Dissociation Between Intrahepatic Triglyceride Content and Insulin Resistance in Familial Hypobetalipoproteinemia

Abstract

Background & Aims: Hepatic steatosis is associated with insulin resistance, but it is not clear whether increased intrahepatic triglyceride (IHTG) content causes the resistance or is a marker. Subjects with familial hypobetalipoproteinemia (FHBL) have high levels of IHTG because of a genetic defect in hepatic export of triglycerides, and provide a unique cohort to study the relationship between steatosis and insulin sensitivity. Methods: One group of lean subjects with normal IHTG content (2.2% ± 0.6% of liver volume) (n = 6), and 3 groups of overweight and obese subjects matched for body mass index, were studied: (1) normal IHTG content (3.3% ± 0.5%; n = 6), (2) high IHTG content (21.4% ± 2.6%) due to nonalcoholic fatty liver disease (NAFLD; n = 6), and (3) high IHTG content (18.1% ± 2.2%) due to FHBL (n = 3). A hyperinsulinemic-euglycemic clamp procedure, in conjunction with glucose tracer infusion, was used to determine multiorgan insulin sensitivity. Results: Hepatic insulin sensitivity (reciprocal of glucose rate of appearance [μmol · kg fat-free mass-1 · min-1] × insulin [mU/L]) was greatest in the Lean group (2.0 ± 0.4); it was the same among subjects with FHBL (0.8 ± 0.1) and the group with normal IHTG content, matched for body mass index (0.7 ± 0.1), but greater than the NAFLD group (0.3 ± 0.1) (P < .01). Muscle insulin sensitivity (percent increase in glucose uptake during insulin infusion) was greatest in the Lean group (576% ± 70%). Muscle insulin sensitivity was similar in subjects with FHBL and those with normal IHTG (319% ± 77%, 326% ± 27%, respectively), but greater than the NAFLD group (145% ± 18%) (P < .01). Conclusions: Steatosis is dissociated from insulin resistance in FHBL, which suggests that increased IHTG content is a marker, not a cause, of metabolic dysfunction. © 2010 AGA Institute.