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What is inflammation relevant to the pathogenesis of insulin resistance?Insulin sensitivity and inflammation -
TNF-α also determines endothelial dysfunction linked to insulin resistance TNF-α signals through at least two known cell surface receptors TNFRs , TNFR1 p60 and TNFR2 p80; Refs. The soluble fractions of these receptors, sTNFR1 and sTNFR2, result from a proteolytic cleavage of the cell surface forms 46 , 47 when TNF-α binds to its receptors.
Measurements of the sTNFR concentrations in healthy individuals at different time lapses showed that the levels in the same subject were quite stable over time 48 and have been validated as sensitive indicators of TNF-α system activation This ratio was significantly greater in type 2 diabetic patients than in type 1 diabetic patients and was greater in both than in control nondiabetic subjects.
Interestingly, shedding of TNFR1 and TNFR2 was found to be associated with insulin resistance and vascular dysfunction in type 2 diabetic patients.
It was concluded that insulin resistance and blood pressure are linked to altered shedding of TNFRs in type 2 diabetes mellitus IL-6 is a multifunctional cytokine produced by many different cell types, including immune cells, endothelial cells, fibroblasts, myocytes, and adipose tissue, mediating inflammatory as well as stress-induced responses.
In recent studies, blood pressure was a significant and independent predictor of circulating IL-6 concentrations in women but not in men 51 , 52 , but not all studies are concordant A polymorphism in the promoter of the IL-6 gene has also been found to show divergent associations with blood pressure 54 , IL-6 stimulates the central nervous system and the sympathetic nervous system, which may result in hypertension 56 , The administration of IL-6 led to increased heart rate in healthy women and increased norepinephrine levels and heart rate in women with fibromyalgia However, other mechanisms cannot be excluded.
IL-6 might increase in concert with the modification of the redox state of the vascular wall in chronic hypertension, as occurs in some hypertensive animal models 59 , and in this vessel wall IL-6 also can lead to increased collagen IL-6 is a well-characterized acute inducer of fibrinogen, and fibrinogen is a major determinant of blood viscosity Finally, IL-6 might result in hypertension via effects on angiotensinogen expression 62 , leading to higher concentration of angiotensin II, which is a potent vasoconstrictor.
Interestingly, a cytokine-like molecule increasingly recognized to regulate several inflammatory pathways acting on a receptor of the IL-6 family leptin; reviewed in Ref.
The leptin signal, via central leptin receptors, is believed to interact with the central sympathetic nervous system Infusion of leptin leads to increases in blood pressure Transgenic mice overexpressing leptin had elevated blood pressure, normalized by α-adrenergic blockade Recent findings implicate the leptin receptor gene locus with blood pressure regulation in men Other cytokines might also play a role.
The secretion of ILβ was significantly increased in peripheral blood monocytes from hypertensive patients vs. healthy individuals after stimulation with LPS Similar findings were observed after stimulation with angiotensin II Up-regulation of this cytokine was also seen at the RNA level in hypertensive patients.
TGF-β1 protein might also play a role in blood pressure regulation in humans reviewed in Ref. The potential link between hypertension and inflammatory mechanisms is summarized in Fig. Proposed pathophysiology of hypertension through inflammatory mechanisms see Section II.
CNS, Central nervous system; SNS, sympathetic nervous system. Lipid metabolic pathways and cytokines seem to share different pathophysiological mechanisms.
During the acute-phase response to infection and inflammation, cytokines induce tissue and plasma events that lead to changes in lipoprotein.
The induced hyperlipidemia may represent a nonspecific immune response that can decrease the toxicity of a variety of harmful biological and chemical agents and serve to redistribute nutrients to cells important in host defense We review the parallelism that exists between injury-induced and insulin resistance-induced changes in lipid metabolism.
TNF-α has important effects on whole-body lipid metabolism. The mechanisms and dynamics of cytokine-induced hypertriglyceridemia have been reviewed elsewhere 69 — TNF-α acutely raises serum triglyceride levels in vivo by stimulating very low-density lipoprotein VLDL production Hypertriglyceridemia is well described in patients with frequent infections and chronic secretion of cytokines such as those with AIDS 73 or in patients with cystic fibrosis In AIDS, other cytokines like interferon-α also contribute to hypertriglyceridemia In apparently healthy people, a positive association between plasma concentration of the soluble fraction of TNFR-2 sTNFR2, a surrogate of previous TNF-α effects and total triglycerides has been described, in parallel to a negative one with HDL cholesterol Because plasma sTNFR2 is thought to reflect insulin resistance 77 , 78 , the possible contribution of the latter to increased plasma triglyceride levels should not be ignored.
Plasma TNF-α correlated positively with VLDL triglycerides in healthy men and postinfarction patients 79 , 80 and negatively with HDL cholesterol in the latter However, difficulties in measuring TNF-α in plasma should be recognized, where it is normally in a very low concentration in the range of picograms per milliliter and usually below the linear range of the assay.
The influence of cytokines on total and LDL cholesterol metabolism has been less well studied and seems species specific. TNF-α administration to cynomolgus monkeys resulted in hypocholesterolemia 81 , and, in humans with chronic infections such as AIDS or with cystic fibrosis, decreased total, LDL, and HDL cholesterol levels are usually found 73 , TNF-α is also capable of inducing sterol regulatory element binding protein-1 maturation, a key transcription factor in cholesterol biosynthesis, in a time- and dose-dependent manner in human hepatocytes The intensity, duration, and timing of TNF-α hypersecretion might contribute to explaining these opposite actions of TNF-α on cholesterol metabolism.
In pathological conditions such as chronic infection, moderate to heavily increased TNF-α concentrations may activate pathways of cholesterol metabolism such as increased LDL-receptor expression leading to increased lipoprotein clearance, increased conversion of newly synthesized cholesterol into bile acids, or enhanced esterification and storage of cholesterol reviewed in Refs.
In other chronic low-level inflammatory diseases, such as those caused by intracellular pathogens, the reverse might also be true. Chlamydia species have been found to induce production of TNF-α, inhibiting the action of lipoprotein lipase LPL , leading to accumulation of serum triglycerides and a decrease in serum HDL cholesterol reviewed in LPS, a bacterial component, binds to both HDL cholesterol and LDL cholesterol, which buffers its toxic capacity.
However, in the long term, when this mechanism is overwhelmed, LPS makes LDL immunogenic or toxic to endothelial cells. In a vicious cycle, the accumulation of cholesteryl esters in macrophages exposed to LDL-immune complexes is again associated with increased synthesis and release of TNF-α 85 , and activated macrophages are better able to form foam cells.
In this context, it is interesting to note that increased plasma cholesterol per se [as observed in hypercholesterolemic rabbits 87 , LDL-receptor knockout mice 88 , or diet-induced 89 ] is associated with increased plasma TNF-α concentration or enhanced endotoxin-stimulated TNF-α and IL-1 gene expression in aortae In apparently healthy subjects, sTNFRs circulate in proportion to total and LDL cholesterol 76 , High cholesterol could lead to an increased activity of TNF-α axis, of which increased sTNFRs would be its reflection.
This rise in soluble fraction of cytokine receptors parallels increases in other soluble factors, such as soluble endothelial leukocyte adhesion molecules and soluble intercellular adhesion molecule-1 sICAM-1 observed in other situations of hypercholesterolemia Damage to the endothelium could provide a link explaining simultaneously increased sTNFRs, soluble endothelial leukocyte adhesion molecules, and sICAM-1, because elevated cholesterol levels are associated with endothelial dysfunction An alternative explanation is that high levels of sTNFRs block the hypocholesterolemic action of TNF-α by inhibiting its interaction with cell surface receptors, resulting in high cholesterol levels.
Another possible mechanism is one related to the stimulatory effect of insulin on LDL-receptor activity through the enhancement of LDL-receptor mRNA expression In this sense, increased LDL cholesterol might be the result of hampered insulin action possibly induced by TNF-α on LDL-receptor activity.
In this sense, IL-6 has been hypothesized to be responsible for the lipid abnormalities occurring in subjects with the insulin resistance syndrome 7 , 8.
This hypothesis is based on the findings of increased blood concentrations of IL-6 and markers of the acute-phase response, including CRP and cortisol in parallel with dyslipidemia decreased plasma HDL cholesterol and increased plasma triglyceride concentration in patients with this syndrome 7 , 8.
IL-6 inhibits adipocyte LPL activity 94 and induces increases in hepatic triglyceride secretion in rats In man, IL-6 infusion leads to increased free fatty acid concentration 96 , and fasting triglycerides, VLDL triglycerides, and post-glucose load free fatty acids are linked to serum IL-6 concentration The link between inflammation, insulin resistance, and CHD might be mediated through different pathways, including fatty acid FA metabolism.
Dietary FA appear to modulate the release of different cytokines The production of IL-1 β, TNF-α, IL-6, and granulocyte and macrophage colony-stimulating factor by peripheral mononuclear cells decreases after dietary polyunsaturated FA supplementation in women 99 , Docosahexaenoic acid DHA and eicosapentaenoic acid inhibited in vitro human endothelial cell production of IL-6 DHA also reduced endothelial expression of IL-6 in response to different stimuli In contrast, the consumption of a diet high in hydrogenated fat increases production of IL-6 and TNF-α Hence, the profile of dietary FA strongly influences cytokine production.
In fact, the proportion of saturated and polyunsaturated ω-3 FA in serum of healthy volunteers was associated with circulating IL-6 concentration Other circulating cytokines such as plasma granulocyte and macrophage colony-stimulating factor concentration appear to be linked to serum DHA and eicosapentaenoic acid levels in healthy volunteers Defects in insulin action on the main insulin-sensitive tissues adipose tissue, muscle, and liver are proposed to lead to a worsening of the chronic, low-grade inflammatory state.
Independent of the triggering agent and of the initial events, the relationship is bidirectional; any process linked to chronic inflammation will decrease insulin action, and insulin resistance will lead to worsening of inflammation in a vicious cycle.
