ORCID Profile
0000-0002-6467-5029
Current Organisations
Lunds Universitet
,
Lund University
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Publisher: Springer Science and Business Media LLC
Date: 12-2014
Publisher: Cold Spring Harbor Laboratory
Date: 27-03-2019
DOI: 10.1101/591586
Abstract: Maternal obesity increases type 2 diabetes (T2D) risk in the offspring. Given that nearly half of women of child-bearing age in many populations are currently overweight/obese, it is key that we improve our understanding of the impact of the in utero /early life environment on offspring islet function. Using a well-established mouse model of diet-induced obesity, we examined offspring islets before the onset of metabolic dysfunction. This allowed us to determine inherent changes, in males and females, which are distinct from the response of islets to an existing obesogenic, insulin resistant milieu hence identifying islet dysregulation reflecting very early manifestation of the disease before the onset of disrupted glucose homeostasis. Female offspring of obese dams displayed higher glucose-stimulated insulin secretion and mitochondrial respiration, increased expression of estrogen receptor α and decreased cleaved-caspase 3 and Bax:Bcl-2 reflecting reduced susceptibility to apoptosis. In contrast, male offspring of obese dams displayed compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration and increased “uncoupled” respiration and reduced docked insulin granules in β-cells. Thus, maternal obesity “programs” sex-differences in offspring islet function. Islets of female but not male offspring appear primed to cope with a nutritionally-rich postnatal environment, which may reflect differences in future T2D risk.
Publisher: Springer Science and Business Media LLC
Date: 07-08-2018
Publisher: Springer Science and Business Media LLC
Date: 29-10-2016
Publisher: Elsevier BV
Date: 07-2017
Publisher: American Chemical Society (ACS)
Date: 21-02-2013
DOI: 10.1021/AC3019125
Abstract: A desire for higher speed and performance in molecular profiling analysis at a reduced cost is driving a trend in miniaturization and simplification of procedures. Here we report the use of a surface acoustic wave (SAW) atomizer for fast s le handling in matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) peptide and protein profiling of Islets of Langerhans, for future type 2 diabetes (T2D) studies. Here the SAW atomizer was used for ultrasound (acoustic) extraction of insulin and other peptide hormones released from freshly prepared islets, stimulated directly on a membrane. A high energy propagating SAW atomizes the membrane-bound liquid into approximately 2 μm diameter droplets, rich in cell-released molecules. Besides acting as a s le carrier, the membrane provides a purification step by entrapping cell clusters and other impurities within its fibers. A new SAW-based s le-matrix deposition method for MALDI MS was developed and characterized by a strong insulin signal, and a limit of detection (LOD) lower than 100 amol was achieved. Our results support previous work reporting the SAW atomizer as a fast and inexpensive tool for ultrasound, membrane-based s le extraction. When interfaced with MALDI MS, the SAW atomizer constitutes a valuable tool for rapid cell studies. Other biomedical applications of SAW-MALDI MS are currently being developed, aiming at fast profiling of biofluids. The membrane s ling is a simplistic and noninvasive collection method of limited volume biofluids such as the gingival fluid and the tearfilm.
Publisher: American Diabetes Association
Date: 04-01-2017
DOI: 10.2337/DB16-0996
Abstract: Current knowledge about the role of epigenetics in type 2 diabetes (T2D) remains limited. Only a few studies have investigated DNA methylation of selected candidate genes or a very small fraction of genomic CpG sites in human pancreatic islets, the tissue of primary pathogenic importance for diabetes. Our aim was to characterize the whole-genome DNA methylation landscape in human pancreatic islets, to identify differentially methylated regions (DMRs) in diabetic islets, and to investigate the function of DMRs in islet biology. Here, we performed whole-genome bisulfite sequencing, which is a comprehensive and unbiased method to study DNA methylation throughout the genome at a single nucleotide resolution, in pancreatic islets from donors with T2D and control subjects without diabetes. We identified 25,820 DMRs in islets from in iduals with T2D. These DMRs cover loci with known islet function, e.g., PDX1, TCF7L2, and