Publications by authors named "Flemming Pociot"

151 Publications

Cathepsin C Regulates Cytokine-Induced Apoptosis in β-Cell Model Systems.

Genes (Basel) 2021 10 25;12(11). Epub 2021 Oct 25.

Translational Type 1 Diabetes Research, Clinical Research, Steno Diabetes Center Copenhagen, 2820 Gentofte, Denmark.

Emerging evidence suggests that several of the lysosomal cathepsin proteases are genetically associated with type 1 diabetes (T1D) and participate in immune-mediated destruction of the pancreatic β cells. We previously reported that the T1D candidate gene cathepsin H is downregulated by pro-inflammatory cytokines in human pancreatic islets and regulates β-cell function, apoptosis, and disease progression in children with new-onset T1D. In the present study, the objective was to investigate the expression patterns of all 15 known cathepsins in β-cell model systems and examine their role in the regulation of cytokine-induced apoptosis. Real-time qPCR screening of the cathepsins in human islets, 1.1B4 and INS-1E β-cell models identified several cathepsins that were expressed and regulated by pro-inflammatory cytokines. Using small interfering RNAs to knock down (KD) the cytokine-regulated cathepsins, we identified an anti-apoptotic function of cathepsin C as KD increased cytokine-induced apoptosis. KD of cathepsin C correlated with increased phosphorylation of JNK and p38 mitogen-activated protein kinases, and elevated chemokine CXCL10/IP-10 expression. This study suggests that cathepsin C is a modulator of β-cell survival, and that immune modulation of cathepsin expression in islets may contribute to immune-mediated β-cell destruction in T1D.
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http://dx.doi.org/10.3390/genes12111694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8622156PMC
October 2021

Plasma Exosome-Enriched Extracellular Vesicles From Lactating Mothers With Type 1 Diabetes Contain Aberrant Levels of miRNAs During the Postpartum Period.

Front Immunol 2021 8;12:744509. Epub 2021 Oct 8.

Translational Type 1 Diabetes Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Type 1 diabetes is an immune-driven disease, where the insulin-producing beta cells from the pancreatic islets of Langerhans becomes target of immune-mediated destruction. Several studies have highlighted the implication of circulating and exosomal microRNAs (miRNAs) in type 1 diabetes, underlining its biomarker value and novel therapeutic potential. Recently, we discovered that exosome-enriched extracellular vesicles carry altered levels of both known and novel miRNAs in breast milk from lactating mothers with type 1 diabetes. In this study, we aimed to characterize exosomal miRNAs in the circulation of lactating mothers with and without type 1 diabetes, hypothesizing that differences in type 1 diabetes risk in offspring from these groups are reflected in the circulating miRNA profile. We performed small RNA sequencing on exosome-enriched extracellular vesicles extracted from plasma of 52 lactating mothers around 5 weeks postpartum (26 with type 1 diabetes and 26 age-matched controls), and found a total of 2,289 miRNAs in vesicles from type 1 diabetes and control libraries. Of these, 176 were differentially expressed in plasma from mothers with type 1 diabetes (167 upregulated; 9 downregulated, using a cut-off of abs(log2FC) >1 and FDR adjusted p-value <0.05). Extracellular vesicles were verified by nanoparticle tracking analysis, transmission electron microscopy and immunoblotting. Five candidate miRNAs were selected based on their involvement in diabetes and immune modulation/beta-cell functions: hsa-miR-127-3p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-24-3p and hsa-miR-30d-5p. Real-time qPCR validation confirmed that hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-24-3p, and hsa-miR-30d-5p were significantly upregulated in lactating mothers with type 1 diabetes as compared to lactating healthy mothers. To determine possible target genes and affected pathways of the 5 miRNA candidates, computational network-based analyses were carried out with TargetScan, mirTarBase, QIAGEN Ingenuity Pathway Analysis and PantherDB database. The candidates showed significant association with inflammatory response and cytokine and chemokine mediated signaling pathways. With this study, we detect aberrant levels of miRNAs within plasma extracellular vesicles from lactating mothers with type 1 diabetes during the postpartum period, including miRNAs with associations to disease pathogenesis and inflammatory responses.
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http://dx.doi.org/10.3389/fimmu.2021.744509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531745PMC
December 2021

Diabetes complications and extracellular vesicle therapy.

Rev Endocr Metab Disord 2021 Oct 14. Epub 2021 Oct 14.

Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA.

Diabetes is a chronic disorder characterized by dysregulated glycemic conditions. Diabetic complications include microvascular and macrovascular abnormalities and account for high morbidity and mortality rates in patients. Current clinical approaches for diabetic complications are limited to symptomatic treatments and tight control of blood sugar levels. Extracellular vesicles (EVs) released by somatic and stem cells have recently emerged as a new class of potent cell-free therapeutic delivery packets with a great potential to treat diabetic complications. EVs contain a mixture of bioactive molecules and can affect underlying pathological processes in favor of tissue healing. In addition, EVs have low immunogenicity and high storage capacity while maintaining nearly the same regenerative and immunomodulatory effects compared to current cell-based therapies. Therefore, EVs have received increasing attention for diabetes-related complications in recent years. In this review, we provide an outlook on diabetic complications and summarizes new knowledge and advances in EV applications. Moreover, we highlight recommendations for future EV-related research.
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http://dx.doi.org/10.1007/s11154-021-09680-yDOI Listing
October 2021

Differences in insulin sensitivity in the partial remission phase of childhood type 1 diabetes; a longitudinal cohort study.

Diabet Med 2022 Feb 6;39(2):e14702. Epub 2021 Oct 6.

Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Herlev and Gentofte Hospital, Herlev, Denmark.

Aims: Studies suggest that type 1 diabetes (T1D) contributes to impaired insulin sensitivity (IS). Most children with T1D experience partial remission but the knowledge regarding the magnitude and implications of impaired IS in this phase is limited. Therefore, we investigate the impact of IS on the partial remission phase.

Methods: In a longitudinal study of children and adolescents, participants were seen at three clinical visits during the first 14.5 months after diagnosis of T1D. Partial remission was defined as IDAA (HbA (%) + 4*daily insulin dose) ≤ 9. Beta-cell function was considered significant by a stimulated c-peptide > 300 pmol/L. Participants were characterized by (i) remission or non-remission and (ii) stimulated c-peptide levels above or below 300 pmol/L. IS, body mass index (BMI), total body fat, sex, age, pubertal status and ketoacidosis at onset were compared.

