Why do anti-inflammatory therapies fail to improve insulin sensitivity?

ABSTRACT Chronic inflammation occurs in obese conditions in both humans and animals. It also contributes to the pathogenesis of type 2 diabetes (T2D) through insulin resistance, a status in

which the body loses its ability to respond to insulin. Inflammation impairs insulin signaling through the functional inhibition of IRS-1 and PPARγ. Insulin sensitizers (such as

rosiglitazone and pioglitazone) inhibit inflammation while improving insulin sensitivity. Therefore, anti-inflammatory agents have been suggested as a treatment strategy for insulin

resistance. This strategy has been tested in laboratory studies and clinical trials for more than 10 years; however, no significant progress has been made in any of the model systems. This

status has led us to re-evaluate the biological significance of chronic inflammation in obesity. Recent studies have consistently asserted that obesity-associated inflammation helps to

maintain insulin sensitivity. Inflammation stimulates local adipose tissue remodeling and promotes systemic energy expenditure. We propose that these beneficial activities of inflammation

provide an underlying mechanism for the failure of anti-inflammatory therapy in the treatment of insulin resistance. Current literature will be reviewed in this article to present evidence

that supports this viewpoint. SIMILAR CONTENT BEING VIEWED BY OTHERS INFLAMMATION AND RESOLUTION IN OBESITY Article 24 October 2024 INFLAMMATION CAUSES INSULIN RESISTANCE IN MICE VIA

INTERFERON REGULATORY FACTOR 3 (IRF3)-MEDIATED REDUCTION IN FAHFA LEVELS Article Open access 30 May 2024 TRENDS IN INSULIN RESISTANCE: INSIGHTS INTO MECHANISMS AND THERAPEUTIC STRATEGY

Article Open access 06 July 2022 INTRODUCTION For about two decades, it has been known that inflammation contributes to obesity-associated insulin resistance. Inflammatory cytokines (_eg_,

TNF-alpha, IL-1, and IL-6) have been shown to induce insulin resistance in multiple organs (fat, muscle and liver). TNF-α elevation was found in adipose tissue of obese mice in 19931. That

study provided the first evidence of the role of chronic inflammation during obesity and its association with insulin resistance in an animal model. Macrophages in adipose tissue are the

major source of inflammatory cytokines in obesity2, 3. Recent studies from multiple groups, including ours, consistently suggest that adipose tissue hypoxia is a root of chronic inflammation

in obesity4. Hypoxia is likely the result of a reduction in blood flow to adipose tissue, which is supported by some studies in humans and animals5, 6, 7. In addition to adipose tissue

hypoxia, metabolites of fatty acids and glucose, including diacylglyceride (DAG), ceramide, and reactive oxygen species, also contribute to the chronic inflammation in obesity. They activate

the inflammatory response in several ways. They can directly interact with signaling kinases (PKCs, JNKs, and IKKs) in cells8; the lipids can also signal through cell membrane receptors for

lipids, such as TLR4, CD36, or GPR8, 9, 10, 11, 12, 13. Fat or glucose oxygenation in the mitochondria can also generate reactive oxygen species (ROS), which can then induce activation of

the inflammatory kinases (JNK and IKK) in the cytoplasm. The lipids also induce endoplasmic reticulum (ER) stress to activate JNK and IKK14, 15. In obesity, these signaling pathways are

activated as a result of the surplus calories and involved in the pathogenesis of chronic inflammation. CHRONIC INFLAMMATION AND INSULIN RESISTANCE At the molecular level, inflammation

induces insulin resistance by targeting IRS-1 and PPARγ. INFLAMMATION AND IRS-1 (INSULIN RECEPTOR SUBSTRATE 1) In cellular models of insulin resistance, the pro-inflammatory cytokine, TNF-α,

is widely used to induce insulin resistance. The data from these cellular studies suggest that TNF-α is a major risk factor for insulin resistance in obesity and other chronic diseases1,

16, 17. TNF-α inhibits insulin signaling by serine phosphorylation of IRS-1, which leads to the dissociation of IRS-1 from the insulin receptor and causes degradation of IRS-1 protein17, 18,

