Inhibition of p38 mitogen-activated protein kinase exerts a hypoglycemic effect by improving β cell function via inhibition of β cell apoptosis in db/db mice

Abstract

The p38 mitogen-activated protein kinase (MAPK) pathway is involved in endoplasmic reticulum stress (ERS) and inflammation, which may play an important role in the pathogenesis of type 2 diabetes (T2DM). This study aimed to investigate whether p38 MAPK contributes to the pathogenesis of T2DM. 6-week-old female db/db mice were randomly assigned to Dmo and Dmi groups, and C57 mice were assigned as controls. The Dmi group was gavaged with the p38 MAPK inhibitor SB203580 for 9 weeks, and the effects on β cell dysfunction and apoptosis were investigated. db/db mice showed higher food intake, body mass, fasting glucose, and plasma insulin levels than C57 mice. After SB203580 administration, blood glucose was significantly lower. HOMA β and HOMA IR were improved. Islet mRNA expression levels of the ERS markers were lower. P38 MAPK inhibition reduced blood glucose and improved β cell function, at least in part by reducing β cell apoptosis.

Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

“…Several reports suggest that activation of the p38s pathway promotes β-cell apoptosis and that p38s activity is increased in pancreatic islets of T2D model mice [182]. Indeed, p38 inhibitor SB203580, which targets p38α and p38β, but not other members of the family, can lower blood glucose by improving β-cell function mediated through a reduction in β-cell apoptosis [183]. Additionally, the inhibition of p38 (both p38α and p38β) or JNKs activity increased paired box 6 (Pax6) levels in high glucose-treated β-cells.…”

Three-Dimensional Culture Promotes the Differentiation of Human Dental Pulp Mesenchymal Stem Cells Into Insulin-Producing Cells for Improving the Diabetes Therapy

“…Lithium chloride (LiCl), in place of recombinant Wnt 3a protein, activates typical Wnt signaling and promotes differentiation of ESCs into DE cells (Li et al, 2011). Retinoic acid can promote the expression of pancreatic endocrine progenitor cells and further differentiate into islet b cells (Oström et al, 2008;Cai et al, 2010); A83-01 is a selective inhibitor of transforming growth factor-b (TGF-b) type 1 receptor ALK5 kinase, which blocks phosphorylation of Smad2, inhibits TGF-b-induced epithelialmesenchymal transition and promotes the expression of pancreatic progenitor cells; LDE225 is an FDA-approved drug for cancer patients and is an inhibitor of the Hedgehog pathway (Rimkus et al, 2016), which replaces FGF2 protein to exclude Hedgehog signaling and promotes pancreatic lineage formation (Kim and Hebrok, 2001;Li et al, 2014); 2-Phospho-L-ascorbic acid trisodium salt (pVc) promotes differentiation and maturation of ESCs and fibroblasts to insulin-secreting cells (Li et al, 2014); SB203580 is a p38 mitogen-activated protein kinase inhibitor that improves insulin-secreting cell function by promoting differentiation and maturation of insulin-secreting cells (Li et al, 2014;Wei et al, 2018).…”

Scutellariae Radix and Coptidis Rhizoma Improve Glucose and Lipid Metabolism in T2DM Rats via Regulation of the Metabolic Profiling and MAPK/PI3K/Akt Signaling Pathway

“…Besides, decreased glycolysis and glycogenesis lead to reduced consumption of blood glucose, contributing to hyperglycemia eventually [ 18 ]. Inflammatory cytokines such as TNF-α and IL-6 promote the development of insulin resistance, and a recent study has reported that anti-inflammation agents showed efficacy in reducing blood glucose level [ 19 ]. Moreover, T2DM is often present for years before becoming clinically apparent.…”