Insulin resistance and inflammation -
Mengwei Li, Xiaowei Chi, … Hanmei Xu. Noha F. Hassan, Azza H. 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 1. 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 obesity 2 , 3.
Recent studies from multiple groups, including ours, consistently suggest that adipose tissue hypoxia is a root of chronic inflammation in obesity 4.
Hypoxia is likely the result of a reduction in blood flow to adipose tissue, which is supported by some studies in humans and animals 5 , 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 cells 8 ; the lipids can also signal through cell membrane receptors for lipids, such as TLR4, CD36, or GPR 8 , 9 , 10 , 11 , 12 , 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 IKK 14 , In obesity, these signaling pathways are activated as a result of the surplus calories and involved in the pathogenesis of chronic inflammation.
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 diseases 1 , 16 , 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 protein 17 , 18 , TNF-α induces insulin resistance by IRS-1 serine phosphorylation through the activation of several serine kinases, including JNK 20 , 21 , IKK 22 , ERK 23 , 24 , 25 , PKC 26 , 27 , 28 , Akt 28 , 29 , GSK-3 30 , 31 , 32 , IRAK 33 , and mTOR 34 , Serine phosphorylation induces IRS-1 degradation and serves as a negative feedback signal to impair insulin action The pathway has been under active investigation in the obesity field after IKKβ was found to induce insulin resistance in obese mice The serine kinase IKK has three major isoforms, including IKKα IKK1 , IKKβ IKK2 , and IKKγ, which requires IKKβ for NF-κB activation 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 acids 11 and hypoxia IKKβ induces NF-κB activation by phosphorylation of the Inhibitor of Kappa B alpha IκBα 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, p, p, p52 These members form a homodimer or heterodimer that regulates gene transcription.
In most cases, NF-κB is a heterodimer of p65 and p P65 contains the transactivation domain and mediates the transcriptional activity of NF-κB. P50 inhibits the transcriptional activity of p65 42 , and the NF-κB activity is enhanced in p50 knockout mice NF-κB inhibits PPARγ function through the competition for transcriptional coactivators or the exchange of corepressors with PPARγ This process is responsible for inhibiting PPAR-target genes, such as CAP and IRS 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.
Elevated plasma free fatty acids FFAs induce insulin resistance in obese and diabetic subjects It was known as early as that lipid infusion caused insulin resistance 46 , PKCθ is a major kinase involved in FFA-induced insulin resistance 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 sensitivity 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 transport Inflammation is associated with increased energy expenditure in patients with chronic kidney disease 51 , cachexia 52 , inflammatory bowel disease 53 and Crohn's disease NF-κB activity can promote energy expenditure, as supported by documents on energy expenditure in cachexia 55 , 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 knockout 57 , 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 night 57 , 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 body 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-α 59 , IL-1 60 , or IL-6 The above literature suggests that energy accumulation induces chronic inflammation. Inflammation may promote energy expenditure in a feedback manner to counteract an energy surplus 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 accumulation These changes were associated with reduced hepatic glucose production and improvements in insulin-stimulated glucose disposal, assessed during hyperinsulinemic-euglycemic clamping 63 , 64 , 65 , 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 phosphorylation 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-1α 65 , 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 glycemia 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 patients, to test the effect of the drug dose. Those getting intensive treatment were 12 percent more likely to have diabetes 71 , 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.
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 diabetes The interleukin-1—receptor antagonist, a naturally occurring competitive inhibitor of interleukin-1 75 , protects human beta cells from glucose-induced functional impairment and apoptosis The expression of the interleukinreceptor 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 diabetes 74 , 34 patients were randomly assigned to receive mg of anakinra a recombinant human interleukinreceptor 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 resistance 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 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 conditions Some animal studies 78 and several clinical trials using TNF antagonism have thus far failed to improve insulin sensitivity 79 , 80 , 81 , 82 , 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 diet 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 unchanged These observations suggest that IL-6 increases energy expenditure.
In the IL-6 mice, insulin levels were elevated, and hypoglycemia was observed 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 The role of the anti-inflammatory cytokine IL has been studied in the pathogenesis of obesity and insulin resistance IL 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 sensitivity 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 in mice was used to study the relationship between IL and insulin resistance 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 from the hematopoietic system does not have an effect on insulin resistance Other studies suggest that IL cannot improve insulin sensitivity in diet-induced obese mice or humans 90 , 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 adipokines 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 cancer 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 SIRT Inhibition of histone deacetylase activity has been reported as a new approach to treat diabetes mellitus 96 , 97 , 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 mice HDAC inhibits insulin resistance on a molecular level by the following means: a reducing the lipid toxicity 44 , 99 , , , ; b reducing chronic systemic inflammation , , , , , ; c promoting beta-cell development, proliferation, differentiation and function 97 ; and d promoting energy expenditure 98 , 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. 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. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.
