ID-ZMM Athens, Sept 2005 Treatment of insulin resistance in cardiology Doc dr Amra Džanković
IR Definition of insulin resistance • Main pathophysiological disturbance in type 2 diabetes and is presenting before diabetes in patients with metabolic syndroma • Reduced answer on own insulin • Strong predictor of type 2 diabetes • Tighty related to obesity 1American Diabetes Association. Diabetes Care 1998; 21:310–314. 2Beck-Nielsen H & Groop LC. J Clin Invest 1994; 94:1714–1721. 3Bloomgarden ZT. Clin Ther 1998; 20:216–231. 4Haffner SM, et al. Circulation 2000; 101:975–980. 5Boden G. Diabetes 1997; 46:3–10.
Type 2 diabetes • It’s caracterised with chronic hyperglicaemia(high level of glucose in blood) • Related with micro- and macrovasular complications • Diabetes occured in combination of insulin resistance and loss of beta-cells in Langerhans’ islands Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
Genetic code, Obesity,sedentary life-style... Insulin resistance Dysfunction of beta cells IR Type 2 diabetes Insulin resistance and dysfunction of beta cells are key factors in progressing of diabetes Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.
How do insulin resistance and dysfunction of beta cells lead to diabetes? Symptoms of diabetes Exhosting of pancreas glycaemia Insulin Insulin resistance is growing by time time
More than 80 % of type 2 diabetes have primary insulin resistance-state Insulin sensitivelow secretion of insulina(16%) Insulin sensitive;enough secretion of insulin (1%) Insulin resistant;low secretion of insulin (54%) 83% Insulin resistant; enough secretion of insulin (29%) Haffner SM, et al. Circulation 2000; 101:975–980.
IR Insulin resistance Reduced answer on circulating insulin Insulin resistance Adipous tissue muscles Liver Get off of glucose get on of glucose Get on of glucose hyperglicaemia
Why do beta-cells distroy?(apoptosis) High secretion of insulin due to compensated insulin resistance Glucotoxicity lipotoxicity Chronic hyperglicemia High circulated fatty acid level Pancreas Dysfunction of Beta cells 1Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23. 2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22. 3Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27.
Enviroment Genetic factors Insulin resistance is the main cause od type 2 diabetes 92% patients with type 2 diabetes is insulin resistant • Family anamnesis • diet • obesity • A lack od physical activities 1. Haffner SM et al. Diabetes Care 1999; 22: 562–568. 2. Bloomgarden ZT. Clin Ther 1998; 20: 216–231.
Insulin resistance is as high risk factor for CVD as smoking 1.8 1.6 1.4 Incidence of CVD 1.2 1.0 0.8 0.6 age smoking Insulin resistance Total chol/ HDL Bonora E, et al. Diabetes Care 2002; 25:1135–1141.
In moment of assesment of dyagnosis type 2 diabetes,50% patients already have complications microvascular macrovascular Retinopatic complications Cerebrovascular disease Coronary disease Nephropatic complications Peripheral arterial disease Neuropatic complications 1UK Prospective Diabetes Study Group. UKPDS 33. Lancet 1998; 352:837–853.