19. In the insulin signaling pathway, IRS-1 undergoes tyrosine in response to insulin stimulation, which leads to activation of the insulin signaling pathway, downstream PI3K/Akt

activation, and Glut4 translocation to the cell membrane for glucose uptake. TNF-α induces insulin resistance by IRS-1 serine phosphorylation through the activation of several serine

kinases, including JNK20, 21, IKK22, ERK23, 24, 25, PKC26, 27, 28, Akt28, 29, GSK-330, 31, 32, IRAK33, and mTOR34, 35. In a recent study, we showed that IKK2 (IKKβ) inhibits IRS-1 function

through the activation of S6K, which directly phosphorylates IRS-1 at multiple sites (such as S312/307 and S270/265) in TNF-α-treated cells22, 36. Serine phosphorylation induces IRS-1

degradation and serves as a negative feedback signal to impair insulin action35. INFLAMMATION INHIBITS PPARΓ FUNCTION The IKKβ/NF-κB (nuclear factor kappa B) pathway is a dominant

inflammatory signaling pathway. The pathway has been under active investigation in the obesity field after IKKβ was found to induce insulin resistance in obese mice37. The serine kinase IKK

has three major isoforms, including IKKα (IKK1), IKKβ (IKK2), and IKKγ, which requires IKKβ for NF-κB activation38. In obesity, IKKβ is activated by several intracellular signals, such as

ROS, ER stress, DAG, and ceramide. IKKβ is also activated by extracellular stimuli, including TNF-α, IL-1, fatty acids11 and hypoxia39. IKKβ induces NF-κB activation by phosphorylation of

the Inhibitor of Kappa B alpha (IκBα)40. NF-κB is a ubiquitous transcription factor that is formed by two subunits of the Rel family, which includes seven members, p65 (RelA), p50 (NF-κB1),

c-Rel, RelB, p100, p105, p5241. These members form a homodimer or heterodimer that regulates gene transcription. In most cases, NF-κB is a heterodimer of p65 and p50. P65 contains the

transactivation domain and mediates the transcriptional activity of NF-κB. P50 inhibits the transcriptional activity of p6542, and the NF-κB activity is enhanced in p50 knockout mice43.

NF-κB inhibits PPARγ function through the competition for transcriptional coactivators or the exchange of corepressors with PPARγ44. This process is responsible for inhibiting PPAR-target

genes, such as CAP and IRS-2. Our study shows that IKK promotes the activity of HDAC3 in the nuclear corepressor complex. IKK induces nuclear translocation of HDAC3 from the cytoplasm. In

the cytosol, HDAC3 associates with IκBα, and the degradation of IκBα promotes HDAC3 translocation into the nucleus. The PPARγ inactivation leads to suppression of IRS-2 expression, a

signaling molecule in insulin signaling pathways for Glut4 translocation. FREE FATTY ACIDS AND INSULIN RESISTANCE Elevated plasma free fatty acids (FFAs) induce insulin resistance in obese

and diabetic subjects45. It was known as early as 1983 that lipid infusion caused insulin resistance46, 47. To examine the mechanism by which FFAs induced insulin resistance _in vivo_, rats

were tested in a hyperinsulinemic-euglycemic clamp after a 5-h infusion of lipids/heparin, which raises plasma FFA concentrations47. FFAs resulted in an approximate 35% reduction in insulin

sensitivity, indicated by the glucose infusion rate (_P_<0.05 _vs_ control), and a 25% reduction in glucose transport activity, as assessed by 2-[1,2-3H]deoxyglucose uptake _in vivo_

(_P_<0.05 _vs_ control). PKCθ is a major kinase involved in FFA-induced insulin resistance48. According to the Randle glucose-fatty acid cycle, the preferential oxidation of free fatty

acids over glucose plays a major role in the pathogenesis of insulin sensitivity49. Local accumulation of fat metabolites, such as ceramides, diacylglycerol or acyl-CoA, inside skeletal

muscle and liver may activate a serine kinase cascade, leading to defects in insulin signaling and glucose transport50. INFLAMMATION AND ENERGY METABOLISM Inflammation is associated with

increased energy expenditure in patients with chronic kidney disease51, cachexia52, inflammatory bowel disease53 and Crohn's disease54. NF-κB activity can promote energy expenditure, as