Results: Seventy-eight children and adolescents aged 3.3-17.7 years were included. At 14.5 months post-diagnosis, 54.5% of the participants with stimulated c-peptide > 300 pmol/L were not in partial remission. Participants not in remission had significant lower IS 2.5 (p = 0.032), and 14.5 (p = 0.022) months after diagnosis compared to participants in partial remission with similar c-peptide levels. IS did not fluctuate during the remission phase.

Conclusions: A number of children and adolescents have impaired IS in the remission phase of paediatric T1D and are not in remission 14.5 months after diagnosis despite stimulated c-peptide > 300 pmol/L.
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http://dx.doi.org/10.1111/dme.14702DOI Listing
February 2022

Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes.

Nat Genet 2021 07 14;53(7):962-971. Epub 2021 Jun 14.

Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.

We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4 effector T cells. Using chromatin-accessibility profiling of CD4 T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.
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http://dx.doi.org/10.1038/s41588-021-00880-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273124PMC
July 2021

Genetic predisposition in the 2'-5'A pathway in the development of type 1 diabetes: potential contribution to dysregulation of innate antiviral immunity.

Diabetologia 2021 Aug 11;64(8):1805-1815. Epub 2021 May 11.

The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen, Denmark.

Aims/hypothesis: The incidence of type 1 diabetes is increasing more rapidly than can be explained by genetic drift. Viruses may play an important role in the disease, as they seem to activate the 2'-5'-linked oligoadenylate (2'-5'A) pathway of the innate antiviral immune system. Our aim was to investigate this possibility.

Methods: Innate antiviral immune pathways were searched for type 1 diabetes-associated polymorphisms using genome-wide association study data. SNPs within ±250kb flanking regions of the transcription start site of 64 genes were examined. These pathways were also investigated for type 1 diabetes-associated RNA expression profiles using laser-dissected islets from two to five tissue sections per donor from the Diabetes Virus Detection (DiViD) study and the network of Pancreatic Organ Donors (nPOD).

Results: We found 27 novel SNPs in genes nominally associated with type 1 diabetes. Three of those SNPs were located upstream of the 2'-5'A pathway, namely SNP rs4767000 (p = 1.03 × 10, OR 1.123), rs1034687 (p = 2.16 × 10, OR 0.869) and rs739744 (p = 1.03 × 10, OR 1.123). We also identified a large group of dysregulated islet genes in relation to type 1 diabetes, of which two were novel. The most aberrant genes were a group of IFN-stimulated genes. Of those, the following distinct pathways were targeted by the dysregulation (compared with the non-diabetic control group): OAS1 increased by 111% (p < 1.00 × 10, 95% CI -0.43, -0.15); MX1 increased by 142% (p < 1.00 × 10, 95% CI -0.52, -0.22); and ISG15 increased by 197% (p = 2.00 × 10, 95% CI -0.68, -0.18).

Conclusions/interpretation: We identified a genetic predisposition in the 2'-5'A pathway that potentially contributes to dysregulation of the innate antiviral immune system in type 1 diabetes. This study describes a potential role for the 2'-5'A pathway and other components of the innate antiviral immune system in beta cell autoimmunity.
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http://dx.doi.org/10.1007/s00125-021-05469-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245375PMC
August 2021

Changes in the lipidome in type 1 diabetes following low carbohydrate diet: Post-hoc analysis of a randomized crossover trial.

Endocrinol Diabetes Metab 2021 04 4;4(2):e00213. Epub 2021 Jan 4.

Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Aims: Lipid metabolism might be compromised in type 1 diabetes, and the understanding of lipid physiology is critically important. This study aimed to compare the change in plasma lipid concentrations during carbohydrate dietary changes in individuals with type 1 diabetes and identify links to early-stage dyslipidaemia. We hypothesized that (1) the lipidomic profiles after ingesting low or high carbohydrate diet for 12 weeks would be different; and (2) specific annotated lipid species could have significant associations with metabolic outcomes.

Methods: Ten adults with type 1 diabetes (mean ± SD: age 43.6 ± 13.8 years, diabetes duration 24.5 ± 13.4 years, BMI 24.9 ± 2.1 kg/m, HbA 57.6 ± 2.6 mmol/mol) using insulin pumps participated in a randomized 2-period crossover study with a 12-week intervention period of low carbohydrate diet (< 100 g carbohydrates/day) or high carbohydrate diet (> 250 g carbohydrates/day), respectively, separated by a 12-week washout period. A large-scale non-targeted lipidomics was performed with mass spectrometry in fasting plasma samples obtained before and after each diet intervention. Longitudinal lipid levels were analysed using linear mixed-effects models.

Results: In total, 289 lipid species were identified from 14 major lipid classes. Comparing the two diets, 11 lipid species belonging to sphingomyelins, phosphatidylcholines and LPC(O-16:0) were changed. All the 11 lipid species were significantly elevated during low carbohydrate diet. Two lipid species were most differentiated between diets, namely SM(d36:1) (β ± SE: 1.44 ± 0.28,  = 0.010) and PC(P-36:4)/PC(O-36:5) (β ± SE: 1.34 ± 0.25,  = 0.009) species. Polyunsaturated PC(35:4) was inversely associated with BMI and positively associated with HDL cholesterol (p < .001).

Conclusion: Lipidome-wide outcome analysis of a randomized crossover trial of individuals with type 1 diabetes following a low carbohydrate diet showed an increase in sphingomyelins and phosphatidylcholines which are thought to reduce dyslipidaemia. The polyunsaturated phosphatidylcholine 35:4 was inversely associated with BMI and positively associated with HDL cholesterol (p < .001). Results from this study warrant for more investigation on the long-term effect of single lipid species in type 1 diabetes.
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http://dx.doi.org/10.1002/edm2.213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029500PMC
April 2021

A Dual Systems Genetics Approach Identifies Common Genes, Networks, and Pathways for Type 1 and 2 Diabetes in Human Islets.

Front Genet 2021 10;12:630109. Epub 2021 Mar 10.