There exists increased evidence that generalized and abdominal obesity constitute low-grade inflammatory states. Adipose tissue, long being misconstrued as a mere tissue of fat storage, is progressively acknowledged to be an active participant in energy homeostasis.
TNF-α seems to play a key role in regulating adipose tissue metabolism — In obese humans — and numerous rodent models — of obesity-diabetes syndromes, TNF-α is overexpressed in the adipose tissue, as compared with tissues from lean individuals. A decreased processing rate of transmembrane TNF-α in mature adipocytes combined with an increase in TNF-α production may be a potential mechanism resulting in elevated membrane-associated TNF-α in adipose tissue in obesity The TNF-α gene locus seems to influence the distribution of body fat according to sex.
Although this locus exerted the most significant effects on waist circumference and suprailiac skinfold in men, the most significant impact in women was on upper thigh circumference and thigh skinfold In fact, the only element in the TNF-α cascade that is known to have gender-specific regional effects is LPL The mRNA level and the enzyme activity of LPL are higher in abdominal than in thigh adipose cells in men and vice versa in women Obese women express approximately 2-fold more TNFR2 mRNA in fat tissue and approximately 6-fold more sTNFR2 in circulation relative to lean control subjects Interestingly, adipose tissue expression of TNFR2 strongly correlates with body mass index BMI and with measures of abdominal obesity [waist-to-hip ratio WHR ; Refs.
However, there exists some discrepancy in the relationships among sTNFR1, sTNFR2, and adiposity measures depending on study design and inclusion or not of morbidly obese subjects — In one study, plasma sTNFR2 concentration was described to cosegregate with measures of obesity but not with insulin resistance in twins However, mechanistically speaking, circulating sTNFR2 concentration changes with systemic insulin action see Section IV.
Subcutaneous adipose tissue also produced sTNFR1 as shown by arteriovenous differences , and diet-induced weight loss led to significantly decreased sTNFR1 levels Administration of LPS or the recombinant cytokines TNF-α and IL-1 has been reported to induce leptin expression and secretion by adipose tissue , Recent works have suggested the existence of a TNF-α-leptin axis, in which leptin and TNF-α would be in a mutual interrelationship.
In fact, TNF-α administration increases serum leptin levels in humans , and plasma sTNFR1 concentration circulates in proportion to leptin However, the possible role of leptin resistance in these interactions is still confusing in humans.
These facts are important in understanding pathophysiology of abdominal obesity because leptin production is dependent on the distribution of body fat Moreover, although leptin was first described for its role in modulating food intake and energy expenditure, there is now substantial evidence that leptin is also involved in immune function 63 , as evidenced by its effect to enhance cytokine production and phagocytosis by macrophages In fact, increased leptin concentrations correlate with increased concentrations of inflammatory markers in morbidly obese individuals However, the role of leptin in human insulin action or obesity-associated inflammation is probably very small IL-6 is secreted from adipose tissue during noninflammatory conditions in humans.
Omental adipose tissue produces 3-fold more IL-6 than sc adipose tissue Dynamic studies of IL-6 concentration in humans showed that IL-6 increases postprandially, in parallel to glucose and insulin levels in the interstitial fluid of sc adipose tissue This finding suggests that IL-6 might modulate adipose glucose metabolism in the fed state.
It has been calculated that one third of total circulating concentrations of IL-6 originate from adipose tissue A positive association between different measures of obesity and plasma IL-6 levels has been described in men and postmenopausal women 51 , 52 , Because venous drainage from omental tissue flows directly into the liver, the increased physiological WHR of men is expected to have more metabolic impact.
Abdominal arterial IL-6 was also associated with BMI In contrast, plasma IL-6 levels were higher in obese patients with sleep apnea but not in obese controls in comparison with normal weight controls In another study, the relationship between BMI and serum IL-6 was only observed in postmenopausal women, and this relationship was lost among those women receiving hormone replacement In fact, estrogens are well-known inhibitors of IL-6 secretion Adipose tissue-derived estrogens in postmenopausal women would not be sufficient to reduce IL-6 in a similar way as endogenous estrogens in premenopausal women It should be stated that an important variable is smoking, which was a significant confounding factor in the relationship between measures of body fat and circulating IL-6 concentration Of the aforementioned, obesity is expected to result in increased secretion of IL-6, with its detrimental metabolic effects see Section IV.
The antiobesity effect of IL-6 was mainly exerted at the level of the central nervous system, being inactive when administered peripherally At first glance, this is puzzling. However, IL-6 acts as a terminator as well as a prompter of inflammation.
It should again be remembered that cytokines act in cascade, and total depletion of IL-6 might be detrimental because other proinflammatory cytokines TNF-α are not adequately down-regulated, as is the case in other knockout models Unfortunately, other cytokines were not studied in that report Obesity is not the only condition in which circulating sTNFR2 concentration is proportional to insulin resistance.
Plasma sTNFR2 concentration has been described as being linked to markers of the muscle compartment as fat-free mass and midarm muscle circumference 78 , , Circulating sTNFR2 concentration is also associated with insulin resistance in other diseases characterized by muscle disease TNF-α is a strong inducer of TNFR2 expression in adipocytes and other cell types , and, in this context, the association between the muscle compartment and insulin resistance might be attributed to increased production by the muscle of sTNFR2, leading to stabilization of TNF-α homotrimers, resulting in insulin resistance at the level of the adipocyte.
These facts are related to the thrifty genotype hypothesis. Neel postulated that a thrifty genotype existed that had a selection advantage as hunter-gatherers fluctuated between feast and famine. The thrifty genotype in type 2 diabetes contributes to the insulin resistance seen in muscle A selective insulin resistance in muscle would have the effect of blunting the hypoglycemia that occurs during fasting but would allow energy storage in fat and liver during feeding.
Both of these features could allow hunter-gatherers to have survival advantages during periods of food shortage — Although mild exercise seems to produce health benefits , strenuous exercise, taken to the extreme or during prolonged fasting conditions, initiates an immune and vascular proinflammatory response.
In fact, acute strenuous exercise is considered to be a model of the acute-phase response that occurs in parallel to insulin resistance — , and the cytokine response to strenuous exercise [both plasma TNF-α and sTNFR2 concentrations increase during exercise ] is similar to that found in sepsis and trauma , As recently hypothesized 9 , the induction of muscle insulin resistance would allow a food-seeking behavior and would prevent the wasting of glucose to nonvital organs, protecting the brain and the immunological system.
In the absence of food shortage, regular physical exercise led to a consistent decrease in circulating sTNFR2 in obese women , and in type 2 diabetic patients 50 , in parallel to improved insulin sensitivity. Several cytokines can be detected in plasma during and after strenuous exercise.
The increase in TNF-α, sTNFR2, IL-1β, IL-1 receptor antagonist, IL-8, and IL is accompanied by a dramatic increase in IL-6 reviewed in Ref. After exercise, IL-6 is produced in larger amounts by the contracting muscle than any other cytokine examined. Both IL-6 mRNA [which increases more than fold after exercise ] and IL-6 receptor mRNA have been detected in muscle.
It has been suggested that depleted glycogen content or an energy crisis in the contracting muscle, rather than muscle damage, may be one stimulus for the IL-6 release Thus, the possibility exists that the elevated serum IL-6 is a consequence of an increased production and release of IL-6 from muscle in response to the impaired insulin sensitivity, allowing hunter-gatherers to have survival advantages during periods of food shortage, in a similar way to the events described above.
After trauma or infection, the human body mounts a highly complex acute-phase response as part of the homeostatic response to injury. In the acute phase, the acute-phase response is protective because it counteracts the effects of injury and improves survival.
Long-term exposure to stressful stimuli mucositis, aging, increased fat intake, periodontitis, etc. may result in disease rather than repair. The liver is the target of systemic inflammatory mediators and is also the organ responsible for determining the level of essential metabolites provided to the organism during the critical stages of stress.
Among the most important aspects of this response is the reprioritization of hepatic protein synthesis with the increased production of a number of plasma proteins positive APP and reduced production of a number of normal export proteins negative APP.
It should be stated that expression of acute-phase reactants at high levels has also been recently identified in adipose tissue of mice, and this was especially remarkable in the diabetic state The induction of APP production is thought to be regulated at the transcriptional level, and at least two signaling pathways have been identified within the hepatocyte.
One pathway activates transcription of class I acute-phase genes such as CRP, serum amyloid A, and complement C3, whereas the other pathway activates transcription of class II acute-phase genes such as α 1 -antitrypsin and fibrinogen Although the concentrations of multiple components of the acute-phase response increase together, not all of them increase uniformly in all patients.
These variations indicate that the components of the acute-phase response are individually regulated, and this may be caused in part by differences in the pattern of production of specific cytokines , These facts would explain increased susceptibility to increased inflammatory activity among healthy volunteers with genetically increased rates of some cytokines The hormonal and cytokine networks acting on the hepatocyte may lend a degree of fine-tuning to the spectrum of APP in response to different stimuli Insulin seems to be one of the main regulators of the cytokine-associated acute-phase reaction , Liver cells respond to many of the factors via their cell surface receptors.
According to one vision , the inflammatory mediators fall into four major categories: 1 IL-6 type cytokines, of which IL-6 is the major representative; 2 IL-1 type cytokines including IL-1α, IL-1β, TNF-α, and TNF-β ; 3 glucocorticoids; and 4 growth factors including insulin.
The cytokines would act as primary stimulators of APP gene expression, whereas the glucocorticoids and growth factors function more as modulators of cytokine action. An adequate balance between these opposite pathways will result in resolution of the acute-phase process Fig.
Balance of proinflammatory and antiinflammatory agents regulating the acute-phase response. An adequate balance will lead to resolution of the process. Insulin attenuates IL and ILtype cytokine stimulation of most APP genes in human hepatoma cells , Thus, the lack of significant insulin action, as found in type 2 diabetes, or unsubstituted insulin deficiency, would not be able to block TNF-α, IL-1, and IL-6 actions, leading to prolonged acute-phase reaction.
The acute-phase response changes are small in insulin resistance in comparison with those found in infection or trauma, but the potential damage is greater because of the chronicity of the changes.
