| 1. |
- Dawed, Adem Y., et al.
(författare)
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Pharmacogenomics of GLP-1 receptor agonists : a genome- wide analysis of observational data and large randomised controlled trials
- 2023
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Ingår i: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 11:1, s. 33-41
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Tidskriftsartikel (refereegranskat)abstract
- Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods:In this genome-wide analysis we included adults (aged & GE;18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings:4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G & RARR;A (Gly168Ser) in the GLP1R (0.08% [95% CI 0.04-0.12] or 0.9 mmol/mol lower reduction in HbA1c per serine, p=6.0 x 10-5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6.7 x 10-8), largely driven by rs140226575G & RARR;A (Thr370Met; 0.25% [SE 0.06] or 2.7 mmol/mol [SE 0.7] greater HbA1c reduction per methionine, p=5.2 x 10-6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6-11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. Interpretation:This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists.
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| 2. |
- Elksnis, Andris, et al.
(författare)
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Imatinib protects against human beta-cell death via inhibition of mitochondrial respiration and activation of AMPK
- 2021
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Ingår i: Clinical Science. - : Portland Press. - 0143-5221 .- 1470-8736. ; 135:19, s. 2243-2263
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Tidskriftsartikel (refereegranskat)abstract
- The protein tyrosine kinase inhibitor imatinib is used in the treatment of various malignancies but may also promote beneficial effects in the treatment of diabetes. The aim of the present investigation was to characterize the mechanisms by which imatinib protects insulin producing cells. Treatment of non-obese diabetic (NOD) mice with imatinib resulted in increased beta-cell AMP-activated kinase (AMPK) phosphorylation. Imatinib activated AMPK also in vitro, resulting in decreased ribosomal protein S6 phosphorylation and protection against islet amyloid polypeptide (IAPP)-aggregation, thioredoxin interacting protein (TXNIP) up-regulation and beta-cell death. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) mimicked and compound C counteracted the effect of imatinib on beta-cell survival. Imatinib-induced AMPK activation was preceded by reduced glucose/pyruvate-dependent respiration, increased glycolysis rates, and a lowered ATP/AMP ratio. Imatinib augmented the fractional oxidation of fatty acids/malate, possibly via a direct interaction with the beta-oxidation enzyme enoyl coenzyme A hydratase, short chain, 1, mitochondrial (ECHS1). In non-beta cells, imatinib reduced respiratory chain complex I and II-mediated respiration and acyl-CoA carboxylase (ACC) phosphorylation, suggesting that mitochondrial effects of imatinib are not beta-cell specific. In conclusion, tyrosine kinase inhibitors modestly inhibit mitochondrial respiration, leading to AMPK activation and TXNIP down-regulation, which in turn protects against beta-cell death.
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| 3. |
- Wang, Xuan, 1984-, et al.
