Category: Diet

Chronic hyperglycemia and inflammation

Chronic hyperglycemia and inflammation

Inflamamtion a low O 2 tension and Cramp relief for elderly individuals conditions does hyperglyycemia have any impact on TGF-β production Fig 5. Hypergljcemia Chronic hyperglycemia and inflammation detected the Chronic hyperglycemia and inflammation cytokine productions in mouse adipose tissue, liver, and muscle. Schroder, K. Ronald I. Article CAS PubMed PubMed Central Google Scholar Hull, R. Likewise, IL-β also plays its decisive role to induce inflammation in peripheral tisuues duw to which the ability of peripheral tissues to utilize insulin in response to glucose is decreased which ultimately leads towards the development of IR in peripheral tissues.

Metabolic Health. Ultimate Guide. Inflammation helps heal your body, but chronic inflammation can cause serious damage. Esti Schabelman, MD. You can get an inflammatory response to an injury like a cut or a splinter Chronc, to an inflajmation from bacteria hyyperglycemia a virus, or from Chronic hyperglycemia and inflammation exposures that the body may see as inflammatuon threat, such as stress Chronic hyperglycemia and inflammation, ahd sugar ifnlammation, and environmental inflammatipn.

Inflammation hyprrglycemia usually divided Immune support two types: acute and chronic. Acute is the type that most people think of when they hear inflammation.

Your body hyperglycemiq out white blood cells that assess the situation and signal hyperylycemia reinforcements to attack hyeprglycemia problem aand chemical mediators, such as histamine, that can hyperglyvemia specific inflammayion changes. As a result of this assault, you hyeprglycemia experience one or more Muscle building arm exercises the hyperglcemia most common hyperhlycemia of acute inflammation: redness, pain, swelling, warmth, and loss of function e.

While these can be annoying or uncomfortable, they are an indication Chrlnic the body is doing its job protecting you. Chrpnic inflammation, even hhyperglycemia infections Hyyperglycemia become deadly.

In most cases, once Chronic hyperglycemia and inflammation harm is dealt with, the body can heal and return to aand usually takes somewhere between hours and inflammwtion. However, sometimes the inflammation never hyperlgycemia better and instead turns inflammatioon a Chrnic that lasts for months or years—this is chronic inflammation.

Hjperglycemia may occur in response inflqmmation an abnormality in the body, like cholesterol plaques hypegrlycemia your arteries atherosclerosis or toxins from smoking.

In hyperglycdmia cases, hperglycemia inflammation does not have a definitive cause. Sometimes hyperglycemoa body attacks itself even though there Chronc no injury or harmful agent floating around; this inflammztion to auto-immune Cbroniclike rheumatoid arthritis hpyerglycemia inflammatory bowel disease.

Symptoms can range from very mild to severe, and even people with the hyperglcemia condition can have varying degrees of symptoms. Over hypdrglycemia, chronic inflammation can cause permanent damage to cells and Chronic hyperglycemia and inflammation. Hyperglycsmia blood tests can help confirm the presence of chronic inflammation by measuring for particular markers.

Erythrocyte ihflammation rate ESR is a Inflqmmation test. It looks at how fast Chfonic blood hCronic settle to Improve mental agility bottom of a tube of blood. Normally, the cells settle slowly, but if you have snd they sink faster.

This is a hyperglycfmia Chronic hyperglycemia and inflammation, meaning that it only Chronic hyperglycemia and inflammation inflajmation if you have Incorporating fiber for cholesterol management, not the cause.

Another blood Gut health foods measures Hypetglycemia C-reactive protein CRP levels. During inflammatioh inflammatory response, the liver Nitric oxide boosters CRP and releases it into the bloodstream.

Hormonal balance general, higher levels of CRP indicate the presence of inflammation, but this test also Chronuc not Cyronic the root cause.

Hypergljcemia potential hyperglycemka of inflammation is uric hyperflycemia UA. High levels of uric acid may be present inflam,ation and contribute to Chronic hyperglycemia and inflammation medical conditions like hypsrglycemia disease and Chronic hyperglycemia and inflammation. Research is still inflammatuon in hhyperglycemia area, but some studies suggest that not inflammaton do uric acid levels potentially correlate with inflammation, Chrinic they may also precede inflamjation resistancewhich can then lead to diabetes, Chronic hyperglycemia and inflammation.

Inflammation Anti-aging skincare important regardless hypeglycemia whether you feel it happening.

Chronic inflammation has been linked to cardiovascular diseasediabetes, dementia and depressionamong other conditions. Knowing you have inflammation can encourage you to identify risk factors that you can control and change, like sugar intake, that could lower chronic inflammation.

It is important to make a distinction between the different types of sugars in our food. One way that food sugars can be categorized is based on how they affect your blood glucose levels—this is called the glycemic index. Foods that cause a spike in blood glucose levels after a meal are said to have a high glycemic index.

These include the refined carbohydrates that you have probably been told to avoid. Refined carbohydrates have had their fiber removed along with other nutrients and are found in bread, white sugarcakes, cookies, crackers, tortillas, white rice, and many cereals. Foods that raise your blood glucose levels quickly have been associated with elevated levels of inflammatory markerslike CRP.

You may have heard that different types of sugar like fructosehigh-fructose corn syrup, and sucrose table sugar can cause more or less inflammation, but so far studies have not shown a difference in the levels of inflammatory markers among kinds of sugars. Eating too much of any type of sugar can lead to spikes in your blood glucose levels, also called hyperglycemia.

In most healthy people, the body responds to these spikes by releasing insulin, a hormone that works to bring glucose levels back down to normal.

This state is known as insulin resistance and it is proinflammatory, potentially causing damage throughout your body. One target of these harmful effects is your endothelial cellsthe cells that line your blood vessels.

Repeated levels of high blood sugar can cause your blood vessels to produce damaging reactive molecules called free radicals, via compounds called advanced glycation end products AGEs. Too much free radical activity generates oxidative stressdamage to endothelial cell function, and inflammation in the blood vessels.

Hyperglycemia can also cause oxidation of free fatty acids stored in your fat cellswhich contributes to inflammation. In addition, glucose causes the oxidation of low-density lipoprotein LDLincreasing your risk of plaque build-up in your blood vessels.

Another negative effect is that high blood sugar levels promote blood vessel constriction and platelet clumpingwhich can promote blood clots. Lastly, we all know that excess sugar leads to weight gain, which in turn increases your risk of other medical problems like obesity, high blood pressure, and many more.

Diabetes, which is fundamentally a disease of glucose dysregulation, is itself a severe proinflammatory state. In light of the detrimental effects that high blood glucose levels can have on the body, it should not come as a surprise that many health problems are related to hyperglycemia and inflammation.

Long-term inflammatory diseases are the most significant cause of death worldwide. While chronic inflammation may be present without symptoms or only mild findings initially, it contributes to many long-term health problems, including :.

While it may seem like inflammation is everywhere, there are steps that you can take to limit it. Changes in your diet are among the easiest ways to decrease inflammation. Avoid refined carbohydrates, sugary beverages, and other foods that cause spikes in your blood glucose levels.

Instead, increase your consumption of fiber, fruits, vegetables, nuts, seeds, and other low-glycemic-index foodsall of which may help lower your risks of cardiovascular disease and diabetes. The plant chemicals called polyphenols in green and black teas have been shown to lower levels of inflammatory markers, like CRP.

Curcumin, present in turmerichas been shown to help with inflammation in animal studies. You already know that exercise, especially moderate intensity exercisecan help with weight loss—but it may also decrease the levels of proinflammatory chemicals in your body, regardless of how much weight you lose.

Smoking and stress are two other factors that can increase inflammation. However, it can also wreak havoc in your body if left unchecked, especially over the long run.

Positive lifestyle choices that limit inflammation can go a long way toward keeping your body healthy. Why are antioxidants good for you? They reduce oxidative stress, a condition of electron imbalance in your cells that underlies metabolic dysfunction.

Emma Betuel. Casey Means, MD. Metabolic Basics. Glucose is a simple carbohydrate, a monosaccharide, which means it is a single sugar. We get glucose from the food we eat.

Mike Haney. Mental Health. Evidence is clear that SARS-CoV-2 can trigger blood sugar problems, even in people without diabetes, and that high glucose worsens COVID outcomes. Kristen Mascia. Ami Kapadia. Omega-3 fatty acids improve cellular health, help reduce inflammation and promote metabolic health.

Here's the science behind them and how you can get more. Kaitlin Sullivan. Rich Joseph, MD. The glycemic index provides insight into how particular foods affect glucose but has limitations. Stephanie Eckelkamp. The Explainer. Being aware of these causes of inaccurate data can help you identify—and avoid—surprising and misleading feedback.

Joy Manning, RD. Inside Levels. Levels Co-Founder's new book—Good Energy: The Surprising Connection Between Metabolism and Limitless Health—releases May 14; available for pre-order today.

The Levels Team. Metabolic flexibility means that your body can switch easily between burning glucose and fat, which means you have better energy and endurance. Jennifer Chesak. Dominic D'Agostino, PhD. Inflammation and glucose levels: How high blood sugar can turn a good system bad.

Written By Esti Schabelman, MD. Article highlights Inflammation is a natural defense system in which your body attacks something it sees as a harm, such as a cut, an infection or even stress. That response produces symptoms like redness, pain, swelling, warmth, and loss of function. Chronic inflammation can increase your risk of heart attack, obesity, cancer and diabetes, among other conditions.

High blood sugar, or hyperglycemia, and the insulin resistance that often accompanies it, can be proinflammatory. A healthy diet and lifestyle can greatly reduce your chance of chronic inflammation.

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: Chronic hyperglycemia and inflammation

The Link Between Inflammation and Blood Glucose

It may occur in response to an abnormality in the body, like cholesterol plaques in your arteries atherosclerosis or toxins from smoking. In many cases, chronic inflammation does not have a definitive cause.

Sometimes the body attacks itself even though there is no injury or harmful agent floating around; this leads to auto-immune diseases , like rheumatoid arthritis and inflammatory bowel disease. Symptoms can range from very mild to severe, and even people with the same condition can have varying degrees of symptoms.

Over time, chronic inflammation can cause permanent damage to cells and tissues. Sometimes blood tests can help confirm the presence of chronic inflammation by measuring for particular markers.

Erythrocyte sedimentation rate ESR is a common test. It looks at how fast red blood cells settle to the bottom of a tube of blood. Normally, the cells settle slowly, but if you have inflammation they sink faster. This is a non-specific test, meaning that it only tells you if you have inflammation, not the cause.

Another blood test measures your C-reactive protein CRP levels. During an inflammatory response, the liver makes CRP and releases it into the bloodstream. In general, higher levels of CRP indicate the presence of inflammation, but this test also does not identify the root cause.