Systemic inflammation, measured by increased serum acute-phase reactants, has been recognized to occur in type 2 diabetes since the early work by McMillan Significantly higher serum concentration of CRP, fibrinogen, α 1 -acid glycoprotein, amyloid A, sialic acid, and orosomucoid have been described in patients with type 2 diabetes mellitus 7 , Serum CRP concentration and the acute-phase reaction have been significantly associated with clinical and biochemical indexes of insulin resistance 51 , — The relationship between increased CRP and decreased insulin action might be intrinsically due to insulin resistance itself 51 , , Elevated serum CRP concentrations have been demonstrated consistently in overweight and obese adults, even among young adults aged 17—39 yr people with diabetes had elevated CRP levels, and this association was not completely explained by increases in BMI Of note was that CRP and IL-6 decreased significantly after improvement of metabolic control in type 2 diabetic patients, indicating that the inflammatory pathways are modulated by insulin CRP may not measure all of the relevant effectors of inflammation because the concentration of CRP may be subject to posttranscriptional regulation In one study, CRP levels were associated with several metabolic parameters in men and women, but in a multiple linear regression analysis, CRP was associated independently with IL-6 only in men Interestingly, both constitutive and ILdependent acute-phase expression of the human CRP transgene require testosterone in transgenic mice, implying a potential mechanism for this gender dimorphism Other acute-phase reactants, such as fibrinogen, plasminogen activator inhibitor-1, and amyloid A are associated with insulin resistance and predict development of type 2 diabetes Ref.
CBG is the major blood transport protein for cortisol, the major antiinflammatory hormone in humans. Scarce data in the literature have suggested that CBG is a negative acute-phase reactant , CBG level was negatively associated with insulin secretion in obese and glucose-tolerant subjects who also had lower CBG levels than obese and glucose-intolerant subjects It has been shown that both insulin secretion and insulin sensitivity independently contributed to CBG changes after glucose-induced insulin stimulation The insulin response after a glucose challenge was linked to acute CBG changes in lean subjects.
CBG has been recently found to be negatively associated with several indexes of insulin resistance such as BMI, WHR, and homeostasis model assessment, and with inflammatory parameters such as sTNFR1, sTNFR2, and IL-6 concentrations A polymorphism of the IL-6 gene promoter, which is linked to increased IL-6 levels and to insulin resistance, was also associated with low CBG levels In women, both decreased CBG and free cortisol independently contributed to homeostasis model assessment variance in a multiple linear regression analysis, suggesting that both mechanisms would be metabolically additive Because CBG secretion has been shown to be negatively regulated by both insulin and IL-6 , , it is tempting to propose that CBG concentration is an index of insulin resistance and inflammation.
On the other hand, constitutive low CBG levels might also contribute to insulin resistance by increasing cortisol biodisposal to target cells, including muscular cells. Interestingly, physiological increments in plasma insulin concentrations have been described to affect synthesis of other hepatic proteins in normal humans In addition, insulin is also able to promote albumin distribution to peripheral tissues by increasing the protein transcapillary escape rate As shown for low serum albumin in the Atherosclerosis Risk in Communities Study 14 , it has been suggested that low CBG, another liver protein, could be an interesting index for the development of type 2 diabetes as well as for incident cardiovascular disease as reported early in postmenopausal women It remains to be established whether low circulating or tissue CBG concentration impacts on systemic insulin action and metabolism.
Aging is usually associated with increased insulin resistance In parallel to age-related insulin resistance, the production of circulating APP , the secretion of cytokines from monocytes and macrophages , and the production of TNF-α and sTNFR2 are all increased with age.
We will review the evidence according to which cytokines are involved in general insulin action. The relative importance of TNF-α in insulin action has been tested by inducing a targeted null mutation in the TNF-α gene.
Mice with this mutation were spared from obesity-induced deficiencies in insulin-receptor signaling in fat and muscle tissues , However, it should be recognized that insulin resistance is alleviated but not eliminated in these models.
In humans, similar information can be obtained by comparing individuals with different transcription rates of the TNF-α gene. Some substitutions in the TNF-α promoter gene lead to different constitutive and inducible levels of transcription of the TNF-α gene than the wild-type allele , Mutations within regulatory elements of the TNF-α gene were not associated with an increase in the prevalence of noninsulin-dependent diabetes mellitus , However, in the latter reports, insulin resistance was not evaluated.
Some associations among obesity, obesity-associated phenotypes, and cytokines have been found to be most significant in nonmorbidly obese individuals Enhanced activity of cytokines due to the development of obesity is, on one hand, predicted to contribute to the development of obesity-associated phenotypes but is, on the other hand, expected to limit the progression of obesity.
These mechanistic relationships are probably lost in subjects with morbid obesity. Differences in study design have also contributed to disparity of results: insulin sensitivity or insulin secretion was not significantly different in healthy young relatives of type 2 diabetic patients with the A allele — Finally, interethnic differences, gene-gene and gene-environment interactions are important confounders of any association between a single polymorphism and disease — Other components of the TNF-α axis seem to be genetically linked to insulin resistance.
In humans, a mutation in the TNFR2 gene has been associated with increased BMI and leptin levels in parallel to insulin resistance in nondiabetic subjects and increased BMI and leptin concentration in diet-treated type 2 diabetic patients Interestingly, other mutations in this locus have been associated with other components of the insulin resistance syndrome such as hypertension , dyslipidemia , and cardiovascular disease 90 , and with other degenerative diseases such as osteoporosis This locus has also been associated with polycystic ovary syndrome, an entity with known defects in insulin action The differences in insulin resistance seem to be restricted to the TNF-α gene because polymorphisms of the TNF-β gene, a closely associated gene, were not associated with this phenotype It should be remembered that much of TNF-α is secreted, whereas most of TNF-β is on the membrane of the lymphocytes.
Again, interethnic differences have also been described. Insulin resistance was significantly lower in variant TNF-β homozygotes vs. wild-type allele in Japanese subjects , whereas hyperinsulinemia, attributed to TNF-β gene polymorphism, was described in Caucasians with CHD TNF-α blocks the action of insulin in cultured cells and whole animals — The induction of insulin resistance is mediated through its ability to produce serine phosphorylation of insulin receptor substrate 1, decreasing the tyrosine kinase activity of the insulin receptor It also reverted the insulin-induced phosphorylation of insulin receptor substrate 1 to levels observed in lean animals In contrast, treatment of type 2 diabetic or obese human subjects with an antibody specific for TNF had no effect on insulin sensitivity , However, one of these studies was performed using one single administration of antibody in adults with established diabetes Moreover, this approach does not affect the autocrine and paracrine effect of TNF-α and is not directed against the primary endogenous stimulus for increased TNF-α secretion.
Again, it should be remembered here that increased sTNFR2 levels circulate in association with insulin resistance in healthy volunteers 77 , 78 , in lean nondiabetic offspring of type 2 diabetic subjects , and in young obese subjects with normal and impaired glucose tolerance , but not in older subjects Mice with a targeted null mutation in the IL-6 gene, made obese by a high-fat diet, became more insulin resistant compared with wild-type controls However, as stated above, total depletion of IL-6 might be detrimental because other proinflammatory cytokines TNF-α are not adequately down-regulated.
This information is apparently at odds with what is observed in humans with different transcription rates of the IL-6 gene.
Again, divergent results have been described in other populations in keeping with the observation that IL-6 promoter haplotypes rather than simply single variant sites influence IL-6 gene expression in vitro Importantly, at least two allelic polymorphisms in the IL-6 promoter region were found to cooperate in the regulation of IL-6 activity in vivo Available data suggest that although TNF-α functions locally at the level of the adipocyte in a paracrine fashion, IL-6 circulates in plasma at high concentrations.
In this sense, IL-6 may be more important systemically and perhaps represents a hormonal factor that induces muscle insulin resistance. In fact, IL-6 is named the endocrine cytokine Although adipose cells contribute to one third of circulating IL-6 concentration , other sources are potentially important.
Although this mechanism is not operative with normal fasting glucose levels, it could be of significance in patients with type 2 diabetes. IL-6 is a pleiotropic cytokine, and some of its metabolic actions have been evaluated after IL-6 administration.
In in vitro studies, IL-6 induced a dose-dependent inhibition of the glucose-stimulated insulin release of rat pancreatic islets , In vivo , administration of recombinant human IL-6 to normal subjects induced metabolic changes usually found in catabolic states, increasing plasma glucose levels in a dose-dependent fashion without altering significantly plasma insulin or C-peptide concentrations In another study in cancer patients, however, recombinant human IL-6 administration led to an increase in the metabolic clearance of glucose To integrate these opposite actions, one has to consider that these metabolic effects of IL-6 have been studied mainly after exogenous treatment at relatively high doses.
It is also important to keep in mind the metabolic milieu in which IL-6 is exerting its effects; cytokines act in cascade, and any single change in a given step could change the final result.
Another way to evaluate IL action is to infer it from IL-6 concentration, but this approach cannot conclude which is the cause and which is the consequence. For instance, plasma IL-6 levels are elevated in type 2 diabetic patients, particularly in those with features of the insulin resistance syndrome 7 , 8.
One interpretation could be that type 2 diabetes mellitus and the insulin resistance syndrome lead to an ongoing acute-phase response through increased IL-6 derived from unsuppressed adipose or immune secretion acting on hepatocytes that are oversensitive Fig.
In fact, this hypothesis is derived from the findings of increased blood concentrations of markers of the acute-phase response, including CRP, serum amyloid-A, α-1 acid glycoprotein, sialic acid, and cortisol in these conditions 7 , 8.
But the reverse could also be true. According to the opposite vision, increased IL-6 and markers of the acute-phase response are perhaps counteracting hyperglycemia and insulin resistance Fig. When proinflammation is enduring, chronic, or uncontrolled and when a challenge becomes overwhelming, the failure to reach the desirable effect results in worsening of hyperglycemia and insulin resistance Fig.
