title: Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance.
abstract: OBJECTIVE
  Chronic hepatitis C (CHC) is associated with insulin resistance (IR), liver steatosis (genotype 3), and increased diabetes risk. The site and mechanisms of IR are unclear.
  
  
  METHODS
  We compared cross-sectionally 29 nonobese, normoglycemic males with CHC (genotypes 1 and 3) to 15 adiposity and age-matched controls using a 2-step hyperinsulinemic-euglycemic clamp with [6,6-(2)H(2)] glucose to assess insulin sensitivity in liver and peripheral tissues and (1)H-magnetic resonance spectroscopy to evaluate liver and intramyocellular lipid. Insulin secretion was assessed after intravenous glucose.
  
  
  RESULTS
  Insulin secretion was not impaired in CHC. Peripheral insulin sensitivity was 35% higher in controls vs CHC (P < .001) during high-dose (264.3 +/- 25 [standard error] mU/L) insulin (P < .001); this was negatively associated with viral load (R(2) = .12; P = .05) and subcutaneous fat (R(2) = .41; P < .001). IR was similar in both genotypes despite 3-fold increased hepatic fat in genotype 3 (P < .001). Hepatic glucose production (P = .25) and nonesterified free fatty acid (P = .84) suppression with insulin were not different between CHC and controls inferring no adipocyte IR, and suggesting IR is mainly in muscle. In CHC, intramyocellular lipid was nonsignificantly increased but levels of glucagon (73.8 +/- 3.6 vs 52.8 +/- 3.1 ng/mL; P < .001), soluble tumor necrosis factor receptor 2 (3.1 +/- 0.1 vs 2.3 +/- 0.1 ng/mL; P < .001), and Lipocalin-2 (36.4 +/- 2.9 vs 19.6 +/- 1.6 ng/mL; P < .001) were elevated.
  
  
  CONCLUSIONS
  CHC represents a unique infective/inflammatory model of IR, which is predominantly in muscle, correlates with subcutaneous, not visceral, adiposity, and is independent of liver fat.
authors: Garvan Institute for Medical Research, University of New South Wales 2010, Sydney, Australia.
authors: Kerry-Lee
authors: KL
authors: Milner
authors: David
authors: D
authors: van der Poorten
authors: Michael
authors: M
authors: Trenell
authors: Arthur B
authors: AB
authors: Jenkins
authors: Aimin
authors: A
authors: Xu
authors: George
authors: G
authors: Smythe
authors: Gregory J
authors: GJ
authors: Dore
authors: Amany
authors: A
authors: Zekry
authors: Martin
authors: M
authors: Weltman
authors: Vincent
authors: V
authors: Fragomeli
authors: Jacob
authors: J
authors: George
authors: Donald J
authors: DJ
authors: Chisholm
mesh_terms: D000209:Acute-Phase Proteins; D050154:Adiposity; D000328:Adult; D001315:Australia; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D016022:Case-Control Studies; D002681:China; D003430:Cross-Sectional Studies; D004739:England; D005838:Genotype; D005934:Glucagon / Q000097:blood; D015309:Glucose Clamp Technique; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology*; D006801:Humans; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism / Q000503:physiopathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D011518:Proto-Oncogene Proteins / Q000097:blood; D012367:RNA, Viral / Q000097:blood; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood; D050151:Subcutaneous Fat / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D019562:Viral Load
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D012367:RNA, Viral; D047889:Receptors, Tumor Necrosis Factor, Type II; C415902:TNFRSF1B protein, human; D005934:Glucagon