title: LPS-Enhanced Glucose-Stimulated Insulin Secretion Is Normalized by Resveratrol.
abstract: Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. Here we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous) together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b, whereas the increased macrophage infiltration was unaltered) without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin/delta0-15glucose) from 13.73 to 22.40 pmol/mmol (P < 0.001). This aberration in insulin and glucose homeostasis was normalized by resveratrol.
  
  
  CONCLUSIONS
  Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion.
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.|Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Nøhr
authors.affiliation: Zoophysiology, Department of Bioscience, Aarhus University, Aarhus, Denmark.
authors.forename: Anete
authors.initials: A
authors.lastname: Dudele
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.|Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Morten M
authors.initials: MM
authors.lastname: Poulsen
authors.affiliation: Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Lene H
authors.initials: LH
authors.lastname: Ebbesen
authors.affiliation: Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Radko
authors.affiliation: Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark.
authors.forename: Lars P
authors.initials: LP
authors.lastname: Christensen
authors.affiliation: Research Laboratory for Biochemical Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.|Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Richelsen
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.|Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Sten
authors.initials: S
authors.lastname: Lund
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.|Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Steen B
authors.initials: SB
authors.lastname: Pedersen
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D004822:Epididymis; D020869:Gene Expression Profiling; D005947:Glucose / Q000737:chemistry*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007249:Inflammation; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007962:Leukocytes / Q000166:cytology; D008070:Lipopolysaccharides / Q000737:chemistry*; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology; D009995:Osmosis; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry*
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D007328:Insulin; D008070:Lipopolysaccharides; D013267:Stilbenes; D005947:Glucose; D000077185:Resveratrol