The protective role of the MKP-5-JNK/P38 pathway in glucolipotoxicity-induced islet β-cell dysfunction and apoptosis

Song, Zhuoyao; Ma, Jie; Lu, Yuanhua; Zhou, Chao; Zhao, Tiesuo; Ai, Xilei; Wei, Xuechen; Lin, Jian; Wang, Wei; Yan, Weiqun; Jiao, Peng

doi:10.1016/j.yexcr.2019.06.012

Cited by 17 publications

(14 citation statements)

References 42 publications

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“…There is evidence that a compensatory increase in the β cell mass, and the consequent insulin secretion, can effectively cope with states of insulin resistance . Therefore, protecting functional β cells is essential for the effective treatment of insulin resistance . The mitochondrial apoptotic pathway, which is an intrinsic pathway leading to β cell apoptosis, is controlled by the balance of proapoptotic and antiapoptotic members of the Bcl-2 family .…”

Section: Introductionmentioning

confidence: 99%

ι-Carrageenan Tetrasaccharide from ι-Carrageenan Inhibits Islet β Cell Apoptosis Via the Upregulation of GLP-1 to Inhibit the Mitochondrial Apoptosis Pathway

Wang

et al. 2020

J. Agric. Food Chem.

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ι-Carrageenan performs diversified biological activities but has low bioavailability. ι-Carrageenan tetrasaccharide (ιCTs), a novel marine oligosaccharide prepared by the marine enzyme Cgi82A, was investigated for its effects on insulin resistance in high-fat and high-sucrose diet mice. Oral administration of ιCTs (ιCTs-L 30.0 mg/kg·bw, ιCTs-H 90.0 mg/kg·bw) decreased fasting blood glucose by 35.1% ± 1.41 (P < 0.01) and 27.4% ± 0.420 (P < 0.05), and enhanced glucose tolerance. Besides, ιCTs-L ameliorated islet vacuolization, decreased the β cell apoptosis by 21.8% ± 0.200 (P < 0.05), and promoted insulin secretion by 5.41% ± 0.0173 (P < 0.01) through pancreatic hematoxylin and eosin (H&E) staining, TUNEL staining, and insulin–glucagon immunostaining analysis. Interestingly, ιCTs-L and ιCTs-H treatment increased the incretin GLP-1 content in serum by 22.1% ± 0.402 (P < 0.01) and 10.7% ± 0.0935 (P < 0.05) respectively, through regulating the bile acid levels, which contributed to the inhibition of β cell apoptosis. Mechanically, ιCTs upregulated the expression of the GLP-1 receptor (GLP-1R) and protein kinase A (PKA) in the GLP-1/cAMP/PKA signaling pathway, and further inhibited the expression of cytochrome C and caspase 3 in the mitochondrial apoptotic pathway. In conclusion, this study suggested that ιCTs alleviated insulin resistance by GLP-1-mediated inhibition of β cell apoptosis and proposed a new strategy for developing potential functional foods that prevent insulin resistance.

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Section: Introductionmentioning

confidence: 99%

ι-Carrageenan Tetrasaccharide from ι-Carrageenan Inhibits Islet β Cell Apoptosis Via the Upregulation of GLP-1 to Inhibit the Mitochondrial Apoptosis Pathway

Wang

et al. 2020

J. Agric. Food Chem.

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“…MIN6 cell was purchased from ZQXZbio (Shanghai, China) and cultured in RPMI-1640 with 10% FBS and 0.05 mM β-mercaptoethanol. To construct T2DM model in vitro , MIN6 cells were incubated in RPMI-1640 with 40 mM glucose and 0.4 mM PA with 0.5% BSA (model group) [ 15 ]. Astragalus polysaccharide (purity > 98%) was purchased from Macklin (No.…”

Section: Methodsmentioning

confidence: 99%

“…In this study, we hypothesize that astragalus polysaccharide can improve insulin secretion in dysfunctional pancreatic β cells through miRNAs. First, MIN6 cells were induced by high glucose (HG) and palmitic acid (PA) to mimic glucolipotoxicity and establish the T2DM cell model [ 15 ]. Additionally, the effect of astragalus polysaccharide on HG+PA induced cells was investigated.…”

Section: Introductionmentioning

confidence: 99%

Astragalus polysaccharide improve the proliferation and insulin secretion of mouse pancreatic β cells induced by high glucose and palmitic acid partially through promoting miR-136-5p and miR-149-5p expression

