The Effects of TNF-α on GLP-1-Stimulated Plasma Glucose Kinetics

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Abstract

Context:

Glucagon-like peptide-1 (GLP-1) analogs have recently been promoted as antihyperglycemic agents in critically ill patients with systemic inflammation, but the effects of TNF-α on glucose metabolism during GLP-1 administration are unknown.

Objective:

The objective of the study was to determine whether the infusion of TNF-α at high physiological levels impairs GLP-1's effects on glucose metabolism.

Design:

This was a randomized, controlled, cross-over trial.

Setting:

The study was conducted at a hospital clinical research laboratory.

Participants:

Twelve healthy males (aged 24 ± 3 y; body mass index 22.9 ± 1.3 kg/m2).

Interventions:

After an overnight fast, either saline (0.9%) or recombinant human TNF-α (1000 ng/m2·h) was infused from t = 0–6 hours. At t = 2 hours, GLP-1 infusion (0.5 pmol/kg·min) began. From t = 4–6 hours, the GLP-1 infusion rate was increased to 1.2 pmol/kg·min. Plasma glucose was clamped at 5 mmol/L throughout via a variable rate 20% dextrose infusion. Trials were 7–14 days apart.

Main Outcome Measures:

Endogenous glucose production (EGP) was measured by the [6,6-2H2]glucose isotope tracer dilution method.

Results:

GLP-1 infusion suppressed plasma glucagon (P < .01), elevated plasma insulin, and C-peptide (P < .01) and suppressed EGP (P < .001) during the saline infusion. In contrast, the infusion of TNF-α increased plasma TNF-α and IL-6, elevated body temperature, and blunted the GLP-1-induced suppression of EGP during high-dose GLP-1 infusion (all P < .05, TNF-α vs saline). However, TNF-α infusion lowered plasma GLP-1 during high-dose GLP-1 infusion (P < .001).

Conclusions:

TNF-α induces systemic inflammation and reduces plasma GLP-1, thereby reducing the suppression of EGP during GLP-1 infusion. This may have clinical relevance if GLP-1 analog drugs are used for the treatment of hyperglycemia in critically ill patients.

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