AJP - Regulatory, Integrative and Comparative Physiology, Vol 261, Issue 1 26-R31, Copyright © 1991 by American Physiological Society
Antagonism of endotoxic glucose dyshomeostasis by protein kinase C inhibitors
H. Inaba and J. P. Filkins
Department of Physiology, Loyola University Chicago Medical Center, Maywood, Illinois 60153.
Activation of protein kinase C (PKC) by bacterial lipopolysaccharide had
recently been implicated in the pathogenetic sequence of gram-negative
sepsis, endotoxicosis, hyperinsulinism, and the alterations in
glucoregulation that eventuate in glucose dyshomeostasis. This study used
the peptide antibiotic polymyxin B (PMX-B) and H-7, an isoquinoline
sulfonamide, as inhibitors of PKC activation to evaluate responses to
provocative insulin and glucose tolerance tests in control vs. endotoxic
rats. Fed male rats were treated with either Salmonella enteritidis
endotoxin (ETX; 0.33 mg/kg iv) or saline 120 min before intravenous insulin
tolerance testing (IVITT) with human insulin (1 U/kg) or intravenous
glucose tolerance testing (IVGTT) with D-glucose (1.2 g/kg). H-7 in
dimethyl sulfoxide at 25 mg/kg, PMX-B in saline at 0.25 mg/kg, or the
respective vehicles were administered 5 min before the tolerance tests.
Neither H-7 nor PMX-B had any significant acute effects on basal plasma
glucose or lactate values. The decline in plasma with IVITT was augmented
by ETX; however, concomitant H-7 or PMX-B attenuated the insulin
hypoglycemia. The computed half-life of glucose in the IVGTT was decreased
by ETX; however, concomitant H-7 or PMX-B decreased the tolerance
alteration. In addition, both H-7 and PMX-B attenuated the rise in insulin
induced by the IVGTT. Thus the hyperinsulinism and the glucoregulatory
disturbances in endotoxicosis may be mediated by PKC activation and
ameliorated by PKC inhibition.
