Ο ρόλοσ τθσ φλεγμονισ ςτο ςακχαρϊδθ διαβιτθ Αναστασία Θανοποφλου Επίκουρθ Κακθγιτρια Β Πακολογικισ Κλινικισ Πανεπιςτθμίου Ακθνϊν Διαβθτολογικό Κζντρο, Ιπποκράτειο Νοςοκομείο
hs-crp ωσ παράγοντασ κινδφνου ΚΑN MRFIT (Kuller 1996) PHS (Ridker 1997) PHS (Ridker 1997) CHS/RHPP (Tracy 1997) PHS (Ridker 1998) WHS (Ridker 1998, 2000) MONICA (Koenig 1999) Helsinki (Roivainen 2000) Caerphilly(Mendall 2000) Britain (Danesh 2000) a high level of CRP is consistently associated with increased risk for vascular disease in several different population groups, both at low and at high absolute risk for these events. Θάνατος ΣΝ ΕΜ ΑΕΕ ΣΝ ΠΑN ΚΑΝ ΣΝ >> >> >> 0 1.0 2.0 3.0 4.0 5.0 6.0 Στετικός κίνδσνος (ανώτερο vs κατώτερο τεταρτημόριο)
C-reactive Protein (mg/dl) C-reactive protein and diabetes 0,8 0,7 0,6 0,5 Women s Health Study (n=27628) 4 years follow-up p<0.05 0,4 0,3 0,2 0,1 0 Controls (n=362) Diabetics (n=168) Pradhan et al. JAMA 2001;286:327-34
CRP και ΚΑΝ ςτο Δ Diabetes Care 2005
C-reactive protein and diabetes CRP and cardiovascular events survival in diabetics (n=746) 5 years follow-up CRP<1 mg/l CRP=1-3 mg/l CRP>3 mg/l Schulze et al. Diabetes Care 2004;27:889-94
CRP και επιβίωςη ςτο ΣΔ2 Casale Monferrato Study n=3200 Diabetes 2009
CRP PREDICTOR OF RISK IN ATHEROSCLEROSIS < 0.1 low risk > 0.1 < 0.2 moderate > 0.2 < 0.3 moderate-high > 0.3 high CRP Polymorphism and incidence of angioplasty restenosis A Fernandez-Cruz et al Atherosclerois 2004; 176:393-96
Αναδυόμενοι παράγοντεσ ή ΔΕΙΚΤΕΣ κινδφνου Lpa Ομοκυςτείνη Προθρομβοτικοί παράγοντεσ Προφλεγμονώδεισ παράγοντεσ IGT Υποκλινική αθηροςκλήρυνςη ΑΣP III, NCEP Αρικμόσ λευκϊν ΙFG Περιοδοντίτισ Πάχοσ καρωτιδικοφ τοιχϊματοσ (IMT) Αςβζςτωςθ ςτεφανιαίων US Preventive Services Task Force 2009
C-reactive protein and plasminogen activator inhibitor-1 are circulating markers of low-grade inflammation, thrombosis, and vascular injury. Together with homocysteine, they have been associated with the underlying inflammatory processes and are considered to be "nontraditional" risk factors of atherosclerosis. The role of their measurement in clinical practice remains unclear. Curr Diab Rep. 2003; 3:248-54.
Προγνωςτική αξία τησ CRP ςτο ΣΔ2 Η προγνωςτικι αξία τθσ CRP δεν υπερζβαινε oφτε αφξανε την προγνωςτική ςημαςία των κλαςικών παραγόντων κινδφνου Δεν ςυνζβαλλε ςε επαναταξινόμθςθ αςκενϊν από άποψθ κινδφνου Η πρακτική ςημαςία τησ αμελητζα Casale Monferrato Study n=3200 Diabetes 2009
A growing body of evidence suggests that chronic subclinical inflammation may play an important role in the pathogenesis of insulin resistance, T2DM and CVD Several markers of inflammation, in particular plasma levels of high-sensitivity C-reactive protein (HSCRP) and interleukin (IL)-6, are independent predictors of T2DM and CVD risk (TNF)-α, IL-1β appear to be associated with insulin resistance and T2DM Conversely, adiponectin, a peptide with antiinflammatory properties, is associated with a decreased risk of developing DM2 or CVD. N Engl J Med 2000; 342:836 843 Clin Endocrinol 2004; 61:75 80
J Clin Endocrinol Metab 2005; 90(7):3983 3988
Ο λιπώδης ιζηός ζηο ΣΔ Τ2 Βιζθαηίμη Αδιπομεκηίμη TNFa IL-6 Ρεζιζηίμη Γσαιζθηζία ζηημ ιμζοσλίμη Αμηίζηαζη ζηημ ιμζοσλίμη
Δ Αντίςταςθ ςτθν ινςουλίνθ Παχυςαρκία
1. Χρόνια φλεγμονι μικρισ οξφτθτασ (αφξθςθ TNFa,.) 2. Αυξθμζνθ λιπόλυςθ με αυξθμζνα ΕΛΟ ςτο ιπαρ και ςτουσ μυσ The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 9 September 2008 ςπλαγχνικι παχυςαρκία οδθγεί ςτθν αντίςταςθ ςτθν ινςουλίνθ
Possible pathway by which inflammation and obesity interact and contribute to the development of an abnormal lipid and lipoprotein profile