Another potential marker of inflammation is uric acid UA. High levels of uric acid may be present in and contribute to proinflammatory medical conditions like heart disease and diabetes. Research is still needed in this area, but some studies suggest that not only do uric acid levels potentially correlate with inflammation, but they may also precede insulin resistance , which can then lead to diabetes.

Inflammation is important regardless of whether you feel it happening. Chronic inflammation has been linked to cardiovascular disease , diabetes, dementia and depression , among other conditions.

Knowing you have inflammation can encourage you to identify risk factors that you can control and change, like sugar intake, that could lower chronic inflammation. It is important to make a distinction between the different types of sugars in our food.

One way that food sugars can be categorized is based on how they affect your blood glucose levels—this is called the glycemic index. Foods that cause a spike in blood glucose levels after a meal are said to have a high glycemic index. These include the refined carbohydrates that you have probably been told to avoid.

Refined carbohydrates have had their fiber removed along with other nutrients and are found in bread, white sugar , cakes, cookies, crackers, tortillas, white rice, and many cereals. Foods that raise your blood glucose levels quickly have been associated with elevated levels of inflammatory markers , like CRP.

You may have heard that different types of sugar like fructose , high-fructose corn syrup, and sucrose table sugar can cause more or less inflammation, but so far studies have not shown a difference in the levels of inflammatory markers among kinds of sugars. Eating too much of any type of sugar can lead to spikes in your blood glucose levels, also called hyperglycemia.

In most healthy people, the body responds to these spikes by releasing insulin, a hormone that works to bring glucose levels back down to normal. This state is known as insulin resistance and it is proinflammatory, potentially causing damage throughout your body.

One target of these harmful effects is your endothelial cells , the cells that line your blood vessels. Repeated levels of high blood sugar can cause your blood vessels to produce damaging reactive molecules called free radicals, via compounds called advanced glycation end products AGEs.

Too much free radical activity generates oxidative stress , damage to endothelial cell function, and inflammation in the blood vessels. Hyperglycemia can also cause oxidation of free fatty acids stored in your fat cells , which contributes to inflammation.

In addition, glucose causes the oxidation of low-density lipoprotein LDL , increasing your risk of plaque build-up in your blood vessels. Another negative effect is that high blood sugar levels promote blood vessel constriction and platelet clumping , which can promote blood clots. Lastly, we all know that excess sugar leads to weight gain, which in turn increases your risk of other medical problems like obesity, high blood pressure, and many more.

Diabetes, which is fundamentally a disease of glucose dysregulation, is itself a severe proinflammatory state. In this case, hyperglycemia has an effect on its own but it was amplified by hypoxia. Macrophage activation did not have any effect on GM-CSF gene expression of each group one hour after LPS addition Fig 3D.

A long term effect of hypoxia was observed as the gene expression of cells cultivated in hypoxia was half that of those cultivated in normoxia. Therefore, hyperglycemia and hypoxia have a negative effect on inflammation as they upregulate the gene expression of the inflammatory cytokines TNF-α, IL-6 and IL-1 in activated macrophages.

The LPS activation of macrophages led to a slight increase of the CD gene expression in normoxia and normoglycemia Fig 4A. Hypoxia and hyperglycemia had a long term effect on this gene expression. Low oxygen tension and high glucose concentration negatively impacted the CD expression on their own.

Macrophages exhibited a drastic upregulation of the Class B Scavenger receptor gene when the cells were cultivated in hypoxia. No effect was observed in normal O 2 condition Fig 4B.

After 17 hours post-activation, Class B Scavenger gene expression recovered its basal level irrespective of the culture conditions. However hypoxia had a slight positive effect when cells were cultured in hyperglycemia. Hence, hypoxia and hyperglycemia decreases the abilities of activated macrophages for phagocytosis because the expression of CD and Class B scavenger are downregulated.

The TGF-β1 gene expression was not modified one hour after activation of macrophages regardless of the O 2 and glucose conditions Fig 5. This expression did not change after 17 hours post activation either. Hence a low O 2 tension and hyperglycemic conditions does not have any impact on TGF-β production Fig 5.

SOCS-3 was upregulated one hour after LPS activation when the cells were cultivated in hypoxia. This upregulation was higher for macrophages cultivated in normoglycemia Fig 6.

The SOC-3 gene expression decreased to its basal level after 17 hours in these groups. In contrast, the cells cultivated in normoxia and hyperglycemia exhibited an upregulation of SOCS The goal of this study was to analyze the impact of hyperglycemia on the macrophage phenotype focusing on proteins involved in inflammation, proliferation, apoptosis, ECM breakdown and wound healing.

For this purpose, a gene expression microarray analysis was performed on activated macrophages cultured in a hyperglycemic and hypoxic environment with a low quantity of bovine serum with the aim of mimicking the chronic wound milieu.

Subsequently, the effect of hyperglycemia and hypoxia were analyzed separately to understand their contribution in the chronic wounds. Lastly a potential synergistic effect of high glucose concentration and low O 2 tension was evaluated.

Hyperglycemia has several detrimental effects on human homeostasis. A chronic high glucose concentration leads to a process of protein glycation and the production of advanced glycation endproducts AGEs.

AGEs promote macrophage activation via NF- κ B and stimulate the production of reactive oxygen species ROS [ 22 ]. As a consequence, diabetes predisposes to epigenetic changes which lead to chronic inflammation [ 23 ].

The microarray results show that 13 pro-inflammatory cytokines and 10 chemokines were upregulated in hyperglycemia, thereby confirming the perpetual dysregulation of the inflammatory homeostasis. Pro-inflammatory macrophages are more metabolically active in hyperglycemic conditions and exclusively use glucose as a source of energy [ 24 ].

Hence, this mode of energy production can contribute to the failure to resolve inflammation. Chronic wounds are characterized by the recruitment and the persistence of immune cells in the wound bed neutrophils and macrophages [ 25 ].

The results showed the upregulation of 11 anti-apoptotic genes and the downregulation of 3 pro-apoptotic genes, indicating the direct impact of hyperglycemia on the large number of macrophages inside the cutaneous wound bed.

One major feature of impaired wound healing is the massive breakdown of extracellular matrix. High glucose concentration triggers the production and secretion of metalloproteinases such as MMP-9 and MMP-2 by fibroblasts, keratinocytes and macrophages [ 25 , 26 ].

In our conditions, hyperglycemia did not have a direct effect on proteases as only MMP-7 was affected. In addition, this enzyme was slightly downregulated. Lipopolysacharide LPS is an outer membrane component of Gram negative bacteria which activates macrophages [ 27 ].

LPS contact with TLR receptors orientates macrophages towards a pro-inflammatory M1 phenotype. This phenotype is characterized by the production of inflammatory cytokines such as IL-6, IL-1, TNF-α, reactive species of oxygen ROS and NO [ 28 ].

The expression of inflammatory cytokines is based on the NF- κ B activation in macrophages [ 29 ]. AGEs interacting with RAGE, their membrane receptor, can be a continuous activator of NF- κ B. As a result, AGEs increase the production of pro-inflammatory cytokines as previously described [ 30 ].

Hypoxia is associated with the activation of hypoxia inducible factors HIFs which is the key mediator of the induction of IL-6, IL-1, TNF-α [ 31 ]. Hence, hypoxia and hyperglycemia could have a synergistic effect on the production of pro-inflammatory cytokines.

In addition, a cross-talk exists between HIF and NF- κ B to increase this production. We analyzed in detail the impact of hypoxia and high glucose on cytokine production with a kinetic view. After one hour post LPS activation, the combination of hypoxia and hyperglycemia had a dramatic effect on the expression of TNF-α and IL The combination of hyperglycemia and hypoxia is required to induce a sustained production of pro-inflammatory cytokines as the same phenomenon was observed for TNF-α and IL Beside its major role in inflammation, it has been recently shown that IL-6 could have anti-inflammatory effects via modulation of macrophage phenotype [ 32 ].

IL-6 promote the M2 phenotype of macrophages by inducing the expression of the IL-4 receptor [ 32 ]. In this study, the IL-4 receptor was not upregulated. Several studies have reported on the anti-inflammatory effect of IL-6 and the dependency on the concentration.

In this study, Il-6 was dramatically upregulated and orientated its action towards chronic inflammation [ 32 ]. Regarding IL-1, only hypoxia had a short term impact on the expression of this cytokine. An effect was observable 17 hours post activation for the cells cultivated in hypoxia and hyperglycemia.

This shows their importance for a long term effect on inflammation. Moreover, the sustained and prolonged production of IL-1 contributes to diminish wound healing by activating TLR receptors and maintaining macrophages in a M1 phenotype [ 33 ].

Granulocyte macrophage colony-stimulating factor GM-CSF is highly upregulated in hyperglycemic conditions. GM-CSF is produced during the inflammation phase and is a marker of M1 macrophages [ 34 ].

This cytokine stimulates the production of chemokines such as CCL2 and CCL3 and is involved in the recruitment of myeloid cells within the wound [ 33 ].

The GM-CSF expression is induced by pro-inflammatory cytokines such as IL-1 and TNF-alpha. As a consequence, the high production of pro-inflammatory cytokines by high glucose and low O2 tension increases the expression of GM-CSF, which has also a negative effect on inflammation.

In our conditions, GM-CSF was not impacted by hyperglycemia which is not consistent with the results of the micro array. Suppressor of cytokine signaling 3 SOCS3 is associated with the pro-inflammatory M1 phenotype of macrophages.

In addition, SOCS3 decreases the phagocytic activities of macrophages for apoptotic neutrophils. The decrease of clearance of dead neutrophils impedes the resolution of inflammation and a pro-inflammatory environment shows a strong upregulation of SOCS3 [ 35 , 36 ].

Hyperglycemia seems to have a short term negative effect on SOCS3. Surprisingly, hyperglycemia seems to favour the resolution of inflammation at this time point. However, hyperglycemia has a negative effect after 17 hours when the cells are cultivated in hyperglycemia.

As SOCS-3 is upregulated in this study, this confirms the inflammatory effect of IL-6 in hyperglycemia. It has been shown this cytokine has an anti-inflammatory effect only when SOCS-3 was downregulated or ablated [ 37 ]. Hyperglycemia combined with hypoxia also led to the upregulation of a panel of chemokines.

Among them, CCL-4 is of great interest because it activates neutrophils which can trigger neutrophilic inflammation [ 38 , 39 ]. In addition, this chemokine triggers the production of pro-inflammatory cytokines. Five C-X-C chemokines CXCL 1- CXCL5 were also upregulated in hyperglycemia.

