Administration of metrnl delays the onset of diabetes in non-obese diabetic mice

Abstract

Type 1 diabetes is a chronic metabolic disease characterized by hyperglycemia due to progressive destruction of pancreatic beta cells via autoimmune attack. Meteorin-like protein (metrnl) is a secreted protein homologous to the neurotrophin metrn and it is induced after exercise in the skeletal muscle. In our paper published previously, we showed that the serum level of metrnl was significantly correlated with the lipid profile, glucose profile and insulin resistance. In this experiment, we asked whether intravenous administration of metrnl could delay the onset of diabetes in non-obese diabetic (NOD) mice. 4-week-old NOD mice were injected intravenously with metrnl. Blood glucose levels were measured weekly. Insulitis scoring, intraperitoneal glucose tolerance test, adoptive T cell transfer, flow cytometry analysis and real-time PCR were performed to investigate the underlying mechanism. The results showed that intravenous administration of metrnl delayed the onset of diabetes in NOD mice. Histology of pancreas showed a decreased infiltration of leukocytes, which was in association with augmentation of regulatory T cells, suppression of autoreactive T cells and altered cytokine secretion. To sum up, the present study showed that intravenous administration of metrnl ameliorated islet lymphocyte infiltration and modulated immune cell responses, raising the possibility that it might be beneficial in improving islet function clinically.

Meteorin-Like Protein (Metrnl) in Obesity, during Weight Loss and in Adipocyte Differentiation

“…Recently, a meta-analysis evaluating data from nine cohort studies could not identify a general association of circulating Metrnl levels with T2D [ 22 ], due to a high number of potential confounding variables. Of note, a recent study reported a protective role of Metrnl in diabetic mice without obesity [ 23 ]. While Metrnl plasma concentrations were found to be elevated in human individuals suffering from T2D and obesity [ 24 ], Pellitero et al reported lower circulating levels in a small cohort of 25 obese patients.…”

Endothelial METRNL determines circulating METRNL level and maintains endothelial function against atherosclerosis

“…For instance, METRNL attenuates HFD associated inflammation in both adipose tissue and skeletal muscle 5 , 9 and decreases inflammatory cell infiltration and pro-inflammatory mediators production in chronic colitis and allergic asthma 49 , 50 , apart from its inhibitory effects on endotoxin induced inflammation responses in endothelial cells 48 . In several disorders including insulin resistance 5 , 9 , diabetes 51 , 52 , chronic colitis 50 , and allergic asthma 49 , METRNL gene and/or protein demonstrate a therapeutic potential. Considering that metabolic disorder and inflammation are both involved in the development of cardiovascular disease, these results indicate that METRNL could be a multifaceted therapeutic target in cardiovascular diseases.…”

Exercise Inhibits NLRP3 Inflammasome Activation in Obese Mice via the Anti-Inflammatory Effect of Meteorin-like

“…During exercise, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α) mediates the release of METRNL from skeletal muscle into the blood, which plays an important role in browning and insulin sensitization of WAT via regulation of macrophage activity, thus suggesting that METRNL may help mediate exercise-induced protection against metabolic disorders [ 22 ]. Notably, intravenous administration of METRNL in non-obese diabetic mice delayed the onset of diabetes with altered cytokine secretion by immune cells, resulting in reduced pancreatic beta-cell destruction [ 46 ]. In another study, METRNL treatment in myoblasts was reported to stimulate glucose uptake via calcium-mediated AMPKα phosphorylation and the downstream p38 MAPK pathway, and intraperitoneal injection of GST-METRNL improved glucose intolerance in HFD mice, as well as in db / db mice [ 47 ], suggesting the therapeutic role of METRNL in metabolic disease.…”