Insulin resistance and substrate utilization in human endotoxemia.
Level 2 - randomized trial
Randomized crossover trial evaluating metabolic response in healthy human subjects.
PubMed 11061537 · doi:10.1210/jcem.85.10.6914
What was done
Six healthy volunteers underwent paired crossover sessions receiving either 20 U/kg intravenous Escherichia coli endotoxin (LPS) or saline control. Injections occurred 120 minutes after initiating a 10-hour euglycemic hyperinsulinemic clamp (insulin infusion rate of 80 mU/m²·min) to evaluate effects on systemic insulin sensitivity and substrate utilization.
What was found
LPS induced fever, tachycardia, and mild arterial hypotension. Glucose utilization initially surged at 120 minutes post-LPS (+64.1 ± 12.0%, P < 0.003) relative to control, followed by a progressive decline resulting in marked insulin resistance by 420 minutes (+1.9 ± 3.5%, P < 0.05). The decrease in utilization was driven by impaired nonoxidative glucose disposal, while glucose oxidation remained intact. Cortisol and growth hormone elevations were of sufficient magnitude and duration to account for the observed insulin resistance.
Why it matters
This study demonstrates that acute LPS challenge accurately mimics the biphasic glucose kinetics and nonoxidative disposal defects seen in clinical sepsis, validating human endotoxemia as a controlled model for critical illness-induced insulin resistance.
Limits
The sample size was very small (n = 6), which limits generalizability and precision. The study evaluated an acute endotoxin bolus in healthy young volunteers, which may not capture the complex, prolonged pathophysiology of polymicrobial sepsis or critically ill patients with preexisting comorbidities. Endocrine involvement (cortisol, growth hormone) was correlational rather than tested via hormone-receptor blockade.
Cited by
- supports Lipopolysaccharide (LPS) drives systemic inflammation and insulin resistance.