Lack of exposure would result in proinflammation only when insulin resistance is severe step 3. These possibilities are summarized in Fig. Proposed mechanisms leading to insulin resistance-related inflammation. Type 2 diabetes mellitus and the insulin resistance syndrome lead to an ongoing acute-phase response through increased IL-6 derived from unsuppressed adipose or immune secretion acting on hepatocytes that are oversensitive step 3.
In fact, this hypothesis is derived from the findings of increased blood concentrations of markers of the acute-phase response, including CRP, serum amyloid-A, α-1 acid glycoprotein, sialic acid, and cortisol in these conditions. According to the opposite vision, increased IL-6 and markers of the acute-phase response are perhaps counteracting hyperglycemia and insulin resistance step 1.
When proinflammation is enduring, chronic, or uncontrolled, and when a challenge becomes overwhelming, the failure to reach the desirable effect results in worsening of hyperglycemia and insulin resistance step 2. According to recent studies, serum IL-6 is associated with insulin action in human subjects 51 , — Insulin sensitivity has been evaluated using euglycemic clamp technique , , the minimal model approach 51 , , or the fasting insulin resistance index 51 , Circulating IL-6 levels in men were associated with insulin sensitivity even after controlling for BMI, absolute fat mass or percentage fat mass Both insulin resistance and insulin secretion seemed to contribute to circulating IL-6 in Pima Indians A threshold of visceral fat-derived IL-6 to impact on insulin action could be speculated.
The influence of estrogens on IL-6 in premenopausal women could predominate on that exerted by insulin resistance. All of these findings are strengthened by the recent description of IL-6 receptors in human adipocytes and by the demonstration that IL-6 impairs insulin signaling in primary mouse hepatocytes and human hepatocarcinoma cell line, HepG2 Plasma IL-6 and insulin sensitivity relationships seem to occur in parallel to increases in plasma nonesterified FA Circulating IL-6 concentration has been described to predict the development of type 2 diabetes mellitus in women.
The relative risk of future type 2 diabetes mellitus for women in the highest vs. lowest quintile of these inflammatory markers was 7. Acute infections determine insulin resistance, and even after clinical recovery, some impairment in carbohydrate metabolism persists Both IL-6 action and acute infections are characterized by a defect in insulin-stimulated glucose use, despite normal carbohydrate oxidation.
It cannot be excluded that chronic or subclinical infections have contributed simultaneously to increased IL-6 levels and insulin resistance. Of note is that a higher peripheral white blood cell count has been associated with insulin resistance since the preliminary observations in In particular, it was observed that peripheral white blood cell count correlated significantly with insulin-mediated glucose disposal during a euglycemic clamp In subsequent studies, it was demonstrated that neutrophil and lymphocyte count correlated positively with several components of the insulin resistance syndrome and that plasma insulin concentration was specifically associated with the number of lymphocytes and monocytes These associations were confirmed in healthy subjects.
Given that IL-6 is involved in hematopoiesis , it has been suggested that these associations might in part be due to different IL-6 concentration. These triggers converge on the activation of the c-Jun N-terminal kinase JNK and nuclear factor-kappa B NF-κB pathways, commonly considered signaling hubs.
The activation of these pathways increases the production of pro-inflammatory cytokines and promotes the infiltration of pro-inflammatory M1 macrophages.
TLR2, Toll like receptor 2; TLR4, Toll like receptor 4; FFA, free fatty acids; UPR, unfolded protein response; HIF-1α, hypoxia-inducible factor-1α; RhoA, ras homolog gene family, member A; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; MCP-1, monocyte chemotactic protein-1; ECM, extracellular matrix.
Saturated fatty acids promote inflammatory activation of macrophages, partially mediated by indirect binding to TLR4 and TLR2 Konner and Bruning, , resulting in the activation of NF-κB and JNK pathways Shi et al.
Once these pathways have been stimulated, many chemokines e. In obesity, in addition to an increased intake of saturated fatty acids, TLR4 and TLR2 expression are increased in the AT, further supporting the role of these receptors in obesity-associated inflammatory signaling Husam et al.
In regard to this, acute lipid infusion is enough to stimulate AT inflammation and systemic IR in wild-type mice, and these effects are prevented in TLR4 -deficient mice Shi et al.
Based on these findings, TLR4 appears to be an interesting candidate for linking dietary fatty acids with AT inflammation and IR Poggi et al.
Despite saturated fatty acids, unsaturated omega-3 and -9 fatty acids have beneficial effects and alleviate AT inflammation Oliveira et al.
WAT plays a major role in regulating systemic energy homeostasis, which acts as a safe reservoir for fat storage. In response to changes in nutritional status, AT expands by increasing the number hyperplasia and size of the adipocytes hypertrophy Sun et al.
Thus, the evidence indicating that adipocyte hypertrophy certainly contributes to AT inflammation is quite convincing at the present. Increased adipocyte size is characterized by a higher rate of adipocyte death and macrophage recruitment.
Larger adipocytes exhibit an altered chemoattractant and immune-related proteins secretion that may promote pro-inflammatory macrophage infiltration Jernas et al. Most of these infiltrated macrophages surround necrotic adipocytes and form crown-like structures.
In obese rodents as well as humans, necrosis-related factors further attract monocytes in AT where they uptake the lipids released by dead adipocytes Cinti et al. As described above, the recruited monocytes have a pro-inflammatory phenotype and secrete cytokines and reactive oxygen species in neighboring adipocytes that interfere with insulin signaling Shapiro et al.
An increase in the number of dead adipocytes has been recognized to prevent normal AT functions and cause inflammation Choe et al. During adipocyte hypertrophy, angiogenesis is initiated to supply oxygen to the expanding tissue. If the AT expansion is very rapid, the vasculature cannot fulfill the oxygen requirement and hypoxia occurs Gealekman et al.
Hypoxia is a strong metabolic stressor. Current evidence reveals that hypoxia develops as AT expands because of a relative under perfusion of the enlarged AT or increased oxygen utilization Gealekman et al.
Cellular hypoxia can initiate inflammation by activating hypoxia-inducible factor-1 HIF-1 gene program. Activated HIF-1α translocates to the nucleus where it recognizes and binds the HREs on DNA. The binding to HREs promotes not only the expression of many genes involved in the angiogenesis but also inflammation Trayhurn, ; Fiory et al.
These include vascular endothelial growth factor, insulin-like growth factor 2, transforming growth factor α, as well as nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 and inflammatory cytokines such as interleukin and 18 Shi and Fang, It has been shown that adipocyte-specific HIF-1 α deletion prevents obesity-induced inflammation and IR Lee et al.
Mitochondria are present in almost all eukaryotic cells and are responsible for cellular energy production, calcium signaling, and apoptosis Osellame et al. Alterations in mitochondrial functions are capable of causing inflammation, oxidative stress, cell death, and metabolic dysfunction Hock and Kralli, ; Kim et al.
A number of studies in obese mice and human subjects have shown that mitochondrial dysfunction is strongly associated with pathological conditions such as inflammation, IR, and T2D Silva et al.
A comparable decrease in mitochondrial activity has also been observed in human AT from obese individuals Yin et al. The mitochondrial dysfunction leads to inflammation through modulating redox-sensitive inflammatory mechanisms such as NF-κB or direct inflammasome activation Vaamonde-García et al.
The activation of both pathways induces an upregulation of inflammatory cytokines and adhesion molecules secretion, resulting in a substantial amplification of the inflammatory response Escames et al.
Petersen et al. Woo et al. ER is a cellular organelle that exhibits high sensitivity to cellular nutrients and energy status Hummasti and Hotamisligil, Many genetic and environmental hits can alter the functions of ER and therefore contribute to ER stress Hummasti and Hotamisligil, Several studies have shown that the incorrect functioning of the UPR i.
It has been shown in mice that obesity results in increased ER stress, particularly in the liver and AT. Indeed, the expression of most ER stress markers and chaperones is strongly BMI-related and associated with AT insulin sensitivity Sharma et al. Additionally, a weight-loss gastric bypass surgery has been shown to enhance insulin sensitivity and decrease ER stress in obese Gregor et al.
Inflammation is the predominant mechanism by which ER stress negatively affects metabolic homeostasis. The primary mechanisms by which ER stress establishes inflammatory mechanisms in AT involve the activation of NF-κB, JNK, and apoptosis signaling pathways.
In response to ER stress, the three UPR branches are activated. The activation of two branches is mediated by protein kinase RNA PKR -like ER kinase PERK and activating transcription factor 6 ATF6. This activation stimulates NF-κB signaling pathway, resulting in the subsequent inhibition of insulin action via IRS-1 phosphorylation.
In addition, the branch mediated by inositol-requiring enzyme 1 results in the activation of the JNK signaling pathway Hotamisligil, ; Hummasti and Hotamisligil, There is also crosstalk between the three branches.
For example, spliced X-box binding protein 1, as well as activating transcription factor 4, induces the production of the inflammatory cytokines IL-6, interleukin-8, and MCP-1 by human endothelial cells Hotamisligil, A further important function of UPR is to activate pro-apoptotic signaling pathways in order to prevent the release and accumulation of misfolded proteins, which may have adverse effects on cellular functions Hotamisligil, However, ER stress-induced apoptosis may also contribute to increased inflammatory signaling and other aspects of metabolic diseases.
For instance, adipocyte death in obesity has been suggested as a potential trigger for the recruitment of macrophages and other inflammatory cells Cinti et al. Evidence also indicates that ER stress is essential for β-cell development and survival Harding et al. In , we have reported that UPR hyper-activation by glucose insult leads to a pro-inflammatory phenotype in preadipocytes.
Cells exposed to hyperglycemia release an increased amount of pro-inflammatory cytokines, chemokines and IL lymphokine, which can trigger inflammation by affecting inflammatory cells.
However, such effects are prevented by a chemical chaperone such as 4-phenyl butyric acid Longo et al. ER stress pharmacological inhibition can reverse metabolic dysfunction also in other tissues, including liver and brain Ozcan et al.
Meta-inflammation and ER dysfunction are emerging as critical mechanisms. If these mechanisms are targeted therapeutically, they can enhance multiple metabolic parameters, as shown in preclinical and clinical studies Hummasti and Hotamisligil, The protein composition and dynamics of the ECM are crucial for the adipocyte function.
