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TRPV1: a Potential Opinion TRPV1: A Potential Therapeutic Target in Type 2 Diabetes and Comorbidities? 1, 2 3 Dorte X. Gram, * Jens J. Holst, and Arpad Szallasi With an estimated 422 million affected patients worldwide in 2016, type 2 Trends diabetes (T2D) has reached pandemic proportions and represents a major T2D is being increasingly recognized as unmet medical need. T2D is a polygenic disease with a chronic, low-grade a disease with a chronic, low-grade inflammatory component; in preclinical inflammatory component. Second-generation transient receptor potential models, elimination of this inflammatory vanilloid-1 (TRPV1) antagonists are potent anti-inflammatory agents with proven response improves glucose homeosta- clinical safety. In rodent models of T2D, TRPV1 blockade was shown to halt sis and halts disease progression. disease progression and improve glucose metabolism. Thus, we propose that T2D is a heterogeneous disease, so a TRPV1 antagonists merit further study as novel therapeutic approaches to ‘one-size-fits-all’ approach in drug potentially treat T2D and its comorbidities. development may not be feasible (elicits the need for personalized medicine). Novel antidiabetic agents that not only The Human and Monetary Cost of Type 2 Diabetes: A Need for Novel return blood glucose to near normal Therapeutic Interventions levels but also treat comorbidities such Globally, the estimated number of diabetic patients has increased from 108 million in 1980 to as obesity and hyperlipidemia at the i same time are needed. 422 million in 2016 and the disease has thus reached pandemic proportions . We posit that TRPV1 antagonists may In the United States, the prevalence of Type 2 diabetes (T2D, see Glossary and Box 1) is also serve as putative antidiabetic agents to on the rise, following the global trend. It is estimated that one in three adults have prediabetes treat T2D; current clinical trials are ii investigating this possibility. and the number of Americans with T2D in 2015 exceeded 30 million . Moreover, the number of diabetic children is also rapidly growing due to an increasing number of overweight youths [1]. The cost of this increase and the prevalence of diabetes have the potential to be crippling; in 2012, Americans had spent over US$100 billion on diagnosis and medications, and another US $145 billion on the treatment of diabetic complications [2]. T2D is typified by insulin resistance in the skeletal muscle and liver combined with progressive pancreatic b-cell failure [3]. Among T2D comorbidities, cardiovascular disease in particular is a leading cause of disability and premature death [4]. Unfortunately, current therapeutic strategies to manage hyperglycemia [5] do not halt (or reverse) disease progression and may even cause undesirable adverse effects and comorbidities on their own. For example, treatment with insulin, sulfonylureas, and glinides may lead to weight gain [6], whereas thiazolidinediones have been associated with bone fractures [7] and an increased risk for congestive heart failure [8]. In addition, antidiabetic agents currently in existence (such as iii 1 fi metformin and sulfonylureas) might lose ef cacy over time, usually within 4 years . Indeed, Pila Pharma, Malmö, Sweden 2 Panum Institute, University of according to the European Medicines Agency, approximately half of T2D patients might need a iii Copenhagen, Copenhagen, Denmark new drug to maintain adequate glucose control . This necessitates the development of new 3 Baptist Medical Center, Jacksonville, therapeutic antidiabetic agents (Box 1). FL, USA There is increasing recognition among both clinicians and researchers that T2D has a low- *Correspondence: grade inflammatory component. T2D is also heterogenous, so a ‘one-size-fits-all’ approach in [email protected] (D.X. Gram). 1002 Trends in Molecular Medicine, November 2017, Vol. 23, No. 11 http://dx.doi.org/10.1016/j.molmed.2017.09.005 © 2017 Elsevier Ltd. All rights reserved. Box 1. Type 2 Diabetes (T2D): The Facts Glossary Globally, more than 422 million people are already affected and the number of T2D patients is still on the rise to reach i Adiponectin: a protein secreted by pandemic proportions . Only half of the patients who have the disease are actually diagnosed with it; it is diagnosed adipocytes. The gene encoding when fasting and postprandial blood glucose levels are found to be elevated. adiponectin ADIPOQ localizes to T2D is a result of impaired insulin secretion and insulin resistance and is associated with obesity and cardiovascular chromosome 3q27, a locus linked to disease. genetic susceptibility to obesity and At an early stage, lifestyle changes (healthy diet and more exercise) can revert blood glucose levels to normal. If T2D in humans. In mouse models, lifestyle changes do