Science ; : 87— CAS PubMed Google Scholar. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest ; : — CAS PubMed PubMed Central Google Scholar.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue.
Ye J, Gao Z, Yin J, He Q. Am J Physiol Endocrinol Metab ; : E— Larsen OA, Lassen NA, Quaade F. Blood flow through human adipose tissue determined with radioactive xenon.
Acta Physiol Scand ; 66 : — Crandall DL, Goldstein BM, Huggins F, Cervoni P. Adipocyte blood flow: influence of age, anatomic location, and dietary manipulation. Am J Physiol ; : R46— West DB, Prinz WA, Francendese AA, Greenwood MR.
Adipocyte blood flow is decreased in obese Zucker rats. Am J Physiol ; : R— Brose N, Rosenmund C. Move over protein kinase C, you've got company: alternative cellular effectors of diacylglycerol and phorbol esters. J Cell Sci ; : — Costanzi S, Neumann S, Gershengorn MC.
Seven transmembrane-spanning receptors for free fatty acids as therapeutic targets for diabetes mellitus: pharmacological, phylogenetic, and drug discovery aspects. J Biol Chem ; : — Aldhahi W, Hamdy O. Adipokines, inflammation, and the endothelium in diabetes. Curr Diab Rep ; 3 : —8. PubMed Google Scholar.
Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, et al. Weigert C, Brodbeck K, Staiger H, Kausch C, Machicao F, Häring HU, et al. Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor-kappaB.
Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, et al. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol Endocrinol ; 18 : — Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, et al.
Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell ; : — Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, et al.
Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science ; : — Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.
J Clin Invest ; 95 : — Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRSmediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance.
Science ; : —8. Hotamisligil GS. The role of TNFalpha and TNF receptors in obesity and insulin resistance.
J Intern Med ; : —5. Peraldi P, Hotamisligil GS, Buurman WA, White MF, Spiegelman BM. Tumor necrosis factor TNF -alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase.
Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH 2 -terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser Chitturi S, Farrell GC.
Etiopathogenesis of nonalcoholic steatohepatitis. Semin Liver Dis ; 21 : 27— Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex.
De Fea K, Roth RA, Modulation of insulin receptor substrate-1 tyrosine phosphorylation and function by mitogen-activated protein kinase.
J Biol Chem ; : —6. Engelman JA, Berg AH, Lewis RY, Lisanti MP, Scherer PE. Mol Endocrinol ; 14 : — Rui L, Aguirre V, Kim JK, Shulman GI, Lee A, Corbould A, et al. J Clin Invest ; : —9. De Fea K, Roth RA. Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine Biochemistry, ; 36 : — CAS Google Scholar.
Li Y, Soos TJ, Li X, Wu J, Degennaro M, Sun X, et al. Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser J Biol Chem ; : —7. Ravichandran LV, Esposito DL, Chen J, Quon MJ.
Protein kinase C-zeta phosphorylates insulin receptor substrate-1 and impairs its ability to activate phosphatidylinositol 3-kinase in response to insulin.
J Biol Chem ; : —9. Paz K, Liu YF, Shorer H, Hemi R, LeRoith D, Quan M, et al. Phosphorylation of insulin receptor substrate-1 IRS-1 by protein kinase B positively regulates IRS-1 function. Eldar-Finkelman H, Krebs EG. Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action.
Proc Natl Acad Sci U S A ; 94 : —4. Ilouz R, Kowalsman N, Eisenstein M, Eldar-Finkelman H. Identification of novel glycogen synthase kinase-3beta substrate-interacting residues suggests a common mechanism for substrate recognition. Liberman Z, Eldar-Finkelman H.
Serine phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 attenuates insulin signaling. J Biol Chem ; : —8. Kim JA, Yeh DC, Ver M, Li Y, Carranza A, Conrads TP, et al.
Ozes ON, Akca H, Mayo LD, Gustin JA, Maehama T, Dixon JE, et al. Proc Natl Acad Sci U S A ; 98 : —5. Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, et al. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate Zhang J, Gao Z, Yin J, Quon MJ, Ye J.
S6K directly phosphorylates IRS-1 on Ser to promote insulin resistance in response to TNF- alpha signaling through IKK2. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, et al.
IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med ; 11 : —8. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol ; 18 : — Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, et al.
Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci U S A ; : —9. Hacker H, Karin M.
Regulation and function of IKK and IKK-related kinases. Sci STKE ; : re Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol ; 12 : — Schmitz ML, Baeuerle PA. The p65 subunit is responsible for the strong transcription activating potential of NF-kappa B.
