Conclusions
These data strongly suggest that the primary metabolic effect of LPS is increased lipolysis and muscle insulin resistance, which, together with secondary insulin resistance, caused by systemic cytokine and stress hormone release may lead to overt glucose intolerance and diabetes.
Objective
We sought to define the direct, placebo-controlled effects of LPS on insulin resistance and protein and lipid metabolism in the infused human leg without systemic interference from cytokines and stress hormones. Design: This was a randomized, placebo-controlled, single-blinded study. Participants and intervention: We studied 8 healthy volunteers with bilateral femoral vein and artery catheters during a 3-hour basal and 3-hour hyperinsulinemic-euglycemic clamp period with bilateral muscle biopsies in each period during infusion with saline and LPS.
Results
Overall, LPS perfusion significantly decreased leg glucose uptake, and during the clamp LPS decreased glucose arteriovenous differences (0.65 ± 0.07 mmol/L vs 0.73 ± 0.08 mmol/L). Net palmitate release was increased by LPS, and secondary post hoc testing indicated increased palmitate isotopic dilution, although primary ANOVA tests did not reveal significant dilution. Leg blood flows, phenylalanine, lactate kinetics, cytokines, and intramyocellular insulin signaling were not affected by LPS. LPS thus directly inhibits insulin-stimulated glucose uptake and increases palmitate release in the perfused human leg without detectable effects on amino acid metabolism. Conclusions: These data strongly suggest that the primary metabolic effect of LPS is increased lipolysis and muscle insulin resistance, which, together with secondary insulin resistance, caused by systemic cytokine and stress hormone release may lead to overt glucose intolerance and diabetes.
Trial registration
ClinicalTrials.gov NCT00929136.