ADCY5. Importantly, binding sites previously identified by ChIP-seq for islet-specific transcription factors, enhancer regions, and different histone marks were enriched in the T2D-associated DMRs. We also identified 457 genes, including NR4A3, PARK2, PID1, SLC2A2, and SOCS2, that had both DMRs and significant expression changes in T2D islets. To mimic the situation in T2D islets, candidate genes were overexpressed or silenced in cultured β-cells. This resulted in impaired insulin secretion, thereby connecting differential methylation to islet dysfunction. We further explored the islet methylome and found a strong link between methylation levels and histone marks. Additionally, DNA methylation in different genomic regions and of different transcript types (i.e., protein coding, noncoding, and pseudogenes) was associated with islet expression levels. Our study provides a comprehensive picture of the islet DNA methylome in in iduals with and without diabetes and highlights the importance of epigenetic dysregulation in pancreatic islets and T2D pathogenesis.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2015
Publisher: Springer Science and Business Media LLC
Date: 31-03-2016
DOI: 10.1038/NCOMMS11089
Abstract: Aging associates with impaired pancreatic islet function and increased type 2 diabetes (T2D) risk. Here we examine whether age-related epigenetic changes affect human islet function and if blood-based epigenetic biomarkers reflect these changes and associate with future T2D. We analyse DNA methylation genome-wide in islets from 87 non-diabetic donors, aged 26–74 years. Aging associates with increased DNA methylation of 241 sites. These sites cover loci previously associated with T2D, for ex le, KLF14 . Blood-based epigenetic biomarkers reflect age-related methylation changes in 83 genes identified in human islets (for ex le, KLF14, FHL2, ZNF518B and FAM123C ) and some associate with insulin secretion and T2D. DNA methylation correlates with islet expression of multiple genes, including FHL2 , ZNF518B, GNPNAT1 and HLTF. Silencing these genes in β-cells alter insulin secretion. Together, we demonstrate that blood-based epigenetic biomarkers reflect age-related DNA methylation changes in human islets, and associate with insulin secretion in vivo and T2D.
Publisher: American Diabetes Association
Date: 16-08-2019
DOI: 10.2337/DB18-0900
Abstract: Type 2 diabetes (T2D) is characterized by insufficient insulin secretion and elevated glucose levels, often in combination with high levels of circulating fatty acids. Long-term exposure to high levels of glucose or fatty acids impair insulin secretion in pancreatic islets, which could partly be due to epigenetic alterations. We studied the effects of high concentrations of glucose and palmitate combined for 48 h (glucolipotoxicity) on the transcriptome, the epigenome, and cell function in human islets. Glucolipotoxicity impaired insulin secretion, increased apoptosis, and significantly (false discovery rate & %) altered the expression of 1,855 genes, including 35 genes previously implicated in T2D by genome-wide association studies (e.g., TCF7L2 and CDKN2B). Additionally, metabolic pathways were enriched for downregulated genes. Of the differentially expressed genes, 1,469 also exhibited altered DNA methylation (e.g., CDK1, FICD, TPX2, and TYMS). A luciferase assay showed that increased methylation of CDK1 directly reduces its transcription in pancreatic β-cells, supporting the idea that DNA methylation underlies altered expression after glucolipotoxicity. Follow-up experiments in clonal β-cells showed that knockdown of FICD and TPX2 alters insulin secretion. Together, our novel data demonstrate that glucolipotoxicity changes the epigenome in human islets, thereby altering gene expression and possibly exacerbating the secretory defect in T2D.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-01-2010
Abstract: Inbred animals with inherited susceptibility to disease can be especially informative regarding pathogenetic mechanisms because they carry naturally occurring genetic variants of the same type that cause disease in humans. This principle is illustrated by Rosengren et al. (p. 217 published online 19 November), whose analysis of an inbred strain of rats prone to develop type 2 diabetes led to the discovery of a gene whose aberrant overexpression suppresses pancreatic insulin secretion in both rats and humans. The culprit gene, ADRA2A, encodes the alpha2A adrenergic receptor and is potentially a valuable lead for diabetes therapy because it can be targeted pharmacologically.
