Abstract 3593: Very-low Dose Endotoxemia Induces Insulin Resistance in the Absence of Clinical Inflammatory Responses
Introduction: Chronic inflammation may contribute to the development of insulin resistance (IR), metabolic syndrome and atherosclerosis although evidence of causality is lacking in humans. We have previously shown that IR develops during experimental endotoxemia (3ng/kg) in humans. However, clinical symptoms and marked counter-regulatory responses suggest that this may not reflect the low-grade inflammation of insulin resistant atherogenic states. We hypothesized that very low-dose human endotoxemia (LPS; 0.6ng/kg) would produce IR both at the whole body and tissue level without any measurable clinical response.
Methods: Ten healthy, human volunteers (50% male, 90% Caucasian, mean age 22.7 ±3.8) were randomized in a double-masked, placebo-controlled, crossover study to separate 36-hour inpatient visits (placebo versus intravenous-LPS 0.6ng/kg). Plasma and serum were collected for measurement of cytokines, C-reactive protein, insulin and glucose, serial whole blood & subcutaneous adipose tissue mRNA expression were measured by real-time PCR. HOMA-IR, a well-validated measure of IR, was calculated using fasting insulin & glucose. Repeated-measures ANOVA was applied to the data.
Results: There was no significant difference between placebo & LPS in clinical responses including body temperature and heart rate. Relative to placebo, LPS produced a peak 20-fold increase in TNFα(p = 0.01) & 15-fold increase in CRP (p <0.001). Endotoxemia increased fasting plasma insulin (p=0.01) & HOMA-IR (p=0.02). Whole blood mRNA levels of the inhibitors of insulin receptor signaling, suppressor of cytokine signaling-1 (SOCS-1) (2.5-fold; 4 hrs) & SOCS-3 (3.5-fold; 4 hrs) increased significantly and, in parallel, SOCS-1 (2-fold) & SOCS-3 (3-fold) also increased in adipose tissue. Further, insulin receptor signaling substrate (IRS)-1 decreased significantly in whole blood (60%; 8 hrs) and adipose (20%; 12 hrs).
Conclusions: Compared to placebo, very low-dose experimental endotoxemia produced a modest innate immune response in the absence of clinical symptoms, but induced IR both at the whole body and adipose tissue level. This model provides evidence of human IR induction during relatively low-grade inflammation in vivo.