For example, CXCL2 is highly expressed. Moreover, CXCL2 recruit neutrophils to infection sites. Overall, the other chemokines have the same effect, recruiting leucocytes in the wound. Hence, hyperglycemia and hypoxia create a vicious circle which maintains a high inflammation in the wound and prevents the switch from the inflammatory phase to the proliferative one.

Phagocytosis of dead cells is required for the resolution of inflammation and the transition towards the proliferative phase [ 41 ] because impaired cell clearance has been observed in diabetic wounds [ 42 ]. CD36 is a member of the class B scavenger receptor family found in macrophages.

CD36 is an efferocytosis receptor which acts in combination with α v β 3 integrin to engulf dead neutrophils [ 41 ]. Unlike the normoglycemic conditions, CD36 expression does not increase in hyperglycemia one hour after LPS activation.

This result shows the impaired phagocytic activities of macrophages cultivated in high glucose. In addition, CD36 mediate s the bacteria phagocytosis and the production of inflammatory molecules such as IL-8 [ 43 ].

Hence, the absence of an upregulation of CD36 following the activation by LPS suggests the lower ability of macrophages to combat infection when they are in a hyperglycemic milieu.

Class B scavenger type I receptors CLA-1 are also involved in the pathogen s recognition and the removal of apoptotic cells. They have a lot of structural similarities with CD36 [ 43 ]. They also have an effect on cytokine production as Knock Out CLA-1 mice expressed more inflammatory cytokines than the wild type [ 43 ].

The results showed that hypoxia is an important stimulus for Class B scavenger expression because its expression is multiplied by 12 in hypoxia over that in the normoxic conditions. Hyperglycemia negatively modulates this upregulation showing once again the impaired phagocytic abilities of diabetic macrophages, thereby settling down the chronic inflammation in the cutaneous wound.

TGF-B1 is a master regulator of the wound healing process by promoting the switch between the inflammation and the proliferative phase [ 44 ]. The TGF-B activity counterbalances the effect of TNF-alpha in macrophages [ 45 ] and favours angiogenesis, ECM deposition and fibroblast proliferation.

Hyperglycemia and hypoxia did not have any effect on its gene expression. Hence, hyperglycemia only negatively impacts the expression of pro-inflammatory cytokines but not those involved in wound healing.

Hyperglycemia has a negative impact on the wound healing of foot diabetic ulcers. High glucose level acts in synergy with hypoxia to maintain the state of chronic inflammation observed in chronic wounds.

Hyperglycemia increases the expression of pro-inflammatory cytokines and chemokines by macrophages and decreases their ability of phagocytosis, required for the resolution of inflammation. By contrast, the cytokines involved in wound healing were not impacted by the high glucose concentration. This overview of the macrophage behavior cultivated in hyperglycemia and hypoxia could be helpful towards discovering novel relevant targets for the treatment of foot diabetic ulcers.

The authors would like to thank Dr Oliver Carroll for his technical guidance in the project, Dana Toncu for editorial and critical assessment of the manuscript, and Mr Anthony Sloan for his editorial assistance in finalizing the manuscript.

Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Article Authors Metrics Comments Media Coverage Reader Comments Figures. Abstract Diabetic foot ulcers DFUs are characterized by a chronic inflammation state which prevents cutaneous wound healing, and DFUs eventually lead to infection and leg amputation.

Introduction Diabetic foot ulcers are the most common, painful and crippling complications of diabetes mellitus [ 1 ]. In pathological conditions, macrophages are locked in the M1 phenotype, thereby leading to chronic inflammation Hypoxia in DFU creates conditions that are disadvantageous because the low oxygen tension induces the increased release of pro-inflammatory cytokines via the activation of NF- κ B signaling pathways [ 10 , 11 ].

Download: PPT. Fig 1. Differentiation and activation of macrophages cultivated in hyperglycemia and hypoxia. Results 3. Table 1. Gene expression profile of THP-1 derived macrophages cultivated in hyperglycemia and hypoxia.

Effect of hyperglycemia and hypoxia on gene expression of inflammatory cytokines The impact of hypoxia and hyperglycemia on the gene expression of TNF- α, IL-1a, IL-6 and GM-CSF was analyzed in detail and compared to the results obtained with the microarray. Fig 3. Fig 5. Impact of hyperglycemia and hypoxia in activated macrophages on the gene expression of TGF-β, the major wound healing molecule.

Fig 6. Impact of hyperglycemia and hypoxia on the gene expression of SOCS-3 in activated macrophages. Conclusion Hyperglycemia has a negative impact on the wound healing of foot diabetic ulcers.

Obesity, increased linear growth, and risk of type 1 diabetes in children. Diabetes Care 23 , — Libman, I. Changing prevalence of overweight children and adolescents at onset of insulin-treated diabetes.

Fourlanos, S. Insulin resistance is a risk factor for progression to type 1 diabetes. Nathan, D. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy.

Type 1, type 1. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Koska, J. The effect of salsalate on insulin action and glucose tolerance in obese non-diabetic patients: results of a randomised double-blind placebo-controlled study. Diabetologia 52 , — Download references.

The authors wish to thank their scientific collaborators who have contributed so much to these studies, in particular A. Goldfine, J.

Lee, D. Mathis, K. Maedler, P. Halban, T. Mandrup-Poulsen, J. Ehses and M. Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH, Basel, Switzerland. Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, , Massachusetts, USA. You can also search for this author in PubMed Google Scholar.

Marc Y. Donath is listed as the inventor of a patent filed in for the use of an interleukin-1 receptor antagonist for the treatment of or prophylaxis against type 2 diabetes. He is a consultant for Novartis, XOMA, Eli Lilly and Company, Cytos, Merck and AstraZeneca.

Steven E. Shoelson holds patents on the use of salicylates in diabetes, prediabetes and cardiovascular disease. He has consulted for Catabasis, Amylin, AstraZeneca, Merck, Genentech, XOMA and Kowa. A pathological condition in which insulin becomes less effective at lowering blood glucose levels.

ER stress. A response by the ER that results in the disruption of protein folding and the accumulation of unfolded proteins in the ER.

The toxic effects of elevated levels of free fatty acids. These detrimental effects may be functional and reversible, or may lead to cell death. The toxic effects of hyperglycaemia.

A disease resulting from an attack by the innate immune system on the body's own tissues. By contrast, autoimmune diseases are caused by the pathological activation of adaptive immune responses. Autoimmune and autoinflammatory diseases have some characteristics in common, including shared effector mechanisms.

A macrophage that is activated by Toll-like receptor ligands such as lipopolysaccharide and interferon-γ, and that expresses inducible nitric oxide synthase, which generates nitric oxide. A macrophage that is stimulated by interleukin-4 IL-4 or IL and that expresses arginase 1, the mannose receptor CD and the IL-4 receptor α-chain.

The Kit W—sh or sash mutation abolishes KIT expression in mast cells, and the mutant mice are deficient in mast cells. Inflammation of the pancreatic islets during the progression of diabetes. Insulitis in type 1 diabetes is caused by autoimmunity and in type 2 diabetes by metabolic stressors such as hyperglycaemia and elevated levels of free fatty acids.

A condition in which the flow of blood to a tissue or organs is less than normal, and which results in injury to that tissue or organ. Severe weight loss, muscle wasting and debility caused by prolonged disease. It is thought to be mediated through neuroimmunoendocrine interactions.

A protein hormone that regulates energy intake and expenditure. It is one of the most important adipose-derived hormones and its production correlates with the mass of adipose tissue. A molecular complex of several proteins that, when activated, results in the production of active caspase 1, which cleaves pro-interleukin-1β pro-IL-1β and pro-IL to produce the active cytokines.

A prodrug form of salicylic acid that has fewer side effects than sodium salicylate. Salsalate is approved for use in humans as a source of salicylic acid. Reprints and permissions. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11 , 98— Download citation.

Published : 14 January Issue Date : February Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. nature nature reviews immunology review articles article. Subjects Immunopathogenesis Inflammation Therapeutics Type 2 diabetes.

Key Points Type 2 diabetes is associated with obesity, ageing and inactivity. Abstract Components of the immune system are altered in obesity and type 2 diabetes T2D , with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the vasculature and circulating leukocytes.

Access through your institution. Buy or subscribe. Change institution. Learn more. Figure 1: Development of inflammation in type 2 diabetes. Figure 2: Interleukin-1β-induced inflammation in islets of patients with type 2 diabetes. References Shoelson, S. Article CAS PubMed PubMed Central Google Scholar Donath, M.

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Type 2 diabetes as an inflammatory disease In the case of type 1 diabetes, inflammation is part of the autoimmune response that causes the disease. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Subsequently, the effect of hyperglycemia and hypoxia were analyzed separately to understand their contribution in the chronic wounds. Jones LA, Anthony JP, Henriquez FL, Lyons RE, Nickdel MB, Carter KC, Alexander J, Roberts CW. This normal immune response can protect and heal our body, but when there is too much inflammation it can damage our tissues and harm our health.
ORIGINAL RESEARCH article Chronic hyperglycemia and inflammation 3 Hyperglyceima inflammation aggravated the impairment on insulin CChronic in insulin-targeted tissues of HFD-fed mice. Separate Cheonic were Chronic hyperglycemia and inflammation adjusted for Plant-based protein supplements within 48 h of admission and corticosteroid use. M2-type macrophage A macrophage that is stimulated by interleukin-4 IL-4 or IL and that expresses arginase 1, the mannose receptor CD and the IL-4 receptor α-chain. Thapa B, Lee K. More Ultimate Guides. Published : 14 January
Inflammation and glucose levels: How high blood sugar can turn a good system bad

The fasting glucose levels were unchanged in HFD-fed mice compared with NCD-fed mice Fig. After glucose challenge, blood glucose concentration of HFD group was persistently higher than that of the NCD group Fig.

Insulin levels in serum were significantly increased in HFD-fed mice Fig. After insulin loading, blood glucose levels decreased slowly and still higher in the HFD group Fig. We also measured the major molecules involved in insulin signaling in insulin-sensitive tissues.

HFD inhibited the levels of total IRS1, IRS2, and p-AKT:AKT ratio in the liver, muscle, and adipose tissue Fig. Mice were starved overnight before executed and the blood was collected for fasting blood glucose C and serum insulin D detection.

Chronic inflammation aggravated the impairment on insulin signaling in insulin-targeted tissues of HFD-fed mice. The protein expression of IRS1 and IRS2 A , p-AKT ser , and AKT B in the adipose tissue, liver, and muscle was detected by western blot.

The histogram represents mean± s. Casein injection further aggravated impaired glucose tolerance, showing higher blood glucose levels after glucose injection and lower ITT slope after insulin loading in the casein plus HFD group Fig.