ECM remodeling is essential for the expansion and contraction of adipocytes to accommodate changes in energy stores Rutkowski et al. During a positive energy balance, ECM accumulation occurs in AT, which contributes to fibrosis and impairs its role as a nutrient storage organ Lee et al.
Abnormal accumulation of ECM components in AT has been shown to cause obesity-associated IR Lin et al. Excessive ECM deposition in AT is suggested for triggering adipocyte necrosis, which attracts pro-inflammatory macrophages and causes AT inflammation and metabolic dysfunction.
In addition, excess ECM deposition causes adipocyte death and AT inflammation by activation of integrins and CD44 signaling pathways Lin et al. Lipid accumulation occurring in obesity may also cause ECM instability and induce various mechanical stresses on these cells. The mechanisms governed by these mechanical stresses in adipocytes have not yet been fully explained, but certain pathways such as RhoA, and NF-κB have been evaluated.
RhoA signaling, for instance, inhibits adipogenesis through PPAR γ suppression and stimulates the secretion of pro-inflammatory cytokines McBeath et al. Meanwhile, Li et al. As mentioned above, some of the potential mechanisms involved in AT inflammation have been identified; however, it is likely that there are still unknown triggers.
The temporal sequence of events leading to AT inflammation, as well as the contribution of each mechanism described above, has not yet been fully established.
In our opinion, adipocyte hypertrophy may be the primary and initial event causing AT inflammation.
In obesity, adipocytes respond to excess energy by storing lipids inside and undergoing dramatic changes in size hypertrophy. Hypertrophy is associated with hypoxia, cellular and tissue stress, and cell death due to the activation of both necrotic and apoptotic mechanisms. Hypertrophic adipocytes are also characterized by excessive lipolysis, resulting in increased release of FFAs acting on TLR4, as previously indicated.
All the above mechanisms promote adipocyte dysfunction, characterized by an altered cytokine secretion pattern. These mechanisms play a dual role; they are able both to trigger individually inflammatory responses and to induce downstream processes, amplifying and eliciting chronic systemic inflammation and thus promoting systemic IR.
The temporal sequence of events suggested here and the relevance that we attribute to adipocyte hypertrophy in the initiation of AT inflammation needs to be further verified.
The role of chronic inflammation, particularly in the AT, in the pathogenesis of T2D and associated complications, is now well established. The association between obesity, AT inflammation, and metabolic disease makes inflammatory pathways an appealing target to treat metabolic disorders.
Inflammation is recognized as the pathologic mediator of these frequently common comorbidities. Several anti-inflammatory approaches have been tested in clinical studies of obese individuals with IR, but clinical trials to confirm the therapeutic potential are still ongoing Goldfine and Shoelson, The number of available drugs that can target different components of the immune system and improve different metabolic aspects is increasing rapidly Donath, Based on the mechanism of action, therapeutic approaches to target inflammation in IR and T2D can be divided into i pharmacologic approaches that directly target inflammation and ii diabetes drugs with anti-inflammatory properties.
Salsalate is an analog of salicylate that belongs to the non-steroidal anti-inflammatory drug classes. Independent studies have shown that salsalate can improve glycemic control in T2D patients.
The mechanism of action of salsalate in reverse hyperglycemia in obese mice is through the inhibition of NF-κB pathway and has been identified in by Shoelson Yuan et al.
Goldfine then translated this initial finding to the clinical study and showed that salsalate decreases fasting glucose and triglyceride levels, increases adiponectin levels and glucose utilization in diabetic patients during hyperinsulinemic—euglycemic clamp, and improves insulin clearance Goldfine et al.
These observations have been confirmed in two multicenter, randomized, placebo-controlled trials in subjects with T2D Goldfine et al. In the first study, treatment with this drug improves insulin sensitivity and decreases HbA1c levels by 0.
This treatment also decreases levels of glycation end products Barzilay et al. Other studies also suggest that metabolic improvement, induced by salsalate treatment, is mediated through AMPK activation Hawley et al. Although the effects on glycemic control are modest, the salsalate is not expensive and has a very safety profile.
In , a preclinical study clearly showed the role of TNF-α in the pathophysiology of IR in the AT Hotamisligil et al. However, the results of clinical studies have so far been disappointing.
For instance, TNF-α neutralizing antibodies have been shown to be effective for the treatment of many other inflammatory diseases, and some patients have shown slight improvements in glycemic control Ofei et al. However, prospective studies in T2D patients have been confusing.
In spite of valuable effects in mice, a human clinical trial showed that anti-TNF-α therapy leads to no improvements in insulin sensitivity in patients with T2D Ofei et al. In contrast, a study performed in obese subjects without T2D showed that an inhibition of TNF-α for 6 months is able to reduce fasting glucose and increase adiponectin levels Stanley et al.
IL-1β is a strong mediator of the obesity-induced inflammation and participates in the pathogenesis of T2D, mediating the adverse consequences of hyperglycemia on pancreatic β-cells Maedler et al. Antagonism of IL-1R for 13 weeks, in a proof-of-concept study of patients with T2D, shows an improved glycemic control and secretory function of the pancreatic β-cells and the reduced markers of systemic inflammation Larsen et al.
The follow-up study on the same population proves that 39 weeks after the last IL-1R antagonist administration, β-cell insulin secretion is still increased and CRP decreased Larsen et al.
The long-term effects are probably due to the block of IL-1β auto induction mechanism Böni-Schnetzler et al. Further studies have also noted that the use of antibodies directed against IL-1β has potential benefits in the treatment of T2D, as it significantly reduces HbA1c levels Cavelti-Weder et al.
Recently, a multicenter randomized controlled trial, specifically designed to evaluate the glycemic outcome, enrolled participants, with RA and T2D followed up for 6 months.
Thirty-nine participants were randomized to IL-1R antagonist anakinra or TNF inhibitors TNFi to assess the efficacy of these drugs in controlling glucose alterations of T2D Ruscitti et al.
Regarding RA, there has been a gradual reduction in disease activity in both groups. In conclusion, results of this research indicate a specific effect of IL-1 inhibition in subjects with RA and T2D, reaching the therapeutic targets of both disorders and improving the main outcome of enrolled participants.
A clearer reduction of HbA1c, comparing this to the previous study on T2D Larsen et al. On this basis, IL-1 pathway can be considered a shared pathogenic mechanism, and a single treatment that manages both diseases appears to be a promising option for improving the care of RA and T2D patients Giacomelli et al.
Thiazolidinediones TZDs are antidiabetic drugs that improve insulin sensitivity and glycemia, as they function as agonists for PPARγ nuclear receptor Yki-Järvinen, TZDs have also anti-inflammatory effects; they repress NF-κB action and reduce the expression of its target genes Pascual et al. The inhibition of NF-κB pathway reduces ATM content Esterson et al.
Furthermore, the ability of TZDs to reduce circulating inflammatory mediators such as CRP and MCP-1 seems to be independent of glycemic control Pfützner et al. Therefore, TZDs act through different mechanisms and the anti-inflammatory properties of these drugs are not definitely established.
The mechanism of metformin action is not completely explained, but it decreases glycemia by reducing hepatic glucose production and raising glucose uptake in peripheral tissues Inzucchi et al. In addition to its clear metabolic effects, metformin has also anti-inflammatory properties; for instance, it directly inhibits the production of reactive oxygen species in the mitochondria and can reduce the production of many cytokines Wheaton et al.
Emerging evidence supports the novel hypothesis that metformin can exhibit immune-modulatory features. Decreased ATP concentration causes AMPK activation, and among several targets, AMPK inhibits the mammalian target of rapamycin mTOR Zhou et al. mTOR is crucial for cellular metabolism, cytokine responses, antigen presentation, macrophage polarization, and cell migration Weichhart et al.
Metformin can also regulate other pathways relevant to immune cells, including NF-kB Hattori et al. Indeed, other studies have proved that metformin is able to inhibit TNF-α-induced activation of the NF-κB axis and IL-6 production Huang et al.
Metformin, in a dose-dependent manner, reduces IL-1β production in lipopolysaccharide-activated macrophages, and the effect is independent of AMPK activation Kelly et al. Moreover, metformin concurrently decreases circulating inflammatory proteins, including CRP, in impaired glucose tolerance and T2D patients De Jager et al.
The anti-inflammatory effects of metformin, like TZDs, appear to be independent of glycemic control Caballero et al. In murine models, the attenuation of the inflammatory state has been shown to be effective in improving the obesity-induced IR; however, there are ongoing clinical trials in humans to confirm the therapeutic potential of metformin.
This issue represents an essential step in proving the translational relevance of these observations. T2D is a heterogeneous disorder, and the absence of clinical biomarkers, showing whether the treatments have anti-inflammatory effects in the AT, is a potential issue complicating the analysis Donath, The identification and profiling of these biomarkers in T2D patients would allow us to predict those that should respond to an anti-inflammatory therapy.
The global obesity epidemic results in a higher incidence of metabolic disorders. The mechanisms underlying the association between obesity and IR have not yet been fully explained. Therefore, further well-designed clinical and basic research studies are needed to establish this relationship. From our point of view, inflammation occurring in the AT during obesity is the primary mechanism for developing local and systemic IR.
AT is the primary whole-body regulator of lipid and glucose homeostasis and is no longer considered merely a storage tissue. Obesity leads to severe adipocyte disorders by altering the amount and activity of almost all resident immune cells.
The imbalance of immunological phenotypes is correlated with the development of persistent local inflammation during which several biologically active molecules are released. These molecules affect distal tissues and organs, such as skeletal muscle and liver.
The inflammatory nature of obesity opens new prospects in the development of therapeutic strategies for the treatment of its related metabolic complications. However, there are still a lot of issues that need to be addressed. Anti-inflammatory strategies have proven to be effective in improving obesity-induced IR in murine models.
However, clinical studies are still ongoing to confirm the therapeutic potential in obese and insulin-resistant individuals. Another issue is the modest effects of anti-inflammatory therapies observed in these studies.
