Insulin Resistance in Liver Diseases Lt Col Prof Dr Shakeel Ahmed Mirza MBBS, MRCP ( UK ), FRCP (...
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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
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
Slide 3
Layout What is Insulin Resistance ? What is mechanism of
Insulin Resistance ? Causes & its Relationship to Obesity
Atherosclerosis Hypertriglyceridemia Epidemiology Diagnosis
Management
Slide 4
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
Slide 9
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.
Slide 21
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
Slide 22
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
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