(författare)
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ZBED6 counteracts high-fat diet-induced glucose intolerance by maintaining beta cell area and reducing excess mitochondrial activation
- 2021
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Ingår i: Diabetologia. - : Springer Nature. - 0012-186X .- 1432-0428. ; 64:10, s. 2292-2305
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesisZBED6 (zinc finger, BED-type containing 6) is known to regulate muscle mass by suppression of Igf2 gene transcription. In insulin-producing cell lines, ZBED6 maintains proliferative capacity at the expense of differentiation and beta cell function. The aim was to study the impact of Zbed6 knockout on beta cell function and glucose tolerance in C57BL/6 mice.MethodsBeta cell area and proliferation were determined in Zbed6 knockout mice using immunohistochemical analysis. Muscle and fat distribution were assessed using micro-computed tomography. Islet gene expression was assessed by RNA sequencing. Effects of a high-fat diet were analysed by glucose tolerance and insulin tolerance tests. ZBED6 was overexpressed in EndoC-βH1 cells and human islet cells using an adenoviral vector. Beta cell cell-cycle analysis, insulin release and mitochondrial function were studied in vitro using propidium iodide staining and flow cytometry, ELISA, the Seahorse technique, and the fluorescent probes JC-1 and MitoSox.ResultsIslets from Zbed6 knockout mice showed lowered expression of the cell cycle gene Pttg1, decreased beta cell proliferation and decreased beta cell area, which occurred independently from ZBED6 effects on Igf2 gene expression. Zbed6 knockout mice, but not wild-type mice, developed glucose intolerance when given a high-fat diet. The high-fat diet Zbed6 knockout islets displayed upregulated expression of oxidative phosphorylation genes and genes associated with beta cell differentiation. In vitro, ZBED6 overexpression resulted in increased EndoC-βH1 cell proliferation and a reduced glucose-stimulated insulin release in human islets. ZBED6 also reduced mitochondrial JC-1 J-aggregate formation, mitochondrial oxygen consumption rates (OCR) and mitochondrial reactive oxygen species (ROS) production, both at basal and palmitate + high glucose-stimulated conditions. ZBED6-induced inhibition of OCR was not rescued by IGF2 addition. ZBED6 reduced levels of the mitochondrial regulator PPAR-γ related coactivator 1 protein (PRC) and bound its promoter/enhancer region. Knockdown of PRC resulted in a lowered OCR.Conclusions/interpretationIt is concluded that ZBED6 is required for normal beta cell replication and also limits excessive beta cell mitochondrial activation in response to an increased functional demand. ZBED6 may act, at least in part, by restricting PRC-mediated mitochondrial activation/ROS production, which may lead to protection against beta cell dysfunction and glucose intolerance in vivo.
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| 4. |
- Krizhanovskii, Camilla, et al.
(författare)
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EndoC-beta H1 cells display increased sensitivity to sodium palmitate when cultured in DMEM/F12 medium
- 2017
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Ingår i: Islets. - : Informa UK Limited. - 1938-2014 .- 1938-2022. ; 9:3, s. 43-48
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Tidskriftsartikel (refereegranskat)abstract
- Aims - Human pancreatic islets are known to die in response to the free fatty acid of sodium palmitate when cultured in vitro. This is in contrast to EndoC-beta H1 cells, which in our hands are not sensitive to the cell death-inducing effects sodium palmitate, making these cells seemingly unsuitable for lipotoxicity studies. However, the EndoC-beta H1 cells are routinely cultured in a nutrient mixture based on Dulbecco's Modified Eagle Medium (DMEM), which may not be the optimal choice for studies dealing with lipotoxicity. The aim of the present investigation was to define culture conditions that render EndoC-beta H1 cells sensitive to toxic effects of sodium palmitate. Methods - EndoC-beta H1 cells were cultured at standard conditions in either DMEM or DMEM/F12 culture medium. Cell death was analyzed using propidium iodide staining and flow cytometry. Insulin release and content was quantified using a human insulin ELISA. Results - We presently observe that substitution of DMEM for a DMEM/Ham's F12 mixture (50%/50% vol/vol) renders the cells sensitive to the apoptotic effects of sodium palmitate and sodium palmitate + high glucose leading to an increased cell death. Supplementation of the DMEM culture medium with linoleic acid partially mimicked the effect of DMEM/F12. Culture of EndoC-beta H1 cells in DMEM/F12 resulted also in increased proliferation, ROS production and insulin contents, but markers for metabolic stress, autophagy or amyloid deposits were unaffected. Conclusions - The culture conditions for EndoC-beta H1 cells can be modified so these cells display signs of lipotoxicity in response to sodium palmitate.
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| 5. |
- Li, Yonghong, et al.
