Alexa Caldwell1, Jan Niklas Morick2, Anne-Marie Jentsch2, Annette Wegner2, Dragan Pavlovic2, Nadia Al-Banna3, Christian Lehmann4. 1. Department of Pharmacology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College St, Halifax, NS B3H 4R2, Canada. 2. Department of Anesthesia and Intensive Care Medicine, University of Greifswald, Ferdinand-Sauerbruch, 17475 Greifswald, Germany. 3. Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College St, Halifax, NS B3H 4R2, Canada. 4. Department of Pharmacology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College St, Halifax, NS B3H 4R2, Canada; Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College St, Halifax, NS B3H 4R2, Canada; Department of Microbiology and Immunology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College St, Halifax, NS B3H 4R2, Canada; Department of Physiology and Biophysics, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College St, Halifax, NS B3H 4R2, Canada. Electronic address: chlehmann@dal.ca.
Abstract
BACKGROUND: Sepsis involves dysfunctional glucose metabolism. Among patients with sepsis, hyperglycemia is frequent and insulin administration has been evaluated for glycemic control to improve patient outcomes. Only few studies have examined the hyperglycemic microcirculation and the impact of insulin on the microvasculature in sepsis. OBJECTIVE: To study the functional capillary density (FCD) and leukocyte activation within the intestinal microcirculation in endotoxin-induced experimental sepsis. METHODS: In 50 male Lewis rats, endotoxemia was induced with lipopolysaccharide (LPS; 5 mg/kg). Low dose (LD) glucose was administered to avoid insulin-induced hypoglycemia. High dose (HD) glucose was administered to model sepsis-related hyperglycemia. Animals in LD and HD glucose groups received an insulin bolus (1.4 IU/kg). Two hours after LPS administration, intravital microscopy (IVM) of the terminal ileum was performed, and FCD and leukocyte adherence were measured in a blinded fashion. Blood glucose levels were measured every 30 min following the onset of endotoxemia. Plasma samples were collected 3 h after the onset of endotoxemia to measure IFN-γ, TNF-α, IL-1α, IL-4, GM-CSF and MCP-1 levels using multiplex bead immunoassay. RESULTS: Endotoxemia significantly reduced FCD and increased leukocyte adherence within the intestinal microvasculature. LD and HD glucose administration combined with insulin improved the FCD and decreased the adherence of leukocytes in endotoxemic animals as did HD glucose administration alone. Consistent with these results, IL-4, IL-1α, GM-CSF and IFN-γ levels were decreased following combined HD glucose and insulin administration in endotoxemic animals. CONCLUSIONS: Insulin administration, as well as an endogenous insulin response triggered by HD glucose administration, improved the FCD and decreased leukocyte activation in endotoxemic rats. The results of this study give insight into the immune and vaso-modulatory role of insulin administration during experimental endotoxemia, and may be extrapolated for clinical sepsis and other critical illnesses with marked microcirculatory dysfunction.
BACKGROUND:Sepsis involves dysfunctional glucose metabolism. Among patients with sepsis, hyperglycemia is frequent and insulin administration has been evaluated for glycemic control to improve patient outcomes. Only few studies have examined the hyperglycemic microcirculation and the impact of insulin on the microvasculature in sepsis. OBJECTIVE: To study the functional capillary density (FCD) and leukocyte activation within the intestinal microcirculation in endotoxin-induced experimental sepsis. METHODS: In 50 male Lewis rats, endotoxemia was induced with lipopolysaccharide (LPS; 5 mg/kg). Low dose (LD) glucose was administered to avoid insulin-induced hypoglycemia. High dose (HD) glucose was administered to model sepsis-related hyperglycemia. Animals in LD and HDglucose groups received an insulin bolus (1.4 IU/kg). Two hours after LPS administration, intravital microscopy (IVM) of the terminal ileum was performed, and FCD and leukocyte adherence were measured in a blinded fashion. Blood glucose levels were measured every 30 min following the onset of endotoxemia. Plasma samples were collected 3 h after the onset of endotoxemia to measure IFN-γ, TNF-α, IL-1α, IL-4, GM-CSF and MCP-1 levels using multiplex bead immunoassay. RESULTS:Endotoxemia significantly reduced FCD and increased leukocyte adherence within the intestinal microvasculature. LD and HDglucose administration combined with insulin improved the FCD and decreased the adherence of leukocytes in endotoxemic animals as did HDglucose administration alone. Consistent with these results, IL-4, IL-1α, GM-CSF and IFN-γ levels were decreased following combined HD glucose and insulin administration in endotoxemic animals. CONCLUSIONS:Insulin administration, as well as an endogenous insulin response triggered by HDglucose administration, improved the FCD and decreased leukocyte activation in endotoxemic rats. The results of this study give insight into the immune and vaso-modulatory role of insulin administration during experimental endotoxemia, and may be extrapolated for clinical sepsis and other critical illnesses with marked microcirculatory dysfunction.