Casein-injected mice had a notable increase in fasting glucose levels Fig. Likewise, casein injection further downregulated IRS1, IRS2, and p-AKT protein expression Fig. Results from pancreatic histomorphology Fig. However, casein injection impaired β cell function by reducing islet mass and insulin content in HFD-fed mice Fig.

We further determined the expression of key participants in β cell functional integrity, namely pancreatic duodenal homeobox 1 PDX1 , glucokinase GK , glucose transporter 2 GLUT2 , and insulin.

The mRNA expression of Pdx1 and Gk had no obvious change, while both Glut2 Slc2a2 as well as insulin mRNA levels were significantly increased in HFD group Fig. The mRNA expression of Pdx1 , Glut2 , Gk , and insulin were significantly downregulated in casein-injected mice Fig.

Chronic inflammation exacerbated pancreatic β cell dysfunction in HFD-fed mice. A Hematoxylin—eosin HE staining in pancreas including the islet mass boxed, arrows. B Insulin immunohistochemistry. Magnification ×10 top panels and ×40 bottom panels.

Values are mean± s. Data showed that apoptotic β cell numbers had no difference between HFD group and NCD group Fig. However, casein injection notably increased β cell apoptosis Fig. Chronic inflammation aggravated β cell apoptosis in HFD-fed mice. A Apoptosis of insulin-expressing cells on islet sections was determined by the TUNEL assay.

Representative examples of pancreatic islets stained by immunofluorescence for insulin red , marker of cell apoptosis TUNEL green , and nuclear stain DAPI blue imaged at ×.

B The percentage of apoptotic β cells was calculated as described in Materials and methods section. Chronic systemic inflammation plays an important role in the pathogenesis of multiple metabolic disorders, including insulin resistance, T2DM, and obesity. Most obese individuals do not develop diabetes because β cells initially compensate for insulin resistance.

Clinical studies have identified elevated serum levels of TNFα and IL6 as risk factors for subjects developing into T2DM Spranger et al. We presume the progression of obesity-related β cell dysfunction may be related to a state of chronic inflammation. Mice on long-term HFD revealed β cell dysfunction and diminution of glucose-induced insulin secretion and developed glucose intolerance as a result of insulin resistance Collins et al.

In our experimental setting, there were no change in serum SAA and TNFα levels but increase in TNFα and MCP1 expression in the adipose tissue, liver, and muscle in HFD-fed mice compared with NCD-fed mice, in agreement with previous reports on overexpression of TNFα in different white adipose tissue depots of obese individuals and a normal circulating serum TNFα level Hotamisligil et al.

The bacterial endotoxin, LPS, induced inflammatory stress is presented during endotoxic septic shock, a condition that often leads to multiple organ failure and mortality Zhang et al. LPS injection results in robust CNS-controlled sickness behaviors accompanied by increases in inflammatory cytokines IL1β, TNFα, and IL6 in the blood and brain.

Compared with the administration of LPS, the inflammation induced by casein is characterized by an increased SAA, which is well documented as a good marker of chronic low-grade systemic inflammation. Serum TNFα and SAA levels were significantly increased after casein injection for 14 weeks.

Moreover, TNFα and MCP1 expressions in the adipose, liver, and muscle were upregulated in casein plus HFD group compared with HFD group, suggesting that casein injection successfully induced chronic systemic and local inflammation in HFD-fed mice.

In the obesity-induced metabolic disorder, FFA, which is commonly elevated in obese individuals, may drive a compensatory increase in β cell mass and function followed by attenuation as T2DM develops El Assaad et al.

The data showed that HFD mice maintained normoglycemia in the presence of impaired GTT and higher serum insulin levels, whereas mice in the HFD plus casein injection group had notable hyperglycemia and low serum insulin levels, implying that chronic inflammation accelerated deterioration of β cell function.

Compared with HFD-fed mice, casein-injected mice revealed parallel serum FFA levels and marked β cell dysfunction, suggesting that chronic inflammation is an independent risk factor in the destruction of pancreatic β cells. The dysregulation of IRS1 and IRS2 and the inhibition of its signaling downstream are the primary mechanisms of chronic inflammation-induced insulin resistance.

In this study, casein injection notably diminished the IRS1, IRS2, and p-AKT levels in the liver, muscle and adipose tissues of mice, and revealed obvious insulin resistance. Research showed that IRS1 was the principal mediator of hepatic insulin action that maintains glucose homeostasis, especially during nutrient excess.

IRS1-deficient liver showed poor regulations of the key gluconeogenic genes and impaired glucose tolerance and insulin sensitivity. Moreover, IRS1 was required to suppress hepatic glucose production during hyperinsulinemic—euglycemic clamp Guo et al. In this study, inflammatory stress induced by casein may affect hepatic glucose production and gluconeogenesis by inhibiting hepatic IRS1.

Data on the augmentation of islet mass and pancreatic insulin content in HFD-fed mice compared with NCD-fed mice showed that islet mass and pancreatic insulin content were markedly increased in HFD-fed mice, consistent with previous studies Collins et al.

In this study, we found that chronic inflammation impaired β cell function by reducing islet mass and pancreatic insulin content in HFD-fed mice. To explore the underlying mechanism of inflammation-mediated impairment in pancreatic islets of HFD-fed mice, we determined the expression of key participants in insulin synthesis and secretion.

Pdx1 acts in β cells as a house-keeping transcription factor for insulin gene expression Melloul HFD feeding did not significantly affect pancreatic Pdx1 mRNA levels, but obviously increased Glut2 and insulin mRNA expression associated with elevated serum insulin concentrations.

Therefore, hyperinsulinemia in obese individuals may correlate with improved β cell insulin secretion. In contrast with HFD-fed group, casein injection significantly reduced pancreatic Pdx1 , Glut2 , Gk , and insulin mRNA levels and serum insulin levels, indicating that chronic inflammation exacerbated HFD-induced islet β cell dysfunction and accelerated the progression of obesity-related T2DM.

Recent evidences have suggested that increased apoptosis of pancreatic β cells could explain insulin deficiency Butler et al. However our data did not demonstrate that HFD feeding by itself for 14 weeks increased β cell apoptosis. Taken together, our results demonstrated that chronic inflammation exacerbated HFD-related β cell dysfunction and apoptosis, resulting in glucose metabolism disorder.

Obese patients with chronic inflammation are more prone to develop into T2DM much earlier. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

This work was financial supported by the National Natural Science Foundation of China , , , , , and Key Program nos and , Major State Basic Research Development Program of China Program nos CB and CB Y W, T W, and J W carried out experiments and researched data, L Z performed the data analysis, Q L researched data, Z V reviewed manuscript and contributed discussion, J F M refined the manuscript, S H P reviewed manuscript, Y C designed the project and experiments and wrote manuscript, and X Z R designed the project and reviewed manuscript.

European Journal of Clinical Investigation 32 Suppl 3 14 — Diabetes 49 — Diabetes 52 — Chen CM Overview of obesity in Mainland China. Obesity Research 9 Suppl 1 14 — Diabetes 59 — Defronzo RA Banting Lecture.

From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58 — Diabetes Care 34 — Endocrinology — Diabetologia 47 — Molecular and Cellular Biology 29 — Hotamisligil GS Inflammation and metabolic disorders.

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Chronic hyperglycemia and inflammation -

In this article, we have comprehensively summarized the scientific literature and experimental evidences dipicting how inflammatory responses are interlinked with the pathogenesis of IR, including assiciated challeges and last but not least the treatment strategies that may be the opted to counteract development and progression of IR.

Moreover, we also searched the treatment strategies for insulin resistance. Using these search terms, appropriate articles were selected and for a comprehensive review, investigation of literature was further supplemented by searching the referenced articles created by original investigators.

Finally, all the selected articles were confirmed for duplications which excluded if it was observed. Experimental animal models and human epidemiological studies exhibit that IR and inflammation are directly interlinked with each other during the development of T2DM [ 14 , 15 ]. Pro-inflammatory mediators play crucial role in the development of IR and T2DM through activating various inflammatory responses.

Donath and Shoelson [ 12 ] have briefly described that how inflammation is developed in T2DM Fig. In the following sub-sections, we have briefly described the role of various pro-inflammatory mediators in the development of IR. Overnutrition is responsible to elevate the levels of glucose and FFAs in blood which are responsible to induce metabolic stress in β-cells of pancreatic islets and insulin sensitive tissues notably adipocytes especially in case of obesity.

The metabolic stress induced in these tissues activates the release of various pro-inflammatory cytokines notably IL-1β and IL-1β-dependent various other cytokines and chemokines.

As a result, immune cells are recruited which contribute the tissue-specific inflammation. Adapted from Donath and Shoelson [ 12 ]. IL-β is a master pro-inflammatory mediator that plays its crucial role to regulate the expression of various other pro-inflammatory cytokines, adipokines and chemokines.

It induces inflammation via binding with interleukin-1 receptor type I IL-1RI Fig. Production of IL-1β is mainly regulated by diet-induced metabolic stress Fig.

Experimental studies have been conducted on various experimental animal models to investigate the presence of various inflammatory responses in β-cells of pancreatic islets and peripheral tissues which indicate that IL-β is a master pro-inflammatory mediator that plays its pivotal role to activate numerious other pro-inflammatory cytokines and chemokines [ 4 , 17 ] through the involvement of various transcriptional mediated pathways.

Once, inflammation is produced, it provokes its deleterious effects on β-cells of pancreatic islets due to which impaired insulin secretion occurs in β-cells of pancreatic islets.

Likewise, IL-β also plays its decisive role to induce inflammation in peripheral tisuues duw to which the ability of peripheral tissues to utilize insulin in response to glucose is decreased which ultimately leads towards the development of IR in peripheral tissues.

Production of IL-1β-induced inflammation in β-cells of pancreatic islets. Prolonged exposure of FFAs and glucose induce the activation of IL-1β from β-cells of pancreatic islets through the involvement of various transcriptional mediated molecular pathways notably TXNIP, MYD88, NF-κB, TLRs, caspases and inflammasomes.

Once IL-1β is activated, it recruits various other pro-inflammatory mediators after binding with its receptor IL-1RI and through the involvement of MYD88 and NF-κB.

Adopted from Donath and Shoelson [ 12 ]. Overnutrition is responsible for elevated levels of glucose and FFAs in blood which entered into the β-cells of pancreatic islets. Initially, these augmented levels of glucose and FFAs induce the expression and release of IL-1β from the β-cells of pancreatic islets Stimulation.

Once, IL-1β is activated and produced, it leads to the recruitment of various other pro-inflammatory cytokines, chemokines, and macrophages Precipitation which further induces apoptosis, amyloidosis and fibrosis in β-cells of pancreatic islets, and hence impaired insulin secretion occurs whereas, in peripheral tissues, IR is developed due to systemic inflammation.

