Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk

Goldfine, Allison B.; Shoelson, Steven E.

doi:10.1172/jci88884

Cited by 143 publications

(112 citation statements)

References 216 publications

(235 reference statements)

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“…Due to the mounting evidence supporting the roles of these pathways in obesity and related conditions, therapeutics targeting inflammation have begun to be tested in clinical trials. Allison Goldfine and Steven Shoelson review the clinical data supporting the link between inflammation and obesity and report on the outcomes of clinical trials of therapeutic strategies targeting inflammation (40).…”

Section: Discussionmentioning

confidence: 99%

Inflammatory mechanisms linking obesity and metabolic disease

Saltiel¹,

Olefsky²

2017

Journal of Clinical Investigation

1,542

1,077

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We are in the midst of a worldwide obesity epidemic. Over 1.9 billion people are now obese or overweight, including more than 50 million children under age 5, and the worldwide prevalence of obesity has doubled since 1980 (1). The complications of obesity are taking a major public health toll, which will only worsen in future years. Among the most devastating of these complications is type 2 diabetes (T2D). Most patients with T2D are obese or overweight, and there are numerous longitudinal studies linking obesity with insulin resistance, a frequent forerunner of diabetes.Over the past two decades, the search for a mechanism linking the pathogenesis of obesity with insulin resistance and diabetes has revealed a close relationship between nutrient excess and activation of the innate immune system in most organs pertinent to energy homeostasis (2-4). Numerous studies indicate that inflammation occurs as a consequence of obesity, and recent insights suggest that it may play a causative role in generating insulin resistance, defective insulin secretion, and disruption of other aspects of energy homeostasis. The nature of obesityinduced inflammation differs from other inflammatory paradigms in that it involves tonic activation of the innate immune system that impacts metabolic homeostasis, in some cases over a lifetime. Inflammation also leads to maladaptive responses such as fibrosis and necrosis that can cause significant tissue damage. Moreover, obesity-induced inflammation is unique in that it involves multiple organs, including adipose, pancreas, liver, skeletal muscle, heart, and brain. These features of obesity-induced inflammation present a challenge to understanding the underlying mechanisms and the manner by which they impact metabolic systems. In this issue of the JCI, a group of experts have provided reviews that dive deeply into the mechanisms by which obesity-induced inflammation influences metabolic homeostasis, surveying the modes and mechanisms of inflammation in different tissues and how they might contribute to disease. These Reviews also discuss how inflammation can lead to other aspects of metabolic syndrome, including hyperphagia, reduced energy expenditure, β cell dysfunction, and liver disease, and summarize the status of therapeutic interventions that target inflammation in the context of metabolic syndrome. Activation of the innate immune system in obesityMuch of what has been learned about the immune response to obesity has come from studies in adipose tissue, although it is clear that inflammation occurs in other organs as well. Adipose depots normally contain multiple immune cells that together surveil and maintain the integrity and hormonal sensitivity of adipocytes. In lean animals, these immune cells operate in an overall Th2 or type 2 state that coordinately controls tissue integrity and metabolism by controlling the activity of subsets of T lymphocytes. These cells release a cascade of cytokines that coordinately regulate other immune cells, including eosinophils, mast cells, and othe...

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Section: Discussionmentioning

confidence: 99%

Inflammatory mechanisms linking obesity and metabolic disease

Saltiel¹,

Olefsky²

2017

Journal of Clinical Investigation

1,542

1,077

View full text Add to dashboard Cite

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“…The collective evidence suggests that chronic inflammation is a risk factor across multiple diseases, some of which are traditionally viewed as pathophysiologically unrelated, such as CVD 157,159,160,220 , diabetes 138,180,221 , chronic kidney disease 11,142,209 , cancer 211,212,222 , depression 13,143,217 , and dementia 12,139,223 . In addition, higher levels of inflammatory markers in blood are associated with a greater loss of muscle mass and strength, accelerated loss of mobility, lower-extremity performance and physical activity, and depression in older individuals 224–228 , all of which are essential elements for defining frailty on the basis of the criteria most often used in the literature 229 .…”

Section: Inflammation and Age-related Frailtymentioning

confidence: 99%

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

2018

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Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty — which affect clinical manifestations, prognosis, and response to treatment — and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.

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“…Although anti-inflammatory agents show some beneficial outcomes in animal studies and clinical trials [4,5,20]. Systemic antiinflammatory therapies are not ideal since inflammatory response is rather critical for host defense.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, antiinflammatory scheme becomes as new treatments for metabolic disorders [4]. Although many preclinical studies support this opinor, results generated from clinical trials are quite controversial and still ongoing [5,6].…”

Section: Introductionmentioning

confidence: 99%