In the name of Allah The Most Compassionate, The Most Merciful Insulin Resistance and Immune Response By: AbdolKarim She

1. In the name of Allah The Most Compassionate, The Most Merciful Insulin Resistance and Immune Response By: AbdolKarim Sheikhi, PhD Assist. Professor, Immunology Department, ZUMSc

2. Year 2001  171 million individuals had diabetes (>90% of them were Type 2 diabetes (T2DM)) • Year 2030  366 million individuals will have diabetes • T2DM is caused by a combination of insulin resistance at skeletal muscle, liver and adipose tissues and impaired insulin secretion from the pancreatic islets • Both of Obesity and T2DM are with Insulin Resistance (IR). • But most obese, insulin-resistant individuals do not develop hyperglycaemia. • Because: Under normal conditions, the pancreatic islet β-cells increase insulin release sufficiently to overcome the reduced efficiency of insulin action, thereby maintaining normal glucose tolerance. • For obesity and IR to be associated with type 2 diabetes, β-cells must be unable to compensate fully for decreased insulin sensitivity.

3. بیماریهایی که ریسک بروزشان همراه با چاقی افزایش می یابد شامل: NATURE|Vol 444|14 December 2006

4. چه ارتباطی میان مسیرهای تماس بدن با مواد غذایی و پاتوژن ها وجود دارد و پاسخ های متابولیک و التهابی بدن چگونه از طریق این ارتباطات باعث بروز بیماریهای متابولیک و مزمن میشوند؟ Metaflammation: metabolically triggered inflammation • This condition is principally triggered by nutrients and metabolic surplus, and engages a similar set of molecules and signalling pathways to those involved in classical inflammation.

5. T2DM is linked to the innate immune system • Studies show that, in initially non-diabetic subjects, circulating concentrations of inflammatory markers, such as CRP, sialic acid and IL-6 are independent predictors of the future development of T2DM. • Treatment with the anti-inflammatory drug aspirin in type 2 diabetic patients reduces the fasting blood-glucose concentration by approximately 25%, triglyceride by 50% and CRP by 17% and increases insulin sensitivity by 30% • Some other drugs that are now known to have a major anti-inflammatory action (e.g. thiazolidinediones and statins) reduce glycemia and circulating inflammatory markers and possibly even reduce the risk of developing type 2 diabetes. • Thus, inflammatory and metabolic pathways run in parallel and show multiple inter-relationships. • in comparison with nondiabetic subjects, circulating concentrations of commonly recognized acute-phase reactants were increased in type 2 but not type 1 diabetic patients

6. Evolutionary perspectivesWhy are metabolic diseases so common and why are they so cruciallylinked to inflammatory processes? چرا بیماریهای متابولیک همه گیر هستند و چرا با فرایند های التهابی لینک هستند؟ جواب را شاید بتوان از طراحی بافتهای یک موجود زنده بدست آورد. مهمترین مکانیسم های زنده ماندن یک موجود زنده عبارتند از: 1- توانایی مقاومت در برابر گرسنگی ( ذخیره سازی کالری های اضافی تا در هنگام نیاز رهاسازی کند): هر موجودی که بتواند بهتر این کار را بکند در طول تکامل انتخاب میشود. ولی اگر بیش از حد مواد غذایی وارد بدن شود منجر به ذخیره بیش از حد و چربی بیش از حد و مشکلات همراه آن میشود. 2- پاسخ ایمنی موثر به پاتوژنها: موجودی که بتواند بهتر این کار را بکند در طول تکامل انتخاب میشود. ترکیبی از این دو صفت موجودی با قابلیت ذخیره سازی مواد غذایی و پاسخ ایمنی موثر بر ضد پاتوژنها ایجاد میکند که انتخاب میشود. • واحدهای فونکشنالی که اعمال کلیدی متابولیک و ایمنی را در موجودات پیشرفته کنترل میکنند از ساختارهای اجدادی مشترکی نشات گرفته اند مثل: • Drosophila fat body • که معجونی از سلولهای مشابه با کبد، سیستم خونساز و سیستم ایمنی پستانداران میباشد..

9. لذا میتوان تصور کرد که مسیرهای مشترکی وجود دارد که اعمال متابولیک و ایمنی را از طریق مولکولهای تنظیم کننده کلیدی و سیستمهای سیگنالدهی مشترکی تنظیم میکنند. این میتواند به مواد غذایی اجازه دهد که از طریق سیستمهای پاسخ دهنده به پاتوژنها همچون گیرنده Toll Like Receptors (TLRs) عمل کرده و باعث بروز التهاب القاء شده توسط مواد غذایی یا متابولیک شوند.

