The effects of TNF-α on GLP-1-stimulated plasma glucose kinetics.

Lehrskov-Schmidt, Louise; Lehrskov-Schmidt, Lars; Nielsen, Signe T; Holst, Jens J; Møller, Kirsten; Solomon, Thomas P J

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/m(2)). INTERVENTIONS After an overnight fast, either saline (0.9%) or recombinant human TNF-α (1000 ng/m(2) · 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-(2)H2]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.