not normalize blood glucose, an oral antidiabetic agent (usually metformin) is prescribed. If adiponectin supplementation can metformin alone is not sufficient, two to three other oral antidiabetic agents are added. If oral antidiabetic agents do improve blood glucose control. In not return blood glucose to near normal levels, an injectable antidiabetic agent (GLP-1 or insulin) is prescribed. iii humans, low adiponectin levels Many T2D patients require a new antidiabetic agent every 3–4 years to maintain adequate blood glucose control . herald the development of insulin- No ideal antidiabetic agent exists (with convenient delivery, good efficacy, no side effects, and low cost). New resistant T2D. antidiabetic agents should reduce blood glucose to near normal levels, reduce blood lipids and body weight, and B2 cells: subclass of lymphocytes thereby reduce the risk of cardiovascular disease. involved in adaptive immunity. They Potential new antidiabetic agents may be second-generation TRPV1 antagonists (that do not cause a febrile reaction differ from B1 cells in their or compromise noxious heat sensation) – they are well tolerated, can be delivered as tablets, may be produced at low immunoglobulin (Ig) class switch (B1 cost, and – if efficacious in regulating glycemia – may provide additional efficacy (body weight, inflammation, pain, cells preferentially produce IgM, etc.). whereas B2 cells secrete IgG). Obese adipose tissue can recruit B2 cells, known as ATB2 cells to drug development does not seem feasible. Here, we present evidence that transient receptor promote insulin resistance. potential vanilloid-1 (TRPV1)-expressing sensory neurons may play a pivotal role in initiating and Calcitonin gene-related peptide (CGRP): neuropeptide with potent maintaining the inflammatory component of T2D in preclinical models. We argue that such vasodilator and proinflammatory TRPV1-mediated inflammationcouldalsoberelevantforT2Dpatients.Ifthishypothesisholdstrue, actions. A main source of CGRP is a subset of T2D patients might potentially benefit from treatment using TRPV1 antagonists. the capsaicin-sensitive neuron. CGRP has been implicated in the pathogenesis of migraine, A Brief Introduction to TRPV1-Positive Sensory Neurons hypertension, and T2D. In mammals, including humans, a specific subset of peptidergic sensory neurons is Capsaicin: pungent principle in hot distinguished by their unique sensitivity to capsaicin, the pungent component in hot peppers chili peppers. A subdivision of [9]. Capsaicin and its ultrapotent analog, resiniferatoxin, are collectively termed vanilloids [9]. sensory neurons is distinguished by its unique sensitivity to capsaicin. The vanilloid (capsaicin) receptor in these neurons was identified as TRPV1 [10]. TRPV1 is Acutely, capsaicin causes pain and highly expressed on capsaicin-sensitive sensory neurons [9]. It is also present, albeit at much triggers neurogenic inflammation. fl lower levels, in rodent and human brain nuclei [11], as well as in rodent in ammatory cells Chronically, capsaicin ‘silences’ (including macrophages and T lymphocytes) [12] and skeletal muscle [13]. Sensory nerves that neurons. Capsaicin desensitization: express TRPV1 innervate all organs including the pancreas [14,15] and adipose tissue [16]. Of capsaicin is unique among naturally note, TRPV1 expression has also been reported in rat pancreatic b cells [17] and rat and human occurring irritant compounds in that adipocytes [18]. However, the physiological role, if any, of the non-neuronal TRPV1 receptor in the initial irritation it causes is adipocytes and pancreatic b cells remains unknown. Nevertheless, the endings of TRPV1- followed by a long-lasting (up to several weeks) refractory state expressing nerves have been identified as sites of release of the neuropeptides substance P (referred to as desensitization) in (SP) and calcitonin gene-related peptide (CGRP), both of which are known to initiate the which the previously activated fl biochemical cascade referred to as neurogenic in ammation in both experimental animals sensory neuron remains unresponsive to various unrelated and humans [9]. chemicals and physical stimuli. Desensitization to capsaicin is in Probing the role of TRPV1-expressing sensory neurons has largely relied on approaches that clinical use as a form of pain relief. render relevant cells quiescent – either transiently or permanently. The initial excitation of Cardiovascular disease (CVD): includes various complications (such TRPV1-positive neurons by capsaicin (or resiniferatoxin) is followed by a long-lasting refractory as stroke and heart attack), many of state, traditionally referred to as capsaicin desensitization, in which the neuron is unrespon- which are related to atherosclerosis. sive not only to repeated
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