treatment of i nsulin resistance in cardiology doc dr amra džanković

Treatment of insulin resistance in cardiology

Doc dr Amra Džanković

Athens, Sept 2005ID-ZMM

• 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

Definition of insulin resistance

IRIR

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

Insulin resistance and dysfunction of beta cells are key factors in progressing of diabetes

Insulinresistance

Genetic code,Obesity,sedentary life-

style...

Type 2 diabetes

IRDysfunction of beta cells

Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.

Insulin resistance is growing by time

Insulin

glycaemiaExhosting

of pancreas

Exhosting of pancreas

Symptoms of diabetes

Symptoms of diabetes

How do insulin resistance and dysfunction of beta cells lead to diabetes?

time

More than 80 % of type 2 diabetes have primary insulin resistance-state

Insulin resistant;low secretion of insulin

(54%)

Insulin resistant; enough secretion of insulin

(29%)

Insulin sensitive;enough secretion of insulin (1%)

Insulin sensitivelow secretion of

insulina(16%)

83%83%

Haffner SM, et al. Circulation 2000; 101:975–980.

Insulin resistanceReduced answer on circulating insulin

Insulin resistance

Get off of glucose get on of glucose Get on of glucose

hyperglicaemia

Liver muscles Adipous tissue

IR

Why do beta-cells distroy?(apoptosis)

Chronic hyperglicemia

High secretion of insulin due to compensated insulin resistance

High circulated fatty acid level

Glucotoxicity

Pancreas

lipotoxicity

Dysfunction ofBeta 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.

1. Haffner SM et al. Diabetes Care 1999; 22: 562–568.2. Bloomgarden ZT. Clin Ther 1998; 20: 216–231.

92% patients with type 2 diabetes is

insulin resistant

Genetic factorsEnviroment

• Family anamnesis

• diet

• obesity

• A lack od physical activities

Insulin resistance is the main cause od type 2 diabetes

Insulin resistance is as high risk factor for CVD as smoking

0.6

0.8

1.0

1.2

1.4

1.6

1.8

Inci

den

ce o

f C

VD

age smoking Total chol/HDL

Insulin resistance

Bonora E, et al. Diabetes Care 2002; 25:1135–1141.

In moment of assesment of dyagnosis type 2 diabetes,

50% patients already have complications

Retinopaticcomplications

Nephropaticcomplications

Neuropatic

complications

microvascular macrovascular

Cerebrovasculardisease

Coronary disease

Peripheral arterial disease

1UK Prospective Diabetes Study Group. UKPDS 33. Lancet 1998; 352:837–853.

The Insulin Signaling Pathway - 2009 (simplified)

PP

IRS

Shc

Grb2 SOS

P85

P110

CrkNck

Fyn

Csk SHP2Raf

MEK

Akt/PKB

PDK1PDK2

GLUT1Biosynthesis

GLUT4 vesicle

PI3-K PKBb

PKCPKC

Glucose Transport

FAK

Rac

PDE

Focal Adhesion

Membrane Ruffling

Antilipolysis

Insulin Receptor

Ras

ERK MAPK

Growth Migration

Insulin

eNOS

NO Vasodilation

Cartoon by Pierre de Meyts published in Trends in Biochemical Sciences, 1979

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 4-6 fold higher than in other persons.Compared to other patients with atherosclerotic lesions, unstable plaques are significantly more frequent in patients with diabetes

Major concerns in type II diabetes


Lipogenesis/adipositas

Waist-to-hip-ratio

Atherogenesis

Hyperinsulinemia

Insulin resistance

Postprandial blood glucose

Gluconeogenesis

Glucose transport

Insulin secretion deficiency

Triglycerides

HDL

Arterialhypertension

Diabetes genes

Microangiopathy

Matthaei S et al., Dt. Ärzteblatt 2001; 98: A 912-18

Stage 3:Type 2 diabetes

Stage 2:Limitedglucose tolerance

Stage 1:Normalglucose tolerance

Macroangiopathy

Diabetes mellitus type 2

Major concerns in type II diabetes

Which pathways are connecting insulin resistance and cardiovascular disease?

How does the impact of antidiabetic and anti-insulin-resistant therapy on cardiovascular disease work?


