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. 2018 Dec;33(1):1494-1500.
doi: 10.1080/14756366.2018.1477138.

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

Xiaowei Wei  1 , Nan Gu  1 , Nan Feng  1 , Xiaohui Guo  1 , Xiaowei Ma  1
Affiliations

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

Xiaowei Wei et al. J Enzyme Inhib Med Chem. 2018 Dec.

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.

Keywords: SB203580; endoplasmic reticulum stress; p38 MAPK; type 2 diabetes; β cell function.

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Figures

Figure 1.
Figure 1.
Metabolic features of the mice. (A) Food intake. (B) Body mass. (C) Fasting glucose levels (FBG). Dmo, vehicle-treated db/db mice; Dmi, SB203580-treated db/db mice; Con, C57 mice (*p < 0.05, Dmo or Dmi vs. Con; #p < 0.05, Dmi vs. Dmo).
Figure 2.
Figure 2.
Blood glucose levels during intraperitoneal glucose tolerance tests (IPGTTs) in db/db mice throughout the experimental period. (A) Before administration of SB203580. (B) After 5 weeks’ administration of SB203580. (C) After 7 weeks’ administration of SB203580. (D) After 9 weeks’ administration of SB203580. Dmo, vehicle-treated db/db mice; Dmi, SB203580-treated db/db mice (#p < 0.05, Dmi vs. Dmo).
Figure 3.
Figure 3.
Fasting plasma insulin levels, HOMA β and HOMA IR of db/db mice. (A) HOMA β of db/db mice. (B) HOMA IR of db/db mice. (C) fasting insulin levels of mice. Con, C57 mice; Dmo, vehicle-treated db/db mice; Dmi, SB203580-treated db/db mice (#p < 0.05, Dmi vs. Dmo; *p < 0.05, Dmo or Dmi vs. Con).
Figure 4.
Figure 4.
Protein expression of p38 and p-p38 in islets. p-p38, phosphorylated p38; Con, C57 mice; Dmo, vehicle-treated db/db mice; Dmi, SB203580-treated db/db mice.
Figure 5.
Figure 5.
mRNA expression levels of BIP and CHOP in islets. Con, C57 mice; Dmo, vehicle-treated db/db mice; Dmi, SB203580-treated db/db mice (*, p < 0.05, Dmo vs. Con; #p < 0.05, Dmi vs. Dmo).
Figure 6.
Figure 6.
mRNA expression of Bcl-2 and Bax in islets. Con, C57 mice; Dmo, vehicle-treated db/db mice; Dmi, SB203580-treated db/db mice (*, p < 0.05, Dmo vs. Con; #p < 0.05, Dmi vs. Dmo).
Figure 7.
Figure 7.
β cell area (insulin immunostaining, shown as a red color) of the pancreas in mice of various ages in each treatment group. A1, 7-week-old C57 mice; A2, 7-week-old db/db mice; B1, 12-week-old C57 mice; B2, 12-week-old vehicle-treated db/db mice; B3, 12-week-old SB203580-treated db/db mice; C1, 14-week-old C57 mice; C2, 14-week-old vehicle-treated db/db mice; C3, 14-week-old SB203580-treated db/db mice; D1, 16-week-old C57 mice; D2, 16-week-old vehicle-treated db/db mice; D3, 16-week-old SB203580-treated db/db mice.
Figure 8.
Figure 8.
A schematic view of the mechanisms whereby the p38 inhibitor SB203580 may reduce β cell apoptosis. ERS leads to cellular apoptosis through activation of the p38 MAPK pathway. Activation of p38 can promote the activation of ERS pathways, thus inducing apoptosis. By contrast, the p38 inhibitor SB203580 attenuates activation of the p38 MAPK pathway, reducing apoptosis mediated through the p38 pathway, but also by inhibition of ERS, as part of a benign cycle.
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This work was supported by National Natural Science Foundation of China [NSFC 30771033]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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