supported by documents on energy expenditure in cachexia55, 56 and infection. However, the role of NF-κB in energy expenditure was not tested in transgenic models. To this end, we have

investigated energy metabolism in transgenic mice with elevated NF-κB activity. The transcriptional activity of NF-κB is enhanced either by over-expression of NF-κB p65 in the fat tissue, or

inactivation of NF-κB p50 by global gene knockout57, 58. In these two models, inflammatory cytokines (TNF-α and IL-6) were elevated in the blood, and energy expenditure was increased both

during the day and at night57, 58. Expression of TNF-α and IL-1 mRNA was increased in adipose tissue and macrophages. These cytokines are positively associated with energy expenditure in the

body56. In transgenic mice with deficiencies in these cytokines or their receptors, energy accumulation is enhanced and energy expenditure is reduced. This positive energy balance has been

reported in transgenic mice deficient in TNF-α59, IL-160, or IL-661. The above literature suggests that energy accumulation induces chronic inflammation. Inflammation may promote energy

expenditure in a feedback manner to counteract an energy surplus62. Inflammation may act in the peripheral organs/tissues, as well as in the central nervous system, to regulate energy

balance. In the peripheral tissues, inflammation induces fat mobilization and oxidation to promote energy expenditure. In the central nervous system, inflammation can inhibit food intake and

activate neurons for energy expenditure, while inhibition of inflammation leads to fat accumulation62. ANTI-INFLAMMATION THERAPIES FOR INSULIN RESISTANCE In clinical trials, high-dose

salicylate was used to inhibit inflammation by targeting IKK/NF-κB37, 63, 64, 65. Salicylate reduces blood glucose by inhibiting IKK/NF-κB, as seen decades ago in patients with diabetes64,

65, 66. More studies demonstrated that high-doses of aspirin (∼7.0 g/d) improved multiple metabolic measures in patients with T2D, including substantial reductions in fasting and

postprandial glucose, triglycerides and FFAs. These changes were associated with reduced hepatic glucose production and improvements in insulin-stimulated glucose disposal, assessed during

hyperinsulinemic-euglycemic clamping63, 64, 65, 67. Aspirin inhibits the activity of multiple kinases induced by TNF-α, such as JNK, IKK, Akt, and mTOR. It may enhance insulin sensitivity by

protecting the IRS proteins from serine phosphorylation68. However, the therapeutic value of high-dose aspirin is limited by its side effects, including gastrointestinal irritation and high

risk of bleeding. Statins, a class of anti-inflammatory drugs, have been shown to downregulate the transcriptional activity of NF-κB, AP-1, and HIF-1α65, 69, with coordinated reductions in

the expression of prothrombotic and inflammatory cytokines. Randomized clinical trials have demonstrated that statins reduces CRP, multiple cytokines, and inflammatory markers in the body.

Even with modest anti-inflammatory properties, statins do not appear to enhance insulin resistance or significantly improve glycemia70. A recent review published in JAMA suggests that statin

therapy is associated with excess risk for diabetes mellitus. The researchers analyzed five earlier trials, involving 32 752 patients, to test the effect of the drug dose. Those getting

intensive treatment were 12 percent more likely to have diabetes71, which translates into a 20 percent increase in developing diabetes in the high-dose statin users compared to those who do

not take the drugs. Glucocorticoids are the most effective anti-inflammatory drugs used to treat inflammatory diseases. Dexamethasone is a potent synthetic member of the glucocorticoid class

of steroid drugs. In a clinical study, the effect of dexamethasone on insulin-stimulated glucose disposal was investigated with a double-blind, placebo-controlled, cross-over trial

comparing insulin sensitivity (measured by the euglycemic hyperinsulinemic clamp) in young healthy males allocated the placebo or 1 mg dexamethasone twice daily for 6 d, each in random

order. Six days of dexamethasone therapy was associated with a 30% decrease in insulin sensitivity72, 73. This indicates that strong inhibition of inflammation may block the beneficial

effects of inflammation on insulin sensitivity. Interleukin-1β induces inflammation in islets of patients with type 2 diabetes74. The interleukin-1–receptor antagonist, a naturally occurring

