| 1. |
- Luo, Xiumei, et al.
(författare)
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Glycolytic enzyme Enolase-1 regulates insulin gene expression in pancreatic β-cell
- 2024
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Ingår i: Biochemical and Biophysical Research Communications. - 0006-291X. ; 706
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Tidskriftsartikel (refereegranskat)abstract
- Enolase-1 (Eno1) plays a critical role in regulating glucose metabolism; however, its specific impact on pancreatic islet β-cells remains elusive. This study aimed to provide a preliminary exploration of Eno1 function in pancreatic islet β-cells. The findings revealed that the expression of ENO1 mRNA in type 2 diabetes donors was significantly increased and positively correlated with HbA1C and negatively correlated with insulin gene expression. A high level of Eno1 in human insulin-secreting rat INS-1832/13 cells with co-localization with intracellular insulin proteins was accordingly observed. Silencing of Eno1 using siRNA or inhibiting Eno1 protein activity with an Eno1 antagonist significantly reduced insulin secretion and insulin content in β-cells, while the proinsulin/insulin content ratio remained unchanged. This reduction in β-cells function was accompanied by a notable decrease in intracellular ATP and mitochondrial cytochrome C levels. Overall, our findings confirm that Eno1 regulates the insulin secretion process, particularly glucose metabolism and ATP production in the β-cells. The mechanism primarily involves its influence on insulin production, suggesting that Eno1 represents a potential target for β-cell protection and diabetes treatment.
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| 2. |
- Yan, Xiaoyu, et al.
(författare)
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MCC950 Ameliorates Diabetic Muscle Atrophy in Mice by Inhibition of Pyroptosis and Its Synergistic Effect with Aerobic Exercise
- 2024
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Ingår i: Molecules. - 1420-3049. ; 29:3
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic muscle atrophy is an inflammation-related complication of type-2 diabetes mellitus (T2DM). Even though regular exercise prevents further deterioration of atrophic status, there is no effective mediator available for treatment and the underlying cellular mechanisms are less explored. In this study, we investigated the therapeutic potential of MCC950, a specific, small-molecule inhibitor of NLRP3, to treat pyroptosis and diabetic muscle atrophy in mice. Furthermore, we used MCC950 to intervene in the protective effects of aerobic exercise against muscle atrophy in diabetic mice. Blood and gastrocnemius muscle (GAS) samples were collected after 12 weeks of intervention and the atrophic state was assessed. We initially corroborated a diabetic muscle atrophy phenotype in db/db mice (D) by comparison with control m/m mice (W) by examining parameters such as fasting blood glucose (D vs. W: 24.47 ± 0.45 mmol L−1 vs. 4.26 ± 0.6 mmol L−1, p < 0.05), grip strength (D vs. W: 166.87 ± 15.19 g vs. 191.76 ± 14.13 g, p < 0.05), exercise time (D vs. W: 1082.38 ± 104.67 s vs. 1716 ± 168.55 s, p < 0.05) and exercise speed to exhaustion (D vs. W: 24.25 ± 2.12 m min−1 vs. 34.75 ± 2.66 m min−1, p < 0.05), GAS wet weight (D vs. W: 0.07 ± 0.01 g vs. 0.13 ± 0.01 g, p < 0.05), the ratio of GAS wet weight to body weight (D vs. W: 0.18 ± 0.01% vs. 0.54 ± 0.02%, p < 0.05), and muscle fiber cross-sectional area (FCSA) (D vs. W: 1875 ± 368.19 µm2 vs. 2747.83 ± 406.44 µm2, p < 0.05). We found that both MCC950 (10 mg kg−1) treatment and exercise improved the atrophic parameters that had deteriorated in the db/db mice, inhibited serum inflammatory markers and significantly attenuated pyroptosis in atrophic GAS. In addition, a combined MCC950 treatment with exercise (DEI) exhibited a further improvement in glucose uptake capacity and muscle performance. This combined treatment also improved the FCSA of GAS muscle indicated by Laminin immunofluorescence compared to the group with the inhibitor treatment alone (DI) (DEI vs. DI: 2597 ± 310.97 vs. 1974.67 ± 326.15 µm2, p < 0.05) or exercise only (DE) (DEI vs. DE: 2597 ± 310.97 vs. 2006.33 ± 263.468 µm2, p < 0.05). Intriguingly, the combination of MCC950 treatment and exercise significantly reduced NLRP3-mediated inflammatory factors such as cleaved-Caspase-1, GSDMD-N and prevented apoptosis and pyroptosis in atrophic GAS. These findings for the first time demonstrate that targeting NLRP3-mediated pyroptosis with MCC950 improves diabetic muscle homeostasis and muscle function. We also report that inhibiting pyroptosis by MCC950 can enhance the beneficial effects of aerobic exercise on diabetic muscle atrophy. Since T2DM and muscle atrophy are age-related diseases, the young mice used in the current study do not seem to fully reflect the characteristics of diabetic muscle atrophy. Considering the fragile nature of db/db mice and for the complete implementation of the exercise intervention, we used relatively young db/db mice and the atrophic state in the mice was thoroughly confirmed. Taken together, the current study comprehensively investigated the therapeutic effect of NLRP3-mediated pyroptosis inhibited by MCC950 on diabetic muscle mass, strength and exercise performance, as well as the synergistic effects of MCC950 and exercise intervention, therefore providing a novel strategy for the treatment of the disease.