Targeting only one inflammatory molecule may not be sufficient to have a beneficial effect; therefore, we could hypothesize the combined use of more anti-inflammatory therapies. In addition, a recent study showed that acute and transient inflammation is essential for healthy AT expansion and remodeling in obesity Asterholm et al.
This finding raises further questions on the effectiveness of anti-inflammatory therapies in the treatment of obesity-induced metabolic disorders. Inflammation is a finely regulated mechanism, and all defects in its balance can cause AT dysfunction.
In the era of personalized and precision medicine, increasing our knowledge of the obesity-induced inflammation mechanisms might enable us to overcome the limitations of the traditional anthropometric indices of obesity.
These anthropometric indices are not correlated with obesity-induced metabolic complications and additional clinical parameters need to be identified for risk assessment Longo et al.
From our point of view, given the strong association between inflammation and obesity complications, circulating inflammatory biomarkers may be used for the risk assessment of these diseases in the future.
The identification and evaluation of these biomarkers in obese patients will allow the prediction of those who will develop obesity-associated metabolic complications.
FB and CM conceived the idea and edited the manuscript. FZ, ML, JN, GR, and AD wrote the manuscript. FZ and ML prepared the figures. All authors reviewed the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Gregor, M. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. M2 macrophages express the surface marker CD and produce antiinflammatory cytokines such as IL 7. The relative and absolute number of M1 macrophages increases in WAT upon obesity, thereby promoting adipose tissue inflammation 7 — Studies in rodents have suggested that adipose tissue inflammation causes local and systemic insulin resistance 9 , 11 — However, it has been demonstrated that immunocompromised mice are not protected from systemic insulin resistance induced by a short-term high-fat diet HFD Furthermore, Tian et al.
have shown that adipose tissue inflammation is dispensable for local and systemic insulin resistance Another study has shown that inhibition of adipose tissue inflammation results in glucose intolerance, suggesting that inflammation may even be a mechanism to counter insulin resistance In humans, expression of the macrophage markers CD68 and TNF-α in WAT correlates with BMI, suggesting that obesity may induce the accumulation of adipose tissue macrophages and inflammation in humans 9 , However, clinical trials targeting TNF-α have shown little or no beneficial effect on systemic insulin sensitivity 18 — Thus, the causal relationship between adipose tissue inflammation and insulin resistance is unclear.
Two models have been proposed to explain the increase in the number of M1 macrophages in WAT upon obesity. The first is that circulating monocytes are recruited to WAT, where they differentiate into M1 macrophages 7 , The second is that obesity induces the proliferation of resident macrophages in WAT However, the mechanism s controlling MCP1 expression in adipocytes upon obesity are poorly understood.
In mammals, mTORC2 consists of mTOR, rapamycin-insensitive companion of mTOR RICTOR , mammalian stress-activated protein kinase—interacting protein 1 mSIN1 , and mammalian lethal with SEC thirteen 8 mLST8 26 — Insulin stimulates mTORC2 to promote glucose uptake in adipose tissue 32 — 34 , liver 35 — 37 , and skeletal muscle 38 , Previously, we and others have shown that adipose-specific Rictor knockout AdRiKO exacerbates obesity-related complications in mice, such as systemic insulin resistance and hepatic steatosis 32 — Here, we used mTORC2-deficient and therefore insulin-resistant AdRiKO mice to investigate the causal relationship between insulin resistance and inflammation.
Furthermore, obesity-induced insulin resistance developed before the accumulation of proinflammatory M1 macrophages in visceral WAT of WT mice. Thus, insulin resistance precedes and causes inflammation in adipose tissue.
AdRiKO exacerbates systemic insulin resistance upon obesity, as evidenced by impaired glucose clearance in response to insulin treatment Figure 1A and refs.
Thus, the AdRiKO mouse is a good model to investigate the causal relationship between insulin resistance and inflammation upon obesity. Furthermore, we confirmed that RICTOR expression, AKT Ser phosphorylation, and PKC expression, readouts for mTORC2 signaling, were decreased, while S6K Thr phosphorylation, a readout for mTORC1 signaling, was not affected in eWAT Figure 1B ; see complete unedited blots in the supplemental material.
Among approximately 3, proteins identified in the proteome, 61 and 16 were up- and downregulated, respectively, in AdRiKO mice compared with controls Figure 1C and Supplemental Table 1.
Gene Ontology GO analysis of the regulated proteins revealed enrichment of immune response—related biological processes Figure 1D , suggesting that insulin resistance due to loss of mTORC2 signaling may cause inflammation upon obesity. A ITT for AdRiKO and control mice fed a HFD for 10 weeks.
Mice were fasted for 5 hours prior to the ITT. Data are presented as the mean ± SEM. B Immunoblots of eWAT from HFD-fed AdRiKO and control mice.
eWAT samples were collected from ad libitum—fed mice. The same lysates were used for proteome analysis. C Regulated proteome with 3 biological replicates.
See also Supplemental Table 1. D GO term analysis of the regulated proteome. To examine further whether mTORC2 in WAT controls inflammation, we quantified immune cells in eWAT of HFD-fed AdRiKO and control mice by flow cytometry.
The numbers of both M1 and M2 macrophages increased in both AdRiKO and control mice during the HFD time course Figure 2, E—G. AdRiKO eWAT showed a disproportionately large increase in M1 macrophages, starting at 6 weeks of HFD feeding Figure 2, E and F.
Quantification of proinflammatory cytokine TNF-α mRNA in SVCs and macrophages isolated from HFD-fed AdRiKO and control mice confirmed the disproportionate increase in M1 macrophages in AdRiKO eWAT Figure 2, H and I , and Supplemental Figure 2, B and C.
These observations indicate that AdRiKO leads to the accumulation of M1 macrophages, confirming that genetically induced insulin resistance due to loss of mTORC2 signaling in WAT promotes inflammation. We note that there was no difference in macrophage numbers between AdRiKO and control mice on a normal diet ND Supplemental Figure 3, A—E , indicating that AdRiKO potentiates inflammation only in response to obesity.
AdRiKO eWAT accumulates M1 macrophages. Representative FACS profiles are shown in A , and quantification is shown in B. C Gene expression of macrophage markers in eWAT from HFD-fed AdRiKO and control mice. Scale bar: μm.
Representative FACS profiles are shown in E , and quantification is shown in F and G. J Immunoblots of eWAT from i-AdRiKO and control mice.
Mice were treated with tamoxifen for 5 days. After 4 weeks, mice were fasted for 5 hours and then treated with PBS or insulin. K ITT for i-AdRiKO and control mice 4 weeks after induction of Rictor knockout.
Our AdRiKO model relies on the adipose-specific promoter aP2 to drive Cre expression and thereby knock out Rictor. However, aP2-Cre can be expressed in cell types other than adipocytes including macrophages 40 , Three lines of evidence suggest that our findings are not due to confounding effects of ectopic knockout of Rictor in macrophages.
First, Rictor expression was unchanged in macrophages isolated from the HFD-fed AdRiKO mice compared with those from control mice Supplemental Figure 4, A and B. HFD-induced insulin resistance precedes the accumulation of adipose tissue M1 macrophages. Our findings indicate that genetically induced local insulin resistance causes the accumulation of M1 macrophages and thus inflammation in WAT upon obesity.
This predicts that HFD-induced insulin resistance precedes inflammation in WT mice. To test this prediction, we performed a longitudinal study with HFD-fed WT mice Supplemental Figure 5A.
WT mice developed eWAT and systemic insulin resistance by week 4 of HFD feeding, as measured by insulin-stimulated glucose uptake and an insulin tolerance test ITT Figure 3, A and B , and Supplemental Figure 5B , respectively.
Mice fed a HFD for 10 weeks remained insulin resistant compared with mice on a ND Figure 3C and Supplemental Figure 5C. The M1 macrophage population in eWAT mildly increased in mice by week 10 of a HFD, but not by 4 or 8 weeks Figure 3D.
Tnfa expression did not increase in mice at 4 or 10 weeks of a HFD Supplemental Figure 5D. These findings are consistent with previous reports showing that mice develop adipose and systemic insulin resistance within several days to 4 weeks of a HFD 44 , 45 , whereas the number of M1 macrophages in WAT increases only within 8 to 10 weeks of a HFD 10 , 15 , 45 , The finding that HFD-induced insulin resistance precedes the accumulation of M1 macrophages is consistent with our above conclusion that insulin resistance leads to inflammation.
HFD-induced insulin resistance precedes the accumulation of M1 macrophages. A Insulin-stimulated 2DGP accumulation in eWAT and muscle from WT mice fed a ND or HFD for 4 weeks.
Mice were fasted for 5 hours, injected with insulin at 0 minutes and 2DG at 10 minutes, and sacrificed at 30 minutes. B and C ITT for WT mice fed a ND or HFD for 4 weeks B or 10 weeks C. Insulin resistance—induced inflammation is specific to visceral WAT.
Adipose-specific loss of mTORC2 signaling directly causes insulin resistance in all WAT depots and indirectly leads to systemic insulin resistance 32 — To test whether AdRiKO causes inflammation in liver or in fat depots other than eWAT see above , we examined macrophage numbers in peri-renal WAT prWAT , subcutaneous WAT sWAT , and liver of HFD-fed AdRiKO and control mice.
AdRiKO prWAT, but not sWAT or liver, had increased numbers of M1 macrophages, Supplemental Figure 6, A—C. Thus, AdRiKO promotes inflammation specifically in visceral WAT eWAT and prWAT. HFD-fed LiRiKO mice had a moderate but nonsignificant increase in the number of hepatic macrophages compared with HFD-fed control mice Supplemental Figure 6D.
Furthermore, the numbers of M1 and M2 macrophages in eWAT were identical in LiRiKO and control mice Supplemental Figure 6E.
Thus, the ability of local insulin resistance to promote inflammation is specific to visceral WAT. Rictor knockout in adipocytes increases expression of the chemokine MCP1. How does insulin resistance in visceral WAT cause local accumulation of M1 macrophages and inflammation?
