Enhanced Glucose Transport, but not Phosphorylation Capacity, Ameliorates Lipopolysaccharide-Induced Impairments in Insulin Stimulated-Muscle Glucose Uptake

Yolanda F. Otero, Kimberly X. Mulligan, Tammy M. Barnes, Eric A. Ford, Carlo M. Malabanan, Haihong Zong, Jeffrey E. Pessin, David H. Wasserman, Owen P. McGuinness

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Abstract

ABSTRACT: Lipopolysaccharide (LPS) is known to impair insulin stimulated muscle glucose uptake. We determined if increased glucose transport (GLUT4) or phosphorylation capacity (hexokinase II; HKII) could overcome the impairment in muscle glucose uptake (MGU). We utilized mice that over-expressed GLUT4 (GLUT4) or HKII (HK) in skeletal muscle. Studies were performed in conscious, chronically catheterized (carotid artery and jugular vein) mice. Mice received an intravenous bolus of either LPS (10?μg/g body weight) or vehicle (VEH). After 5?h, a hyperinsulinemic-euglycemic clamp was performed. As MGU is also dependent on cardiovascular function that is negatively affected by LPS, cardiac function was assessed using echocardiography. LPS decreased whole body glucose disposal and MGU in WT and HK mice. In contrast, the decrease was attenuated in GLUT4 mice. While membrane-associated GLUT4 was increased in VEH-treated GLUT4 mice, LPS impaired membrane-associated GLUT4in GLUT4 mice to the same level as LPS-treated WT mice. This suggested that overexpression of GLUT4 had further benefits beyond preserving transport activity. In fact, GLUT4 overexpression attenuated the LPS-induced decrease in cardiac function. The maintenance of MGU in GLUT4 mice following LPS was accompanied by sustained anaerobic glycolytic flux as suggested by increased muscle Pdk4 expression, and elevated lactate availability. Thus, enhanced glucose transport, but not phosphorylation capacity, ameliorates LPS-induced impairments in MGU. This benefit is mediated by long-term adaptations to the overexpression of GLUT4 that sustain muscle anaerobic glycolytic flux and cardiac function in response to LPS.

Original languageEnglish (US)
JournalShock
DOIs
Publication statusAccepted/In press - Dec 14 2015

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ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Emergency Medicine

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