Abstract
ObjectivesThe 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.MethodsMale 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.MeasurementsAnd 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).ConclusionsThe 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.
Highlights
Sepsis is a devastating public health problem killing nearly 300,000 people in the U.S each year [1]
We examine the hypothesis that circulating glucose and the systemic inflammatory response syndrome combine to drive a cycle of metabolic dysfunction and hyperglycemia in early sepsis, which may contribute to adverse outcome in the setting of early nutritional support
Our study extends these prior observations to demonstrate a novel interaction between endotoxemia and exogenous glucose administration that results in profound insulin resistance and glucose intolerance, and importantly leads to a state of relative pancreatic insufficiency which we have previously shown to be associated with poor outcome in endotoxemic mice [12]
Summary
Sepsis is a devastating public health problem killing nearly 300,000 people in the U.S each year [1]. Hyperglycemia frequently complicates this illness imparting a worse prognosis when it develops [2,3]. Further complicating the issue of glucose homeostasis in critical illness, parenteral nutritional support has been linked to the development of hyperglycemia in critically ill patients [9], and more recently, its early initiation has been associated with increased infection rates, duration of mechanical ventilation, duration of renal replacement therapy, hospital length of stay, and incremental health care costs [8]
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