Amano et al. have suggested that a HFD induces local proliferation of macrophages Alternatively, others have proposed that WAT recruits circulating monocytes, which then differentiate into M1 macrophages 7 , To distinguish between these 2 models, we used flow cytometry to measure the proliferation marker Ki in macrophages in eWAT of HFD-fed mice.
To investigate the possibility that WAT recruits monocytes, we examined the expression of WAT-derived chemokines in eWAT from HFD-fed AdRiKO and control mice. A chemokine array and ELISA revealed increased expression of monocyte chemoattractant protein 1 MCP1, also known as C-C motif ligand 2 [CCL2] in AdRiKO eWAT Figure 4, A and B.
Increased levels of MCP1 were also detected in the plasma of HFD-fed AdRiKO mice Figure 4C. Furthermore, in SVCs isolated from AdRiKO eWAT, we observed significantly increased expression of C-C chemokine receptor type 2 Ccr2 , encoding an MCP1 receptor, as a result of increased numbers of Ccr2 -expressing cells such as monocytes and macrophages Figure 4D.
These findings suggest that insulin-resistant visceral WAT, via MCP1 expression, recruits monocytes, which then differentiate into M1 macrophages.
A Adipokine array of eWAT from HFD-fed AdRiKO and control mice. Immunoblots show the reduction of RICTOR expression and mTORC2 signaling.
B MCP1 protein levels in eWAT from HFD-fed AdRiKO and control mice. C MCP1 protein levels in plasma from HFD-fed AdRiKO and control mice. D Ccr2 mRNA levels in SVCs isolated from eWAT of HFD-fed AdRiKO and control mice. Mice were fed a HFD for 8 weeks and treated with a control or MCP1-neutralizing antibody for 2 weeks with ongoing HFD feeding.
F Percentage of inflammatory monocytes in peripheral blood mononuclear cells PBMCs. Mice were treated as in E. We next tested whether the increase in MCP1 is responsible for M1 macrophage accumulation in AdRiKO eWAT.
Mice were fed a HFD for 8 weeks and then treated with an MCP1-neutralizing or control antibody for 2 weeks along with ongoing HFD feeding. The antibody treatments had no impact on body weight Supplemental Figure 7B. Thus, MCP1 appears to mediate the increase in M1 macrophages in AdRiKO eWAT.
Altogether, our data suggest that mTORC2 inhibition in WAT results in Mcp1 expression, followed by infiltration of monocytes in an MCP1-CCR2—dependent manner. Expression of the Mcp1 gene was increased in the eWAT of HFD-fed AdRiKO and i-AdRiKO mice compared with expression levels in control eWAT Figure 5, A and B , suggesting that MCP1 is upregulated in AdRiKO WAT at the transcriptional level.
Furthermore, we note that the increase in Mcp1 expression Figure 5A coincided with an increase in the number of M1 macrophages in AdRiKO eWAT Figure 2F. The number of macrophages and expression levels of Mcp1 were unchanged in AdRiKO and control eWAT in ND-fed mice Supplemental Figure 3 and Supplemental Figure 8A.
To identify the cells in which Mcp1 expression was induced, we measured Mcp1 mRNA levels in adipocytes and SVCs isolated from eWAT of HFD-fed AdRiKO and control mice Supplemental Figure 2B.
AdRiKO adipocytes, but not SVCs, showed increased Mcp1 expression Figure 5, C and D. To determine whether the regulation of Mcp1 transcription by mTORC2 is cell autonomous, we first treated 3T3-L1 adipocytes with the mTOR inhibitor torin 1 Next, we generated 2 Rictor -knockout 3T3-L1 adipocyte cell lines Figure 5F and Supplemental Figure 8B using the genome-editing CRISPR-Cas9 system Rictor- knockout 3T3-L1 adipocytes were able to differentiate, albeit at a slower rate compared with control cells Supplemental Figure 8C.
Consistent with our in vivo data, Mcp1 expression was increased in the Rictor -knockout 3T3-L1 adipocytes Figure 5G and Supplemental Figure 8B. Serum and insulin treatment suppressed Mcp1 expression in control but not Rictor- knockout 3T3-L1 adipocytes Figure 5H and Supplemental Figure 8D. In WT mice, Mcp1 expression increased by 10 weeks, but not 4 weeks, of HFD feeding Supplemental Figure 8E.
These data support the notion that insulin resistance precedes and promotes Mcp1 transcription in adipocytes. We note that Rictor knockout in liver LiRiKO did not result in hepatic Mcp1 expression Supplemental Figure 8F , consistent with our above finding that LiRiKO failed to stimulate inflammation in liver.
A Mcp1 mRNA levels in eWAT from AdRiKO and control mice during the HFD time course. B Mcp1 mRNA levels in eWAT from HFD-fed i-AdRiKO and control mice. C and D Mcp1 mRNA levels in adipocytes C and SVCs D isolated from eWAT of HFD-fed AdRiKO and control mice. E Mcp1 mRNA levels in 3T3-L1 adipocytes treated with DMSO or nM torin 1 for 6 hours.
F 2DGP accumulation in insulin-stimulated Rictor -knockout or control 3T3-L1 adipocytes treated with DMSO or the JNK inhibitor SP 20 μM. G Mcp1 mRNA levels in Rictor -knockout and control 3T3-L1 adipocytes.
H Mcp1 mRNA levels in Rictor -knockout and control 3T3-L1 adipocytes treated with or without serum and insulin. I Mcp1 mRNA levels in Rictor -knockout and control 3T3-L1 cells treated with DMSO or the JNK inhibitor SP 20 μM for 6 hours. J Immunoblots of Rictor -knockout and control 3T3-L1 adipocytes treated with DMSO or the JNK inhibitor SP 20 μM for 6 hours.
K In vitro JNK kinase assay.
Journal of Biomedical Boosted metabolism benefits Arthritis and chiropractic care 23 Healthy vitamin providers, Article number: 87 Inlammation this article. Metrics details. Sensitivith resistance IR is one of sensitovity Insulin sensitivity and inflammation hallmark inflwmmation pathogenesis and etiology of type 2 diabetes mellitus Insulin sensitivity and inflammation. IR is directly aensitivity with various inflammatory responses which play crucial role in the development of IR. Inflammatory responses play a crucial role in the pathogenesis and development of IR which is one of the main causative factor for the etiology of T2DM. A comprehensive online English literature was searched using various electronic search databases. Different search terms for pathogenesis of IR, role of various inflammatory responses were used and an advanced search was conducted by combining all the search fields in abstracts, keywords, and titles.Insulin sensitivity and inflammation -
Endothelial and smooth muscle cells produce IL-6 and IL-6 gene transcripts that are expressed in human atherosclerotic lesions , Prospective studies of apparently healthy and high-risk individuals indicate that increased IL-6 levels 54 , , and elevated CRP concentration , , a surrogate of IL-6 activity, predicted cardiovascular mortality and future myocardial infarction Substantive interrelationships among circulating IL-6, CRP, and traditional risk factors have been described in women IL-6 has been demonstrated that is a strong independent marker of increased mortality in unstable coronary artery disease and identifies patients who benefit most from a strategy of early invasive management Promoter polymorphisms regulating IL-6 gene expression have been found to be simultaneously associated with circulating levels of CRP , carotid artery atherosclerosis , and peripheral artery occlusive disease , but not with coronary artery disease , probably reflecting the heterogeneity of this disease and study designs.
Recently, genetic variants of Toll-like receptor 4, which confers differences in the inflammatory response elicited by bacterial LPS, were associated with differences in circulating IL-6, acute-phase reactants, and development of atherosclerosis Inflammatory markers predict the development of type 2 diabetes, but evidence is less extensive compared with that for cardiovascular disease.
The Atherosclerosis Risk in Communities ARIC study reported that higher fibrinogen, white cell count, and lower serum albumin predicted later type 2 diabetes. A high leukocyte count also predicted a worsening of insulin action and the development of type 2 diabetes in Pima Indians In the Insulin Resistance Atherosclerosis Study, subjects with diabetes at follow-up 5 yr had higher baseline levels of fibrinogen, CRP, and plasminogen activator inhibitor-1, but the latter association was independent of insulin resistance In the Cardiovascular Health Study, however, baseline fibrinogen, white blood cell and platelet counts, albumin, and factor VIIIc were not associated with development of diabetes, whereas elevated baseline CRP anticipated glucose progression even after adjustment for known baseline predictors of fasting glucose status CRP was associated with progression in glucose status in those subjects with lower BMI.
The later finding suggested to the authors that their results were not due to the production of proinflammatory cytokines by adipose cells In contrast, the Atherosclerosis Risk in Communities ARIC study, sialic acid and orosomucoid remained significant predictors after adjustment for baseline BMI A different prevalence of cytokine polymorphisms in obese and lean subjects cannot be excluded as significant confounders of these associations.
More recently, different studies have confirmed that CRP and other inflammation-sensitive plasma proteins predict incident diabetes mellitus, metabolic syndrome — , and, simultaneously, cardiovascular events Gammaglobulin levels, a nonspecific marker of immune activation, have also been found to predict type 2 diabetes mellitus, whereas rheumatoid factor did not Increased serum ferritin, another acute-phase reactant, predicted the development of diabetes in epidemiological studies However, in this case, a role for increased iron stores cannot be excluded Recent information also suggests that inflammatory markers might predict not only diabetes mellitus but also diabetic-associated complications.
The longitudinal development of increased urinary albumin excretion was significantly and independently determined by increased baseline CRP and fibrinogen in type 2 diabetics and nondiabetic individuals , In fact, in early work by McMillan , progressive increases in plasma levels of CRP, α-1 glycoprotein, haptoglobin, and plasma viscosity correlated with increasing evidence of microangiopathy in type 2 diabetic subjects.
Interestingly, TNF polymorphisms seem also to modulate the risk of diabetic retinopathy — Insulin is increasingly recognized as an antiinflammatory molecule reviewed in Refs. This general antiinflammatory activity has been advocated to explain the remarkable improvements in mortality and morbidity after low doses of insulin in patients with acute myocardial infarction and in patients admitted to a surgical intensive care unit In fact insulin, at physiologically relevant concentrations, causes a suppression of intranuclear nuclear factor-κB which induces the transcription of proinflammatory genes like TNF-α and IL-6 , ICAM-1, and monocyte chemoattractant peptide in human aortic endothelial cells and in mononuclear cells in vivo.