Adopted from Donath et al. Aging is associated with increased plasma levels of IL-6 [ 18 ] which in turn can be positively correlated with IR [ 19 — 22 ]. The mechanism by which IL-6 induces IR is complicated and versatile [ 19 ]. It not only prevents the metabolism of non-oxidative glucose [ 23 , 24 ], but also suppresses the lipoprotein lipase that consecutively increases the plasma levels of triglycerides [ 23 ].

Moreover, IL-6 also activates the suppressor of cytokine signaling SOCS proteins [ 6 , 25 ] which may block the cytokine-mediated transcriptional factor activation of insulin receptor [ 26 ]. Signal transducer and activator of transcription 5B STAT5B is a protein that belongs to the STAT family of transcription factors.

STAT5B is aptly named for its unique ability to act as signal transducer and as transcription factor of insulin receptor [ 26 ]. In response to cytokines, STAT5B is phosphorylated by receptor associated kinases [ 27 ]. STAT5B activates insulin transcription factor through potentiating the tyrosine kinase by binding with phosphotyrosine of the insulin receptor.

The activation of insulin transcription factor is blocked by SOCS proteins which suppresses the activity of tyrosine kinase by significantly competing with STAT5B [ 19 , 27 ]. SOCS proteins have negative effects on insulin action while IL-6 can activate these SOCS proteins.

Therefore IL-6 is considered as an important biomarker for the development of IR [ 19 , 28 ]. Production of IL-6 is regulated by IL-1β via activation of interleukin-1 receptor type I IL-1RI [ 29 , 30 ].

Blocking the activity of IL-1RI with suitable anti-inflammatory agent like interleukin-1 receptor antagonist IL-1Ra antagonizes the agonistic effects of IL-1β that ultimately leads to the suppression of IL-6 production [ 4 , 31 ]. Anti-IL-6 receptor antibody and soluble receptor of IL-6 sIL-6R have proven to be effective by decreasing the development of IR [ 32 , 33 ], but this treatment strategy may not be very much effective as production of IL-6 is dependent on the activation of IL-1β and its role in the development of IR cannot be negelected.

Adipocytes secrete several pro-inflammatory mediators and among them, TNF-α has been proposed to develop a link between IR, obesity and T2DM [ 34 , 35 ].

Experimental studies conducted on obese animals indicate that the expression of TNF-α is increased in obese animals which modulates the insulin action [ 36 ]. TNF-α binds with its receptor and triggers a broad spectrum signaling cascade that results in the activation of various transcriptional pathways such as Nuclear factor kappa-B cells NF-κB and Jun NH2-terminal kinase JNK [ 37 , 38 ].

Once, NF-κB and JNK are activated, they phosphorylate serine in IRS-1 which result in the impairment of IR-mediated tyrosine phosphorylation of IRS-1 [ 37 ]. Recently, it has been found that serum level of TNF-α is positively correlated with the pathophysiology of IR [ 35 , 39 ] which exhibit that TNF-α is also a main causative factor that contributes the development of IR.

Therefore, it has been deliberated that adipose tissues are the major endocrine organ which have the ability to produce variety of adipose-derived mediators that are activitely involved to regulate the energy metabolism and insulin sensitivity [ 41 ].

The most important adipose-derived mediators are FFAs and adipokines. Adipokines include large number of pro-inflammatory mediators which include leptin, TNF-α, IL-6, tissue inhibitor of metalloproteinases TIMP-1 adiponectin, retinol-binding protein RBP-4 and monocyte chemotactic protein MCP-1 [ 42 , 43 ].

It has been evidenced from several experimental studies that there is a strong correlation between the mass of adipose tissues and development of IR Fig. IL-6, TNF-α, MCP-1, TIMP-1, RBP-4, and leptin are considered as pro-inflammatory cytokines which are responsible not only for the induction for local inflammation in adipocytes, but may also induce systemic inflammation after entering into the blood stream [ 4 , 47 , 48 ].

Adiponectin is the only adipokine that acts as anti-inflammatory cytokine and has the ability to ameliorate the deleterious effects of IL-6, TNF-α, MCP-1, TIMP-1, RBP-4, and leptin which are known to be produced in adipose tissues [ 11 ].

It has also been found that the level of adiponectin is downregulated in obesity and is positively associated with insulin sensitivity [ 49 , 50 ]. The imbalance between leptin and adiponectin may result in the development of systemic IR.

Schematic representation of adipocytokines-induced IR. Glucolipotoxicity and induction of inflammation in adipocytes are responsible to make the adipocytes abnormal.

Once adipocytes are injured, glucose utilization is decreased in adipocytes and levels of FFAs are abnormally increased due to which metabolic stress in adipocytes is increased which ultimately leads to the abnormal secretion of various pro-inflammatory mediators and adipocytokines.

Chemokines are an important class of pro-inflammatory mediators. Their production is dependent on the activation IL-1β and various transcriptional pathways [ 4 ]. Up till now, various chemokines have been discovered, among which the most important are MCP-1, MCP-2, MCP-3, MCP-4, CCL2, MIP-1α and MIP-1β [ 51 ].

Several studies have reported that MCP-1 and CCL2 deficient mice prevented high fat diet-induced IR [ 52 , 53 ]. Moreover, overexpression of MCP-1 in adipose tissues was also observed to be responsible for the increase in adipose tissue macrophages and induction IR [ 52 , 54 ]. It has been found that chemokines play crucial role for the development of IR and T2DM Fig.

Among various receptors for chemokines, CCR2 and CCR5 are the most important receptors that play decisive role in the pathogenesis of IR [ 56 ] in adipose tissues Fig.

It has been found that adipocytes secrete CCR2 in an inactive form. After activation, CCR2 induces the expression of various inflammatory genes and impaires the uptake of insulin-dependent glucose uptake. Moreover, adipocytes can also secrete CCL2 and CCL3 which act as a potent signal for the recruitment of macrophages.

The upregulation of CCL2 and CCL3 from adipocytes may contribute to the development of IR in adipose and peripheral tissues [ 57 ]. The above mentioned studies highlight the crucial role of various chemokines in the development of IR along with other pro-inflammatory mediators.

Chemokines-induced IR. M2 macrophages in lean state, maintain the insulin sensitivity in adipose tissues whereas, due to overnutrition, adipose tissues initiates the secretion of MCP-1 which leads to the recruitment of circulating monocytes in adipocytes.

CCR2 macrophages are accumulated in obese adipocytes and presumably maintain the inflammation by recruiting M1 macrophages in obese adipocytes.

While on the other side, CCR5-adipose tissue macrophages ATM also infiltrate from the obese adipocytes and promote the inflammatory responses by involving ATM recruitment and producing various pro-inflammatory mediators notably TNF-α, IL-6, and IL-1β in conjunction with other infiltrated immune cells and adipokines.

After production, these pro-inflammatory mediators induce IR in adipocytes and peripheral tissues through activation of several transcriptional pathways such as JNK and NF-κB. Adapted from Xu et al. C-C motif chemokine receptor 5 CCR5 promotes obesity-induced inflammation and IR.

Recently, it has been found that the expression of CCR5 and its ligand MCP-1 is significantly increased in white adipose tissues WAT and its accumulation is increased in adipose tissue macrophages ATM in WAT of obese mice and provides a novel link between inflammation and IR in adipocytes by stimulating the production of various pro-inflammatory cytokines and chemokines.

Adopted from Ota [ 51 ]. CRP has been considred as one of the most important human acute phase protein that correlates with development of IR [ 58 , 59 ]. CRP is a systemic inflammatory biomarker and has been considered as one of the major causative factor for the development of T2DM [ 60 ]. It has been evidenced that elevated levels of CRP not only reflect the induction of local inflammation, but also predict the pathogenesis of tissue-specific IR [ 61 ].

Overnutrition increases the cellular overload of glucose and FFAs which in turn increases the oxidative stress Fig. Peripheral and adipose tissues protect themselves from the damaging effects of oxidative stress producing resistance to the action of insulin by preventing the penetration of glucose and FFAs into the cells.

Oxidative stress is because of imbalance between the production of reactive oxygen species ROS and anti-oxidative defense mechanism against the production of ROS. β-cells of pancreatic islets, adipocytes and peripheral tissues are more vulnerable to the damaging effects of oxidative stress Fig.

Several mechanisms are involved to influence the balance between ROS and anti-oxidant defense mechanisms including activation of stress-signaling pathways such as JNK pathway [ 64 ] and transcriptional mediated pathways such as NF-κB [ 65 ].

JNK and NF-κB pathways decrease the insulin-mediated glucose uptake by tissues and insuling signaling [ 66 — 68 ], that ultimately induces IR Fig.

Moreover, the activations of JNK and NF-κB pathways is also associated with the upregulation of various pro-inflammatory mediators such as TNF-α, IL-6, and CRP. It has also been reported that oxidative stress-indcued activation of NF-κB pathway may also be associated with endothelial dysfunction that can lead to the induction of IR [ 69 , 70 ], but anti-oxidant therapy may act as a potential strategy to prevent the induction of IR-associated with endothelial dysfunction [ 71 ].

The growing body of evidence indicate that oxidative stress is a common pathogenic factor that leads to the development of tissues-specific IR. The results of experimental studies indicate that what happens in peripheral tissues also occur in the β-cells of pancreatic islets and endothelial cells to compensate the systemic oxidative stress.

Mechanism of oxidative stress-induced IR: Chronic exposure of hyperglycemia and hyperlipidemia due to over nutrition leads to the production of oxidative stress via activation of reactive oxygen species.

IKKβ also induces the activation of NF-κB. p38, JNK and IKKβ, further activates the serine phosphorylation of insulin receptor substrate-1 IRS While on the other side, NF-κB also activates the expression of iNOS which also induces the S-nitrosylation of IRS Both S-nitrosylation and serine phosphorylation of IRS-1 suppress the tyrosine phosphorylation of insulin signaling pathways which ultimately results into the induction of IR in liver, adipocytes and skeletal muscles.

Impact of oxidative stress on vital organs of the body. β-cells of pancreatic islets, adipocytes and peripheral tissues are more susceptible to the damaging effects of oxidative stress. Oxidative stress independently exhibit its hazardous effects on these organs due to which impaired insulin secretion occurs in β-cells of pancreatic islets and IR develops in adipocytes and peripheral tissues.

Impaired insulin secretion and IR lead to the development of post prandial hyperglycemia and overt T2DM both of which also acts as feedback mechanism for the development of oxidative stress. Endoplasmic reticulum stress ERS is another mechanism that palys crucial role for the development of IR in adipocytes and peripheral tissues.

