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(-)-Leucophyllone, a Tirucallane Triterpenoid from Cornus walteri, Enhances Insulin Secretion in INS-1 Cells.

ABSTRACT: Phytochemical examination of the MeOH extract from the stems and stem bark of Cornus walteri (Cornaceae) led to the isolation and verification of a tirucallane triterpenoid, (-)-leucophyllone, as a major component. Its structure was elucidated using NMR spectroscopy and liquid chromatography-mass spectrometry. The effect of (-)-leucophyllone on insulin secretion in INS-1 cells was investigated. (-)-Leucophyllone increased glucose-stimulated insulin secretion (GSIS) at concentrations showing no cytotoxic effect in rat INS-1 pancreatic β-cells. Moreover, we attempted to determine the mechanism of action of (-)-leucophyllone in the activation of insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), Akt, and pancreatic and duodenal homeobox-1 (PDX-1). Treatment of INS-1 cells with (-)-leucophyllone markedly increased the expression of these proteins. Our findings indicate the potential of (-)-leucophyllone as an antidiabetic agent.

SUBMITTER: Lee D

PROVIDER: S-EPMC7996230 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tirucallane Triterpenoids from the Stems and Stem Bark of <i>Cornus walteri</i> that Control Adipocyte and Osteoblast Differentiations.

Project description:Cornus walteri Wanger (Cornaceae) has been broadly used in traditional East Asian medicine for the treatment of various disorders, including skin inflammation and diarrhea. As part of our efforts to identify structurally and/or biologically new compounds from Korean medicinal plants, we have explored potentially new bioactive constituents from C. walteri. In the present study, seven triterpenoids (1?7) were isolated from C. walteri stems and stem bark. Compounds 1?3 were new tirucallane triterpenoids (cornusalterins N-P) and compounds 4?7 were isolated for the first time from C. walteri. The structures of the new compounds were determined based on 1D and 2D NMR spectroscopic data interpretations and HR-ESIMS, as well as a computational method coupled with a statistical procedure (DP4+). The regulatory effects of the isolated triterpenoids (1?7) on mesenchymal stem cell (MSC) differentiation to adipocytes and osteoblasts were examined in the C3H10T1/2 cell line. Although these compounds had little effect on MSC differentiation to osteoblasts, lipid droplet formation in adipocyte-differentiated MSCs decreased in the presence of the seven triterpenoids. Compounds 1 and 4 each had a relatively distinct correlation between dose and efficacy, showing adipogenesis suppression at higher concentrations. Our findings demonstrate that the active compounds 1 and 4 can exert beneficial effects in regulation of adipocyte differentiation.

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Loureirin B activates GLP-1R and promotes insulin secretion in Ins-1 cells.

Project description:Loureirin B (LB) is a natural product derived from Sanguis draconis, which has hypoglycaemic effects. In order to research the possible target of LB in the treatment of diabetes, molecular docking was used to simulate the interaction between LB and potential targets, and among them, glucagon-like peptide-1 receptor (GLP-1R) had the optimal results. Further, spectroscopy and surface plasmon resonance (SPR) experiments were applied to detect the interaction between LB and GLP-1R. Ultimately, after GLP-1R siRNA interfering the expression of GLP-1R in Ins-1 cell, the promoting insulin secretion of LB was weaken, which directly proved that GLP-1R plays an important role. These results show that LB promotes insulin secretion of Ins-1 cells through GLP-1R. Hence, the strategy of LB as a prodrug will provide a potential approach for non-peptide GLP-1R agonist.

| S-EPMC7812269 | biostudies-literature

Overexpression of native IF1 downregulates glucose-stimulated insulin secretion by pancreatic INS-1E cells.