These effects have been related to the ability of insulin to induce the release of NO and to enhance the expression of constitutive NOS Ref. The insulin sensitizer thiazolidinediones decrease the plasma concentrations of TNF-α, sICAM-1, monocyte chemoattractant peptide-1, and CRP, in parallel to improved insulin action — These agents also cause an increase in the antiinflammatory cytokine IL and decrease reactive oxygen species generation by mononuclear cells , In the last few years, the adipocyte protein adiponectin has also been recognized to exhibit antiinflammatory actions.
Interestingly, adiponectin is paradoxically decreased in obesity — in parallel with reduced insulin sensitivity , Recent works show how adiponectin deficiency leads to increased TNF-α activity Weight reduction leads to increases of its plasma levels , and adiponectin administration reverses insulin resistance associated with obesity Salicylates have been described to improve insulin action in vitro and in vivo in animal models , High doses of salicylate and inactivation of IκB kinase-β prevent fat-induced insulin resistance in skeletal muscle by blocking fat-induced defects in insulin signaling and action.
On the other hand, genetic variability in insulin action inhibitor IκB kinase-β does not play a major role in the development of type 2 diabetes in humans Given the antiinflammatory effects of this statin [it has been shown to reduce circulating levels of IL-6 and TNF-α ], this might be the mechanism by which pravastatin favorably influences the development of diabetes.
Similarly, a reduction in the incidence of type 2 diabetes in patients treated with ramipril , , an ACE inhibitor with presumed antiinflammatory effects, is consistent with type 2 diabetes being an inflammatory state.
α-Lipoic acid, a naturally occurring compound, is able to stimulate glucose uptake in cytokine-treated cells that are insulin resistant Oral treatment with α-lipoic acid also improved insulin sensitivity in patients with type 2 diabetes as demonstrated during isoglycemic glucose-clamp Humans live in close association with vast numbers of microorganisms that are present on the external and internal surfaces of our bodies.
The ability to mount a prominent inflammatory response to bacterial pathogens confers an advantage in innate immune defense.
Different nutrient-sensing and metabolic pathways might have evolved in parallel with several mechanisms involved in our fight against infection Fig. Even first-line immune defenses seem to be associated with metabolic pathways. For instance, overweight seems to be a medium-term complication of tonsillectomy Recent evidence shows that adipose cells play a role in the local immune defense during inflammatory processes.
A link between the immune system and adipose tissue has been suggested on the basis of the adipocytokines. TNF-α has been hypothesized to arise by divergence from a primordial recognition molecule of the innate immune system Interestingly, studies of the structure of C1q have revealed an unexpected homology to the TNF family, firmly establishing an evolutionary link between the C1q and TNF families Other factors have been added recently to the list of primordial molecules implicated in the recognition of microbial surfaces that are simultaneously involved in immune system function and in the regulation of energy balance — Soluble CD14, detectable at high concentrations constitutively present in the circulation, is believed to play a key role as intermediate in the neutralization of bacterial LPS under physiological conditions.
Decreased sCD14 is associated with insulin resistance in healthy controls and in patients with type 2 diabetes CRP is a member of the pentraxin family of oligomeric proteins involved with pattern recognition in innate immunity , Myeloperoxidase, an enzyme principally associated with host defense mechanisms, has also been associated with CRP levels and cardiovascular risk Myeloperoxidase seems to modulate vascular signaling and vasodilatory function of NO, linking the fight against infection with metabolic events Glucose sensing is among the most conserved pathways in human evolution, given its vital importance for brain and immune system metabolism.
These two systems are hypothesized to interact to obtain glucose, no matter the cost, from adipose, liver, and muscle tissues, even at the expense of pancreas exhaustion.
Evolutively, the price to pay was very low. The association between several acute-phase reactants, insulin resistance, and IHD might be interpreted as the response of a body to chronic tissue infection, and decreased insulin action would be a byproduct of the inflammatory cascade triggered by physical, environmental, and infectious agents.
Although it seems unlikely that one specific pathogen causes atherosclerosis, the infectious burden is increasingly claimed to be involved in the development of atherosclerosis and possibly insulin resistance.
The association between pathogen burden and extent of atherosclerosis was mainly driven by seropositivities to bacterial and viral infections.
Similar proportions are probably shared by other cytokines. Wilson et al. It may be that specific cytokine genotypes are beneficial in the eradication of infectious diseases, but by creating a proinflammatory phenotype, they predispose to chronic inflammatory diseases or to a more severe form of inflammatory disease with a worse clinical outcome, irrespective of whether the initial triggering event is an infectious agent, autoimmunity, or, indeed, any cause sufficient to stimulate an inflammatory response.
Moreover, prenatal cytokine exposure may result in persisting metabolic and hormonal changes in the fetus by inducing gender-specific programming, leading to insulin resistance Some ethnic groups such as American Indians display a high incidence of obesity and type 2 diabetes mellitus.
In contrast, the frequency of type 2 diabetes is of the lowest in the world, despite increasing obesity among Europeans. It has been suggested that, because most diabetogenes are recessive, the greater the genetic heterogeneity of a population, the lower the chances of homozygosity, thus explaining this European paradox In the presence of numerous infectious diseases, different alleles, protecting against individual pathogens, could make heterozygosity advantageous overall South European history provides explanations of a much higher degree of interbreeding than almost any other area of the world On the opposite side, American Indians, after centuries of relative isolation, have a dramatic history of recent epidemics of infectious disease after their first contact with Europeans.
Those Pima Indians with the better defense against pathogens high cytokine responder eradicated this injury, but at the expense of developing insulin resistance nowadays. The G allele was also more frequently present among Caucasians with type 2 diabetes This allele had been previously found to be associated with both increased serum IL-6 concentration and insulin resistance Hence, genetic diversity might have contributed, simultaneously, to defense against infection and to the lower prevalence of insulin resistance and type 2 diabetes mellitus among Europeans—and to its increased prevalence among Pima Indians However, it should be stated that the genetic-environmental interactions are otherwise complex.
For instance, Africans are one of the most genetically diverse populations [high cytokine responders? according to Ref. On the other hand, glucose sensing is among the most conserved pathways in human evolution, given its vital importance for brain and immune system metabolism.
Thus, it is not surprising that these two systems interact to obtain glucose, no matter the cost, from adipose, liver, and muscle tissues, even at the expense of pancreas exhaustion. Evolutively, the price to pay was very low; the priority was the defense against pathogens, and the mean survival was limited to 35—40 yr.
Glucose is only one component of the metabolic network. A network consists of nodes connected by edges. Biologically speaking, substrates are the nodes, and the metabolic reactions are the connecting edges. Metabolic networks seem to belong to the class of scale-free networks that are highly inhomogeneous because they contain nodes that have a significantly higher number of connections than the average, acting like hubs.
There are a few highly connected substrates that turned out to be the same across the species. Despite being robust and error-tolerant, scale-free networks are also sensitive to attacks on the highly connected nodes That is, perhaps, one of the reasons why former therapeutic agents for insulin resistance were selected on the basis of their effects on serum glucose.
We should take advantage of the glucose hub to treat other aspects of insulin resistance. The moment has arrived to look for earlier markers and hubs for cardiovascular disease, and insulin resistance-mediated inflammation is, perhaps, one of the keys.
In the last few years, insulin action was increasingly recognized as an important effector mechanism of the inflammatory pathways. These interactions occur at all levels of the immune response.
Given the crucial importance of insulin resistance and inflammation in cardiovascular disorders, the study of the interactions of these important pathophysiological mechanisms will shed light on new therapeutic strategies.
Genetic research on factors involved in the inflammatory cascade will probably help to characterize individuals simultaneously prone to obesity, hypertension, dyslipidemia, insulin resistance, and cardiovascular disease. Reaven GM Role of insulin resistance in human disease.
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Antioxidant and Gene Regulation Lab, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, , LA, USA. You can also search for this author in PubMed Google Scholar.
Correspondence to Jian-ping Ye. Reprints and permissions. Gao, Zg. Why do anti-inflammatory therapies fail to improve insulin sensitivity?. Acta Pharmacol Sin 33 , — Download citation. Received : 01 August Accepted : 06 September Published : 31 October Issue Date : February Anyone you share the following link with will be able to read this content:.
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nature acta pharmacologica sinica review article. Why do anti-inflammatory therapies fail to improve insulin sensitivity? Download PDF. Abstract Chronic inflammation occurs in obese conditions in both humans and animals.
The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities Article 13 December Trends in insulin resistance: insights into mechanisms and therapeutic strategy Article Open access 06 July Cytokine modulation by etanercept ameliorates metabolic syndrome and its related complications induced in rats administered a high-fat high-fructose diet Article Open access 23 November Introduction For about two decades, it has been known that inflammation contributes to obesity-associated insulin resistance.
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.
Free fatty acids and insulin resistance Elevated plasma free fatty acids FFAs induce insulin resistance in obese and diabetic subjects Inflammation and energy metabolism Inflammation is associated with increased energy expenditure in patients with chronic kidney disease 51 , cachexia 52 , inflammatory bowel disease 53 and Crohn's disease 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.
Conclusions Type 2 diabetes is one of the major diseases associated with obesity. Similar content being viewed by others. References Hotamisligil GS, Shargill NS, Spiegelman BM.
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Review Series Free inflammatio Joslin Diabetes Center Arthritis and chiropractic care Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. Address correspondence to: Steven E. Shoelson, Joslin Diabetes Center, One Joslin Place, Boston, MassachusettsUSA. E-mail: steven. Thank you for visiting nature. Wensitivity are using a browser inflammahion with zensitivity support sensitiviyt CSS. To obtain the Arthritis and chiropractic care Leg cramp causes, we recommend Enhancing recovery from intense workouts use a more up to date browser infpammation turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. 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.
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