Experimental evidence for the use of CCR2 antagonists in the treatment of type 2 diabetes

Sullivan, Timothy J.; Miao, Zhenhua; Zhao, Bin; Ertl, Linda; Wang, Yu; Krasinski, Antoni; Walters, Matthew J.; Powers, Jay P.; Dairaghi, Daniel J.; Baumgart, Trageen; Seitz, Lisa; Berahovich, Robert; Schall, Thomas J.; Jaén, Juan C.

doi:10.1016/j.metabol.2013.06.008

Cited by 48 publications

(40 citation statements)

References 42 publications

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“…69,70) but only few have been tested for activity against obesity-induced inflammation in vivo . 29,52,68,71,72,73 A phase 2 clinical trial has indicated beneficial effects of the CCR2 antagonist CCX140-B on glycemic parameters in human subjects. 71 It is, however, well acknowledged that suboptimal pharmacokinetics/pharmacodynamics, low AT penetrance, and toxicity are significant problems associated with the use of pharmacological inhibitors as intervention for AT inflammation.…”

Section: Discussionmentioning

confidence: 99%

Silencing CCR2 in Macrophages Alleviates Adipose Tissue Inflammation and the Associated Metabolic Syndrome in Dietary Obese Mice

Kim

Chung

Choi

et al. 2016

Molecular Therapy - Nucleic Acids

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Adipose tissue macrophage (ATM)-mediated inflammation is a key feature contributing to the adverse metabolic outcomes of dietary obesity. Recruitment of macrophages to obese adipose tissues (AT) can occur through the engagement of CCR2, the receptor for MCP-1 (monocyte chemoattractant protein-1), which is expressed on peripheral monocytes/macrophages. Here, we show that i.p. administration of a rabies virus glycoprotein-derived acetylcholine receptor-binding peptide effectively delivers complexed siRNA into peritoneal macrophages and ATMs in a mouse model of high-fat diet-induced obesity. Treatment with siRNA against CCR2 inhibited macrophage infiltration and accumulation in AT and, therefore, proinflammatory cytokines produced by macrophages. Consequently, the treatment significantly improved glucose tolerance and insulin sensitivity profiles, and also alleviated the associated symptoms of hepatic steatosis and reduced hepatic triglyceride production. These results demonstrate that disruption of macrophage chemotaxis to the AT through cell-targeted gene knockdown strategies can provide a therapeutic intervention for obesity-related metabolic diseases. The study also highlights a siRNA delivery approach for targeting specific monocyte subsets that contribute to obesity-associated inflammation without affecting the function of other tissue-resident macrophages that are essential for host homeostasis and survival.

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Section: Discussionmentioning

confidence: 99%

Silencing CCR2 in Macrophages Alleviates Adipose Tissue Inflammation and the Associated Metabolic Syndrome in Dietary Obese Mice

Kim

Chung

Choi

et al. 2016

Molecular Therapy - Nucleic Acids

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“…The CCR2 antagonist CCX140-B in mice reduces adipose tissue macrophage content and improves insulin sensitivity 223,224 . Clinical trials of CCX140-B demonstrated improved fasting glucose and a modest decrease in hemoglobin A1c of 0.14% 225 .…”

Section: Therapeutic Implications Of Macrophage Biologymentioning

confidence: 99%

Macrophage functions in lean and obese adipose tissue

2017

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Summary Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes.

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“…Pharmacological inhibition of CCR2 in animal models of T2DM can reduce inflammation in adipose tissue, alter hepatic metabolism and ameliorate multiple diabetic parameters [177]. In diabetic transgenic human CCR2 knock-in mice, the CCR2 antagonist CCX140-B resulted in decreased levels of FPG and fasting insulin, normalization of HOMA-IR values, and decreased numbers of adipose tissue inflammatory macrophages [178].…”

Section: Approaches Using Mammalian Target Of Rapamycin Inhibitorsmentioning

confidence: 99%

Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease

Esser

Paquot

Scheen

2014

Expert Opinion on Investigational Drugs

222

150

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The available data supports the concept that targeting inflammation improves insulin sensitivity and β-cell function; it also ameliorates glucose control in insulin-resistant patients with inflammatory rheumatoid diseases as well in patients with metabolic syndrome or T2DM. Although promising, the observed metabolic effects remain rather modest in most clinical trials. The potential use of combined anti-inflammatory agents targeting both insulin resistance and insulin secretion appears appealing but remains unexplored. Large-scale prospective clinical trials are underway to investigate the safety and efficacy of different anti-inflammatory drugs. Further evidence is needed to support the concept that targeting inflammation pathways may represent a valuable option to tackle the cardiometabolic complications of obesity.

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Experimental evidence for the use of CCR2 antagonists in the treatment of type 2 diabetes

Cited by 48 publications

References 42 publications

Silencing CCR2 in Macrophages Alleviates Adipose Tissue Inflammation and the Associated Metabolic Syndrome in Dietary Obese Mice

Silencing CCR2 in Macrophages Alleviates Adipose Tissue Inflammation and the Associated Metabolic Syndrome in Dietary Obese Mice

Macrophage functions in lean and obese adipose tissue

Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease

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