The Insulin Signaling Pathway - 2009 (simplified) Insulin Insulin Receptor FAK P P Focal Adhesion Shc Ras Fyn Grb2 Crk SOS Nck IRS Membrane Ruffling Rac Raf Csk SHP2 P85 PDE Antilipolysis MEK P110 GLUT1 ERK MAPK Biosynthesis PKC PKC Akt/PKB PDK2 PDK1 PI3-K PKBb GLUT4 vesicle eNOS Growth Migration Glucose Transport NO Vasodilation
Cartoon by Pierre de Meyts published in Trends in Biochemical Sciences, 1979
Major concerns in type II diabetes ID-ZMM Athens, Sept 2005 • Macrovascular events due to atherosclerosis • stroke • myocardial infarction • other thromboembolic events are significantly more frequent in patients with diabetes. Their risk of an acute myocardial infarction is 4-6fold higher than in other persons. Compared to other patients with atherosclerotic lesions, unstable plaques are significantly more frequent in patients with diabetes
Diabetes mellitus type 2 Stage 3: Type 2 diabetes Macroangiopathy Microangiopathy Stage 2: Limited glucose tolerance Postprandial blood glucose Gluconeogenesis Glucose transport Insulin secretion deficiency Stage 1: Normal glucose tolerance Lipogenesis/ adipositas Atherogenesis Hyperinsulinemia Insulin resistance Triglycerides HDL Waist-to-hip-ratio Arterial hypertension Diabetes genes Matthaei S et al., Dt. Ärzteblatt 2001; 98: A 912-18
Major concerns in type II diabetes ID-ZMM Athens, Sept 2005 Which pathways are connecting insulin resistance and cardiovascular disease? How does the impact of antidiabetic and anti-insulin-resistant therapy on cardiovascular disease work?
Hyper-coagulability Smooth muscle proliferation State of inflammation Endothelial findings Progression = Earliest manifestation of vascular disease Endothelial dysfunction Clinical appearance Atherosclerosis, thromboembolic events, cardiovascular disorders ID-ZMM Athens, Sept 2005 History of vascular disease
Contributors to atherogenesis ID-ZMM Athens, Sept 2005 • Endothelial dysfunction • NO-allocation, vessel wall adaptability • Hypercoagulability • Platelet activation, dysbalance of pro- and anti coagulatory factors, disturbed haemodynamics • Inflammatory status • Pro-inflammatory cytokines, adipocytes, free fatty acids
Hyper-glycaemia Free fatty acids Insulin resistance oxidative stress protein kinase C activation RAGE activation endothelium NO PAI-1 TF NO ET-1 ATII NFB AP-1 Vasoconstriction, hypertension, VSMCproliferation Inflammation, cellular adhesion Hypercoagulation, platelet activation ID-ZMM Athens, Sept 2005 Diabetes and vascular disease
ID-ZMM Athens, Sept 2005 Endothelial dysfunction • Endothelial dysfunction is feeded by • NO deficiency • Insufficient compliance of the vessel wall • Insulin resistance and metabolic syndrome are strongly associated with • Decreased NO availability • Proliferative activity in smooth muscle cells • Increased intima media thickness
Hypercoagulability ID-ZMM Athens, Sept 2005 Coagulatory balance is frequently disturbed in patients with cardiovascular diseases Elevated levels of PAI-1 and fibrinogen are found in patients with decreased insulin sensitivity. Levels of the pro-coagulatory agents correlate with the BMI
Inflammatory status ID-ZMM Athens, Sept 2005 In patients with coronary heart disease, elevated serum levels of pro-inflammatory cytokines are associated with an impaired prognosis In patients with decreased insulin sensitivity, elevated plasma levels of pro-inflammatory cytokines (IL-6 and TNF-) are found
IR Increase in circulating NEFAs Gly + NEFA Lipolysis in Adipocytes Insulin ID-ZMM Athens, Sept 2005 Metabolism of insulin resistant adipocytes
ID-ZMM Athens, Sept 2005 Metabolism of insulin resistant adipocytes Insulin supports lipogenesis and inhibits lipolysis Lack of insulin activity will increase lipolysis to form glycerin and free, non-esterified fatty acids (NEFAs) Insulin resistant adipocytes produce higher amounts of circulating NEFAs
ID-ZMM Athens, Sept 2005 Cytokines, NEFAs and IR • Insulin resistant adipocytes provide • Higher amounts of NEFAs • Cytokines which ameliorate insulin sensitivity • Together, cytokines and free fatty acids will inhibit the tyrosine phosphorylation and favour serine phosphorylation • Phosphorylation of serine instead of tyrosine will block the physiological insulin signaling cascade Deficiency of tyrosine kinase activity is a key factor in insulin resistance
ID-ZMM Athens, Sept 2005 obesity insulin levels IL-6, TNF- - - adipose tissue adiponectine - muscle insulin sensitivity liver
ID-ZMM Athens, Sept 2005 Adipose tissue and inflammation Adipose tissue has proved to be not only an energy store, but shows secretory activity. Adipocytes, besides monocytes, lymphocytes, or granulocytes, were found to produce and store specific cytokines. Cytokines derived from adipocytes are summarised as adipokines.