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| 3. |
- Ye, Yingying, et al.
(författare)
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A critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic beta-cells
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Glucose-induced insulin secretion depends on beta-cell electrical activity. Inhibition of ATP-regulated potassium (K-ATP) channels is a key event in this process. However, K-ATP channel closure alone is not sufficient to induce beta-cell electrical activity; activation of a depolarizing membrane current is also required. Here we examine the role of the mechanosensor ion channel PIEZO1 in this process. Yoda1, a specific PIEZO1 agonist, activates a small membrane current and thereby triggers beta-cell electrical activity with resultant stimulation of Ca2+-influx and insulin secretion. Conversely, the PIEZO1 antagonist GsMTx4 reduces glucose-induced Ca2+-signaling, electrical activity and insulin secretion. Yet, PIEZO1 expression is elevated in islets from human donors with type-2 diabetes (T2D) and a rodent T2D model (db/db mouse), in which insulin secretion is reduced. This paradox is resolved by our finding that PIEZO1 translocates from the plasmalemma into the nucleus (where it cannot influence the membrane potential of the beta-cell) under experimental conditions emulating T2D (high glucose culture). beta-cell-specific Piezo1-knockout mice show impaired glucose tolerance in vivo and reduced glucose-induced insulin secretion, beta-cell electrical activity and Ca2+ elevation in vitro. These results implicate mechanotransduction and activation of PIEZO1, via intracellular accumulation of glucose metabolites, as an important physiological regulator of insulin secretion. Insulin secretion depends on action potential firing in pancreatic islet beta-cells, but the underlying mechanism is unclear. Here, the authors show that activation of the mechanosensor ion channel PIEZO1 plays a central role in beta-cell electrical activity and insulin release.
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| 4. |
- Zhang, Zenglei, et al.
(författare)
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Insulin resistance and its relationship with long-term exposure to ozone : Data based on a national population cohort
- 2024
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Ingår i: Journal of Hazardous Materials. - 0304-3894. ; 472
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Tidskriftsartikel (refereegranskat)abstract
- The relationship of ozone (O3), particularly the long-term exposure, with impacting metabolic homeostasis in population was understudied and under-recognised. Here, we used data from ChinaHEART, a nationwide, population-based cohort study, combined with O3 and PM2.5 concentration data with high spatiotemporal resolution, to explore the independent association of exposure to O3 with the prevalence of insulin resistance (IR). Among the 271 540 participants included, the crude prevalence of IR was 39.1%, while the age and sex standardized prevalence stood at 33.0%. Higher IR prevalence was observed with each increase of 10.0 μg/m3 in long-term O3 exposure, yielding adjusted odds ratios (OR) of 1.084 (95% CI: 1.079–1.089) in the one-pollutant model and 1.073 (95% CI: 1.067–1.079) in the two-pollutant model. Notably, a significant additive interaction between O3 and PM2.5 on the prevalence of IR was observed (P for additive interaction < 0.001). Our main findings remained consistent and robust in the sensitivity analyses. Our study suggests long-term exposure to O3 was independently and positively associated with prevalence of IR. It emphasized the benefits of policy interventions to reduce O3 and PM2.5 exposure jointly, which could ultimately alleviate the health and economic burden related to DM.
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| 5. |
- Barghouth, Mohammad, et al.
(författare)
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The structure of insulin granule core determines secretory capacity being reduced in type-2 diabetes
- 2022
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Exocytosis in excitable cells is essential for their physiological functions. Although the exocytotic machinery controlling cellular secretion has been well investigated, the function of the vesicular cargo, i.e. secretory granular content remains obscure. Here we combine dSTORM imaging and single-domain insulin antibody, to dissect the in situ structure of insulin granule cores (IGCs) at nano level. We demonstrate that the size and shape of the IGCs can be regulated by the juxta-granular molecules Nucleobindin-2 and Enolase-1, that further contribute to the stimulated insulin secretion. IGCs located at the plasma membrane are larger than those in the cytosol. The IGCs size is decreased by ∼20% after glucose stimulation due to the release of the peripheral part of IGCs through incomplete granule fusion. Importantly, the reduction of the IGCs size is also observed in non-stimulatory pancreatic β-cells from diabetic db/db mice, Akita (Ins2+/-) mice and human Type-2 diabetic donors, in accordance with impaired secretion. These findings overall highlight the structure of exocytotic insulin cores as a novel modality amenable to targeting in the stimulated exocytosis in β-cells with impaired insulin secretion.Competing Interest StatementThe authors have declared no competing interest.