Project description:We have previously reported that transient knock-down of ATPase inhibitory factor 1 (IF1) by siRNA upregulates ATP levels and subsequently augments insulin secretion in model pancreatic β-cells INS-1E. Here we investigated how long-term IF1-overexpression impacts pancreatic β-cell bioenergetics and insulin secretion. We generated INS-1E cell line stably overexpressing native IF1. We revealed that IF1 overexpression leads to a substantial decrease in ATP levels and reduced glucose-stimulated insulin secretion. A decrease in total cellular ATP content was also reflected in decreased free ATP cytosolic and mitochondrial levels, as monitored with ATeam biosensor. Consistently, cellular respiration of IF1-overexpressing cells was decreased. 3D structured illumination microscopy (SIM) revealed a higher amount of insulin granules with higher volume in IF1-overexpressing cells. Similar effects occurred when cells were incubated at low glucose concentrations. Noteworthy, activation of PKA by dibutyryl cAMP entirely abolished the inhibitory effect of IF1 overexpression on ATP production and insulin secretion. Mitochondrial network morphology and cristae ultrastructure in INS-1E overexpressing IF1 remained mostly unchanged. Finally, we show that INS-1E cells decrease their IF1 protein levels relative to ATP synthase α-subunit in response to increased glucose. In conclusion, IF1 actively downregulates INS-1E cellular metabolism and reduces their ability to secrete insulin.

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Deficiency of transcription factor Nkx6.1 does not prevent insulin secretion in INS-1E cells.

Project description:Pancreatic-β-cell-specifying transcription factor Nkx6.1, indispensable for embryonic development of the pancreatic epithelium and commitment to β-cell lineage, directly controls the expression of a glucose transporter (Glut2), pyruvate carboxylase (Pcx), and genes for insulin processing (endoplasmic reticulum oxidoreductase-1β, Ero1lb; zinc transporter-8, Slc30a8). The Nkx6.1 decline in aging diabetic Goto-Kakizaki rats contributes to β-cell trans-differentiation into δ-cells. Elucidating further Nkx6.1 roles, we studied Nkx6.1 ablation in rat INS-1E cells, prepared by CRISPR/Cas9 gene editing from single colonies. INS-1ENkx6.1-/- cells exhibited unchanged glucose-stimulated insulin secretion (GSIS), moderately decreased phosphorylating/non-phosphorylating respiration ratios at high glucose; unchanged but delayed ATP-elevation responses to glucose; delayed uptake of fluorescent glucose analog, but slightly improved cytosolic Ca2+-oscillations, induced by glucose; despite approximately halved Glut2, Pcx, Ero1lb, and Slc30a8 expression, and reduced nuclear receptors Nr4a1 and Nr4a3. Thus, ATP synthesis was time-compensated, despite the delayed GLUT2-mediated glucose uptake and crippled pyruvate-malate redox shuttle (owing to the PCX-deficiency) in INS-1ENkx6.1-/- cells. Nkx6.1 thus controls the expression of genes that are not essential for acute insulin secretion, the function of which can be compensated for. Considerations that Nkx6.1 deficiency is an ultimate determinant of β-cell pathology beyond cell trans-(de-)differentiation or β-cell identity are not supported by our results.

| S-EPMC9839711 | biostudies-literature

Alpha-Mangostin Improves Insulin Secretion and Protects INS-1 Cells from Streptozotocin-Induced Damage.