Department of Translational T1D Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Type 1 and 2 diabetes (T1/2D) are complex metabolic diseases caused by absolute or relative loss of functional β-cell mass, respectively. Both diseases are influenced by multiple genetic loci that alter disease risk. For many of the disease-associated loci, the causal candidate genes remain to be identified. Remarkably, despite the partially shared phenotype of the two diabetes forms, the associated loci for T1D and T2D are almost completely separated. We hypothesized that some of the genes located in risk loci for T1D and T2D interact in common pancreatic islet networks to mutually regulate important islet functions which are disturbed by disease-associated variants leading to β-cell dysfunction. To address this, we took a dual systems genetics approach. All genes located in 57 T1D and 243 T2D established genome-wide association studies (GWAS) loci were extracted and filtered for genes expressed in human islets using RNA sequencing data, and then integrated with; (1) human islet expression quantitative trait locus (eQTL) signals in linkage disequilibrium (LD) with T1D- and T2D-associated variants; or (2) with genes transcriptionally regulated in human islets by pro-inflammatory cytokines or palmitate as models of T1D and T2D, respectively. Our systems genetics approaches created two interaction networks consisting of densely-connected T1D and T2D loci genes. The "T1D-T2D islet eQTL interaction network" identified 9 genes (, and ) in common T1D and T2D loci that harbor islet eQTLs in LD with disease-associated variants. The "cytokine and palmitate islet interaction network" identified 4 genes (, and ) in common T1D and T2D loci whose expression is mutually regulated by cytokines and palmitate. Functional annotation analyses of the islet networks revealed a number of significantly enriched pathways and molecular functions including cell cycle regulation, inositol phosphate metabolism, lipid metabolism, and cell death and survival. In summary, our study has identified a number of new plausible common candidate genes and pathways for T1D and T2D.
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http://dx.doi.org/10.3389/fgene.2021.630109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987941PMC
March 2021

Human pathways in animal models: possibilities and limitations.

Nucleic Acids Res 2021 02;49(4):1859-1871

Center for non-coding RNA in Technology and Health, University of Copenhagen, 1871 Frederiksberg, Denmark.

Animal models are crucial for advancing our knowledge about the molecular pathways involved in human diseases. However, it remains unclear to what extent tissue expression of pathways in healthy individuals is conserved between species. In addition, organism-specific information on pathways in animal models is often lacking. Within these limitations, we explore the possibilities that arise from publicly available data for the animal models mouse, rat, and pig. We approximate the animal pathways activity by integrating the human counterparts of curated pathways with tissue expression data from the models. Specifically, we compare whether the animal orthologs of the human genes are expressed in the same tissue. This is complicated by the lower coverage and worse quality of data in rat and pig as compared to mouse. Despite that, from 203 human KEGG pathways and the seven tissues with best experimental coverage, we identify 95 distinct pathways, for which the tissue expression in one animal model agrees better with human than the others. Our systematic pathway-tissue comparison between human and three animal modes points to specific similarities with human and to distinct differences among the animal models, thereby suggesting the most suitable organism for modeling a human pathway or tissue.
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http://dx.doi.org/10.1093/nar/gkab012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913694PMC
February 2021

, a Candidate Gene for Type 1 Diabetes, Regulates β-Cell Apoptosis and Glycemic Control in Newly Diagnosed Patients.

Diabetes 2021 02 17;70(2):464-476. Epub 2020 Nov 17.

Translational Type 1 Diabetes Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark

The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2 () gene is associated with type 1 diabetes (T1D), suggesting as a causal candidate gene. The objective of the study was to investigate if SKAP2 has a functional role in the β-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycemic control and residual β-cell function during the 1st year after diagnosis. In INS-1E cells and rat and human islets, proinflammatory cytokines reduced the content of SKAP2. Functional studies revealed that knockdown of SKAP2 aggravated cytokine-induced apoptosis in INS-1E cells and primary rat β-cells, suggesting an antiapoptotic function of SKAP2. In support of this, overexpression of SKAP2 afforded protection against cytokine-induced apoptosis, which correlated with reduced nuclear content of S536-phosphorylated nuclear factor-κB (NF-κB) subunit p65, lower nitric oxide production, and diminished CHOP expression indicative of decreased endoplasmic reticulum stress. Knockdown of CHOP partially counteracted the increase in cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our results suggest that SKAP2 controls β-cell sensitivity to cytokines possibly by affecting the NF-κB-inducible nitric oxide synthase-endoplasmic reticulum stress pathway.
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http://dx.doi.org/10.2337/db20-0092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881866PMC
February 2021

Characterization of plasma lipidomics in adolescent subjects with increased risk for type 1 diabetes in the DiPiS cohort.

Metabolomics 2020 10 8;16(10):109. Epub 2020 Oct 8.

Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, Gentofte, Denmark.

Introduction: Type 1 diabetes (T1D) is caused by the destruction of pancreatic islet beta cells resulting in total loss of insulin production. Recent studies have suggested that the destruction may be interrelated to plasma lipids.

Objectives: Specific lipids have previously been shown to be decreased in children who develop T1D before four years of age. Disturbances of plasma lipids prior to clinical diagnosis of diabetes, if true, may provide a novel way to improve prediction, and monitor disease progression.

Methods: A lipidomic approach was utilized to analyze plasma from 67 healthy adolescent subjects (10-15 years of age) with or without islet autoantibodies but all with increased genetic risk for T1D. The study subjects were enrolled at birth in the Diabetes Prediction in Skåne (DiPiS) study and after 10-15 years of follow-up we performed the present cross-sectional analysis. HLA-DRB345, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1 genotypes were determined using next generation sequencing. Lipidomic profiles were determined using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. Lipidomics data were analyzed according to genotype.

Results: Variation in levels of several specific phospholipid species were related to level of autoimmunity but not development of T1D. Five glycosylated ceramides were increased in insulin autoantibody (IAA) positive adolescent subjects compared to adolescent subjects without this autoantibody. Additionally, HLA genotypes seemed to influence levels of long chain triacylglycerol (TG).

Conclusion: Lipidomic profiling of adolescent subjects in high risk of T1D may improve sub-phenotyping in this high risk population.
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http://dx.doi.org/10.1007/s11306-020-01730-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544716PMC
October 2020

Systemic TNFα correlates with residual β-cell function in children and adolescents newly diagnosed with type 1 diabetes.

BMC Pediatr 2020 09 23;20(1):446. Epub 2020 Sep 23.

Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Background: Type 1 diabetes (T1D) is caused by immune-mediated destruction of the β-cells. After initiation of insulin therapy many patients experience a period of improved residual β-cell function leading to partial disease remission. Cytokines are important immune-modulatory molecules and contribute to β-cell damage in T1D. The patterns of systemic circulating cytokines during T1D remission are not clear but may constitute biomarkers of disease status and progression. In this study, we investigated if the plasma levels of various pro- and anti-inflammatory cytokines around time of diagnosis were predictors of remission and residual β-cell function in children with T1D followed for one year after disease onset.