(författare)
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Novel strains with superior degrading efficiency for lincomycin manufacturing biowaste
- 2021
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Ingår i: Ecotoxicology and Environmental Safety. - : Elsevier BV. - 1090-2414 .- 0147-6513. ; 209
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Tidskriftsartikel (refereegranskat)abstract
- As the antibiotic pollution source in the environment, a large amount of biowastes generated from antibiotic fermentation manufacture needs proper disposal. Recycling the biowaste as resources and nutrients is of great interest. Besides, degradation or removal of antibiotics is indispensable for the reclamation of antibiotic manufacturing biowaste. To establish environmentally friendly disposal strategies for lincomycin manufacturing biowaste (LMB), we screened the microbial strains that could efficiently degrade lincomycin from the antibiotic wastewater treatment plant. Among them, three novel strains were identified as Bacillus subtilis (strain LMB-A), Rhodotorula mucilaginosa (strain LMB-D) and Penicillium oxalicum (strain LMB-E), respectively. LMB-A and LMB-D could degrade 92.69% and 74.05% of lincomycin with an initial concentration of 1117.55 mg/L in 144 h, respectively. The lincomycin degradation products were formed by the breakage of amide bond or losing N-demethyl/thiomethyl group from the pyrrolidine/pyranose ringcata cata catalyzed by the strains. Moreover, LMB-A could decontaminate LMB, and the decontaminated LMB could be used as a nitrogen source to culture salt-resistant bacteria and other useful microorganisms. LMB-A and LMB-D have the potential to be used for the bioremediation of water and soil polluted by lincomycin and its analogs. LMB-E could degrade 88.20% LMB after 144-h cultivation. In summary, this study gives an insight into the green disposal of LMB, and the established strategy has potential application for biotreatment of other antibiotic fermentation manufacturing biowastes.
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| 6. |
- Nazemosadat Arsanjani, Seyedeh Bentolhoda, 1984, et al.
(författare)
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Hot-Cavity Spectroscopy of Dark Pulse Kerr Combs in Microresonators
- 2019
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Ingår i: 2019 Conference on Lasers and Electro-Optics Europe and European Quantum Electronics Conference, CLEO/Europe-EQEC 2019. ; June 2019
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Konferensbidrag (refereegranskat)abstract
- Kerr frequency combs are generated through cascaded four-wave mixing in high-Q microresonators [1]. These devices are pumped with a continuous-wave laser and modulational instability (MI) is responsible for the growth of the initial comb lines. Since it is easier to satisfy the MI phase matching condition in the anomalous dispersion regime, most studies on Kerr combs have focused on anomalous dispersion microresonators. However, coherent microresonator combs can also take place in the normal dispersion regime. In these combs, phase matching is attained with the aid of the mode coupling between transverse modes of the microresonator [2]. One particularly interesting comb state that operates in the normal dispersion regime is the dark pulse Kerr comb [3]. The time domain pulses of these combs arise as interlocking switching waves that connect the upper and lower homogenous steady state solutions of the bi-stability curve in the continuous-wave-driven Kerr cavity [see Fig. (a)] [3]. These combs are of high interest as most nonlinear materials suitable for fabricating microresonators display normal dispersion in the visible and near infrared ranges. Moreover, these combs provide a much higher power conversion efficiency compared to bright-soliton combs, which makes them particularly useful for telecommunications [4].
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| 7. |
- Nazemosadat Arsanjani, Seyedeh Bentolhoda, 1984, et al.
(författare)
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Switching dynamics of dark-pulse Kerr frequency comb states in optical microresonators
- 2021
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Ingår i: Physical Review A. - 2469-9934 .- 2469-9926. ; 103:1
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Tidskriftsartikel (refereegranskat)abstract
- Dissipative Kerr solitons are localized structures that exist in nonlinear optical cavities. They lead to the formation of microcombs - chip-scale frequency combs that could facilitate precision frequency synthesis and metrology by capitalizing on advances in silicon photonics. Previous demonstrations have mainly focused on anomalous dispersion cavities. Notwithstanding, localized structures also exist in the normal dispersion regime in the form of circulating dark pulses, but their physical dynamics is far from being understood. Here, we explore dark-pulse Kerr combs generated in normal dispersion optical microresonators and report the discovery of reversible switching between coherent dark-pulse combs, whereby distinct states can be accessed deterministically. Furthermore, we reveal that the formation of dark-pulse Kerr combs is associated with the appearance of another resonance, a feature that has never been observed for dark pulses and is ascribed to soliton behavior. These results contribute to understanding the nonlinear physics in normal dispersion nonlinear cavities and provide insight into the generation of microcombs with high conversion efficiency.