ID-ZMM Athens, Sept 2005 Adipokines and impact on IR
ID-ZMM Athens, Sept 2005 Role of inflammation in vascular disease: MIF Monocytes/macrophages play a pronounced role in proliferation and inflammation in the atherosclerotic vessel wall MIF is responsibe for accumulation of the phagocytes in the cells of the vascular tissue, and Jab 1 is its cellular mediator MIF: Macrophage Migration Inhibitory Factor Jab 1: mediates MIF effects in vascular tissues
ID-ZMM Athens, Sept 2005 Role of inflammation in vascular disease: MIF Oxidized LDL supports formation of foam cells (fat storing macrophages which are key cells in the development of atherosclerotic lesions) Foam cells secrete proinflammatory cytokines After stimulation by MIF, macrophages secrete cytokines, such as TNF, IL-1, IL-8 MIF is supposed to support, or even cause, inflammatory changes in atherogenesis
ID-ZMM Athens, Sept 2005 MIF, endothelial inflammation and obesity Dandona P e al. 2004: Comparison of non-diabetic, hyperinsulinaemic, obese individuals and healthy lean individuals • Fasting plasma insulin levels and insulin resistance indices are higher in obese individuals • Plasma MIF levels correlate significantly with BMI • Levels of NEFAs correlated significantly with BMI and insulin resistance indices • There was an association between NEFAs levels and CRP values
Metformin + adiponectine - - insulin resistance ID-ZMM Athens, Sept 2005 One mechanism of metformin to improve insulin sensitivity is mediated by an increase of adiponectine
ID-ZMM Athens, Sept 2005 Role of metformin in the process of endothelial inflammation • Metformin contributes to antiatherogenic activity, probably by a mechanism independent from the metabolic changes • Metformin dominantly reduced IR in liver and indirectly IR in sceletal muscle and adipose tissue • This part of its mechanism of action might be a basic contributor to its cardiovascular benefits
Effect of metformin on cardiovascular risk factors - beyond glycemic control Metformin Hypofibrinolysis Inflammation Reduces PAI-1 levels2 Decreases CRP1 Dyslipidemia Increases HDL-c levels Reduces free fatty acid, triglyceride and LDL-c levels2,3 Reduced CV disease 1Chu NV, et al. Diabetes Care 2002; 25:542–549. 2Kirpichnikov D, et al. Ann Int Med 2002; 137:25–33. 3DeFronzo RA, et al. New Eng.J Med 1995; 333:541–549.
