Syndrom of Insulinoresistance

= group of risk factors leading to early progressive (accelerated) atherosclerosis Atherosclerosis could lead to the ischaemic heart disease, ischaemic disease of the brain or peripheral artery disease and ischaemia of lower limbs

Syndrom of Insulinoresistance insulinresistance, hyperinsulinaemia hyperglycaemia (or DM2T) abdominal obesity hypertension insulinoresistant dyslipidaemia hypercoagulation (hyperhomocysteinaemia hyperleptinaemia, hyperuricaemia  CRP (marker of inflammation) hirsutismus; polycystic ovarian syndrom,...)

5 main components SIR insulinresistance, hyperinsulinaemia, DM2T abdominal obesity hypertension insulinoresistant dyslipidaemia hypercoagulation status

Prevalence of SIR SIR (as a reason of atherosclerosis) is vera frequent disease in western world is still rising in developing countries due to western- life style (high-energy food, reduction of traditionally high physical activity)

Patophysiology of SIR Genetic predisposition is dominant (is responsible of development SIR cca 66%) - changes in insulin receptor, glucose transporters, cell enzymes, PPAR gama etc. and is modified by external environment (cca 33%) – hormonal, metabolic changes, low physical activity, high energy intake..

Insulinoresistance Peripheral tissues are less sensitive to insulin The insulin in circulation is not able to cover the full glucose uptake in peripheral tissues   insulin secretion in β-cells (=compensatory hyperinsulinemia)

Target tissues for effect of insulin: Muscle – glucose uptake and oxidation Liver – supression of glucose production (gluconeogenesis and glycogenolysis) Fat tissue – supression of lipolysis (and FFA release into circulation Beta cells, brain, endotelium, trombocytes….

Lack of insulin effect influences the intermediate metabolismus: sugars – hyperglycaemia fat – lipolysis, ↑ TG, ↑ FFA, ↓ HDL proteins – protein degradation changes in ionts – enhanced natrium reabsorption in renal tubuli, changes in calcium metabolismus

Waist circumference: men> 102 cm women> 88 cm Triglycerids:  1,7 mmol/l HDL-cholesterol: men< 1,0 mmol/l women< 1,3 mmol/l Blood pressure:  130/85 mm Hg Fasting glycaemia:  5,6 mmol/l Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA (2001) 285 : Clinical criteria of SIR according to the NCEP- ATP III Presence of 3 and moreof these 5 factors is sufficient for syndrom of insulinoresistance diagnosis

Type 2 Diabetes Insulin resistance insuficient supression of glucose production from liver Disturbances in insulin secretion

 20  Natural history in T2DM Duration of DM (years)  -cell function Plasma glucose level insulinresistance insulinsecretion 7 mmol/l Fasting glucose level postprandial glucose 6-6

Hypertension hyperinzulinemia stimulates the sympathetic nerve system Increases vasoconstriction and Na reabsorption in renal tubuli = results to hypertension

starting startingtarget 140/90 mmHg < 130/80 mmHg Hypertension treatment in diabetics

Dyslipidaemia – insulinoresistant, diabetic = typical changes in lipids      Tg  HDL  LDL:  small LDL particles  large LDL particles = enhances risk for atherosclerosis Hyperinsulinemia increases hepatic VLDL secretion   plasma levels of Tg

Disturbances in coagulation ­ plasminogen activator inhibitor-1 (PAI-1) ® disturbances in fibrinolytic system ­ factor VII, VIII ¯ antitrombin III Disturbances in trombocytes functions (aggregation)

Obesity = total fat proportion of the body: men  25 women  30 % = according to the BMI: oveweight obesity  30 optimal BMI: 20-22

Obesity: abdominal X gynoid

Abdominal obesity: waist circumference: men  102 cm women  88 cm = insulinresistance Visceral fat  production: PAI-1, leptin, TNF alfa, adipsin, interleukin 6,…

Prevalence of obesity Is rising in all age groups including children

Therapy of  insulinoresistance BASAL: Diet – weight loss Physical activity MEDICAMENTS: Probably metformin

Obesity treatment Diet and weight loss Physical activity Psychoterapy Drug therapy (sibutramin, orlistat) Surgical treatment (gastric by-passes, gastric banding)

Gastric banding

The weight loss – how much? „moderate weight loss“ Is effective :  weight reduction of 5-10%   metabolic complications and cancer (50% reduction) I ineffective: in mechanical complications of obesity ( artrosis, low back pain, venous insuficiency…)

Complexity of treatment of SIR Diet, weight loss Physical activity Treatment of: T2DM Hypertension Dyslipidaemia Aspirin Obesity