treatment of i nsulin resistance in cardiology doc dr amra džanković
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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
Athens, Sept 2005ID-ZMM
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?
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
Lipolysis in Adipocytes
Gly + NEFA
Insulin
IR
Increase in circulating NEFAs
Metabolism of insulin resistant adipocytes
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
adiponectine
obesity
liver
muscle
adipose tissue
insulin sensitivity
-
-
insulin levels
IL-6, TNF-
-
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
One mechanism of metformin to
improve insulin sensitivity is
mediated by an increase of
adiponectine
adiponectine
Metformin
insulin resistance
-
+
-
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
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
Athens, Sept 2005ID-ZMM
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
insulin-resistantlarge adipocytes
Thiazolidinediones shift fat cell populations in favour of small insulin-sensitive adipocytes
Insulin resistant state
Smith S A (2003) Biochimie 85: 1219-1230
Thiazolidinediones shift fat cell populations in favour of small insulin-sensitive adipocytes
pre-adipocytesinsulin-responsivesmall adipocytes
insulin-resistantlarge adipocytes
+ TZD insulin sensitive state
Smith S A (2003) Biochimie 85: 1219-1230
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!
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