EMBO J ; 10 : — Bohuslav J, Kravchenko VV, Parry GC, Erlich JH, Gerondakis S, Mackman N, et al. Regulation of an essential innate immune response by the p50 subunit of NF-kappaB. Gao Z, He Q, Peng B, Chiao PJ, Ye J. Regulation of nuclear translocation of HDAC3 by IkappaBalpha is required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptor gamma function.
Boden G. Free fatty acids FFA , a link between obesity and insulin resistance. Front Biosci ; 3 : d— Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA. Effect of fatty acids on glucose production and utilization in man. J Clin Invest ; 72 : — Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, et al.
Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade.
Diabetes ; 48 : —4. Schmitz-Peiffer C, Oakes ND, Browne CL, Kraegen EW, Biden TJ. Reversal of chronic alterations of skeletal muscle protein kinase C from fat-fed rats by BRL Am J Physiol ; : E— Delarue J, Magnan C.
Free fatty acids and insulin resistance. Curr Opin Clin Nutr Metab Care ; 10 : —8. Thompson AL, Cooney GJ. Acyl-CoA inhibition of hexokinase in rat and human skeletal muscle is a potential mechanism of lipid-induced insulin resistance.
Diabetes ; 49 : —5. Utaka S, Avesani CM, Draibe SA, Kamimura MA, Andreoni S, Cuppari L. Inflammation is associated with increased energy expenditure in patients with chronic kidney disease.
Am J Clin Nutr ; 82 : —5. Moldawer LL, Georgieff M, Lundholm K. Interleukin 1, tumour necrosis factor-alpha cachectin and the pathogenesis of cancer cachexia.
Clin Physiol ; 7 : — Barot LR, Rombeau JL, Steinberg JJ, Crosby LO, Feurer ID, Mullen JL. Energy expenditure in patients with inflammatory bowel disease. Arch Surg ; : —2. Chan AT, Fleming CR, O'Fallon WM, Huizenga KA.
Estimated versus measured basal energy requirements in patients with Crohn's disease. Gastroenterology ; 91 : 75—8. Strasser F. Appraisal of current and experimental approaches to the treatment of cachexia. Curr Opin Support Palliat Care ; 1 : —6.
Tisdale MJ. Biology of cachexia. J Natl Cancer Inst ; 89 : — Tang T, Zhang J, Yin J, Staszkiewicz J, Gawronska-Kozak B, Jung DY, et al.
Uncoupling of inflammation and insulin resistance by NF-kappaB in transgenic mice through elevated energy expenditure. Gao Z, Yin J, Zhang J, He Q, McGuinness OP, Ye J. Inactivation of NF-kappaB p50 leads to insulin sensitization in liver through post-translational inhibition of p70S6K.
Pamir N, McMillen TS, Kaiyala KJ, Schwartz MW, LeBoeuf RC. Receptors for tumor necrosis factor-alpha play a protective role against obesity and alter adipose tissue macrophage status. Endocrinology ; : — Chida D, Osaka T, Hashimoto O, Iwakura Y.
Combined interleukin-6 and interleukin-1 deficiency causes obesity in young mice. Diabetes ; 55 : —7. Wallenius V, Wallenius K, Ahrén B, Rudling M, Carlsten H, Dickson SL, et al. Interleukindeficient mice develop mature-onset obesity.
Nat Med ; 8 : 75—9. Ye J, Keller JN. Regulation of energy metabolism by inflammation: a feedback response in obesity and calorie restriction.
Aging Albany NY ; 2 : —8. How does inflammation contribute to insulin resistance? Over time, poor diet and lifestyle, environmental toxins, and changes in the microbiome can contribute to systemic inflammation throughout the body. Firstly, inflammation within the skeletal muscle and adipose tissue can cause increased adiposity and risk of obesity, exacerbating the inflammatory cycle and affecting the regulation of myocyte metabolism and mitochondrial function.
However, higher concentrations of inflammatory cytokines such as TNF-α inactivate IRS-1 which ultimately leads to impaired GLUT-4 translocation, further reducing insulin dependent transport of glucose to cells.
Specifically, increased production of inflammatory cytokines such as TNF-α, and IL-6 were shown in individuals who were overweight, and these were associated with the development of metabolic diseases. Clinical Takeaway: Inflammation is involved in insulin resistance in several ways: inflammation increases insulin resistance by interfering with the insulin signaling pathways, and inflammation in the skeletal muscle and adipose tissue further exacerbates the inflammatory cycle.
When developing a comprehensive treatment plan to support metabolic health, inflammatory triggers and mediators should always be considered. Learn more about the role of systemic inflammation in metabolic dysfunction and how to treat patients using the functional medicine approach at the upcoming Cardio Advanced Practice Module APM.
References: Saad MJ, Santos A, Prada PO. Linking gut microbiota and inflammation to obesity and insulin resistance.
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