Methods: In a cohort of 63 newly diagnosed children (33% females) with T1D with a mean age of 11.3 years (3.3-17.7), ten cytokines were measured of which eight were detectable in plasma samples by Mesoscale Discovery multiplex technology at study start and after 6 and 12 months. Linear regression models were used to evaluate association of cytokines with stimulated C-peptide.

Results: Systemic levels of tumor necrosis factor (TNF)-α, interleukin (IL)-2 and IL-6 inversely correlated with stimulated C-peptide levels over the entire study (P < 0.05). The concentrations of TNFα and IL-10 at study start predicted stimulated C-peptide level at 6 months (P = 0.011 and P = 0.043, respectively, adjusted for sex, age, HbA1c and stage of puberty).

Conclusions: In recent-onset T1D, systemic cytokine levels, and in particular that of TNFα, correlate with residual β-cell function and may serve as prognostic biomarkers of disease remission and progression to optimize treatment strategies.

Trial Registration: The study was performed according to the criteria of the Helsinki II Declaration and was approved by the Danish Capital Region Ethics Committee on Biomedical Research Ethics (journal number H-3-2014-052). The parents of all participants gave written consent.
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http://dx.doi.org/10.1186/s12887-020-02339-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510056PMC
September 2020

Circulating Inflammatory Markers Are Inversely Associated with Heart Rate Variability Measures in Type 1 Diabetes.

Mediators Inflamm 2020 18;2020:3590389. Epub 2020 Aug 18.

Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Introduction: A neuroimmune communication exists, and compelling evidence suggests that diabetic neuropathy and systemic inflammation are linked. Our aims were (1) to investigate biomarkers of the ongoing inflammation processes including cytokines, adhesion molecules, and chemokines and (2) to associate the findings with cardiovascular autonomic neuropathy in type 1 diabetes by measuring heart rate variability and cardiac vagal tone.

Materials And Methods: We included 104 adults with type 1 diabetes. Heart rate variability, time domain, and frequency domains were calculated from a 24-hour Holter electrocardiogram, while cardiac vagal tone was determined from a 5-minute electrocardiogram. Cytokines (interleukin- (IL-) 1, IL-4, IL-12p70, IL-13, IL-17, and tumor necrosis factor- (TNF-) ), adhesion molecules (E-selectin, P-selectin, and intercellular adhesion molecule- (ICAM-) 1), and chemokines (chemokine (C-C motif) ligand (CCL)2, CCL3, CCL4, and C-X-C motif chemokine (CXCL)10) were assessed using a Luminex multiplexing technology. Associations between concentrations of inflammatory biomarkers and continuous variables of heart rate variability and cardiac vagal tone were estimated using multivariable linear regression adjusting for age, sex, disease duration, and smoking.

Results: Participants with the presence of cardiovascular autonomic neuropathy had higher systemic levels of IL-1, IL-4, CCL2, and E-selectin than those without cardiovascular autonomic neuropathy. IL-1, IL-4, IL-12, TNF-, and E-selectin were inversely associated with both sympathetic and parasympathetic heart rate variability measures ( > 0.01). . Our results show that several pro- and anti-inflammatory factors, believed to be involved in the progression of diabetic polyneuropathy, are associated with cardiovascular autonomic neuropathy, suggesting that these factors may also contribute to the pathogenesis of cardiovascular autonomic neuropathy. Our findings emphasize the importance of the neuroimmune regulatory system in the pathogenesis of neuropathy in type 1 diabetes.
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http://dx.doi.org/10.1155/2020/3590389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450314PMC
August 2021

The Rac2 GTPase contributes to cathepsin H-mediated protection against cytokine-induced apoptosis in insulin-secreting cells.

Mol Cell Endocrinol 2020 12 16;518:110993. Epub 2020 Aug 16.

Translational Type 1 Diabetes Research, Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, DK-2820, Gentofte, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark. Electronic address:

The type 1 diabetes (T1D) risk locus on chromosome 15q25.1 harbors the candidate gene CTSH (cathepsin H). We previously demonstrated that CTSH regulates β-cell function in vitro and in vivo. CTSH overexpression protected insulin-secreting INS-1 cells against cytokine-induced apoptosis. The purpose of the present study was to identify the genes through which CTSH mediates its protective effects. Microarray analysis identified 63 annotated genes differentially expressed between CTSH-overexpressing INS-1 cells and control cells treated with interleukin-1β and interferon-γ for up to 16h. Permutation test identified 10 significant genes across all time-points: Elmod1, Fam49a, Gas7, Gna15, Msrb3, Nox1, Ptgs1, Rac2, Scn7a and Ttn. Pathway analysis identified the "Inflammation mediated by chemokine and cytokine signaling pathway" with Gna15, Ptgs1 and Rac2 as significant. Knockdown of Rac2 abolished the protective effect of CTSH overexpression on cytokine-induced apoptosis, suggesting that the small GTPase and T1D candidate gene Rac2 contributes to the anti-apoptotic effect of CTSH.
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http://dx.doi.org/10.1016/j.mce.2020.110993DOI Listing
December 2020

Lipidomics of human adipose tissue reveals diversity between body areas.

PLoS One 2020 16;15(6):e0228521. Epub 2020 Jun 16.

Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Background And Aims: Adipose tissue plays a pivotal role in storing excess fat and its composition reflects the history of person's lifestyle and metabolic health. Broad profiling of lipids with mass spectrometry has potential for uncovering new knowledge on the pathology of obesity, metabolic syndrome, diabetes and other related conditions. Here, we developed a lipidomic method for analyzing human subcutaneous adipose biopsies. We applied the method to four body areas to understand the differences in lipid composition between these areas.

Materials And Methods: Adipose tissue biopsies from 10 participants were analyzed using ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. The sample preparation optimization included the optimization of the lipid extraction, the sample amount and the sample dilution factor to detect lipids in an appropriate concentration range. Lipidomic analyses were performed for adipose tissue collected from the abdomen, breast, thigh and lower back. Differences in lipid levels between tissues were visualized with heatmaps.

Results: Lipidomic analysis on human adipose biopsies lead to the identification of 186lipids in 2 mg of sample. Technical variation of the lipid-class specific internal standards were below 5%, thus indicating acceptable repeatability. Triacylglycerols were highly represented in the adipose tissue samples, and lipids from 13 lipid classes were identified. Long polyunsaturated triacylglycerols in higher levels in thigh (q<0.05), when compared with the abdomen, breast and lower back, indicating that the lipidome was area-specific.