competitive inhibitor of interleukin-175, protects human beta cells from glucose-induced functional impairment and apoptosis76. The expression of the interleukin-1-receptor antagonist is

reduced in pancreatic islets of patients with type 2 diabetes mellitus. High glucose induces the production of interleukin-1β in human pancreatic beta cells, leading to impaired insulin

secretion, decreased cell proliferation, and enhanced apoptosis. In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes74, 34 patients were randomly assigned

to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks. In the control group, 36 patients received placebo. All patients

underwent an oral glucose-tolerance test. At the end of the study, the two study groups exhibited no difference in insulin resistance, insulin-regulated gene expression in skeletal muscle,

serum adipokine levels, and the body-mass index. However, the therapy did improve blood glucose levels. The authors conclude that the improvement is from enhanced pancreatic β-cell function.

This study indicates that inhibition of IL-1β improves glucose metabolism, independent of insulin sensitivity. TNF-α expression is elevated in the adipose tissue of obese rodents and

humans. In animal studies, administration of exogenous TNF-α induced insulin resistance, whereas neutralization of TNF-α improved insulin sensitivity. TNF-α knockout mice were used to

examine the role of TNF-α in obesity-associated insulin resistance77. The KO mice were compared with WT mice in lean and obese (induced by gold-thioglucose [GTG]-injection) conditions at 13,

19, and 28 weeks of age. In the lean condition, the KO mice exhibited a 14% reduction in body weight at 28 weeks of age. The epididymal fat pad was decreased by 25% in weight, relative to

those of the wild-type littermate controls. Fasting glucose was reduced slightly by 10%, but the glucose response in an oral glucose tolerance test (OGTT) was not affected. In the obese

condition, the body weight was identical between the KO and WT mice. Glucose levels were significantly increased in both groups during the OGTT. This indicates that the absence of TNF-α is

not sufficient to protect mice from insulin resistance in obese conditions77. Some animal studies78 and several clinical trials using TNF antagonism have thus far failed to improve insulin

sensitivity79, 80, 81, 82, 83. These facts suggest that there are many unknowns in the relationship of obesity-associated inflammation and insulin resistance. The role of IL-6 in the

pathogenesis of obesity and insulin resistance is controversial. IL-6 knockout (KO) mice were compared with WT littermate mice in lean or obese conditions. IL-6 KO mice displayed obesity,

hepatosteatosis, liver inflammation and insulin resistance when compared with the lean condition on a standard chow diet84. Overexpression of IL-6 was also used to test insulin resistance in

mice. In the study, IL-6 overexpression was generated in skeletal muscle, and the IL-6 protein levels were increased in the circulation. The mice lost both body weight and body fat in

response to IL-6 in this model, even though their food intake remained unchanged85. These observations suggest that IL-6 increases energy expenditure. In the IL-6 mice, insulin levels were

elevated, and hypoglycemia was observed85. In another study, Sadagurski _et al_ demonstrated that a high level of IL-6 in the circulation reduces obesity and improves metabolic homeostasis

_in vivo_86. The role of the anti-inflammatory cytokine IL-10 has been studied in the pathogenesis of obesity and insulin resistance87. IL-10 is a critical cytokine of M2 (type 2)

macrophages. A recent study has identified the roles of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages in the regulation of insulin sensitivity88. An increase in M2 macrophages

and a decrease in M1 macrophages within the adipose tissue are associated with enhanced insulin sensitivity. In another study, the hematopoietic-cell-restricted deletion of IL-10 in mice

was used to study the relationship between IL-10 and insulin resistance89. The mice were assessed for insulin sensitivity in an insulin tolerance test in lean (chow diet) and obese (high fat

diet) conditions. The results show that deletion of IL-10 from the hematopoietic system does not have an effect on insulin resistance89. Other studies suggest that IL-10 cannot improve

insulin sensitivity in diet-induced obese mice or humans90, 91. NEW POTENTIAL DRUG CANDIDATES FOR INSULIN RESISTANCE The antidiabetic drug thiazolidinedione (TZD) restores insulin action by

activating PPARγ, thus lowering the levels of FFAs in the blood. Activation of PPARγ improves insulin sensitivity in rodents and humans through a combination of metabolic actions, including

