UNIGASTRO Il fegato come centrale metabolica e i fattori di danno oltre ai virus epatitici IL METABOLISMO EPATICO DEI CARBOIDRATI IN FISIOLOGIA E PATOLOGIA Dr Elisabetta Bugianesi Divisione di Gastro-Epatologia Università di Torino
Glucose metabolism and NAFLD
Insulin Resistance: What is it DEFINITION a) Condition in which normal insulin concentrations fail to achieve a normal metabolic response b) Condition in which higher than normal insulin concentrations are needed to achieve a normal metabolic response Olefsky JM. In: Ellenberg and Rifkin s Diabetes Mellitus. 5th ed. 1997:513-552. The phenotipic expression of insulin resistance is dependent upon a genetically determined trait and environmental conditions physiologic pathologic
Pathophysiology of the Insulin Resistance Syndrome INSULIN RESISTANCE Inadequate insulin response Compensatory Hyperinsulinaemia Type 2 Diabetes Insulin Resistance Syndrome CardioVascular Disease
Relationship between glucose production and utilization
Sites and mechanisms of Insulin Resistance Glucose metabolism Muscle: reduced glucose uptake (peripheral IR) Liver: decreased suppression of hepatic glucose production (hepatic IR) Lipid metabolism Adipose tissue: decreased suppression of lipolysis
Insulin resistance in the muscle impairs the ability of insulin to promote glucose uptake Normal Glucose Normal insulin action Insulin resistance Glucose Glucose N Insulin Impaired insulin action to promote glucose uptake
Insulin resistance in the liver impairs the ability of insulin to inhibit glucose production Normal Normal Glucose Normal insulin action Insulin resistance Glucose Impaired insulin action to inhibit glucose production Insulin Glucose N Insulin
Peripheral and Hepatic insulin resistance in non-diabetic patients with NAFLD Total Glucose Disposal (µmol kg -1 min -1 ) Hepatic Glucose Output (µmol kg -1 min -1 ) 45 40 35 30 25 20 15 10 5 0 CONT DM2 NAFLD 20 15 10 5 0 CONT DM2 NAFLD Marchesini et al, Diabetes 2001
FFAs and Hepatic IR FFA impairs intrahepatic insulin signalling FFA inhibit the insulin signal transduction system by phosphorylation of serine/threonine sites on insulin receptor substrates (IRS-1 and IRS-2) FFA and glycerol increases gluconeogenesis (GNG) FFA activate key enzymes of GNG FFA oxidation provides a source of energy (ATP) for GNG Raised FFA are accompanied by raised glycerol levels, preferential substrates for GNG.
Components of Hepatic Glucose Production in Hepatic Insulin Resistance 18 16 glycogenolysis gluconeogenesis Glucose output (µmol min -1 kg -1 FFM ) 14 12 10 8 6 4 2 0 lean obese lean obese controls diabetics
Main determinants of gluconeogenesis in NAFLD GNG correlated with visceral fat but not with liver fat enhanced lipolytic activity in visceral fat results in increased flux of FFA and gluconeogenic substrates to the liver, leading to increased GNG Liver fat most likely represents a depot of inert lipids (triglycerides) Gastaldelli et al Gastro 2007
Adipose tissue and adipokines Rajala M et al Endocrinology 2003
Cytokines in NAFLD and NASH Hepatic TNFα and TNFR-1 mrna in NASH versus obese controls Crespo et al 2001 Adiponectin plasma levels are decreased in NAFLD and inversely related to hepatic fat content and hepatic insulin resistance Bugianesi et al 2005 mrna expression of AdipoRII in the liver is inversely associated with the degree of fibrosis Kaser et al 2005 High TNF and low adiponectin plasma levels independent predictors of NASH in NAFLD subjects Hui et al 2004
Peripheral insulin resistance in obese patients with NAFLD and NASH Glucose Infusion Rate (mg kg -1 min -1 ) 15 10 5 0 CONT NAFLD NASH Sanyal et al, Gastroenterology 2001
Ahima Gastro 2007
Regulators of liver fat content in humans Hepatic insulin sensitivity Yki-Jarvinen Ann Med 2005
Effects of 8% weight loss on liver fat 8 23 women Hypocaloric diet 4-6 months Weight loss 7.0 kg (90.1 to 83.1 kg) S.c. fat -14% Liver fat 6.2±0.1 8 Serum Adiponectin NS 7.2±0.4 7.3±0.4 % 6 *** 3.3±0.4 4-39% mg/l 6 4 2 2 0 Before After 0 Before After *** p<0.001 for before vs after Tiikkainen M et al, Diabetes 52: 701-707, 2003
Glucose metabolism and HCV
Prevalence of type 2 diabetes in persons with and without HCV infection (NHANES, n=9841 > 20 yrs old) 35 30 25 20 15 HCV neg HCV pos 10 5 0 20-29 30-39 40-49 50-59 60-90 Persons > 40 yrs: OR for T2DM 3.77 (95%CI:1.81-7.87) after adjustment for risk factors Mehta, S. H. et. al. Ann Intern Med 2000
HCV infection impairs insulin signalling in the liver In humans In liver biopsies of patients with CHC, exposure of liver tissue to insulin resulted in defective activation of PI3 kinase and Akt Aytug et al, Hepatology 2003 In HCV Core Protein transgenic mice Insulin resistance is caused by the suppression of insulin-induced tyrosine-phosphorylation of IRS-1, probably mediated by elevated intrahepatic TNF-α levels Shintani et al, Hepatology 2004
Hyperinsulinemic-euglycemic clamp: in HCV core protein transgenic mice the ability of insulin to suppress the hepatic glucose production is impaired Shintani et al, Hepatology 2004
Main determinants of steatosis according to HCV Genotype Genotype 3 Genotype1 Adinolfi et al Hepatology 2001
Steatosis and probability of progression of fibrosis Fartoux, Hepatology 2005
Distribution of fibrosis according to steatosis and insulin resistance in CHC-3 (n=132) and in matched NAFLD (n=132) CHC-3 NAFLD 2,5 3 2 2,5 1,5 1 2 1,5 1 0,5 0,5 0 Mild Moderate Severe 0 First Second Third Fourth Bugianesi et al Hepatology 2006
Main determinants of fibrosis in Cronica hepatitis C Moucariet al Gastro 2008
Insulin resistance and fibrosis High glucose levels and hyperinsulinemia cause upregulation of connective growth factor Paradis et al, Hepatology 2001 Hyperinsulinemia can directly stimulate hepatic stellate cells to proliferate and to secrete extracellular matrix Svegliati-Baroni et al, Hepatology 1999 In an in vitro model of HCV replicon, insulin enhances HCV replication and blocks the IFN-induced suppression of HCV replication by a PI3 Kinase-mediated pathway Sanyal Hepatology 2004 The role of IR is as a low-grade, chronic inflammatory state needs to be evaluated
Insulin resistance influences SVR to antiviral therapy SVR rate in genotype 1 patients varies according to HOMA-R value Romero-Gomez et al, Gastroenterology 2005
Therapeutic perspectives of insulin resistance and type 2 diabetes in chronic hepatitis C Metformin acts primarily on hepatic insulin sensitivity. By sensitizing the liver to insulin, metformin may also reverse fatty liver. The insulin sensitizing agents of the thiazolidinedione (TDZ) class cause a shift in fat topography from liver to subcutaneous fat. TDZ also have anti-inflammatory properties by inhibiting TNF-α gene expression, and stimulating adiponectin gene expression in adipocytes. Lifestyle changes have a primary role in increasing insulin sensitivity.
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