Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance.
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.
Milner
Kerry-Lee
KL
Garvan Institute for Medical Research, University of New South Wales 2010, Sydney, Australia.
van der Poorten
David
D
Trenell
Michael
M
Jenkins
Arthur B
AB
Xu
Aimin
A
Smythe
George
G
Dore
Gregory J
GJ
Zekry
Amany
A
Weltman
Martin
M
Fragomeli
Vincent
V
George
Jacob
J
Chisholm
Donald J
DJ
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
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