partitioning of lipid stores and regulating metabolic and inflammatory mediators, termed adipokines92. However, TZD-based medicines for insulin sensitization have many side effects:

troglitazone (Rezulin) was associated with massive hepatic necrosis; rosiglitazone (Avandia) and muraglitazone, with increased cardiovascular events; and now, pioglitazone has been

associated with bladder cancer93. These adverse events suggest that the thiazolidinedione-based drugs may not be safe in the long-run. It is necessary to discover a new class of drug to

treat insulin resistance. Recent studies indicate that histone deacetylase (HDAC) inhibitors may be a new class of drug candidates for insulin sensitization. HDACs are key enzymes in

regulating gene expression. Protein acetylation is one type of epigenetic regulation of gene expression. Acetylation is controlled by histone acetyltransferases (HATs) and histone

deacetylases (HDACs). Histone acetylation by HATs opens the chromatin structure to activate gene transcription, while histone deacetylases (HDACs) repress gene expression. HDACs are divided

into three classes: class I HDACs (1, 2, 3, 8, 11), class II HDACs (4, 5, 6, 7, 9, 10)94 and class III HDACs (SIRT1-7)95. Inhibition of histone deacetylase activity has been reported as a

new approach to treat diabetes mellitus96, 97, 98. In our study, supplementation of histone deacetylase inhibitors, butyrate or Trichostatin A, prevented high-fat diet-induced obesity and

improved insulin sensitivity in mice. HDAC inhibition promoted energy expenditure, and reduced blood glucose and triglyceride levels in mice98. HDAC inhibits insulin resistance on a

molecular level by the following means: a) reducing the lipid toxicity44, 99, 100, 101, 102; b) reducing chronic systemic inflammation103, 104, 105, 106, 107, 108; c) promoting beta-cell

development, proliferation, differentiation and function97; and d) promoting energy expenditure98, 109. Based on their multiple beneficial effects, HDAC inhibitors may represent a novel drug

in the treatment of insulin resistance. However, clinical trials are needed to test this concept. CONCLUSIONS Type 2 diabetes is one of the major diseases associated with obesity. It is

known that obesity promotes type 2 diabetes through insulin resistance, a state in which bodies lose their responsiveness to insulin. Many studies confirm that inflammation and free fatty

acids (FFAs) are major pathogenic factors for insulin resistance in obese conditions. The most effective therapy for insulin resistance is to reduce both FFA and inflammation. Diminishing

inflammation by anti-inflammatory drugs does not significantly improve insulin sensitivity in animal models or in clinical trials because inflammation is beneficial in regulating energy

metabolism. Inhibiting this beneficial activity is likely to cause the failure of anti-inflammatory drugs in treating insulin resistance. Current literature consistently reports that fatty

acids remain a therapeutic target in the treatment of insulin resistance. As an insulin sensitization-drug, TZD reduces both FFA and inflammation in the body. However, TZDs have many side

effects such as obesity, heart attacks, and bladder cancer. HDAC inhibitors may be a new class of drug for treating insulin resistance by promoting energy expenditure and preventing obesity.

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110: 258–63. CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS This work is partially supported by NIH grants DK068036 and DK085495 to Jian-ping YE and an NIH COBRE grant

(2P20RR021945) and ADA grant (1-09-JF-17) to Zhan-guo GAO. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Antioxidant and Gene Regulation Lab, Pennington Biomedical Research Center, Louisiana

State University System, Baton Rouge, 70808, LA, USA Zhan-guo Gao & Jian-ping Ye Authors * Zhan-guo Gao View author publications You can also search for this author inPubMed Google

Scholar * Jian-ping Ye View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Jian-ping Ye. RIGHTS AND PERMISSIONS

Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Gao, Zg., Ye, Jp. Why do anti-inflammatory therapies fail to improve insulin sensitivity?. _Acta Pharmacol Sin_ 33, 182–188

(2012). https://doi.org/10.1038/aps.2011.131 Download citation * Received: 01 August 2011 * Accepted: 06 September 2011 * Published: 31 October 2011 * Issue Date: February 2012 * DOI:

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * inflammation * insulin resistance * type 2 diabetes *

insulin sensitizer * obesity