10. Ferna´ndez-Real, J.M. and Pickup, J.C., Innate immunity, insulin resistance and type 2 diabetes, Trends Endocrinol. Metab. (2007),

11. A major component of innate immunity is a series of sentinel cells (classically macrophages, antigen-presenting B-cells, and dendritic cells, but probably also intestinal epithelial cells, endothelium, Kupffer cells in the liver, adipocytes, and others) that act as “trouble detectors.” • A number of germ line–encoded (i.e., nonclonal) pattern recognition receptors (PRRs) on and in these cells recognize conserved molecular structures (pathogen- associated molecular patterns= pamp) that are characteristic of a class of harmful agents. • The most studied PRRs are probably the family of at least 10 toll-like receptors (TLRs) (named after the toll receptor, first identified in the fruit fly, drosphophila)

12. Ferna´ndez-Real, J.M. and Pickup, J.C., Innate immunity, insulin resistance and type 2 diabetes, Trends Endocrinol. Metab. (2007),

16. Insulin stimulates tyrosine phosphorylation of IRS proteins, which is a crucial event in mediating insulin action. • This step in insulin-receptor signalling is defective in most cases of systemic insulin resistance, both in experimental models and in humans (3). • TNF-α also targets this element of insulin-receptor signalling through inhibitory serine phosphorylation of IRS-1 (12). • Activation of JNK, IKK and conventional protein kinase C (PKC) is central to mediating insulin resistance in response to various stresses that occur in obesity and other conditions of insulin resistance (inhibit insulin action by serine phosphorylation of IRS-1) • These kinases also exert powerful effects on gene expression, including promoting further inflammatory gene expression through activation of activator protein-1 (AP-1) complexes and NF-κB. • Most importantly, in obesity there is a striking increase in JNK activity in critical metabolic sites such as adipose and liver tissues as well as in the hypothalamus (13).

17. JNK is activated upon exposure to cytokines such as TNF-α, as well as by free fatty acids and internal cues such as endoplasmic reticulum stress, all of which might underlie the obesity- induced activity. • Genetic JNK1-deficiencyprotects mice from obesity-induced JNK activation, IRS-1 serine phosphorylation, and, consequently, insulin resistance, fatty liver and diabetes (14=Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002).). • interventions to block JNK activity in established models of obesity and diabetes improved systemic glucose homeostasis and insulin sensitivity, as well as atherosclerosis, suggesting that JNK inhibition might be a promising therapeutic avenue for diabetes (15. Kaneto, H. N. Y. et al. Possible novel therapy for diabetes with cell-permeable JNKinhibitory peptide. Nature Med. 10, 1128–1132 (2004). • 16. Liu, G. & Rondinone, C. M. JNK: bridging the insulin signaling and inflammatory pathway. Curr. Opin. Investig. Drugs 6, 979–987 (2005).).

18. Another inflammatory kinase that is critical in the development of insulin resistance and metabolic dysfunction is IKK-β. • Mice that are heterozygous for a null mutation in IKK-β are partly protected from obesity-induced insulin resistance • inhibition of IKK-β by administration of high-dose salicylates improves insulin action in experimental models and humans (16-17). • Similarly to JNK, experimental activation of this kinase in the liver seems to be sufficient to generate systemic insulin resistance (18=Cai, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nature Med. 11, 183–190 (2005).). • Protein kinase C is also important in interaction between the inflammatory and metabolic pathways, and in particular has been implicated as a kinase downstream of lipid signals (19. Kim, J. K. et al. PKC-theta knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest. 114, 823–827 (2004). 20. Boden, G. et al. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes 54, 3458–3465 (2005) ). • Fatty acid metabolites such as fatty acyl coenzyme As and diacylglycerides can activate PKC-θ in muscles or PKC-δ in the liver and inhibit insulin action (20). • Mice deficient in PKC-θ are protected against fatty-acid-induced insulin resistance, confirming the contribution of this kinase to metabolic regulation in vivo • At the mechanistic level, PKC-θ is known to activate IKK and might contribute to insulin resistance through this pathway. Interestingly, interactions also occur between PKC, JNK and IKK • Characterization of the isoforms of these kinases involved in disruptinginsulin action among different species, especially humans, is a critical issue that has so far been addressed only in part.

19. Endoplasmic reticulum stress • Accumulation of unfolded proteins, energy and nutrient fluctuations, hypoxia, toxins, viral infections and increased demand on the synthetic machinery give rise to perturbations in the ER lumen and create stress. • Under these conditions, the ER activates a complex response system known as the unfolded protein response (UPR) to restore the functional integrity of the organelle. • The principal branches of UPR signalling are mediated through three molecules: inositol-requiring enzyme 1 (IRE-1), PKR-like endoplasmic-reticulum kinase (PERK) and activating transcription factor 6 (ATF6). • the two principal inflammatory pathways that disrupt insulin action, JNK–AP-1 and IKK–NF-κB, are linked to IRE-1 and PERK activity during ER stress. • IRE-1 interacts with IKK-β through TNF-receptor-activated factor 2 (TRAF2) • PERK activation leads to degradation of IκB and therefore facilitates the activity of NF-κB. • So, we can postulate that the ER might be a site for the sensing of metabolic stress and the translation of that stress into inflammatory signalling and responses. • In fact, the ER could be considered an essential and ancient site of integration between nutrient and pathogen responses as it is very sensitive to glucose and energy availability, lipids, pathogens and pathogen-associated components.

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