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| 6. |
- Barghouth, Mohammad, et al.
(författare)
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The T-type calcium channel CaV3.2 regulates insulin secretion in the pancreatic β-cell
- 2022
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Ingår i: Cell Calcium. - : Elsevier BV. - 0143-4160. ; 108
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Tidskriftsartikel (refereegranskat)abstract
- Voltage-gated Ca2+ (CaV) channel dysfunction leads to impaired glucose-stimulated insulin secretion in pancreatic β-cells and contributes to the development of type-2 diabetes (T2D). The role of the low-voltage gated T-type CaV channels in β-cells remains obscure. Here we have measured the global expression of T-type CaV3.2 channels in human islets and found that gene expression of CACNA1H, encoding CaV3.2, is negatively correlated with HbA1c in human donors, and positively correlated with islet insulin gene expression as well as secretion capacity in isolated human islets. Silencing or pharmacological blockade of CaV3.2 attenuates glucose-stimulated cytosolic Ca2+ signaling, membrane potential, and insulin release. Moreover, the endoplasmic reticulum (ER) Ca2+ store depletion is also impaired in CaV3.2-silenced β-cells. The linkage between T-type (CaV3.2) and L-type CaV channels is further identified by the finding that the intracellular Ca2+ signaling conducted by CaV3.2 is highly dependent on the activation of L-type CaV channels. In addition, CACNA1H expression is significantly associated with the islet predominant L-type CACNA1C (CaV1.2) and CACNA1D (CaV1.3) genes in human pancreatic islets. In conclusion, our data suggest the essential functions of the T-type CaV3.2 subunit as a mediator of β-cell Ca2+ signaling and membrane potential needed for insulin secretion, and in connection with L-type CaV channels.
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| 8. |
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| 9. |
- Guo, Qingqing, et al.
(författare)
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LGANet : Local-Global Augmentation Network for Skin Lesion Segmentation
- 2023
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Ingår i: 2023 IEEE International Symposium on Biomedical Imaging, ISBI 2023. - 1945-7928 .- 1945-8452. - 9781665473583 ; 2023-April
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Konferensbidrag (refereegranskat)abstract
- Automatic segmentation of skin lesion is still challenging due to ambiguous boundary and noise interference of lesion regions. Recent exiting Transformer-based methods often directly apply Transformer to obtain long-range dependency to overcome these problems. However, they generally do not consider that patch partitioning strategy of Transformer could lead to the loss of local details around boundaries. Furthermore, dependencies across local windows only represent global information at a coarse level. Therefore, to overcome the limitations, two novel modules, Local Focus Module (LFM) and Global Augmentation Module (GAM) are proposed in this paper. LFM learns the local context around boundary regions to strengthen the discrimination between classes. And GAM learns the global context at a finer level to enhance global feature representation. Integrating LFM and GAM, a new Transformer encoder based framework, Local-Global Augmentation Network (LGANet), is proposed. LGANet is efficient in segmenting lesions with ambiguous boundary and with noise interference and its performances are demonstrated with extensive experiments on two public skin lesion segmentation datasets.
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| 10. |
- Guo, Qingqing, et al.
(författare)
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Parallel matters : Efficient polyp segmentation with parallel structured feature augmentation modules
- 2023
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Ingår i: IET Image Processing. - 1751-9659. ; 17:8, s. 2503-2515
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Tidskriftsartikel (refereegranskat)abstract
- The large variations of polyp sizes and shapes and the close resemblances of polyps to their surroundings call for features with long-range information in rich scales and strong discrimination. This article proposes two parallel structured modules for building those features. One is the Transformer Inception module (TI) which applies Transformers with different reception fields in parallel to input features and thus enriches them with more long-range information in more scales. The other is the Local-Detail Augmentation module (LDA) which applies the spatial and channel attentions in parallel to each block and thus locally augments the features from two complementary dimensions for more object details. Integrating TI and LDA, a new Transformer encoder based framework, Parallel-Enhanced Network (PENet), is proposed, where LDA is specifically adopted twice in a coarse-to-fine way for accurate prediction. PENet is efficient in segmenting polyps with different sizes and shapes without the interference from the background tissues. Experimental comparisons with state-of-the-arts methods show its merits.
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