Endocrine Abstracts

Introduction: In humans bacterial lipopolysaccharide (LPS/endotoxin) causes chronic low-grade and acute inflammatory responses, which decrease insulin sensitivity and may lead to chronic type 2 diabetes and acute stress diabetes. Systemic LPS invariably generates cytokine release, which triggers release of anti-insulin stress hormones and it is not known whether insulin resistance is secondary to stress hormones or LPS per se. Our study was designed to test whether local placebo controlled leg perfusion with LPS directly induces insulin resistance and affects protein and lipid metabolism.

Methods: We studied eight healthy volunteers with bilateral femoral vein and artery catheters during 3-h basal and 3-h hyperinsulinemic euglycemic clamp conditions. One femoral artery was perfused with saline and the other with LPS (0.025 ng/kg/h). Lipid metabolism was quantified with 3H-Palmitate and arterio-venous differences of FFA. Amino acid metabolism was quantified with 15N-Phenylalanine tracer and lactate and glucose by raw arterio-venous differences.

Results: Overall LPS perfusion significantly decreased leg glucose uptake (P=0.015); Basal glucose a-v differences were not significantly reduced (0.02±0.05 mmol/1 vs. 0.06±0.06 mmol/1 in the placebo leg, P=0.19); during the clamp LPS decreased glucose a-v differences (0.65±0.21 mmol/1 in the LPS leg, and 0.73±0.23 mmol/1 in the placebo leg, P=0.021). Akt308 phosphorylation was inhibited in the LPS leg both during the basal period (P=0.021) and clamp (P=0.027). Phosphorylation of AS160 was unaltered by LPS. Regional leg phenylalanine, palmitate, FFA and lactate kinetics were unaffected by LPS.

Conclusion: LPS directly inhibits insulin-stimulated glucose uptake in the perfused human leg without detectable effects on amino acid metabolism, lipolysis or lactate release. The mechanism in all likelihood involves inhibition of insulin mediated Akt308 phosphorylation. These data strongly suggest that a primary metabolic effect of LPS is muscle insulin resistance, which together with secondary insulin resistance caused by stress hormones may trigger diabetes.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.