Publisher: Oxford University Press (OUP)
Date: 10-06-2014
DOI: 10.1093/HMG/DDU288
Abstract: We have previously identified transcription factor B1 mitochondrial (TFB1M) as a type 2 diabetes (T2D) risk gene, using human and mouse genetics. To further understand the function of TFB1M and how it is associated with T2D, we created a β-cell-specific knockout of Tfb1m, which gradually developed diabetes. Prior to the onset of diabetes, β-Tfb1m(-/-) mice exhibited retarded glucose clearance owing to impaired insulin secretion. β-Tfb1m(-/-) islets released less insulin in response to fuels, contained less insulin and secretory granules and displayed reduced β-cell mass. Moreover, mitochondria in Tfb1m-deficient β-cells were more abundant with disrupted architecture. TFB1M is known to control mitochondrial protein translation by adenine dimethylation of 12S ribosomal RNA (rRNA). Here, we found that the levels of TFB1M and mitochondrial-encoded proteins, mitochondrial 12S rRNA methylation, ATP production and oxygen consumption were reduced in β-Tfb1m(-/-) islets. Furthermore, the levels of reactive oxygen species (ROS) in response to cellular stress were increased whereas induction of defense mechanisms was attenuated. We also show increased apoptosis and necrosis as well as infiltration of macrophages and CD4(+) cells in the islets. Taken together, our findings demonstrate that Tfb1m-deficiency in β-cells caused mitochondrial dysfunction and subsequently diabetes owing to combined loss of β-cell function and mass. These observations reflect pathogenetic processes in human islets: using RNA sequencing, we found that the TFB1M risk variant exhibited a negative gene-dosage effect on islet TFB1M mRNA levels, as well as insulin secretion. Our findings highlight the role of mitochondrial dysfunction in impairments of β-cell function and mass, the hallmarks of T2D.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2019
DOI: 10.1007/S00125-019-05037-Y
Abstract: Obesity during pregnancy increases offspring type 2 diabetes risk. Given that nearly half of women of child-bearing age in many populations are currently overweight/obese, it is key that we improve our understanding of the impact of the in utero/early life environment on offspring islet function. Whilst a number of experimental studies have examined the effect of maternal obesity on offspring islet architecture and/or function, it has not previously been delineated whether these changes are independent of other confounding risk factors such as obesity, postnatal high-fat-feeding and ageing. Thus, we aimed to study the impact of exposure to maternal obesity on offspring islets in young, glucose-tolerant male and female offspring. Female C57BL/6J mice were fed ad libitum either chow or obesogenic diet prior to and throughout pregnancy and lactation. Offspring were weaned onto a chow diet and remained on this diet until the end of the study. An IPGTT was performed on male and female offspring at 7 weeks of age. At 8 weeks of age, pancreatic islets were isolated from offspring for measurement of insulin secretion and content, mitochondrial respiration, ATP content, reactive oxygen species levels, beta and alpha cell mass, granule and mitochondrial density (by transmission electron microscopy), and mRNA and protein expression by real-time RT-PCR and Western blotting, respectively. Glucose tolerance was similar irrespective of maternal diet and offspring sex. However, blood glucose was lower ( p 0.001) and plasma insulin higher ( p 0.05) in female offspring of obese dams 15 min after glucose administration. This was associated with higher glucose- ( p 0.01) and leucine/glutamine-stimulated ( p 0.05) insulin secretion in these offspring. Furthermore, there was increased mitochondrial respiration ( p 0.01) and density ( p 0.05) in female offspring of obese dams compared with same-sex controls. Expression of mitochondrial and nuclear-encoded components of the electron transport chain, L-type Ca 2+ channel subtypes that play a key role in stimulus-secretion coupling [ Cacna1d ( p 0.05)], and oestrogen receptor α ( p 0.05) was also increased in islets from these female offspring of obese dams. Moreover, cleaved caspase-3 expression and BAX:Bcl-2 were decreased ( p 0.05) reflecting reduced susceptibility to apoptosis. In contrast, in male offspring, glucose and leucine/glutamine-stimulated insulin secretion was comparable between treatment groups. There was, however, compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration ( p 0.05) and increased uncoupled respiration ( p 0.01), reduced docked insulin granules ( p 0.001), decreased Cacna1c ( p 0.001) and Cacna1d ( p 0.001) and increased cleaved caspase-3 expression ( p 0.05). Maternal obesity programs sex differences in offspring islet function. Islets of female but not male offspring appear to be primed to cope with a nutritionally-rich postnatal environment, which may reflect differences in future type 2 diabetes risk.