Conclusion: The method presented here is suitable for the analysis of lipid profiles in 2 mg of adipose tissue. The amount of fat across the body is important for health but we argue that also the distribution and the particular profile of the lipidome may be relevant for metabolic outcomes. We suggest that the method presented in this paper could be useful for detecting such aberrations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228521PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297320PMC
August 2020

Increased levels of inflammatory factors are associated with severity of polyneuropathy in type 1 diabetes.

Clin Endocrinol (Oxf) 2020 10 24;93(4):419-428. Epub 2020 Jun 24.

Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Objective: Distal symmetrical polyneuropathy (DSPN) is a severe common long-term complication of type 1 diabetes caused by impaired sensory-motor nerve function. As chronic low-grade inflammation may be involved in the pathogenesis of DSPN, we investigated the circulating levels of inflammatory markers in individuals with type 1 diabetes with and without DSPN. Furthermore, we determined to what extent these factors correlated with different peripheral sensory nerve functions.

Design: Cross-sectional study.

Patients: The study included 103 individuals with type 1 diabetes with (n = 50) and without DSPN (n = 53) as well as a cohort of healthy controls (n = 21).

Measurements: Circulating levels of various inflammatory markers (cytokines, chemokines and soluble adhesion molecules) were determined in serum samples by Luminex multiplexing technology. Peripheral sensory nerve testing, for example vibration, tactile and thermal perception, was assessed by standardized procedures.

Results: The cytokines IL-1α, IL-4, IL-12p70, IL-13, IL-17A and TNF-α; the chemokine MCP-1; and the adhesion molecule E-selectin were significantly increased in individuals with type 1 diabetes with DSPN compared to those without DSPN (P < .001). These observations were independent of age, sex, BMI, disease duration and blood pressure. Additionally, higher serum concentrations of cytokines and chemokines were associated with higher vibration and tactile perception thresholds, but not with heat tolerance threshold.

Conclusions: Individuals with type 1 diabetes and concomitant DSPN display higher serum levels of several inflammatory markers. These findings support that systemic low-grade inflammation may play a role in the pathogenesis of DSPN.
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http://dx.doi.org/10.1111/cen.14261DOI Listing
October 2020

Anti-diabetic potential of plant alkaloids: Revisiting current findings and future perspectives.

Pharmacol Res 2020 05 24;155:104723. Epub 2020 Feb 24.

University of Belgrade, Faculty of Agriculture, Department of Food Technology and Biochemistry, 11080 Belgrade, Serbia.

Diabetes mellitus (DM) is a chronic metabolic disease which causes millions of death all over the world each year, and its incidence is on increase. The most prevalent form, type 2 DM, is characterized by insulin resistance and β-cell dysfunction, whereas type 1 DM is due to insulin deficiency as a result of β-cell destruction. Various classes of synthetic drugs have been developed to regulate glucose homeostasis and combat the development of late-diabetic complications. However, several of these chemical agents are either sub-optimal in their effect and/or may have side effects. Biologically, alkaloids unveiled a wide range of therapeutic effects including anti-diabetic properties. The chemical backbones of these compounds have the potential to interact with a wide range of proteins involved in glucose homeostasis, and thus they have received increasing attention as reliable candidates for drug development. This review sets out to investigate the anti-diabetic potential of plant alkaloids (PAs), and therefore, scientific databases were comprehensively screened to highlight the biological activity of 78 PAs with a considerable anti-diabetic profile. There are not enough clinical data available for these phytochemicals to follow their fingerprint in human, but current studies generally recommending PAs as potent α-glucosidase inhibitors. Except for some classes of monoterpene alkaloids, other compounds showed similar features as well as the presently available anti-diabetic drugs such as amino sugars and other relevant drugs. Moreover, the evidence suggests that PAs have the potential to be used as alternative additives for the treatment of DM, however, further in vitro and in vivo studies are needed to validate these findings.
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http://dx.doi.org/10.1016/j.phrs.2020.104723DOI Listing
May 2020

Decreased markers of bone turnover in children and adolescents with type 1 diabetes.

Pediatr Diabetes 2020 05 3;21(3):505-514. Epub 2020 Feb 3.

Department of Paediatrics and Adolescent Medicine, Herlev Hospital, Herlev, Denmark.

Background And Aim: Adults with type 1 diabetes (T1D) have increased risk of bone fractures and decreased bone mineral density (BMD). Alterations in bone turnover have been suggested as the link between T1D and the impaired bone health. Furthermore, bone turnover has been suggested to have beneficial effects on glucose metabolism. This study aimed at describing bone turnover markers (BTM), and the relationship with glycemic control, in children and adolescents with T1D.

Methods: A total of 173 (47% girls) children and adolescents aged 7.7 to 17.5 years with T1D for more than 1 year were included. Participants were evaluated by BMD together with measurements of selected BTM; two formation markers: osteocalcin (OCN) and procollagen type-1 amino-terminal propeptide (P1NP) and one resorption marker, C-terminal cross-linked telopeptide of type-1 collagen (CTX). BTM were converted into Z-scores utilizing new national references.

Results: Mean OCN Z-score (-0.68 ± 1.31), P1NP Z-score (-0.33 ± 1.03) and CTX Z-score (-0.43 ± 1.10) were all significantly lower than the reference population (P < .001). No associations were seen between BTM and T1D duration. BMD Z-score was comparable to the reference population and associated with none of individual BTMs. CTX Z-score was negatively associated with HbA1c (P = .007) independent of both exogenous and residual endogenous insulin.

Conclusions: Markers of bone formation and resorption were decreased in children and adolescents with T1D. CTX Z-score associated negatively with HbA1c adjusted for insulin treatment and endogenous insulin production indicating a potential association between CTX and insulin sensitivity. The long-term consequences of decreased BTM on BMD need further attention.
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http://dx.doi.org/10.1111/pedi.12987DOI Listing
May 2020

Bone turnover markers during the remission phase in children and adolescents with type 1 diabetes.

Pediatr Diabetes 2020 03 27;21(2):366-376. Epub 2019 Dec 27.

Department of Children Adolescents, Copenhagen University Hospital Herlev, Herlev, Denmark.

Background And Aim: In rodents, osteocalcin (OCN) stimulates insulin production and insulin sensitivity, both important factors during partial remission in humans with type 1 diabetes (T1D). However, decreased OCN has been reported in both adult and pediatric T1D. This study aims at investigating bone turnover and partial remission in children and adolescents with recent onset T1D.

