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Insulin Resistance in Liver Diseases Lt Col Prof Dr Shakeel Ahmed Mirza MBBS, MRCP ( UK ), FRCP ( London ) Classified Medical Specialist Gastroenterologist MH Rwp Hepatologist & Endocrinologist Prof of Medicine AFPGMI

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Layout What is Insulin Resistance ? What is mechanism of Insulin Resistance ? Causes & its Relationship to Obesity Atherosclerosis Hypertriglyceridemia Epidemiology Diagnosis Management

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Introduction The condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells.

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Insulin Resistance Hyperinsulinemic individuals are at risk for developing Diabetes, Dyslipidemia, Hypertension & ultimately Cardiovascular disease Patients with Metabolic Syndrome are 3.5 times as likely to die from Cardiovascular disease compared to normal people

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Insulin Resistance Hyperinsulinemia increases serum free fatty acid levels. Chronic hyperinsulinemia promotes de novo hepatic lipogenesis Activate profibrotic cytokines

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Mechanism It includes Genetic or Primary target cell defects Autoantibodies to insulin & Accelerated insulin degradation

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CAUSES of IR Obesity PCOD Lipodystrophic states -. Werner syndrome Rabson-Mendenhall syndrome Pineal hypertrophic syndrome Immune insulin resistance Low titer immunoglobulin (Ig) G anti-insulin antibodies are present in most patients receiving insulin. Cushing syndrome and Acromegaly

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What Happens When Insulin Reaches Cells ? 9 Insulin binding to IR will cause autophosphorylation and phosphorylation of IRS at Tyrosine, then IRS will be activated and bind to following components to activate the signal cascade. Glucose will be transport from blood into cells. Phosphorylation at Serine will block the IRS function.

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GLUT4 Is The Transporter Of Glucose In Muscle And Adipose Tissue 10 GLUT4 will be relocated from the cytoplasm to membrane Foster et al, J. Biol. Chem., 2001 Blue: DNA Red: GLUT4 Green: Transferon

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What Will Happen If GLUT4 Doesnt move right? Insulin Resistance: An impaired biological response to insulin -Resistance to insulin-stimulated glucose uptake -Increased lipolysis/FFAs 11 McFarlane SI, et al. J Clin Endocrinol Metab. 2001

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Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Live r Insulin IR X FFA

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Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Live r Insulin IR X TG Apo B VLDL VLDL FFA

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(hepati c lipase) Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Live r Kidne y Insulin IR X (CETP ) CE TG Apo B VLDL HD L TG Apo A- 1 FFA

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(hepati c lipase) Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Live r Kidne y Insulin IR X (CETP ) CE TG Apo B VLDL (CETP ) VLD L HD L (lipoprotein or hepatic lipase) SD LDL LD L TG Apo A- 1 TGCE FFA

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Relation Between Insulin Resistance and Hypertriglyceridemia Olefsky JM et al. Am J Med. 1974;57:551-560. * Total area under 3-hour response curve (mean of 2 tests). 625 500 400 300 200 100 200300400500600 Insulin Response to Oral Glucose* Plasma TG (mg/dL) r = 0.73 P < 0.0001

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NAFLD Fatty liver disease can range from fatty liver alone (steatosis) fatty liver associated with inflammation (steatohepatitis). This condition can occur with the use of alcohol (alcohol- related fatty liver) or in the absence of alcohol (nonalcoholic fatty liver disease [NAFLD]).

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What is NASH ?? Nonalcoholic steatohepatitis (NASH) is the term used to describe the distinct clinical entity in which patients lack a history of significant alcohol consumption but have liver biopsy findings indistinguishable from alcoholic steatohepatitis

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NAFLD Epidemiology Most common cause for elevated liver function tests in the United States due to the ongoing obesity epidemic in the United States. Associated with the use of alcohol. This may occur with as little as 10 oz of alcohol ingested per week. Identical lesions also can be caused by other diseases or toxins.

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According to National Cholesterol Education Program Adult Treatment Panel III, insulin resistance syndrome is affecting about 24% of US adults aged greater than 20 years. The syndrome is more common in older people and in Mexican Americans, and will increase in prevalence as populations age and become more obese

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It consists of the co-occurrence of metabolic risk factors for type 2 diabetes and cardiovascular disease, including Overall obesity Central obesity Dyslipidemia Hyperglycemia & Hypertension.

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Obesity 60% of adults have BMI>25 (85 th %) 22% of adults have BMI>30 (95 th %) In 1990, there was no state with over 15% adults with BMI>30 25% of children have BMI over 85 th % Lee, Arch Peds Ad Med, 162(7):682 July 2008

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Abdominal obesity is linked to an increased risk of coronary heart disease Waist circumference has been shown to be independently associated with increased age-adjusted risk of CHD, even after adjusting for BMI and other cardiovascular risk factors 0.0 0.5 1.0 1.5 2.0 2.5 3.0

Variable clinical presentation Typically asymptomatic, but may have hepatomegaly and abdominal discomfort Liver enzymes may be normal in >75% of cases, making them insensitive in detecting NAFLD When increased, usually only modestly and limited to aminotransferases ALT upper limits of normal:

Lipid Control - How Important? Goals:HDL >40 mg% (>1.1 mmol /l) LDL 40 mg% (>1.1 mmol /l) LDL

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The END! Thank You! Oh, sorry, not the end, just the beginning .. 63