Obesity is associated with low-grade chronic inflammation characterised by inflamed adipose tissue with increased macrophage infiltration. This inflammation is now widely believed to be the key link between obesity and development of insulin resistance. Activation of pro-inflammatory pathways can cross talk with insulin signalling pathways via a number of mechanisms: down-regulation of insulin signalling pathway proteins (e.g. GLUT4 and insulin receptor substrate (IRS)-1) serine phosphorylation of IRS-1 blocking its tyrosine phosphorylation in response to insulin induction of cytokine signalling molecules that sterically hinder insulin signalling by blocking coupling of the insulin receptor to IRS-1. Proc Nutr Soc. 2010;69(2):232-43
Curr Diab Rep (2010) 10:306 315
Genes Dev. 2006 20: 2193-2201
Φλεγμονϊδεισ παράγοντεσ ΛΙΠΟΚΤΣΑΡΟ ΦΕΓΜΟΝΗ χζςθ φλεγμονισ, IR και ακθροςκλιρυνςθσ ΗΠΑΡ
Μοριακι βάςθ τθσ ςχετιηόμενθσ με φλεγμονι αντίςταςθσ ςτθν ινςουλίνθ Οι φλεγμονϊδεισ διεργαςίεσ ξεκινοφν από «stress» του ενδοπλαςματικοφ δικτφου εξαιτίασ πλθκϊρασ ερεκιςμάτων (υποξία, τοξίνεσ, ιϊςεισ, μεταβολικά παράγωγα λιπιδίων κα) Σο «stress» του ενδοπλαςματικοφ δικτφου ενεργοποιεί το ςφςτθμα «απόκριςθσ» UPR (Unfolded Protein Response). Κφρια ςτοιχεία του ςυςτιματοσ είναι τα ζνηυμα IRE -1 (Inositol requiring enzyme 1) και PERK (PKR like endoplasmic reticulum kinase). Όταν τα ζνηυμα αυτά δραςτθριοποιθκοφν [= διζγερςθ των πακοφυςιολογικϊν οδϊν του JNK (c jun amino terminal kinase) και του NFκΒ, τα υποςτρώματα των υποδοχζων ινςουλίνησ IRS -1 και IRS -2 φωςφορυλιώνονται ςε θζςη ςερίνησ και όχι τυροςίνησ, με ςυνζπεια παρεμπόδιςθ τθσ ενδοκυττάριασ δράςθσ τθσ ινςουλίνθσ Σο «stress» του ενδοπλαςματικοφ δικτφου προάγει επίςθσ τθν παραγωγι ελευκζρων ριηϊν, που οδθγεί ςε οξειδωτικό stress το ςφνολο του κυττάρου DOI: 10.2337/db08-1746 2009
Cytokine-induced insulinoresistance Insulin TNFa, IL-6 IRS-Ser P PI 3 Kinase JNK IKKß SOCS Glucose transport Metabolic effects JNK = Jun kinase IKKß = Inhibitor of kappa B kinase ß SOCS =Suppressor of cytokine signaling
TZDs have potent anti-inflammatory effects, which may play an important role in their insulin sensitizing mechanism Br J Clin Pharmacol 2005; 62 :4 391 402
In the metformin group, body mass index, PPG, HbA1c, IL-6, ICAM-1, and TNF-α levels were significantly decreased after 12 weeks compared with the basal levels. Acta Diabetol 2011; 48(4):297-302.
Nowadays atherosclerosis is considered to be an inflammatory disease and the fact that atherosclerosis and resulting cardiovascular disease is more prevalent in patients with chronic inflammatory diseases like rheumatoid arthritis, systemic lupus erythematosus and ankylosing spondylitis than in the healthy population supports this statement. Hindawi Publishing Corporation Mediators of Inflammation Volume 2010, Article ID 792393, 15 pages doi:10.1155/2010/792393
Arterial stiffness assessed as apwv is increased in patients with type 1 diabetes without clinical cardiovascular disease, independently of classical cardiovascular risk factors. In men with type 1 diabetes, low-grade inflammation is independently associated with arterial stiffness. Diabetes Care Publish Ahead of Print, published online February 22, 2012
Insulin-resistant men with T1DM have an increase in plasma concentrations of hs-crp. Central obesity and HbA1c are its main determinants. Acta Diabetol 2012; 49(1):33-9
Intensive therapy in patients with type 1 diabetes mellitus increased levels of stnf-r1 and of hscrp among those who gained weight. These data demonstrate that the effect of intensive therapy on inflammation is complex and, to the extent that hscrp is a risk factor, suggest that the risk of atherosclerosis among diabetic patients may be influenced by the degree of weight gain while undergoing intensive therapy. Circulation 2005; 111:2446-2453
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