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. 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.
Highlights
Obesity and type 2 diabetes are interrelated and the current understanding is that as obesity develops, the body becomes increasingly insulin resistant which can progress into type 2 diabetes
I.e., endotoxins or LPS in the blood derived from gram-negative bacteria due to increased epithelial permeability, has been suggested as a possible mechanism of low-grade inflammation [8]
Recent reports have not been able to replicate the effects of LPS on obesity and insulin resistance, and instead suggest that the glucose-stimulated insulin secretion (GSIS) is enhanced by LPS via the GLP-1 pathway [10, 11]
Summary
Obesity and type 2 diabetes are interrelated and the current understanding is that as obesity develops, the body becomes increasingly insulin resistant which can progress into type 2 diabetes. The origin of the developing insulin resistance is not fully known but the concomitantly presence of a chronic low-grade inflammation seems to play an important role [1, 2]. It was shown decades ago that the proinflammatory cytokine tumor necrosis factor alpha (TNFa) induces insulin resistance [3, 4]. Other proinflammatory cytokines such as interleukin 1 beta (IL1b) [5] and interleukin 6 (IL6) [6, 7] have been found to induce insulin resistance in experimental settings. It has been shown that chronic infusion of low-dose LPS commences obesity and insulin resistance in a CD14-dependent manner [8, 9], suggesting a causative link between LPS and development of insulin resistance. Recent reports have not been able to replicate the effects of LPS on obesity and insulin resistance, and instead suggest that the glucose-stimulated insulin secretion (GSIS) is enhanced by LPS via the GLP-1 pathway [10, 11]
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