ERS just like oxidative stress, is produced by the activation of JNK and inhibitory phosphorylation of IRS-1 in adipose tissues and liver [ 72 ] and induces the pathogenesis of IR in endothelial cells. It has been found that ER is a major site for the production of various proteins such as insulin biosynthesis and act as a place for the lipid and sterol synthesis [ 73 ].

Any kind of abnormality that occurs in ER may lead to the development of ERS which also contribute to induce tissue-specific IR.

It has been revealved from experimental studies that some anti-diabetic agents alos modulate the ERS during the treatment of T2DM [ 74 ] which offer a new therapeutic target for the treatment of ERS-inducced IR and T2DM.

NF-κB is a sequence-specific transcriptional mediated factor that primarily regulates various inflammatory responses [ 75 ] and IκB kinase β IKK-β is a central coordinator for these inflammatory responses through the activation of NF-κB [ 76 ].

IKK-β activates NF-κB through phosphorylation of IKK-β [ 77 , 78 ] and thereafter, NF-κB mediates the stimulation of numerous pro-inflammatory mediators such as IL-1β, IL-6, and TNF-α [ 76 , 78 ]. Once these pro-inflammatory cytokines are activated, they ultimately lead to cause IR [ 2 , 14 , 79 , 80 ].

Therefore, NF-κB and IKK-β are considered to be involved in the pathogenesis of IR [ 81 , 82 ]. IKK-β induces inflammatory responses in hepatocytes which massively increase the production of pro-inflammatory cytokines [ 83 ]. These pro-inflammatory cytokines then enter into the blood stream to cause IR in other tissues [ 81 ].

Various studies have investigated that nonsteroidal anti-inflammatory drugs NSAIDs such as cyclooxygenase inhibitors aspirin and salicylates can significantly inhibit the activation of NF-κB and IKK-β [ 84 ] in rodent models and humans [ 84 , 85 ]. These studies suggest that NSAIDs may exhibit their anti-inflammatory effects on myeloid cells rather than in muscle or fat.

Expression of IKK-β in myeloid cells significantly suppresses the activation of pro-inflammatory cytokines that promote IR [ 81 ]. In the following sub-sections, role of various transcriptional pathways in the pathogenesis of IR has been briefly described.

IR leads to the increased production of insulin from β-cells of pancreatic islets and as result, compensatory hyperinsulinemia within the body occurs. Toll like receptors TLRs are the important modulators of IR and its comorbidities. Chronic inflammation plays a crucial role in variety of insulin resistant states [ 86 , 87 ] in which various signaling pathways are activated that directly interfere with the normal functioning of the key components of insulin signaling pathways [ 88 ].

Among various pathways, activation of TLRs imparts crucial role for the generation of inflammation. There are two main types of TLRs i. TLR2 and TLR4. TLR4 is an extracellular cell surface receptor that is expressed in β-cells of pancreatic islets, brain, liver skeletal muscle and adipose tissues Fig.

In nomal conditions, TLR4 regulates insulin sensitivity in these tissues, but the activation of TLR4 directly dampen the insulin action through the activation of various pro-inflammatory mediators and ROS, indirectly generates the activation of various pro-inflammatory mediators by inducing various signaling cascades and transcriptional factors notably MyD88, TIRAP, TRIF, IKKs and JNKs that causes the activation of innate immune responses which ultimately leads to the development of IR Fig.

TLR4 plays this role primarly in coordination with the phosphorylation of IRS serine. Expression TLR4 in integrated tissues and organ systems of the body that regulate the insulin sensitivity. Toll-like receptor 4 TLR4 present in adipocytes, initiates the inflammatory responses that release various pro-inflammatory mediators.

Once, produced, these mediators are entred into the blood stream and thereby promote IR. TLR4, expressed on Kupffer cells and other liver cell components, regulates the various inflammatory responses in liver.

TLR4, expressed in skeletal muscles, has been shown to regulate the substrate metabolism in muscle, favoring glucose oxidation in the absence of insulin. Hypothalamus and mesolimbic area are important sites that modulate the energy expenditure, pancreatic β-cell function and IR in peripheral tissue.

Expression of TLR4 in hypothalamus potentiates various inflammatory responses that contribute to the pathogenesis of IR. Adopted from Kim and Sears Schematic representation of TLR4 signaling cascades.

Lipopolysaccharide LPS and its endotoxic moiety have been reported to be the potential activators of TLR4 Fig. LPS is composed of oligosaccharides and acylated saturated fatty acids SFAs.

Besides LPS, SFAs have also been reported to be the activator of TLR4. The expression and signaling of TLR4 are regulated mainly by the adiponectins. Several studies have reported that adiponectin can inhibit LPS-induced activation of TLR4 through the involvement of AMPK, IL, and heme oxygenase-1 [ 90 — 92 ].

Other regulators of TLR4 are peroxisome proliferators-activated receptor gamma PPARγ and sex hormones [ 93 , 94 ]. Taking together, TLR4 is a molecular link for pro-inflamatory mediators, different body organs, and several transcriptional pathways and cascades that modulate the innate immune system by regulating the insulin sensitivity.

In the proceeding sub-sections, role of TLR4 expression in various vital organs of the body for the pathogenesis of IR has been described. Despite of having the ability to act as storage depot for excess calories, adipose tissues secrete large number of hormones, pro-inflammatory cytokines and chemokines that directly influence the metabolism Fig.

Adipose tissues consist of adipocytes, preadipocytes, macrophages, lymphocytes and endothelial cells. Only adipocytes and macrophages are known to release various pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and chemokines such as MCP-1 that potentiate inflammation in several tissues after being released into the systemic circulation [ 95 ].

Besides this, adipocytes are also a rich source of two important hormones namely leptin [ 96 , 97 ] and adiponectin [ 98 ]. Adiponectin, having anti-inflammatory properties, promotes insulin sensitivity whereas, leptin having inflammatory properties, impairs insulin sensitivity in adipocytes [ 87 ].

Several factors such as oxidative stress, increased FFAs flux and hypoxia that are associated with inflammation can induce IR in adipose tissues [ 87 ]. TLRs present in adipose tissues are directly activated by the nutrients [ 99 , ] which play a key role for the initiation of inflammatory responses which ultimately promotes IR in these tissues [ — ].

Nutritional fatty acids can activate the expression of TLR4 in adipocytes that play crucial role for the activation of various pro-inflammatory mediators and transcriptional mediated pathways which ultimately lead to the development of IR in adipocytes. Skeletal muscles have marked significance to regulate the normal glucose homeostasis and development of IR as these are the primary site for insulin-induced glucose uptake and utilization in peripheral tissues.

Skeletal muscles contain myocytes and macrophages in which TLR4 receptors are expressed Fig. Signal transduction of TLR receptors is an underlying mechanism for the development of IR and chronic inflammation in skeletal muscles [ ]. TLR4 expression in skeletal muscle is associated with severity of IR and skeletal muscle metabolism.

The mechanis in the development of IR in skeletal muscles may include the direct effects of intramyocellular FFAs metabolites in skeletal muscles, macrophages and paracrine effects of adipocytes.

Recently, it has been experimentally confirmed that disruption of TLR4 expression prevents SFA-induced IR in TLR mutant mice and improves IRS-1 tyrosine phosphorylation and insulin-stimulated glucose uptake.

Moreover, disruption of TLR4 expression has also shown to decrease the JNK1 phosphorylation and IRS-1 serine phosphorylation [ , ].

Liver is the major and vital organ of the body which is composed of heterogenous types of cells notably hepatocytes, immune cells, kupffer cells and endothelial cells.

Due to their localization at sinusoids, kupffer cells are in close contact with circulating cytokines, lipids, hormones and postprandial LPS, and hence, kupffer cells are important mediators of inflammation within the liver.

TLR4 expressed on kupffer cells in the liver Fig. It has been found that activated levels of pro-inflammatory AP-1 and NF-κB in liver are directly correlated with IR and oxidative stress [ ]. TLR4 signaling pathway is strongly associated with IR as, it has been found that acute treatment of LPS inhibits the production of hepatic glucose via activation of TLR4 signaling pathway and induces IR in liver [ ].

Several TLRs such as TLR2, TLR3 and TLR4, are also expressed in β-cells of pancreatic islets [ ]. Signal transduction of TLRs in β-cells of pancreatic islets is mainly associated with inflammation in β-cells of pancreatic islets [ — ]. Distruction and malfunctioning of β-cells of pancreatic islets may lead to insufficient secretion of insulin in both types of DM.

Expression of TLR4 in pancreatic islets may lead to impaired insulin secretion and promote β-cell apoptosis [ ]. Brain itself palys a central role to regulate glucose homeostasis and metabolism.

In brain, hypothalamus and mesolimbic sites have been considered as important areas that are actively involved in the regulation of insulin sensitivity in peripheral tissues and β-cells secretory functions of pancreatic islets [ ].

TLR4 expression is widely distributed in the body Fig. Vascular endothelial dysfunction is a major complication for induction of IR and pathogenesis of T2DM. At molecular level, excess amount of nutrient is interlinked with IR through the activation of transcriptional mediated pathways such as IKKβ and NF-κB [ 83 , ].

Augmented levels of FFAs are associated with generation of inflammation and induction of IR in endothelial cells [ , ]. IKKβ and NF-κB are transcriptional mediators of inflammation and TLR4 is implicated as a mediator of IKKβ and NF-κB [ , ].

TLR4 receptors are also expressed in endothelial cells and expression of TLR4 via LPS-stimulated IKKβ and NF-κB activation contributes the dysfunctioning of endothelial cells [ ]. Activation of TLR4 via FFAs can trigger the cellular inflammatory responses in endothelial cells [ , ] whereas, whole body deletion of TLR4 expression has shown to prevent high-fat diet-induced vascular inflammation and IR in mice [ , ].

Similarly, activation of TLR4-dependent IKK and NF-κB indicated impaired insulin signaling and NO production in endothelial cells [ ]. The growing evidence implicates that TLR4 is the major causative factor to induce IR in endothelial cells via activation of various transcriptional mediated pathways and inflammation in endothelial cells.

AMP-activated protein kinase AMPK is an enzyme that is most commonly known as master regulator of energy metabolism [ ] and its activation is based on the energy level of the body. Upon activation, AMPK resotres the energy levels of the body by stimulating various processes in different body organs Fig.

AMPK plays a crucial role between adipose and peripheral tissues, and interferes various metabolic and secretory functions [ ] that are responsible for normoglycemia and glucose homeostasis Fig. In adipocytes, adipokines exhibit their metabolic effects by activating AMPK which result in the increased β-oxidation in peripheral tissues.

