title: Exogenous glucose administration impairs glucose tolerance and pancreatic insulin secretion during acute sepsis in non-diabetic mice.
abstract: OBJECTIVE
  The development of hyperglycemia and the use of early parenteral feeding are associated with poor outcomes in critically ill patients. We therefore examined the impact of exogenous glucose administration on the integrated metabolic function of endotoxemic mice using our recently developed frequently sampled intravenous glucose tolerance test (FSIVGTT). We next extended our findings using a cecal ligation and puncture (CLP) sepsis model administered early parenteral glucose support.
  
  
  METHODS
  Male C57BL/6J mice, 8-12 weeks, were instrumented with chronic indwelling arterial and venous catheters. Endotoxemia was initiated with intra-arterial lipopolysaccharide (LPS; 1 mg/kg) in the presence of saline or glucose infusion (100 µL/hr), and an FSIVGTT was performed after five hours. In a second experiment, catheterized mice underwent CLP and the impact of early parenteral glucose administration on glucose homeostasis and mortality was assessed over 24 hrs.
  
  
  METHODS
  AND MAIN RESULTS: Administration of LPS alone did not impair metabolic function, whereas glucose administration alone induced an insulin sensitive state. In contrast, LPS and glucose combined caused marked glucose intolerance and insulin resistance and significantly impaired pancreatic insulin secretion. Similarly, CLP mice receiving parenteral glucose developed fulminant hyperglycemia within 18 hrs (all > 600 mg/dl) associated with increased systemic cytokine release and 40% mortality, whereas CLP alone (85 ± 2 mg/dL) or sham mice receiving parenteral glucose (113 ± 3 mg/dL) all survived and were not hyperglycemic. Despite profound hyperglycemia, plasma insulin in the CLP glucose-infused mice (3.7 ± 1.2 ng/ml) was not higher than sham glucose infused mice (2.1 ± 0.3 ng/ml).
  
  
  CONCLUSIONS
  The combination of parenteral glucose support and the systemic inflammatory response in the acute phase of sepsis induces profound insulin resistance and impairs compensatory pancreatic insulin secretion, leading to the development of fulminant hyperglycemia.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Srikanth
authors.initials: S
authors.lastname: Singamsetty
authors.forename: Baobo
authors.initials: B
authors.lastname: Zou
authors.forename: Lanping
authors.initials: L
authors.lastname: Guo
authors.forename: Darko
authors.initials: D
authors.lastname: Stefanovski
authors.forename: Laura C
authors.initials: LC
authors.lastname: Alonso
authors.forename: Adolfo
authors.initials: A
authors.lastname: Garcia-Ocana
authors.forename: Christopher P
authors.initials: CP
authors.lastname: O'Donnell
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: McVerry
mesh_terms: D000208:Acute Disease; D000818:Animals; D002432:Cecum / Q000187:drug effects / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019446:Endotoxemia / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005947:Glucose / Q000008:administration & dosage* / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005951:Glucose Tolerance Test; D006439:Hemodynamics / Q000187:drug effects; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010288:Parenteral Nutrition; D011677:Punctures; D018805:Sepsis / Q000150:complications* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D007328:Insulin; D005947:Glucose