Format

Send to

Choose Destination
J Immunol. 2017 Nov 15;199(10):3634-3643. doi: 10.4049/jimmunol.1700820. Epub 2017 Oct 16.

Lipopolysaccharide Potentiates Insulin-Driven Hypoglycemic Shock.

Author information

1
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
3
Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
4
Division of Intramural Research, National Institute for Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
5
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219.
6
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
7
Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and.
8
North Carolina Jaycee Burn Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
9
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; emiao@med.unc.edu.

Abstract

Critically ill patients typically present with hyperglycemia. Treatment with conventional insulin therapy (targeting 144-180 mg/dl) improves patient survival; however, intensive insulin therapy (IIT) targeting normal blood glucose levels (81-108 mg/dl) increases the incidence of moderate and severe hypoglycemia, and increases mortality. Septic patients are especially prone to IIT-induced hypoglycemia, but the mechanism remains unknown. Here, we show that codelivery of insulin with otherwise sublethal doses of LPS induced hypoglycemic shock in mice within 1-2 h. LPS impaired clearance of insulin, which amplified insulin receptor signaling. These effects were mediated by caspase-11, TLR4, and complement, each of which trigger eicosanoid production that potentiates insulin signaling. Finally, in an animal model of sepsis, we observed that Salmonella typhimurium-infected mice exhibited simultaneous impaired insulin clearance coexisting with insulin resistance. Our results raise the possibility that septic patients have impaired insulin clearance, which could increase their susceptibility to hypoglycemia during IIT, contraindicating its use.

PMID:
29038248
PMCID:
PMC5685187
DOI:
10.4049/jimmunol.1700820
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center