Subjects And Methods: Ninety-nine individuals (33% girls) were recruited within 3 months of T1D onset and examined three times, 6 months apart. Outcome variables were bone formation markers OCN and procollagen type 1 amino-terminal propeptide (P1NP) and the bone resorption marker C-terminal crosslinked telopeptide of type 1 collagen (CTX). Dependent variables included IDAA1c (surrogate marker of partial remission), total body bone mineral density (BMD) and stimulated C-peptide as representative of endogenous insulin production.

Results: OCN- and P1NP Z-scores were significantly decreased throughout the study, whereas CTX Z-scores were increased. None of the bone turnover markers changed significantly between visits. Total body BMD Z-score did not change during the study but was significantly higher than the reference population at visit 2 (P = .035). There were no differences in the bone turnover markers for those in partial remission as defined by either C-peptide or IDAA1c at any visit. The individual change in CTX Z-score was negatively associated with the increase of IDAA1c (P = .030) independent of C-peptide decline (P = .034).

Conclusion: Bone turnover markers indicate increased bone resorption and decreased bone formation during the first year of T1D. The negative association between bone resorption and IDAA1c might represent compensatory mechanisms affecting insulin sensitivity.
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http://dx.doi.org/10.1111/pedi.12963DOI Listing
March 2020

Linking glycemic dysregulation in diabetes to symptoms, comorbidities, and genetics through EHR data mining.

Elife 2019 12 10;8. Epub 2019 Dec 10.

Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.

Diabetes is a diverse and complex disease, with considerable variation in phenotypic manifestation and severity. This variation hampers the study of etiological differences and reduces the statistical power of analyses of associations to genetics, treatment outcomes, and complications. We address these issues through deep, fine-grained phenotypic stratification of a diabetes cohort. Text mining the electronic health records of 14,017 patients, we matched two controlled vocabularies (ICD-10 and a custom vocabulary developed at the clinical center Steno Diabetes Center Copenhagen) to clinical narratives spanning a 19 year period. The two matched vocabularies comprise over 20,000 medical terms describing symptoms, other diagnoses, and lifestyle factors. The cohort is genetically homogeneous (Caucasian diabetes patients from Denmark) so the resulting stratification is not driven by ethnic differences, but rather by inherently dissimilar progression patterns and lifestyle related risk factors. Using unsupervised Markov clustering, we defined 71 clusters of at least 50 individuals within the diabetes spectrum. The clusters display both distinct and shared longitudinal glycemic dysregulation patterns, temporal co-occurrences of comorbidities, and associations to single nucleotide polymorphisms in or near genes relevant for diabetes comorbidities.
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http://dx.doi.org/10.7554/eLife.44941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904221PMC
December 2019

Unaffected bone mineral density in Danish children and adolescents with type 1 diabetes.

J Bone Miner Metab 2020 May 21;38(3):328-337. Epub 2019 Nov 21.

Department of Children Adolescents, Copenhagen University Hospital Herlev, Herlev Ringvej 75, 2730, Herlev, Denmark.

Aims: Adults with type 1 diabetes mellitus (T1D) have decreased bone mineral density (BMD). Our study aimed at determining BMD and the association to metabolic control in children and adolescents with T1D.

Methods: 244 patients (113 girls) with a median age of 14.3 years and T1D duration of 1-16 years were included. A dual-energy X-ray absorptiometry scan assessed BMD Z-scores excluding the head (total body less head, TBLH). TBLH-BMD were then investigated for associations to diabetes relevant variables such as HbA1c, insulin treatment, anthropometry and physical activity.

Results: In all participants the TBLH-BMD Z-score (0.22 ± 0.96) was significantly higher than the references. Separated by sex, TBLH-BMD Z-score in boys (0.11 ± 0.84) was no different from healthy peers whereas TBLH-BMD Z-score was significantly higher in girls (0.36 ± 1.09). The higher TBLH-BMD Z-score in girls were explained by higher BMI Z-scores. Participants with assumed final height (based on age) had an average TBLH-BMD Z-score of 0.78 ± 1.06, significantly higher than references independent of gender, HbA1c, height- and weight Z-scores. Multiple regression analyses showed that TBLH BMD Z-score associated negatively to HbA1c (P = 0.003), pump treatment (P = 0.019) and screen-time (P = 0.005) and positively to weight Z-score (P < 0.001). Physical activity, sex and puberty did not significantly associate to TBLH-BMD Z-score.

Conclusion: Unlike adults with T1D, BMD is not decreased in children and adolescents with T1D and even elevated after attained final height. As HbA1c negatively associates to BMD, decreased BMD may progress over time. Whether changes in microarchitecture or bone metabolism precede changes in BMD needs further investigation.
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http://dx.doi.org/10.1007/s00774-019-01058-0DOI Listing
May 2020

Breast Milk-Derived Extracellular Vesicles Enriched in Exosomes From Mothers With Type 1 Diabetes Contain Aberrant Levels of microRNAs.

Front Immunol 2019 25;10:2543. Epub 2019 Oct 25.

Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The breast milk plays a crucial role in shaping the initial intestinal microbiota and mucosal immunity of the infant. Interestingly, breastfeeding has proven to be protective against the early onset of immune-mediated diseases including type 1 diabetes. Studies have shown that exosomes from human breast milk are enriched in immune-modulating miRNAs suggesting that exosomal miRNAs (exomiRs) transferred to the infant could play a critical role in the development of the infant's immune system. We extracted exomiRs from breast milk of 52 lactating mothers (26 mothers with type 1 diabetes and 26 healthy mothers), to identify any differences in the exomiR content between the two groups. Small RNA-sequencing was performed to identify known and novel miRNAs in both groups. A total of 631 exomiRs were detected by small RNA sequencing including immune-related miRNAs such as hsa-let-7c, hsa-miR-21, hsa-miR-34a, hsa-miR-146b, and hsa-miR-200b. In addition, ~200 novel miRNAs were identified in both type 1 diabetes and control samples. Among the known miRNAs, nine exomiR's were found differentially expressed in mothers with type 1 diabetes compared to healthy mothers. The highly up-regulated miRNAs, hsa-miR-4497, and hsa-miR-3178, increased lipopolysaccharide-induced expression and secretion of tumor necrosis factor α (TNFα) in human monocytes. The up-regulated miRNA target genes were significantly enriched for longevity-regulating pathways and FoxO signaling. Our findings suggest a role of breast milk-derived exomiRs in modulating the infant's immune system.
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http://dx.doi.org/10.3389/fimmu.2019.02543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823203PMC
November 2020

Perinatal Whole Blood Zinc Status and Cytokines, Adipokines, and Other Immune Response Proteins.

