title: Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis.
abstract: Pioglitazone treatment improves insulin resistance (IR), glucose metabolism, hepatic steatosis, and necroinflammation in patients with nonalcoholic steatohepatitis (NASH). Because abnormal lipid metabolism/elevated plasma free fatty acids (FFAs) are important to the pathophysiology of NASH, we examined the impact of pioglitazone therapy on adipose tissue insulin resistance (Adipo-IR) during the treatment of patients with NASH. To this end, we assessed glucose/lipid metabolism in 47 patients with impaired glucose tolerance/type 2 diabetes mellitus and NASH and 20 nondiabetic controls. All individuals underwent a 75-g oral glucose tolerance test (OGTT) in which we measured glucose tolerance, IR, and suppression of plasma FFAs. We also measured Adipo-IR index (fasting, FFAs x insulin), hepatic fat by magnetic resonance spectroscopy, and liver histology (liver biopsy). Patients were randomized (double-blind) to diet plus pioglitazone (45 mg/day) or placebo for 6 months, and all measurements were repeated. We found that patients with NASH had severe Adipo-IR and low adiponectin levels. Fasting FFAs were increased and their suppression during the OGTT was impaired. Adipo-IR was strongly associated with hepatic fat (r= 0.54) and reduced glucose clearance both fasting (r=0.34) and during the OGTT (r=0.40, all P <0.002). Pioglitazone significantly improved glucose tolerance and glucose clearance, steatosis and necroinflammation (all P<0.01-0.001 versus placebo). Fasting/postprandial plasma FFAs decreased to levels of controls with pioglitazone (P<0.02 versus placebo). Adipo-IR decreased by 47% and correlated with the reduction of hepatic fat (r=0.46, P=0.009) and with the reduction in hepatic necroinflammation (r=0.47, P=0.0007).
  
  
  CONCLUSIONS
  Patients with NASH have severe Adipo-IR independent of the degree of obesity. Amelioration of Adipo-IR by pioglitazone is closely related to histological improvement and plays an important role during treatment of patients with NASH.
authors: Diabetes Division, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: Amalia
authors: A
authors: Gastaldelli
authors: Stephen A
authors: SA
authors: Harrison
authors: Renata
authors: R
authors: Belfort-Aguilar
authors: Lou Jean
authors: LJ
authors: Hardies
authors: Bogdan
authors: B
authors: Balas
authors: Steven
authors: S
authors: Schenker
authors: Kenneth
authors: K
authors: Cusi
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D000328:Adult; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D004311:Double-Blind Method; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione