LPS-Enhanced Glucose-Stimulated Insulin Secretion Is Normalized by Resveratrol

TY - JOUR

T1 - LPS-Enhanced Glucose-Stimulated Insulin Secretion Is Normalized by Resveratrol

AU - Nøhr, Mark Klitgaard

AU - Dudele, Anete

AU - Poulsen, Morten Møller

AU - Ebbesen, Lene Hyldahl

AU - Radko, Yulia

AU - Christensen, Lars P.

AU - Jessen, Niels

AU - Richelsen, Bjørn

AU - Lund, Sten

AU - Pedersen, Steen Bønløkke

PY - 2016/1/11

Y1 - 2016/1/11

N2 - 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 glucosestimulated 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. In conclusion: 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.

AB - 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 glucosestimulated 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. In conclusion: 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.

KW - Adipose Tissue/pathology

KW - Animals

KW - Antioxidants/chemistry

KW - Blood Glucose/analysis

KW - Body Weight

KW - Epididymis

KW - Gene Expression Profiling

KW - Glucose/chemistry

KW - Glucose Tolerance Test

KW - Homeostasis

KW - Inflammation

KW - Insulin/secretion

KW - Insulin Resistance

KW - Leukocytes/cytology

KW - Lipopolysaccharides/chemistry

KW - Liver/pathology

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Obesity/drug therapy

KW - Osmosis

KW - Stilbenes/chemistry

U2 - 10.1371/journal.pone.0146840

DO - 10.1371/journal.pone.0146840

M3 - Journal article

C2 - 26751381

SN - 1932-6203

VL - 11

JO - PloS one

JF - PloS one

IS - 1

M1 - e0146840

ER -