Nutrients 2019 08 22;11(9). Epub 2019 Aug 22.

Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Denmark.

(1) Background: Zinc is an essential micronutrient and zinc deficiency is associated with immune dysfunction. The neonatal immune system is immature, and therefore an optimal neonatal zinc status may be important. The aim of this study was to investigate the possible association between neonatal whole blood (WB)-Zinc content and several immune markers. (2) Methods: In total, 398 healthy newborns (199 who later developed type 1 diabetes and 199 controls) from the Danish Newborn Screening Biobank had neonatal dried blood spots (NDBS) analyzed for WB-Zinc content and (i) cytokines: Interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10, IL-12 (p70), interferon gamma, tumor necrosis factor alpha, and transforming growth factor beta; (ii) adipokines: leptin and adiponectin; (iii) other immune response proteins: C-reactive protein (CRP), and mannose-binding lectin (MBL), and soluble triggering receptors expressed on myeloid cells1 (sTREM-1). WB-Zinc content was determined using laser ablation inductively coupled plasma mass spectrometry. For each analyte, the relative change in mean level was modelled by a robust log-normal model regression. (3) Results: No association was found between WB-Zinc content and all the immune response markers in either the unadjusted or adjusted models overall or when stratifying by case status. (4) Conclusions: In healthy Danish neonates, WB-Zinc content was not associated with cytokines, adipokines, CRP, MBL or sTREM, which does not indicate a strong immunological function of neonatal zinc status.
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http://dx.doi.org/10.3390/nu11091980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769600PMC
August 2019

Bone turnover markers in children and adolescents with type 1 diabetes-A systematic review.

Pediatr Diabetes 2019 08 22;20(5):510-522. Epub 2019 May 22.

Department of Pediatrics, Herlev University Hospital, Copenhagen, Denmark.

Type 1 diabetes (T1D) is associated with impaired bone health and both osteocalcin (OCN) and procollagen type 1 amino terminal propetide (P1NP) (markers of bone formation) and C-terminal cross-linked telopeptide (CTX) (marker of bone resorption) are decreased in adult patients with T1D. We review the existing literature characterizing these bone turnover markers in children and adolescents with T1D and by meta-analysis examine whether alterations in OCN, P1NP, and CTX are evident and if potential changes correlate to the metabolic control (hemoglobin A1c, HbA1c). Systematic searches at MEDLINE and EMBASE were conducted in January 2018 identifying all studies describing OCN, P1NP, or CTX in children and adolescents with T1D. A total of 26 studies were included, representing data from more than 1000 patients with T1D. Pooled analyses of standard mean difference and summary effects analysis were performed when sufficient data were available. Pooled analysis revealed mean OCN to be significantly lower in children and adolescents with T1D compared to healthy controls (standard mean difference: -1.87, 95% confidence interval, CI: -2.83; -0.91) whereas both P1NP and CTX did not differ from the controls. Only data on OCN was sufficient to make pooled correlation analysis revealing a negative correlation between OCN and HbA1c (-0.31 95% CI: -0.45; -0.16). In conclusion, OCN is decreased in children and adolescents with T1D, whether CTX and P1NP are affected as well is unclear, due to very limited data available. New and large studies including OCN, P1NP, and CTX (preferably as z-scores adjusting for age variability) is needed to further elucidate the status of bone turnover in children and adolescents with T1D.
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http://dx.doi.org/10.1111/pedi.12853DOI Listing
August 2019

Association between Neonatal Whole Blood Iron Content and Cytokines, Adipokines, and Other Immune Response Proteins.

Nutrients 2019 Mar 4;11(3). Epub 2019 Mar 4.

Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Denmark.

(1) Background: High iron associates with inflammation and type 1 diabetes (T1D). Iron is essential not only for neonatal development but also for infectious microorganisms. The neonatal immune system is immature, and innate immunity prevails before immunocompetence develops. (2) Methods: In 398 newborns from the Danish Newborn Screening Biobank, we examined if whole blood iron (WB-Iron) content were associated with cytokines, adipokines, C-reactive protein (CRP), and mannose-binding lectin (MBL) in non-infected healthy neonates, and if these associations differed in newborns who later developed T1D (cases) ( = 199). WB-Iron was quantified using laser ablation inductively coupled plasma mass spectrometry on the neonatal dried blood spots. For each analyte, the relative change (RC) in the mean level was modeled by robust log-normal regression. (3) Results: A one unit increase in neonatal WB-Iron was associated with a 38% decrease in mean interleukin (IL)-6 levels (0.62; 95% CI: 0.40⁻0.95, = 0.03), and a 37% decrease in mean MBL levels (0.63; 95% CI: 0.41⁻0.95, = 0.03), but was not statistically significant after correction for multiple testing. (4) Conclusions: In summary, we found that higher neonatal WB-iron content was inversely associated with IL-6 and MBL, which may increase susceptibility to infections.
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http://dx.doi.org/10.3390/nu11030543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470999PMC
March 2019

Plasma lipid species at type 1 diabetes onset predict residual beta-cell function after 6 months.

Metabolomics 2018 12 4;14(12):158. Epub 2018 Dec 4.

Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, Melbourne, Australia.

Introduction: The identification of metabolomic dysregulation appears promising for the prediction of type 1 diabetes and may also reveal metabolic pathways leading to beta-cell destruction. Recent studies indicate that regulation of multiple phospholipids precede the presence of autoantigens in the development of type 1 diabetes.

Objectives: We hypothesize that lipid biomarkers in plasma from children with recent onset type 1 diabetes will reflect their remaining beta-cell function and predict future changes in beta-cell function.

Methods: We performed targeted lipidomic profiling by electrospray ionization tandem mass spectrometry to acquire comparative measures of 354 lipid species covering 25 lipid classes and subclasses in plasma samples from 123 patients < 17 years of age followed prospectively at 1, 3, 6 and 12 months after diagnosis. Lipidomic profiles were analysed using liner regression to investigate the relationship between plasma lipids and meal stimulated C-peptide levels at each time point. P-values were corrected for multiple comparisons by the method of Benjamini and Hochberg.