Project description:Alpha (α)-mangostin, a yellow crystalline powder with a xanthone core structure, is isolated from mangosteen (Garcinia mangostana), which is a tropical fruit of great nutritional value. The aim of the present study was to investigate the anti-diabetic effects of α-mangostin and to elucidate the molecular mechanisms underlying its effect on pancreatic beta (β)-cell dysfunction. To assess the effects of α-mangostin on insulin production, rat pancreatic INS-1 cells were treated with non-toxic doses of α-mangostin (1⁻10 μM) and its impact on insulin signaling was examined by Western blotting. In addition, the protective effect of α-mangostin against pancreatic β-cell apoptosis was verified by using the β-cell toxin streptozotocin (STZ). Our results showed that α-mangostin stimulated insulin secretion in INS-1 cells by activating insulin receptor (IR) and pancreatic and duodenal homeobox 1 (Pdx1) followed by phosphorylation of phospho-phosphatidylinositol-3 kinase (PI3K), Akt, and extracellular signal regulated kinase (ERK) signaling cascades, whereas it inhibited the phosphorylation of insulin receptor substrate (IRS-1) (Ser1101). Moreover, α-mangostin was found to restore the STZ-induced decrease in INS-1 cell viability in a dose-dependent manner. In addition, treatment of INS-1 cells with 50 μM STZ resulted in an increase in intracellular reactive oxygen species (ROS) levels, which was represented by the fluorescence intensity of 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). This oxidative stress was decreased by co-treatment with 5 μM α-mangostin. Similarly, marked increases in the phosphorylation of P38, c-Jun N-terminal kinase (JNK), and cleavage of caspase-3 by STZ were decreased significantly by co-treatment with 5 μM α-mangostin. These results suggest that α-mangostin is capable of improving insulin secretion in pancreatic β-cells and protecting cells from apoptotic damage.

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High-dose clevudine impairs mitochondrial function and glucose-stimulated insulin secretion in INS-1E cells.

Project description:BACKGROUND: Clevudine is a nucleoside analog reverse transcriptase inhibitor that exhibits potent antiviral activity against hepatitis B virus (HBV) without serious side effects. However, mitochondrial myopathy has been observed in patients with chronic HBV infection taking clevudine. Moreover, the development of diabetes was recently reported in patients receiving long-term treatment with clevudine. In this study, we investigated the effects of clevudine on mitochondrial function and insulin release in a rat clonal ?-cell line, INS-1E. METHODS: The mitochondrial DNA (mtDNA) copy number and the mRNA levels were measured by using quantitative PCR. MTT analysis, ATP/lactate measurements, and insulin assay were performed. RESULTS: Both INS-1E cells and HepG2 cells, which originated from human hepatoma, showed dose-dependent decreases in mtDNA copy number and cytochrome c oxidase-1 (Cox-1) mRNA level following culture with clevudine (10 ?M-1 mM) for 4 weeks. INS-1E cells treated with clevudine had reduced total mitochondrial activities, lower cytosolic ATP contents, enhanced lactate production, and more lipid accumulation. Insulin release in response to glucose application was markedly decreased in clevudine-treated INS-1E cells, which might be a consequence of mitochondrial dysfunction. CONCLUSIONS: Our data suggest that high-dose treatment with clevudine induces mitochondrial defects associated with mtDNA depletion and impairs glucose-stimulated insulin secretion in insulin-releasing cells. These findings partly explain the development of diabetes in patients receiving clevudine who might have a high susceptibility to mitochondrial toxicity.

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Down-regulation of ZnT8 expression in INS-1 rat pancreatic beta cells reduces insulin content and glucose-inducible insulin secretion.

Project description:The SLC30A8 gene codes for a pancreatic beta-cell-expressed zinc transporter, ZnT8. A polymorphism in the SLC30A8 gene is associated with susceptibility to type 2 diabetes, although the molecular mechanism through which this phenotype is manifest is incompletely understood. Such polymorphisms may exert their effect via impacting expression level of the gene product. We used an shRNA-mediated approach to reproducibly downregulate ZnT8 mRNA expression by >90% in the INS-1 pancreatic beta cell line. The ZnT8-downregulated cells exhibited diminished uptake of exogenous zinc, as determined using the zinc-sensitive reporter dye, zinquin. ZnT8-downregulated cells showed reduced insulin content and decreased insulin secretion (expressed as percent of total insulin content) in response to hyperglycemic stimulus, as determined by insulin immunoassay. ZnT8-depleted cells also showed fewer dense-core vesicles via electron microscopy. These data indicate that reduced ZnT8 expression in cultured pancreatic beta cells gives rise to a reduced insulin response to hyperglycemia. In addition, although we provide no direct evidence, these data suggest that an SLC30A8 expression-level polymorphism could affect insulin secretion and the glycemic response in vivo.

| S-EPMC2682581 | biostudies-literature

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