ID-ZMM Athens, Sept 2005 Impact of metformin • Metformin shows direct and probably glycaemia independent effects: • Improved endothelial function and NO availability • Improved capacity of vasodilation • Improved responsiveness to vasodilatory agents • Decrease of pro-coagulatory factors • Decrease of plasma MIF levels
BRL 49653 - rosiglitazone • normalises glycaemic control in rodent models of type 2 diabetes - orally active • reduces insulin resistance • potent (~1mg/kg) • no hypoglycaemia • most selective Bioorg. Med. Chem. Lett., 1994, 1181 J. Med. Chem., 1994, 37, 3977
PPAR subtypes are molecular targets for fibrate hypolipidaemic and TZD anti-diabetic drugs PPARa PPARd PPARg Fibrate hypolipidaemic agents TZD insulin-sensitising anti-diabetic drugs
ligand ligand retinoic retinoic p65 p50 Fos Jun STAT1 STAT2 PPAR PPAR RXR RXR AGGTCA X AGGTCA CTGGGA GGGACTTTCCC TGAGTCA ISGF-RE NF-KB-RE TRE PPRE PPARg regulates genes controlling lipid & glucose metabolism & inflammation TZDs Target gene Trans-activation Lipid and glucose homeostasis Trans-repression Anti-inflammatory properties
Blocks lipolysis & inflammatory cytokine release. Pro-apoptotic Potentiates insulin-stimulated differentiation TZD PPAR is the master regulator of pre-adipocyte differentiation insulin-resistant large adipocytes insulin-responsive small adipocytes pre-adipocytes PPARg Smith S A (2003) Biochimie 85: 1219-1230
Thiazolidinediones shift fat cell populations in favour of small insulin-sensitive adipocytes insulin-resistant large adipocytes insulin-responsive small adipocytes pre-adipocytes Insulin resistant state Smith S A (2003) Biochimie 85: 1219-1230
Thiazolidinediones shift fat cell populations in favour of small insulin-sensitive adipocytes insulin-responsive small adipocytes insulin-resistant large adipocytes pre-adipocytes + TZD insulin sensitive state Smith S A (2003) Biochimie 85: 1219-1230
Free fatty acids TNF a Leptin Resistin Adiponectin Angiotensin II PAI-1 Insulin resistant adipocytes secrete multiple signalling molecules linked with inflammation & insulin resistance
PPARg Thiazolidinediones favorably modify adipocyte secretory profiles Free fatty acids TNF a Leptin Resistin Adiponectin Angiotensin II PAI-1
Thiazolidinediones - redefining type 2 diabetes Type 2 diabetes is a lipid-driven disorder: oversupply of FFA to liver & muscle produces insulin resistance metabolic status of fat depots influences whole body insulin action Thiazolidinediones increase metabolic “size”: reduced FFA supply from fat to liver and muscle restores insulin sensitivity - “lipid steal” adiponectin - new fat-derived insulin- sensitising molecule - increased ” Thiazolidinediones are anti-inflammatory: direct actions in fat depots, vascular tissue and other PPARg-rich cells reduce inflammation Insulin resistance is pro-inflammatory: vascular inflammation drives accelerated atherosclerosis
Insulin sensitiser Type 2 diabetes - 2009 - evolution from a glucose-driven to a cardiovascular disease Genetic susceptibility obesity, sedentary lifestyle Insulin resistance Metabolic syndrome b-cell dysfunction Diabetes prevention Glucose control Type 2 diabetes Blindness, amputations CV mortality Cardiovascular disease Microvascular disease
Conclusions • Treatment of insulin resistance is optimal therapeutic option for prediabetic and early stage diabetic patients,just as obesity diabetic patients with preserve renal function,as • monoterapy or • in combination with insulin or other peroral hypoglicemic agents and other therapies(statins,antihypertensives-ACEi or ARB have priority,antitrombotic agents etc)
Conclusions • Novel drugs such as DPP-4 inhibitors or GLP -1 mimetics are offering new options without adverse effects,but they are not more effective concerning lowering HbA1C compared with old drugs and they are very expensive in our circumstances. • Very dissapointing results arrived from 3 recent studies(ACCORD,ADVANCE and VADIT).new antidiabetic combinations didn’t result in reduced CV morbidity and mortality • High doses of all kinds of insulin analogues are mitogenic,cancerogenic-warning with application of high doses od insulin-high incidence of malignant diseases in recent publications • Metformin and TZD(attention with Rosiglitazone) ,in fact insulin resistance treatment ,is nowadays good choice of treatment of diabetic patients and patients with metabolic syndrome,in monotherapy or in combination with drugs or insulin analogues but surely,with life-style change and more physical activity.