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

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-alpha on glucose metabolism during GLP-1 administration are unknown. Objective: The objective of the study was to determine whether the infusion of TNF-alpha 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-alpha (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-H-2(2)] 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-alpha increased plasma TNF-alpha 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-alpha vs saline). However, TNF-alpha infusion lowered plasma GLP-1 during high-dose GLP-1 infusion (P < .001). Conclusions: TNF-alpha 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.