news/health/2005-06-26-health-spending-obesity.htm).
Type 1 diabetes mellitus (T1DM) is an autoimmune disease that results from T-cell-mediated destruction of insulin-secreting pancreatic islet β cells [1]. The non-obese diabetic (NOD) mouse is an attractive model for studying the human disease because it shares many of its salient features, including spontaneous onset and expression of disease-susceptible major histocompatibility complex (MHC) molecules [2]. The primary function of MHC class II molecules is to present peptide antigens to CD4+ T cells. Human and NOD MHC class II molecules share many genetic, structural and functional properties 2, 3, 4, 5, 6, 7. The cascade of pathogenic events (diabetogenesis) is initiated when autoreactive T cells that recognize islet β-cell antigens are activated in the lymph nodes draining the pancreas 8, 9, 10. Next the pancreatic islets are infiltrated by various leukocyte subsets, ultimately resulting in the apoptotic death of β cells. A crucial role for soluble mediators, including proinflammatory cytokines and chemokines, has been noted in maintaining islet inflammation and β-cell death [11]. More recently, an important protective role for CD4+ regulatory T cells in controlling islet autoimmunity has also been described, although the underlying molecular details are yet to be delineated [12].
By contrast, T2DM is a consequence of ‘insulin resistance’ (cells do not respond to insulin properly even if it is present at normal levels) and is closely associated with obesity and a sedentary lifestyle (Table 1). Biochemical markers of low-grade inflammation (e.g. C-reactive protein, CRP) are persistently high in T2DM patients 13, 14, implying that T2DM might be (at least in part) an inflammatory disorder. This explanation is relatively simple, yet frustratingly incomplete, and, despite extensive research, the management of diabetes still relies on life-long insulin replacement and/or the use of oral hypoglycemic agents. The medical treatment of obesity is even less satisfactory. Recently, two commonly prescribed diabetes drugs (pioglitazone and rosiglitazone) were implicated in the exacerbation of congestive heart failure [15], clearly indicating the need for novel therapeutic approaches.
Here, we review the emerging experimental evidence that the capsaicin receptor transient receptor potential vanilloid subfamily member 1 (TRPV1, see Table 2) could be an attractive new target for both weight control 16, 17 and diabetes 18, 19. TRPV1 is a nonselective cation channel with a preference for calcium and it is directly activated by capsaicin and high temperature (>43°C) [20]. TRPV1 is highly expressed on primary sensory neurons where it functions as a polymodal nociceptor [20]. Of note, TRPV1 is also present in brain nuclei and non-neuronal tissues: the biological role of these receptors is yet to be determined [20]. Consistent with its role in nociception, TRPV1 exhibits a dynamic threshold of activation that could be lowered under inflammatory conditions by agents that range from mild acidification, through lipoxygenase products, bradykinin and nerve growth factor, to endovanilloids (endogenous TRPV1 agonists) 20, 21. In other words, TRPV1 acts as a molecular integrator of painful stimuli [21]. Indeed, TRPV1-homozygous-null mice (knockouts) are devoid of the thermal hypersensitivity that occurs in response to the administration of proinflammatory agents 22, 23. These findings identify TRPV1 blockers as a novel therapeutic intervention for pain relief. At present, two alternative, but not mutually exclusive, strategies are pursued to prevent TRPV1 activation: one is the use of TRPV1 agonists such as capsaicin to desensitize TRPV1-expressing sensory nerves [24], and the other is the administration of TRPV1 antagonists for receptor blockade [20]. In fact, capsaicin-containing preparations have been in clinical use for decades. Potent and selective small molecule TRPV1 antagonists are currently undergoing phase II clinical trials 20, 25. Capsaicin desensitization is, per definition, reversible [26]. High-dose capsaicin can, however, destroy TRPV1-positive neurons, especially when given to newborn animals [27]. This protocol is used to delineate the contribution of TRPV1-expressing nerves to various biological functions.
As to the role of TRPV1 in T1DM, in a much simplified way it was suggested that a faulty control circuit between insulin-producing islet cells and their associated TRPV1-expressing sensory nerves renders the islet cells vulnerable to attacks by the immune system [19]. If this does occur, ablation of these nerves in the pancreas might halt islet-cell destruction and resultant T1DM. Furthermore, a pharmacological blockade by TRPV1 antagonists might increase satiety and improve glucose control in obese T2DM patients. Because TRPV1 antagonists are already undergoing phase II clinical trials for chronic pain caused by diabetic neuropathy [20], a beneficial effect on weight and glucose control would make them even more attractive drugs in clinical practice. Indeed, TRPV1 ligands, both agonists – Free Patents Online (http://www.freepatentsonline.com/20060292254.html) – and antagonists – World Intellectual Property Organization (www.wipo.int/pctdb/en/wo.jsp?wo=2006007851), have already been patented for treating obesity and related disorders. In short, we propose that TRPV1 is a promising new target for therapeutic interventions in both diabetes and obesity.
Section snippets
A possible role for TRPV1 in autoimmune diabetes: is T1DM a nerve defect?
Recent data obtained in NOD mice revealed the close interplay between components of the peripheral nervous system (PNS) and endocrine autoimmunity against the islet β cells [19]. Candidate diabetogenic autoantigens have been shown to be present on neuronal cells in addition to islet β cells; for example, earlier work in the NOD mouse and in human patients identified glutamic acid decarboxylase (GAD), a neuronal enzyme, as a target of autoreactive T and B cells 28, 29. This contribution of
TRPV1, obesity and T2DM: are obesity and T2DM inflammatory disorders?
Given the high prevalence of obesity and T2DM, surprisingly little is known about the etiology of these apparently related diseases. Low-grade inflammation appears to precede the onset of T2DM and is believed to play a role in the development of insulin resistance 13, 14. Markers of low-grade inflammation (e.g CRP) are persistently high in T2DM patients 13, 14. Peroxisome proliferator activated receptor γ (PPARγ) agonist drugs used in the medical management of T2DM patients (e.g. rosiglitazone
Role of TRPV1 in immune cell functions
As discussed above, ablation of TRPV1 stops insulitis and the resultant β-cell destruction in NOD mice despite the persistence of pathogenic T cells 18, 19. Indeed, autoimmune infiltration is progressing elsewhere in the capsaicin-treated animals [18]. It is puzzling that the protective capsaicin action is specific to the pancreas in the NOD mouse, although other organs are also innervated by TRPV1-positive nerves. Regardless of the underlying mechanism, it could be concluded that TRPV1
Conclusions and future research directions
The discovery that removal of TRPV1-expressing nerves abrogates autoimmune T-cell infiltration into the Langerhans islets of mice genetically prone to develop autoimmune diabetes (NOD) opens a totally new avenue for diabetes treatment and gives a glimmer of real hope that T1DM can not only be treated but also cured 18, 19. Importantly, as also reported by Dosch's laboratory – Banting and Best Diabetes Centre (www.bbdc.org/research/highlights2005.htm) – the beneficial action of TRPV1 blockade is
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