Louise Lehrskov-Schmidt1, Lars Lehrskov-Schmidt, Signe T Nielsen, Jens J Holst, Kirsten Møller, Thomas P J Solomon. 1. Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (Lo.L.-S., La.L.-S., S.T.N., K.M., T.P.J.S.), Department of Infectious Diseases, Rigshospitalet, Novo Nordisk Foundation Centre for Basic Metabolic Research and Department of Biomedical Sciences (J.J.H.), Faculty of Health Sciences, Neurointensive Care Unit (K.M.), Department of Neuroanesthesiology, Rigshospitalet, Faculty of Health Sciences, and Department of Biomedical Sciences (P.J.S.), Panum Institute, University of Copenhagen, Copenhagen 2200, Denmark.
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/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.
RCT Entities:
CONTEXT: Glucagon-like peptide-1 (GLP-1) analogs have recently been promoted as antihyperglycemic agents in critically illpatients 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 illpatients.
Authors: Corinna Lebherz; Florian Kahles; Katja Piotrowski; Michael Vogeser; Ann Christina Foldenauer; Kirsten Nassau; Erich Kilger; Nikolaus Marx; Klaus G Parhofer; Michael Lehrke Journal: Cardiovasc Diabetol Date: 2016-02-03 Impact factor: 9.951