ΦΛΕΓΜΟΝΗ ΚΑΙ ΔΙΑΒΗΤΗΣ ΘΩΜΑΣ ΠΑΠΑΔΟΠΟΥΛΟΣ, MD, PHD ΕΠΕΜΒΑΤΙΚΟΣ ΚΑΡΔΙΟΛΟΓΟΣ ΙΑΤΡΙΚΟ ΔΙΑΒΑΛΚΑΝΙΚΟ ΚΕΝΤΡΟ
Inflammation as a cause of disease has entered the popular imagination. Diet ( macronutrients ) is rightly perceived as a factor in causing inflammation.
ΤΑ ΣΑΛΙΚΥΛΙΚΑ ΕΧΟΥΝ ΕΥΡΓΕΤΙΚΗ ΔΡΑΣΗ ΣΤΟ ΔΙΑΒΗΤΗ ΤΥΠΟΥ 2
Hypertrophic Obesity is Associated With Local and Systemic Inflammation and Insulin Resistance
Diseases Associated with Obesity Diabetes: 80% related to obesity Hypertension: prevalence is >40% in obesity Heart disease: 70% related to obesity Cancer: Obesity accounts for 15-20% of cancer-related deaths Death: Obese individuals have a 50-100% increased risk of death from all causes compared to lean individuals (most of this risk is due to cardiovascular disease)
Steps Leading from Positive Energy Balance to Type 2 Diabetes Weight loss Increasing adipose tissue storage capacity Oxidation of lipids Storing of excess lipids in safe forms Increasing beta cell number or function Positive energy balance Failure in adipose tissue expansion Increased lipid flux to nonadipose organs Toxic lipid accummulation in non-adipose organs Beta cell compensation Beta cell failure Increased insulin demand Local inflammation Insulin resistance Hyperglycemia Adapted from Virtue S & Vidal-Puig A Biochim Biophys Acta 2010:1801:338-49
White Adipose Tissue (WAT) Many different adipose tissue beds throughout the whole organism Many distinct cell types: adipocytes, pre-adipocytes, fibroblasts, macrophages, vascular cells Heterogeneous metabolic capabilities, depending on visceral or subcutaneous location of fat depot Secrete adipokines with systemic effects
Secretory Products of Adipose Tissue Resistin Adiponectin Bone Morphogenic Protein IGF-1 IGFBP Adipose Tissue TNF-α Interleukins TGF β FGF EGF Fatty Acids Lactate Adenosine Prostaglandins Glutamine Unknown Factors Estrogen Ang II Angiotensinogen Leptin PAI-1 Adapted from: Roth, J, et al, Obesity Research, Vol 12, supplement Nov 2004:88S-101S
Adipokines Vascular Disease Related Angiotensinogen PAI-1 Insulin Resistance Related ASP (Acylation-stimulating protein) TNFa IL-6 Resistin Leptin Adiponectin
Adiponectin (Acrp 30, AdipoQ) Discovered in mid-1990 s Protein highly expressed in adipocytes and circulates at high concentrations Collagenous tail and globular head Plasma concentrations are reduced in obesity and insulin resistance TNFa and IL-6 inhibit adiponectin expression Administration of recombinant adiponectin ameliorates IR in obese and lipodystrophic mice Adiponectin is anti-atherogenic
Resistin Discovered in 2001 Expressed in adipocytes in mice and in macrophages in humans Increased in obesity Recombinant resistin Promotes insulin resistance in mice Decreased insulin stimulated glucose uptake in WAT
IL-6 10-30% of circulating IL-6 is from WAT Highly correlated with body mass and inversely related to insulin sensitivity Alters insulin signaling in the liver IL-6 KO mice develop mature-onset obesity and glucose intolerance
The Metabolic Syndrome Central obesity Glucose intolerance Hypertension Insulin resistance High TG Low HDL-C Small, dense LDL particles 1998 PPS
The Metabolic Syndrome Complex Dyslipidemia TG, LDL HDL Disordered Fibrinolysis Endothelial Dysfunction Insulin Resistance Systemic Inflammation Atherosclerosis Hypertension Type 2 Diabetes Visceral Obesity Adapted from the ADA. Diabetes Care. 1998;21:310-314; Pradhan AD et al. JAMA. 2001;286:327-334.
So, food kills! Calorie restricted mice live 30% longer than normally fed mice.
Hyperglycemia damages ( activates ) the endothelium. HYPERGLYCEMIA CAUSES INFLAMMATION. Reinhart K 2002, Dandona P 2005 J Clin Invest, Dandona P 2003 Curr Drug Targets
Hyperglycemia, sepsis and pre-eclampsia all activate (damage) endothelium, white cells and platelets, leading to white cell adhesion and infiltration, thrombosis and edema (inflammation). WBC WBC Hyperglycemia, sepsis or pre-eclampsia Platelet Platelets Protein (edema) Archer TL 2006 unpublished
INFLAMMATORY MECHANISMS IN DM2 HYPOXIA Rapid growth of the adipose tissue and lack of new vasculature, macrophages accumulate the sites of ishaemia CELL DEATH Hypoxia causes cell death and macrophages accumulate to clear cellular debris The NF-kβ and JNK pathways Activation of the JN kinases, by the metabolic stresses that promote insulin resistance and induction of the NF-kβ expressed genes, such as pro-inflammatory cytokines Il-6 and Insulin resistance The Il-1 system as a sensor of metabolic stress Il-1β contribute to both glucose induced impairment of β-cell secretory function and apoptosis Chemokines they have a crucial role in tissue infiltration by immune cells Adipokines Leptin and Adiponectin
B cells secrete a proinflammatory cytokine profile in response to obesity. Jason DeFuria et al. PNAS 2013;110:5133-5138 2013 by National Academy of Sciences
Angiotensin II (AngII) inhibits insulin secretion in human and mouse islets and induces β-cell apoptosis. Nadine S. Sauter et al. Diabetes 2015;64:1273-1283 2015 by American Diabetes Association
Chronic Inflammatory Disorders and Risk of Type 2 Diabetes Mellitus, Coronary Heart Disease, and StrokeCLINICAL PERSPECTIVE by Alex Dregan, Judith Charlton, Phil Chowienczyk, and Martin C. Gulliford Circulation Volume 130(10):837-844 September 2, 2014 Copyright American Heart Association, Inc. All rights reserved.
Forest plot displaying random-effects meta-analysis of the influence of diverse chronic inflammatory conditions on multiple cardiovascular and type 2 diabetes mellitus outcomes. Alex Dregan et al. Circulation. 2014;130:837-844 Copyright American Heart Association, Inc. All rights reserved.
ΑΝΤΙΦΛΕΓΜΟΝΩΔΕΙΣ ΘΕΡΑΠΕΙΕΣ ΣΤΟ ΔΙΑΒΗΤΗ ΤΥΠΟΥ 2
ΕΥΧΑΡΙΣΤΩ ΓΙΑ ΤΗΝ ΠΡΟΣΟΧΗ ΣΑΣ