History of vascular disease

Earliest manifestation of vascular disease=Endothelial

dysfunction

Hyper-coagulability

State of inflammation

Smooth muscle proliferation

Atherosclerosis, thromboembolic events, cardiovascular disorders

Endothelial findings

Progression

Clinical appearanc

e


Endothelial dysfunctionNO-allocation, vessel wall adaptability

HypercoagulabilityPlatelet activation, dysbalance of pro- and anti coagulatory factors, disturbed haemodynamics

Inflammatory statusPro-inflammatory cytokines, adipocytes, free fatty acids

Contributors to atherogenesis


Diabetes and vascular disease

Hyper-glycaemia

Free fatty acids

Insulin resistance

oxidative stressprotein kinase C

activationRAGE activation

NO ET-1 ATII

NFB AP-1

NO PAI-1 TF

endotheliumVasoconstriction,

hypertension, VSMCproliferation

Inflammation, cellular adhesion

Hypercoagulation, platelet activation


Endothelial dysfunction

Insulin resistance and metabolic syndrome are strongly associated with

1. Decreased NO availability

2. Proliferative activity in smooth muscle cells

3. Increased intima media thickness

Endothelial dysfunction is feeded by

NO deficiency

Insufficient compliance of the vessel wall


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

Hypercoagulability


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-6IL-6 and TNF-TNF-) ) are found

Inflammatory status


Lipolysis in Adipocytes

Gly + NEFA

Insulin

IR

Increase in circulating NEFAs

Metabolism of insulin resistant adipocytes


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


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

Cytokines, NEFAs and IR

Deficiency of tyrosine kinase activity is a key Deficiency of tyrosine kinase activity is a key factor in insulin resistancefactor in insulin resistance


adiponectine

obesity

liver

muscle

adipose tissue

insulin sensitivity

-

-

insulin levels

IL-6, TNF-

-


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 adipokinesadipokines.

Adipose tissue and inflammation


Adipokine I mpact on insulin sensitivity Adiponectine increasing IL-6 decreasing Leptin not fully elucidated, leptin

resistance may occur and interfere TNF- decreasing/ not conclusively

proved for humans Resistin decreasing/not conclusively

proved for humans

Adipokines and impact on IR


Role of inflammation in vascular disease: MIF

MIF: Macrophage Migration Inhibitory Factor

Jab 1: mediates MIF effects in vascular tissues

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


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


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


One mechanism of metformin to

improve insulin sensitivity is

mediated by an increase of

adiponectine

adiponectine

Metformin

insulin resistance

-

+

-


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


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.

Effect of metformin on cardiovascular risk factors - beyond glycemic control

Dyslipidemia

HypofibrinolysisInflammationReduces PAI-1 levels2

Increases HDL-c levels

Decreases CRP1

Reduces free fatty acid, triglyceride and LDL-c levels2,3

Metformin

Reduced CV disease

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

OS

NH

O

O

NN

Me• 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

PPAR PPAR PPAR

Fibratehypolipidaemic

agents

TZDinsulin-sensitisinganti-diabetic drugs

PPAR regulates genes controlling lipid & glucose metabolism &

inflammation

p65 p50

RXRretinoic

PPARligand

PPRE

PPARligand

RXRretinoic

AGGTCA X AGGTCATarget gene

Trans-activationLipid and glucose homeostasis

Trans-repressionAnti-inflammatory properties

NF-KB-RE

GGGACTTTCCC

STAT1 STAT2

TRE

TGAGTCA

ISGF-RE

CTGGGA

Fos Jun

TZDs

PPAR is the master regulator of pre-adipocyte differentiation

pre-adipocytes insulin-responsivesmall adipocytes

insulin-resistantlarge adipocytes

PPAR

TZD

Potentiates insulin-stimulateddifferentiation

Blocks lipolysis & inflammatory cytokine release. Pro-apoptotic

Smith S A (2003) Biochimie 85: 1219-1230

pre-adipocytes insulin-responsivesmall adipocytes


Thiazolidinediones shift fat cell populations in favour of small insulin-sensitive adipocytes

Insulin resistant state


Thiazolidinediones shift fat cell populations in favour of small insulin-sensitive adipocytes

pre-adipocytesinsulin-responsivesmall adipocytes


+ TZD insulin sensitive state


Insulin resistant adipocytes secrete multiple signalling molecules linked

with inflammation & insulin resistance

Adiponectin

Resistin

Angiotensin II

TNF

PAI-1

Free fatty acids

Leptin

Thiazolidinediones favorably modify adipocyte secretory profiles

Adiponectin

Resistin

Angiotensin II

TNF

PAI-1

Free fatty acids

Leptin PPAR

Thiazolidinediones - redefining type 2 diabetes

Type 2 diabetes is a lipid-driven disorder:

oversupply of FFA to liver & muscleproduces insulin resistance

metabolic status of fat depotsinfluences 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 ”

Insulin resistance is pro-inflammatory:

vascular inflammation drives accelerated atherosclerosis

Thiazolidinediones are anti-inflammatory:

direct actions in fat depots, vascular tissue and other PPAR-rich cells reduce inflammation

Type 2 diabetes - 2009 - evolution from a

glucose-driven to a cardiovascular disease

Insulinresistance

-celldysfunction

Genetic susceptibilityobesity, sedentary lifestyle

Type 2 diabetes

Cardiovascular disease

Metabolic syndrome

Microvascular disease

Insulinsensitiser

Glucose controlDiabetes prevention

CV mortality

Blindness, amputations

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.

Thanks for Thanks for attention!attention!

treatment of i nsulin resistance in cardiology doc dr amra džanković

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