Disassociation of liver and muscle insulin resistance from ectopic lipid accumulation in low-birth-weight individuals.

CONTEXT: Low birth weight (LBW) is a marker of fetal stress and is associated with an increased prevalence of type 2 diabetes (T2D). Insulin resistance plays a prominent role in the development of T2D; however, the pathogenesis of T2D in LBW is controversial. OBJECTIVE: The objective of the study was to assess whole-body and tissue-specific insulin sensitivity and intramyocellular lipid (IMCL) and hepatic lipid content in LBW and matched control subjects. DESIGN: These were prospective and pair-matched studies. SETTING: The study was conducted at Yale University Center for Clinical Investigation. PARTICIPANTS: Young, lean, nonsmoking, sedentary LBW (n = 45) and matched control subjects participated in the study. INTERVENTION: Interventions included an oral glucose tolerance test and hyperinsulinemic-euglycemic clamps and (1)H magnetic resonance spectroscopy. MAIN OUTCOMES MEASURES: The main outcomes measures included insulin sensitivity index; whole-body and tissue-specific insulin sensitivity; liver lipid and IMCL contents; and fasting concentrations of cortisol, GH, and IGF-I as markers of the hypothalamic-pituitary-adrenal and IGFI/GH axes. RESULTS: The LBW subjects were insulin resistant as reflected by a 20% reduction in insulin sensitivity index as compared with the controls (P = 0.0017), which could be attributed to both liver and muscle insulin resistance. There were no differences in IMCL or hepatic triglyceride content between LBW and control groups. In the LBW group, fasting plasma concentrations of cortisol (P = 0.01) and GH (P = 0.01) were increased, and IGF-I concentrations reduced (P < 0.05) a pattern, which may suggest potential dysregulation of the hypothalamic-pituitary-adrenal and IGF-I/GH axes. CONCLUSION: These results support the hypothesis that fetal stress and LBW lead to liver and muscle insulin resistance and show that this is independent of lipid deposition in these organs.