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| 8. |
- Nazemosadat Arsanjani, Seyedeh Bentolhoda, 1984, et al.
(författare)
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Switching Dynamics of Dark Solitons in Kerr Microresonators
- 2019
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Ingår i: Optics InfoBase Conference Papers. - 2162-2701. ; paper ef_8_4
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Konferensbidrag (refereegranskat)abstract
- Dissipative Kerr solitons (DKS) are localized structures in optical resonators that arise from a double balance between dispersion and Kerr effect, and linear loss and parametric gain [1]. The periodic nature of DKS corresponds to frequency combs. DKS can be generated in high-Q microresonators for diverse applications, from coherent communications to precision frequency synthesis [1]. Most studies of DKS have focused on microresonator cavities operating in the anomalous dispersion regime, where the waveforms correspond to bright soliton pulses. Coherent microresonator combs can also be formed in the normal dispersion regime [2]. The time-domain waveform corresponds to a localized dark-pulse structure, interpreted as two interlocked switching waves connecting the two branches of the bi-stability curve in continuous-wave-pumped Kerr resonators [2, 3]. Each switching wave connects the two branches following an oscillating behavior. These type of Kerr combs are relevant for practical applications because they display unusually high power-conversion efficiency [4, 5], but their physical dynamics remain largely unexplored. Here, we report the discovery of deterministic switching of dark pulse Kerr combs, where the number of oscillations that appear between the switching waves can be either increased or decreased one at a time. The switching dynamics observed here have intriguing similarities to the switching behavior of bright temporal solitons in anomalous dispersion microresonators [6], and they indicate that dark pulse Kerr combs arise as a complex interplay of dark solitons circulating in the cavity.
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| 9. |
- Ngamjariyawat, Anongnad, 1976-, et al.
(författare)
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GDF15 Protects Insulin-Producing Beta Cells against Pro-Inflammatory Cytokines and Metabolic Stress via Increased Deamination of Intracellular Adenosine
- 2024
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:2
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Tidskriftsartikel (refereegranskat)abstract
- It has been proposed that antidiabetic drugs, such as metformin and imatinib, at least in part, promote improved glucose tolerance in type 2 diabetic patients via increased production of the inflammatory cytokine GDF15. This is supported by studies, performed in rodent cell lines and mouse models, in which the addition or production of GDF15 improved beta-cell function and survival. The aim of the present study was to determine whether human beta cells produce GDF15 in response to antidiabetic drugs and, if so, to further elucidate the mechanisms by which GDF15 modulates the function and survival of such cells. The effects and expression of GDF15 were analyzed in human insulin-producing EndoC-betaH1 cells and human islets. We observed that alpha and beta cells exhibit considerable heterogeneity in GDF15 immuno-positivity. The predominant form of GDF15 present in islet and EndoC-betaH1 cells was pro-GDF15. Imatinib, but not metformin, increased pro-GDF15 levels in EndoC-betaH1 cells. Under basal conditions, exogenous GDF15 increased human islet oxygen consumption rates. In EndoC-betaH1 cells and human islets, exogenous GDF15 partially ameliorated cytokine- or palmitate + high-glucose-induced loss of function and viability. GDF15-induced cell survival was paralleled by increased inosine levels, suggesting a more efficient disposal of intracellular adenosine. Knockdown of adenosine deaminase, the enzyme that converts adenosine to inosine, resulted in lowered inosine levels and loss of protection against cytokine- or palmitate + high-glucose-induced cell death. It is concluded that imatinib-induced GDF15 production may protect human beta cells partially against inflammatory and metabolic stress. Furthermore, it is possible that the GDF15-mediated activation of adenosine deaminase and the increased disposal of intracellular adenosine participate in protection against beta-cell death.
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| 10. |
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