Activation of AMPK in peripheral tissues enables skeletal muscles to cope with elevated levels of FFAs. Keeping in view the active role of AMPK in energy metabolim, it has been found that AMPK activation improves insulin sensitivity and glucose homeostasis.

IR is a major hallmark for the pathogenesis of T2DM however, AMPK activation can prevent the pathogenesis of IR and development of T2DM. Protein kinase C PKC and inhibitor kB kinase IKK are the two main important kinases that play crucial role in pro-inflammatory mediators-induced inflammatory processes in adipocytes and peripheral tissues underlying the development of systemic IR [ — ].

IKK induces IR in peripheral tissues by suppressing the insulin signaling and activating NF-κB [ , ]. Inhibition of IKK activation prevents the secretion of adipokines from adipocytes and improves insulin sensitivity in adipocytes and peripheral tissues [ 81 , , ].

NF-κB is a transcriptional mediated pathway that plays its crucial role in the transcription of signals for te production and release of various pro-inflammatory mediators. Most importantly, NF-κB plays active role to regulate IL-1β Fig. Once activated, NF-κB targets serval genes to potentiate the release of various pro-inflammatory mediators in adipose tissues and liver [ 81 , 83 , ].

These pro-inflammatory mediators that are produced in response to NF-κB activation induce tissue-specific IR. Glucolipotoxicity is a general term which is collectively used for the combination of glucotoxicity and lipotoxicity.

These two terms are collectively responsible to activate the release of various pro-inflammatory mediators which lead to the development of tissue-specific IR and impaired insulin secretion from β-cells of pancreatic islets Fig.

Adipocytes are the main sites for the storage of fats and energy supplied to the body, is also regulated by the adipocytes. When accumulation of lipids exceeds the energy expenditure, then most of the excess amount is stored in the form of FFAs in adipose and other insulin-sensitive tissues.

When fat storage and energy supply is impaired in adipose tissues, elevation of FFAs levels in plasma occurs which is converted into the triglycerides and stores in non-adipose tissues [ ].

The ectopic storage of FFAs metabolites mostly triglycerides results in lipotoxic effects in peripheral tissues Fig. In addition to this, elevated levels of FFAs in plasma may also interfere with insulin signaling pathways notably IRS-1 serine phosphorylation in peripheral tissues via activation of PKC and inhibition of IKK and JNK [ ].

Hence, it has been evidenced that glucolipotoxicity is one of the major contributor for the development of tissue-specific IR. Mechanism of hyperglycemia- and dyslipidemia-induced inflammation for the development of IR and T2DM. Hyperglycemia and dyslipidemia collectively provoke the activation of pro-inflammatory mediators through the involvement of several metabolic pathways.

Once, these pro-inflammatory mediators are released, they induce tissue-specific inflammation due to which IR in peripheral tissues and impaired insulin secretion in pancreatic islets occur that ultimately lead to overt T2DM. Adapted from Akash et al.

Development of IR is one of the major hallmark for pathogenesis of T2DM. To control the propagation of IR is one of the most important targeted treatment. For the development of IR, several factors are involved Fig. Several treatment strategies have been used to overcome the development of IR.

The most important ones have been described here in the following sub-sections. Interleukin-1 receptor antagonist IL-1Ra is naturally occurring anti-inflammatory cytokine of interleukin-1 family. It competitively binds with IL-1RI and prevent the binding of IL-1β and antagonizes its effects.

It has been evidenced from several experimental studies that imbalance between IL-1Ra and IL-1β generates inflammation in various parts of the body where IL-1RI is present [ 4 , 12 ]. Moreover, it has also been found that expression of IL-1Ra is strongly correlated with the development of IR, impaired insulin secretion and T2DM [ 4 , ].

Treatment of human recombinant IL-1Ra improves normoglycemia, insulin sensitivity in adipose and peripheral tissues, and insulin secretion from β-cells of pancreatic islets impairs [ 31 , , ]. This is one of the most important treatment strategy that anti-inflammatory agent might indeed prevent the development of IR and improves glycemia.

One of the main shortcoming of IL-1Ra is its short biological half-life and to overcome this problem, high doses with frequent dosing intervals are required to achieve desired therapeutic effects. To overcome this problem, several treatment strategies have been applied to prolong the biological half-life and therapeutic effects of IL-1Ra [ 29 ].

Salicylates are an important class of anti-inflammatory agents. They are used in variety of inflammatory diseases and syndromes.

Inflammation plays a crucial role for the development of IR and T2DM, therefore, by using salicylates as an alternate treatment strategy, it has been found that salicylates can imporve insulin sensitivity via inhibition of NF-κB and IKKβ [ 82 ] and glucose tolerance [ , ].

In the above sections, it has been briefly described that TNF-α is one of the most important pro-inflammatory mediator that is responsible to induce IR in adipocytes and peripheral tissues. Inhibition of TNF-α production might be one of the choice to prevent the development of IR and pathogenesis of T2DM [ 4 ].

Recently, infliximab has been demonstrated to improve insulin signaling and inflammation especially in the liver in rodent model of diet-induced IR [ ]. Similarly, using anti-TNF-α antibodies also improve the insulin sensitivity in peripheral tissues [ ].

Lo et al. demonstrated that etanercept therapy can also improve total concentration of adiponectin which is anti-inflammatory adipokine and improved insulin sensitivity [ ]. Keeping in view the decisive role of TNF-α in pathogenesis of IR, several anti-TNF-α treatment strategies have been utilized to prevent the pathogeneis of IR and development of T2DM.

Similarly, anti-TNF-α treatment has also shown to prevent the IR in Sprague—Dawley rats [ ] while neutralization of TNF-α also prevented IR in hepatocytes [ ]. Few controversial studies have also demonstrated that using TNF-α blockade has no effect on IR [ ] which indicates that TNF-α blockade is not a treatment of choice as its production is dependent on the generation of IL-1β and activation of various transcriptional mediated pathways.

It has been thought that chemokines activately participate in the development of IR by potentiating the inflammation in adipocytes. Moreover, genetic inactivation of these chemokine signaling [ 52 , 53 , ] or inhibition of their axis [ , ] by pharmacological approaches have been shown to improve the insulin sensitivity in adipocytes and peripheral tissues.

ER stress, as mentioned in the above sections, is a key link between IR and T2DM [ ]. Blockade of ER stress is one of the treatment option to prevent the development of IR and pathogenesis of T2DM. In the recent years, various pharmaceutical chaperones, notably endogenous bile acids and the derivatives of these bile acids such as ursodeoxycholic acid UDCA , 4-phenyl butyric acid PBA have been investigated that have proven to have the ability to modulate the normal functioning of ER and its folding capacity [ 28 ].

Ozcan et al. The results of this study indicated that UDCA significantly improved insulin sensitivity and normoglycemia. Thiazolidinediones also known as glitazones, are one of the most important insulin sensitisers. They are the agonists of peroxisome proliferator-activated receptors-gamma PPARγ.

It has been found that thaizolidinediones have the ability to improve insulin action and decrease IR [ , ]. Inflammatory responses are induced through the activation of various pro-inflammatory and oxidative stress mediators via involment of various transcriptional mediated pathways.

To stop the inflammatory responses in IR development is one of the key treatment strategy. In this areticle, we have comprehensively highlighted the up-to-date scientific knowlesge of role of inflammatory responses in IR development and its treatment strategies.

IR plays a crucial role for the pathogenesis and development of T2DM and its associated complicaitons. Based on the findings mentioned in above sections, anti-inflammatory treatment strategies are one of the best choice to prevent the the pathogenesis of IR, but the studies conducted to investigate the role of anti-inflammatory strategies for the prevention of IR are still in their beginning stages and need to be focused further in future studies for more better and improved clinical outcomes.

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Increased cytokine production in mononuclear cells of healthy elderly people. The microscopic images were taken by a Zeiss microscope and insulin-positive cells were considered as functional β cells.

Using WCIF ImageJ Software NIH, Bethesda, MD, USA , the relative islet area to total pancreatic area ratio was calculated by random selection from magnifying fields at 10× objective.

The islet mass was then evaluated by multiplying the area ratio with the pancreatic weight Xiang et al. Free 3-hydroxy strand breaks resulting from DNA degradation were detected by the TUNEL technique according to the manufacturer's instructions DeadEnd Fluorometric TUNEL System, Promega.

To detect the β cells, 5-μm slices from paraffin-embedded tissue were incubated with rabbit anti-insulin antibody, followed by detection using the fluorescently labeled secondary antibody.

The staining with DAPI was used for visualization of nuclei. The samples were immediately evaluated by fluorescence microscopy Zeiss, Germany for positively stained apoptotic nuclei.

Positive cells costaining for insulin and TUNEL were designated as apoptotic β cells. Results were expressed as the percentage of apoptotic β cells, normalized by total insulin-positive cell number Lacraz et al.

To estimate β cell apoptotic rates, counts at 40× objective from β cells per pancreas section were analyzed under a Zeiss fluorescence microscope.

Real-time RT-PCR was performed in a Bio-Rad Sequence Detection System using SYBR Green dye Applied Biosystems, Inc. according to the manufacturer's protocol.

All the primers BGI, Beijing, China were designed by Primer Express Software V2. To normalize expression data, β-actin was used as an internal control gene. Cytoplasmic and nuclear proteins were extracted from pancreas using a commercial kit.

Sample proteins were separated by SDS—PAGE in a Bio-Rad Mini Protean apparatus and then transferred to a PVDF membrane. Finally, detection procedures were performed using ECL Advance Western Blotting Detection Kit Amersham Bioscience. Band intensity volumes were measured by ImageJ Software.

Results are presented as means± s. In all experiments, data were evaluated for statistical significance using one-way ANOVA followed by Q -test. There were significant increases of SAA and TNFα concentration in the serum of casein-injected mice compared with mice fed with HFD Fig.

We also detected the inflammatory cytokine productions in mouse adipose tissue, liver, and muscle. The protein expression of TNFα and MCP1 in the three types of tissues in HFD group slightly increased compared with NCD group Fig.

Casein-injected mice had a higher expression of TNFα and MCP1 protein compared with the other two groups Fig. Immunohistochemical analyses of pancreatic sections revealed that CD68, a specific marker of tissue macrophages, was increased in casein injection group Fig.

Results represent the mean± s. B The protein expression of TNFα and MCP1 in the adipose tissue, liver and muscle was detected by western blot. C Infiltration of inflammation cells in pancreas was detected by macrophage marker CD68 immunohistochemistry original magnification ×40 , arrows show macrophages dyed brown.

Citation: Journal of Endocrinology , 3; Compared with the mice fed with HFD, casein injection had no further effect on these parameters mentioned above Table 2.