Publisher: Rockefeller University Press
Date: 09-02-2004
Abstract: We have explored whether γ-aminobutyric acid (GABA) is released by regulated exocytosis of GABA-containing synaptic-like microvesicles (SLMVs) in insulin-releasing rat pancreatic β-cells. To this end, β-cells were engineered to express GABAA-receptor Cl−-channels at high density using adenoviral infection. Electron microscopy indicated that the average diameter of the SLMVs is 90 nm, that every β-cell contains ∼3,500 such vesicles, and that insulin-containing large dense core vesicles exclude GABA. Quantal release of GABA, seen as rapidly activating and deactivating Cl−-currents, was observed during membrane depolarizations from −70 mV to voltages beyond −40 mV or when Ca2+ was dialysed into the cell interior. Depolarization-evoked GABA release was suppressed when Ca2+ entry was inhibited using Cd2+. Analysis of the kinetics of GABA release revealed that GABA-containing vesicles can be ided into a readily releasable pool and a reserve pool. Simultaneous measurements of GABA release and cell capacitance indicated that exocytosis of SLMVs contributes ∼1% of the capacitance signal. Mathematical analysis of the release events suggests that every SLMV contains 0.36 amol of GABA. We conclude that there are two parallel pathways of exocytosis in pancreatic β-cells and that release of GABA may accordingly be temporally and spatially separated from insulin secretion. This provides a basis for paracrine GABAergic signaling within the islet.
Publisher: American Diabetes Association
Date: 27-07-2021
DOI: 10.2337/DB20-0324
Abstract: The prevalence of type 2 diabetes (T2D) is increasing worldwide, but current treatments have limitations. miRNAs may play a key role in the development of T2D and can be targets for novel therapies. Here, we examined whether T2D is associated with altered expression and DNA methylation of miRNAs using adipose tissue from 14 monozygotic twin pairs discordant for T2D. Four members each of the miR-30 and let-7-families were downregulated in adipose tissue of subjects with T2D versus control subjects, which was confirmed in an independent T2D case-control cohort. Further, DNA methylation of five CpG sites annotated to gene promoters of differentially expressed miRNAs, including miR-30a and let-7a-3, was increased in T2D versus control subjects. Luciferase experiments showed that increased DNA methylation of the miR-30a promoter reduced its transcription in vitro. Silencing of miR-30 in adipocytes resulted in reduced glucose uptake and TBC1D4 phosphorylation downregulation of genes involved in demethylation and carbohydrate/lipid/amino acid metabolism and upregulation of immune system genes. In conclusion, T2D is associated with differential DNA methylation and expression of miRNAs in adipose tissue. Downregulation of the miR-30 family may lead to reduced glucose uptake and altered expression of key genes associated with T2D.
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.MCE.2012.08.009
Abstract: Reduced insulin release has been linked to defect exocytosis in β-cells. However, whether expression of genes suggested to be involved in the exocytotic process (exocytotic genes) is altered in pancreatic islets from patients with type 2 diabetes (T2D), and correlate to insulin secretion, needs to be further investigated. Analysing expression levels of 23 exocytotic genes using microarray revealed reduced expression of five genes in human T2D islets (χ(2)=13.25 p<0.001). Gene expression of STX1A, SYT4, SYT7, SYT11, SYT13, SNAP25 and STXBP1 correlated negatively to in vivo measurements of HbA1c levels and positively to glucose stimulated insulin secretion (GSIS) in vitro in human islets. STX1A, SYT4 and SYT11 protein levels correspondingly decreased in human T2D islets. Moreover, silencing of SYT4 and SYT13 reduced GSIS in INS1-832/13 cells. Our data support that reduced expression of exocytotic genes contributes to impaired insulin secretion, and suggest decreased expression of these genes as part of T2D pathogenesis.
Publisher: American Society for Clinical Investigation
Date: 15-02-2023
DOI: 10.1172/JCI163612
Publisher: Public Library of Science (PLoS)
Date: 06-03-2014
Publisher: Springer Science and Business Media LLC
Date: 14-08-2009
Publisher: Springer Science and Business Media LLC
Date: 09-2021
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.CMET.2012.10.009
Abstract: A plethora of candidate genes have been identified for complex polygenic disorders, but the underlying disease mechanisms remain largely unknown. We explored the pathophysiology of type 2 diabetes (T2D) by analyzing global gene expression in human pancreatic islets. A group of coexpressed genes (module), enriched for interleukin-1-related genes, was associated with T2D and reduced insulin secretion. One of the module genes that was highly overexpressed in islets from T2D patients is SFRP4, which encodes secreted frizzled-related protein 4. SFRP4 expression correlated with inflammatory markers, and its release from islets was stimulated by interleukin-1β. Elevated systemic SFRP4 caused reduced glucose tolerance through decreased islet expression of Ca(2+) channels and suppressed insulin exocytosis. SFRP4 thus provides a link between islet inflammation and impaired insulin secretion. Moreover, the protein was increased in serum from T2D patients several years before the diagnosis, suggesting that SFRP4 could be a potential biomarker for islet dysfunction in T2D.
No related grants have been discovered for Lena Eliasson.