Abstract
Metabolic endotoxemia has been suggested to play a role in the pathophysiology of metaflammation, insulin-resistance and ultimately type-2 diabetes mellitus (T2DM). The role of endogenous antimicrobial peptides (AMPs), such as the cathelicidin LL-37, in T2DM is unknown. We report here for the first time that patients with T2DM compared to healthy volunteers have elevated plasma levels of LL-37. In a reverse-translational approach, we have investigated the effects of the AMP, peptide 19-2.5, in a murine model of high-fat diet (HFD)-induced insulin-resistance, steatohepatitis and T2DM. HFD-fed mice for 12 weeks caused obesity, an impairment in glycemic regulations, hypercholesterolemia, microalbuminuria and steatohepatitis, all of which were attenuated by Peptide 19-2.5. The liver steatosis caused by feeding mice a HFD resulted in the activation of nuclear factor kappa light chain enhancer of activated B cells (NF-ĸB) (phosphorylation of inhibitor of kappa beta kinase (IKK)α/β, IκBα, translocation of p65 to the nucleus), expression of NF-ĸB-dependent protein inducible nitric oxide synthase (iNOS) and activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, all of which were reduced by Peptide 19-2.5. Feeding mice, a HFD also resulted in an enhanced expression of the lipid scavenger receptor cluster of differentiation 36 (CD36) secondary to activation of extracellular signal-regulated kinases (ERK)1/2, both of which were abolished by Peptide 19-2.5. Taken together, these results demonstrate that the AMP, Peptide 19-2.5 reduces insulin-resistance, steatohepatitis and proteinuria. These effects are, at least in part, due to prevention of the expression of CD36 and may provide further evidence for a role of metabolic endotoxemia in the pathogenesis of metaflammation and ultimately T2DM. The observed increase in the levels of the endogenous AMP LL-37 in patients with T2DM may serve to limit the severity of the disease.
Highlights
Obesity and type-2 diabetes mellitus (T2DM) are associated with metabolic endotoxemia, which has shown to play a key role in the pathophysiology of diabetes
When compared to HFD-fed mice treated with vehicle, HFD-fed mice treated with Peptide 19-2.5, significantly attenuated the increase in weight gain from the start of drug treatment until the end of the experiment (Figure 2A), indicating the effectiveness of Pe2.5 to attenuate the increase in body weight caused feeding mice a HFD
To gain a better insight into the potential mechanism underlying the reduced insulin resistance after HFD feeding, we investigated the effects of Peptide 19-2.5 on the insulin signaling pathway in the liver
Summary
Obesity and type-2 diabetes mellitus (T2DM) are associated with metabolic endotoxemia, which has shown to play a key role in the pathophysiology of diabetes. The leak of lipopolysaccharide (LPS) underlying metabolic endotoxemia is due to changes in the gut microbiota [1]. The gut epithelium is an efficient barrier, but many factors, such as dietary alterations can lead to changes to the intestinal epithelium. The membrane becomes ‘leaky’ allowing LPS to enter the bloodstream. This increase in plasma LPS in response to dietary alterations is termed metabolic endotoxemia [2]. Once LPS has entered the bloodstream it can activate Toll-like receptor-4 (TLR4), resulting in low-grade systemic inflammation [3]
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