Deng

Yang

et al. 2021

Bioengineered

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The current drugs for the treatment of type 2 diabetes mellitus (T2DM) can cause side effects after long-time use. Hence, the novel drugs were urgent need to developed for T2DM patients. In this study, the effect of astragalus polysaccharide on dysfunctional insulin cells was investigated to clarify whether astragalus polysaccharide could be a novel drug for T2DM treatment. MIN6 cells (mouse pancreatic β-cell line) were treated with high glucose (HG)+ palmitic acid (PA) and then treated with astragalus polysaccharide. The proliferation, apoptosis, and insulin secretion were measured using CCK8, flow cytometry, and ELISA, respectively. Pancreatic and duodenal homeobox 1 (PDX1), miR-136-5p, and miR-149-5p expression levels were measured by RT-qPCR. The combination of EF-hand domain family member 2 (EFHD2) and miR-136-5p or miR-149-5p was analyzed by luciferase reporter assay. EFHD2 protein level was measured by western blot. We found that HG+PA treatment reduced MIN6 cell viability, insulin secretion, and PDX1 expression and promoted MIN6 cell apoptosis. Astragalus polysaccharide treatment reversed the effect of HG+PA on MIN6 cells. Additionally, astragalus polysaccharide treatment promoted miR-136-5p and miR-149-5p expression. Silencing of miR-136-5p and miR-149-5p expression partially reversed the therapeutic effects of astragalus polysaccharide. Furthermore, EFHD2 was the target of miR-136-5p and miR-149-5p. Meanwhile, astragalus polysaccharide treatment inhibited EFHD2 protein level in HG+PA treated MIN6 cell. Finally, EFHD2 overexpression partially reversed the therapeutic effects of astragalus polysaccharide. In conclusion, astragalus polysaccharide treatment improved proliferation and insulin secretion in HG+PA-treated MIN6 cells partially by promoting miR-136-5p and miR-149-5p expression to inhibit EFHD2 expression.

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“…The increase of reactive oxygen species (ROS) in beta cells exposed to glucolipotoxicity appears to reflect increased ROS production by both NADPH oxidase 2 (NOX2) and by mitochondria; the mechanisms driving this increase are still only partially understood, although the increase in mitochondrial oxidant production is at least partially a function of increased Krebs cycle activity, stemming from increased metabolism of glucose and of FFAs [ 15 , 16 , 17 , 18 , 19 , 20 ]. How ROS activate JNK in failing beta cells also requires further clarification; oxidant-induced ER stress, as well as activation of apoptosis signal-related kinase-1 (ASK-1) may play a role [ 21 , 22 , 23 , 24 ]. In any case, measures that suppress the activity of NOX2, and that optimize the structural and functional integrity of mitochondria, such that they can oxidize large amounts of substrate while keeping ROS production at a moderate level, have potential for lessening the JNK-driven nuclear export of PDX1.…”

Section: A Key Role For Loss Of Pdx1 Activity and Glucokinase Expression Driven By Rosmentioning

confidence: 99%

Maintaining Effective Beta Cell Function in the Face of Metabolic Syndrome-Associated Glucolipotoxicity—Nutraceutical Options

McCarty

DiNicolantonio

2021

Healthcare

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In people with metabolic syndrome, episodic exposure of pancreatic beta cells to elevated levels of both glucose and free fatty acids (FFAs)—or glucolipotoxicity—can induce a loss of glucose-stimulated insulin secretion (GSIS). This in turn can lead to a chronic state of glucolipotoxicity and a sustained loss of GSIS, ushering in type 2 diabetes. Loss of GSIS reflects a decline in beta cell glucokinase (GK) expression associated with decreased nuclear levels of the pancreatic and duodenal homeobox 1 (PDX1) factor that drives its transcription, along with that of Glut2 and insulin. Glucolipotoxicity-induced production of reactive oxygen species (ROS), stemming from both mitochondria and the NOX2 isoform of NADPH oxidase, drives an increase in c-Jun N-terminal kinase (JNK) activity that promotes nuclear export of PDX1, and impairs autocrine insulin signaling; the latter effect decreases PDX1 expression at the transcriptional level and up-regulates beta cell apoptosis. Conversely, the incretin hormone glucagon-like peptide-1 (GLP-1) promotes nuclear import of PDX1 via cAMP signaling. Nutraceuticals that quell an increase in beta cell ROS production, that amplify or mimic autocrine insulin signaling, or that boost GLP-1 production, should help to maintain GSIS and suppress beta cell apoptosis in the face of glucolipotoxicity, postponing or preventing onset of type 2 diabetes. Nutraceuticals with potential in this regard include the following: phycocyanobilin—an inhibitor of NOX2; agents promoting mitophagy and mitochondrial biogenesis, such as ferulic acid, lipoic acid, melatonin, berberine, and astaxanthin; myo-inositol and high-dose biotin, which promote phosphatidylinositol 3-kinase (PI3K)/Akt activation; and prebiotics/probiotics capable of boosting GLP-1 secretion. Complex supplements or functional foods providing a selection of these agents might be useful for diabetes prevention.

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The protective role of the MKP-5-JNK/P38 pathway in glucolipotoxicity-induced islet β-cell dysfunction and apoptosis

Cited by 17 publications

References 42 publications

ι-Carrageenan Tetrasaccharide from ι-Carrageenan Inhibits Islet β Cell Apoptosis Via the Upregulation of GLP-1 to Inhibit the Mitochondrial Apoptosis Pathway

ι-Carrageenan Tetrasaccharide from ι-Carrageenan Inhibits Islet β Cell Apoptosis Via the Upregulation of GLP-1 to Inhibit the Mitochondrial Apoptosis Pathway

Astragalus polysaccharide improve the proliferation and insulin secretion of mouse pancreatic β cells induced by high glucose and palmitic acid partially through promoting miR-136-5p and miR-149-5p expression

Maintaining Effective Beta Cell Function in the Face of Metabolic Syndrome-Associated Glucolipotoxicity—Nutraceutical Options

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