Results: Linear regression analysis showed that the relative levels of cholesteryl ester, diacylglycerol and triacylglycerol at 1 month were associated to the change in c-peptide levels from 1 to 6 months (corrected p-values of 4.06E-03, 1.72E-02 and 1.72E02, respectively). Medium chain saturated and monounsaturated fatty acids were the major constituents of the di- and triacylglycerol species suggesting a link with increased lipogenesis.

Conclusion: These observations support the hypothesis of lipid disturbances as explanatory factors for residual beta-cell function in children with new onset type 1 diabetes.
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http://dx.doi.org/10.1007/s11306-018-1456-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280838PMC
December 2018

The emerging role of lncRNAs in inflammatory bowel disease.

Exp Mol Med 2018 12 6;50(12):1-14. Epub 2018 Dec 6.

Type 1 Diabetes Biology, Department of Clinical Research, Steno Diabetes Center Copenhagen, Copenhagen, Denmark.

Dysregulation of long noncoding RNA (lncRNA) expression is linked to the development of various diseases. Recently, an emerging body of evidence has indicated that lncRNAs play important roles in the pathogenesis of inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative Colitis (UC). In IBD, lncRNAs have been shown to be involved in diverse processes, including the regulation of intestinal epithelial cell apoptosis, association with lipid metabolism, and cell-cell interactions, thereby enhancing inflammation and the functional regulation of regulatory T cells. In this review, we aim to summarize the current knowledge regarding the role of lncRNAs in IBD and highlight potential avenues for future investigation. We also collate potentially immune-relevant, IBD-associated lncRNAs identified through a built-by association analysis with respect to their neighboring protein-coding genes within IBD-susceptible loci. We further underscore their importance by highlighting their enrichment for various aspects of immune system regulation, including antigen processing/presentation, immune cell proliferation and differentiation, and chronic inflammatory responses. Finally, we summarize the potential of lncRNAs as diagnostic biomarkers in IBD.
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http://dx.doi.org/10.1038/s12276-018-0188-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283835PMC
December 2018

Cell Type-Selective Expression of Circular RNAs in Human Pancreatic Islets.

Noncoding RNA 2018 Nov 27;4(4). Epub 2018 Nov 27.

Steno Diabetes Center Copenhagen, 2820 Gentofte, Denmark.

Understanding distinct cell-type specific gene expression in human pancreatic islets is important for developing islet regeneration strategies and therapies to improve β-cell function in type 1 diabetes (T1D). While numerous transcriptome-wide studies on human islet cell-types have focused on protein-coding genes, the non-coding repertoire, such as long non-coding RNA, including circular RNAs, remains mostly unexplored. Here, we explored transcriptional landscape of human α-, β-, and exocrine cells from published total RNA sequencing (RNA-seq) datasets to identify circular RNAs (circRNAs). Our analysis revealed that circRNAs are highly abundant in both α- and β-cells. We identified 10,830 high-confidence circRNAs expressed in human α-, β-, and exocrine cells. The most highly expressed candidates were , , and across the three cell-types. Alternate circular isoforms were observed for circRNAs in the three cell-types, indicative of potential distinct functions. Highly selective α- and β-cell circRNAs were identified, which is suggestive of their potential role in regulating β-cell function.
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http://dx.doi.org/10.3390/ncrna4040038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316812PMC
November 2018

Influence of Disease Duration on Circulating Levels of miRNAs in Children and Adolescents with New Onset Type 1 Diabetes.

Noncoding RNA 2018 Nov 21;4(4). Epub 2018 Nov 21.

Copenhagen Diabetes Research Centre (CPH-DIRECT), Department of Paediatrics, Herlev and Gentofte Hospitals, Herlev Ringvej 75, 2730 Herlev, Denmark.

Circulating microRNAs (miRNAs) have been implicated in several pathologies including type 1 diabetes. In the present study, we aimed to identify circulating miRNAs affected by disease duration in children with recent onset type 1 diabetes. Forty children and adolescents from the Danish Remission Phase Cohort were followed with blood samples drawn at 1, 3, 6, 12, and 60 months after diagnosis. Pancreatic autoantibodies were measured at each visit. Cytokines were measured only the first year. miRNA expression profiling was performed by RT-qPCR. The effect of disease duration was analyzed by mixed models for repeated measurements adjusted for sex and age. Eight miRNAs (hsa-miR-10b-5p, hsa-miR-17-5p, hsa-miR-30e-5p, hsa-miR-93-5p, hsa-miR-99a-5p, hsa-miR-125b-5p, hsa-miR-423-3p, and hsa-miR-497-5p) were found to significantly change in expression (adjusted -value < 0.05) with disease progression. Three pancreatic autoantibodies, ICA, IA-2A, and GAD65A, and four cytokines, IL-4, IL-10, IL-21, and IL-22, were associated with the miRNAs at different time points. Pathway analysis revealed associations with various immune-mediated signaling pathways. Eight miRNAs that were involved in immunological pathways changed expression levels during the first five years after diagnosis and were associated with variations in cytokine and pancreatic antibodies, suggesting a possible effect on the immunological processes in the early phase of the disease.
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http://dx.doi.org/10.3390/ncrna4040035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316625PMC
November 2018

Capturing residual beta cell function in type 1 diabetes.

Authors:
Flemming Pociot

Diabetologia 2019 01 3;62(1):28-32. Epub 2018 Nov 3.

Steno Diabetes Center Copenhagen, Niels Steensensvej 2, DK-2820, Gentofte, Denmark.

Since the 1970s, C-peptide has been used as a surrogate marker for monitoring the progression of type 1 and type 2 diabetes and to determine the effects of interventions designed to preserve or improve residual beta cell function. C-peptide measurement is a well-established surrogate of residual beta cell activity and of clinical significance as it is associated with HbA, risk for microvascular complications and the incidence of hyperglycaemia in longitudinal studies. Measurement of C-peptide after a mixed meal tolerance test is considered the gold standard of measuring beta cell function in type 1 diabetes, but the method is laborious and inconvenient. In this issue of Diabetologia, Wentworth et al ( https://doi.org/10.1007/s00125-018-4722-z ) report an algorithm for estimating C-peptide (CP) based on six routine clinical measures. These do not include stimulated C-peptide measurement and outperform other prevailing algorithms for estimating residual beta cell function. Going forward it is very likely that this new algorithm will serve as a simple measure of beta cell function in routine practice and as a more acceptable primary outcome measure in future trials of disease-modifying therapies.
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http://dx.doi.org/10.1007/s00125-018-4768-yDOI Listing
January 2019
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