The fasting glucose levels were unchanged in HFD-fed mice compared with NCD-fed mice Fig. After glucose challenge, blood glucose concentration of HFD group was persistently higher than that of the NCD group Fig.

Insulin levels in serum were significantly increased in HFD-fed mice Fig. After insulin loading, blood glucose levels decreased slowly and still higher in the HFD group Fig. We also measured the major molecules involved in insulin signaling in insulin-sensitive tissues.

HFD inhibited the levels of total IRS1, IRS2, and p-AKT:AKT ratio in the liver, muscle, and adipose tissue Fig. Mice were starved overnight before executed and the blood was collected for fasting blood glucose C and serum insulin D detection.

Chronic inflammation aggravated the impairment on insulin signaling in insulin-targeted tissues of HFD-fed mice. The protein expression of IRS1 and IRS2 A , p-AKT ser , and AKT B in the adipose tissue, liver, and muscle was detected by western blot.

The histogram represents mean± s. Casein injection further aggravated impaired glucose tolerance, showing higher blood glucose levels after glucose injection and lower ITT slope after insulin loading in the casein plus HFD group Fig. Casein-injected mice had a notable increase in fasting glucose levels Fig.

Likewise, casein injection further downregulated IRS1, IRS2, and p-AKT protein expression Fig. Results from pancreatic histomorphology Fig. However, casein injection impaired β cell function by reducing islet mass and insulin content in HFD-fed mice Fig. We further determined the expression of key participants in β cell functional integrity, namely pancreatic duodenal homeobox 1 PDX1 , glucokinase GK , glucose transporter 2 GLUT2 , and insulin.

The mRNA expression of Pdx1 and Gk had no obvious change, while both Glut2 Slc2a2 as well as insulin mRNA levels were significantly increased in HFD group Fig. The mRNA expression of Pdx1 , Glut2 , Gk , and insulin were significantly downregulated in casein-injected mice Fig.

Chronic inflammation exacerbated pancreatic β cell dysfunction in HFD-fed mice. A Hematoxylin—eosin HE staining in pancreas including the islet mass boxed, arrows.

B Insulin immunohistochemistry. Magnification ×10 top panels and ×40 bottom panels. Values are mean± s. Data showed that apoptotic β cell numbers had no difference between HFD group and NCD group Fig.

However, casein injection notably increased β cell apoptosis Fig. Chronic inflammation aggravated β cell apoptosis in HFD-fed mice. A Apoptosis of insulin-expressing cells on islet sections was determined by the TUNEL assay.

Representative examples of pancreatic islets stained by immunofluorescence for insulin red , marker of cell apoptosis TUNEL green , and nuclear stain DAPI blue imaged at ×.

B The percentage of apoptotic β cells was calculated as described in Materials and methods section. Chronic systemic inflammation plays an important role in the pathogenesis of multiple metabolic disorders, including insulin resistance, T2DM, and obesity.

Most obese individuals do not develop diabetes because β cells initially compensate for insulin resistance. Clinical studies have identified elevated serum levels of TNFα and IL6 as risk factors for subjects developing into T2DM Spranger et al.

We presume the progression of obesity-related β cell dysfunction may be related to a state of chronic inflammation. Mice on long-term HFD revealed β cell dysfunction and diminution of glucose-induced insulin secretion and developed glucose intolerance as a result of insulin resistance Collins et al.

In our experimental setting, there were no change in serum SAA and TNFα levels but increase in TNFα and MCP1 expression in the adipose tissue, liver, and muscle in HFD-fed mice compared with NCD-fed mice, in agreement with previous reports on overexpression of TNFα in different white adipose tissue depots of obese individuals and a normal circulating serum TNFα level Hotamisligil et al.

The bacterial endotoxin, LPS, induced inflammatory stress is presented during endotoxic septic shock, a condition that often leads to multiple organ failure and mortality Zhang et al.

LPS injection results in robust CNS-controlled sickness behaviors accompanied by increases in inflammatory cytokines IL1β, TNFα, and IL6 in the blood and brain. Compared with the administration of LPS, the inflammation induced by casein is characterized by an increased SAA, which is well documented as a good marker of chronic low-grade systemic inflammation.

Serum TNFα and SAA levels were significantly increased after casein injection for 14 weeks. Moreover, TNFα and MCP1 expressions in the adipose, liver, and muscle were upregulated in casein plus HFD group compared with HFD group, suggesting that casein injection successfully induced chronic systemic and local inflammation in HFD-fed mice.

In the obesity-induced metabolic disorder, FFA, which is commonly elevated in obese individuals, may drive a compensatory increase in β cell mass and function followed by attenuation as T2DM develops El Assaad et al.

The data showed that HFD mice maintained normoglycemia in the presence of impaired GTT and higher serum insulin levels, whereas mice in the HFD plus casein injection group had notable hyperglycemia and low serum insulin levels, implying that chronic inflammation accelerated deterioration of β cell function.

Compared with HFD-fed mice, casein-injected mice revealed parallel serum FFA levels and marked β cell dysfunction, suggesting that chronic inflammation is an independent risk factor in the destruction of pancreatic β cells.

The dysregulation of IRS1 and IRS2 and the inhibition of its signaling downstream are the primary mechanisms of chronic inflammation-induced insulin resistance. In this study, casein injection notably diminished the IRS1, IRS2, and p-AKT levels in the liver, muscle and adipose tissues of mice, and revealed obvious insulin resistance.

Research showed that IRS1 was the principal mediator of hepatic insulin action that maintains glucose homeostasis, especially during nutrient excess.

IRS1-deficient liver showed poor regulations of the key gluconeogenic genes and impaired glucose tolerance and insulin sensitivity. Moreover, IRS1 was required to suppress hepatic glucose production during hyperinsulinemic—euglycemic clamp Guo et al.

In this study, inflammatory stress induced by casein may affect hepatic glucose production and gluconeogenesis by inhibiting hepatic IRS1.

Data on the augmentation of islet mass and pancreatic insulin content in HFD-fed mice compared with NCD-fed mice showed that islet mass and pancreatic insulin content were markedly increased in HFD-fed mice, consistent with previous studies Collins et al. In this study, we found that chronic inflammation impaired β cell function by reducing islet mass and pancreatic insulin content in HFD-fed mice.

To explore the underlying mechanism of inflammation-mediated impairment in pancreatic islets of HFD-fed mice, we determined the expression of key participants in insulin synthesis and secretion.

Pdx1 acts in β cells as a house-keeping transcription factor for insulin gene expression Melloul HFD feeding did not significantly affect pancreatic Pdx1 mRNA levels, but obviously increased Glut2 and insulin mRNA expression associated with elevated serum insulin concentrations.

Therefore, hyperinsulinemia in obese individuals may correlate with improved β cell insulin secretion. In contrast with HFD-fed group, casein injection significantly reduced pancreatic Pdx1 , Glut2 , Gk , and insulin mRNA levels and serum insulin levels, indicating that chronic inflammation exacerbated HFD-induced islet β cell dysfunction and accelerated the progression of obesity-related T2DM.

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toolbar search search input Search input auto suggest. Table 1 Demographic and clinical characteristics by DM status. View Large. Figure 1. View large Download slide. Figure 2. Figure 3. contributed equally to this article. John Hopkins University Coronavirus Resource Center. Accessed 27 September Search ADS.

Letter to the editor: COVID in patients with diabetes: risk factors that increase morbidity. Association of blood glucose control and outcomes in patients with COVID and pre-existing type 2 diabetes. Hyperglycaemia increases mortality risk in non-diabetic patients with COVID even more than in diabetic patients.

Presenting characteristics, comorbidities, and outcomes among patients hospitalized with COVID in the New York City area. Diabetes as a risk factor for poor early outcomes in patients hospitalized with COVID Importance of hyperglycemia in COVID intensive-care patients: mechanism and treatment strategy.

Diabetes predicts severity of COVID infection in a retrospective cohort: a mediatory role of the inflammatory biomarker C-reactive protein. Bias in random forest variable importance measures: illustrations, sources and a solution. Factors associated with death in critically ill patients with coronavirus disease in the US.

Clinical and immunological features of severe and moderate coronavirus disease Phenotypic charac-teristics and prognosis of inpatients with COVID and diabetes: the CORONADO study. Clinical features of patients infected with novel coronavirus in Wuhan, China.

Fatty acid metabolites combine with reduced β oxidation to activate Th17 inflammation in human type 2 diabetes.

Cardiovascular disease biomarkers and suPAR in predicting decline in renal function: a prospective cohort study. Predicting mortality in African Americans with type 2 diabetes mellitus: soluble urokinase plasminogen activator receptor, coronary artery calcium, and high-sensitivity C-reactive protein.

Soluble urokinase-type plasminogen activator receptor and high-sensitivity troponin levels predict outcomes in nonobstructive coronary artery disease.

Samman Tahhan. Circulating soluble urokinase plasminogen activator receptor levels and peripheral arterial disease outcomes.

Soluble urokinase plasminogen activator receptor suPAR as an early predictor of severe respiratory failure in patients with COVID pneumonia. Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population.

The pro-inflammatory biomarker soluble urokinase plasminogen activator receptor suPAR is associated with incident type 2 diabetes among overweight but not obese individuals with impaired glucose regulation: effect modification by smoking and body weight status.

Immune cells profiling in ANCA-associated vasculitis patients-relation to disease activity. Blood suPAR, Th1 and Th17 cell may serve as potential biomarkers for elderly sepsis management. Admission hyperglycaemia as a predictor of mortality in patients hospitalized with COVID regardless of diabetes status: data from the Spanish SEMI-COVID Registry.

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For more hyperglycwmia about PLOS Subject Hy;erglycemia, click here. Diabetic Chronic hyperglycemia and inflammation ulcers DFUs are Hypertension prevention methods by a chronic inflammatikn state which prevents cutaneous wound healing, and DFUs eventually lead to infection and leg amputation. Chronic hyperglycemia and inflammation located in Strength training workouts are locked in hyperglycmeia pro-inflammatory phenotype. In this study, the effect of hyperglycemia and hypoxia on the macrophage phenotype was analyzed. For this purpose, a microarray was performed to study the gene expression profile of macrophages cultivated in a high glucose concentration. Hyperglycemia upregulated the expression of pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, chemokines and downregulated the expression of two receptors involved in phagocytosis CD 36 and Class B scavenger type I receptors. In addition, eleven anti-apoptotic factors were upregulated whereas three pro-apoptotic genes were downregulated. Nathalie de RekeneireRita Chronic hyperglycemia and inflammationJingzhong Ding Chornic, Lisa H. ColbertMarjolein VisserRonald I. ShorrStephen B. KritchevskyLewis H. KullerElsa S. StrotmeyerAnn V. Chronic hyperglycemia and inflammation

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