Simranjeet Kaur

Steno Diabetes Center Copenhagen · Translational Type 1 Diabetes Research

Diabetes is characterized by an insufficient physiological response to increases in blood glucose. There are two major types of diabetes: type 1 diabetes (T1D) and type 2 diabetes (T2D). T1D is the result of an immune-mediated destruction of the pancreatic β cells, whereas T2D is characterized by reduced β-cell function and insulin resistance. The...

Background Long non-coding RNAs (lncRNAs) are a sub-class within non-coding RNA repertoire that have emerged as crucial regulators of the gene expression in various pathophysiological conditions. lncRNAs display remarkable versatility and wield their functions through interactions with RNA, DNA, or proteins. Accumulating body of evidence based on m...

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...

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: Specifc lipids have previously been shown to be decreased in children who develop T1D before four years of...

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...

Identifying biomarkers of functional β-cell loss is critical in risk stratification for Type 1 Diabetes (T1D). We report a microRNA-based dynamic (responsive to environment) risk score developed using multi-center, multi-ethnic/country (“multi-context”) cohorts. Discovery (wet-lab and dry-lab) analysis identified 50 microRNAs that were measured acr...

It is internationally recognized to use clinical decision limits (CDL) when interpreting the lipid levels in both adults and children, even though the evidence for children is scarce. The purpose of this study is to describe how lipid levels progress in healthy Danish children ages 5 to 17 years. This study is based on the Childhood Health, Activit...

Aims: Heterogeneity in the rate of β-cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease-modifying clinical trials. Integrative analyses of baseline multi-omics data obtained after the diagnosis of type 1 diabetes may provide mechanistic insight into the diverse rat...

Immune-mediated beta cell destruction and lack of alpha cell responsiveness to hypoglycaemia are hallmarks of type 1 diabetes pathology. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) may hold therapeutic potential for type 1 diabetes due to its insulinotropic and glucagonotropic effects as well as its beta cell protective...

Aims/hypothesis Type 1 diabetes is an heterogenous condition. Characterising factors explaining differences in an individual’s clinical course and treatment response will have important clinical and research implications. Our aim was to explore type 1 diabetes heterogeneity, as assessed by clinical characteristics, autoantibodies, beta cell functio...

Immune-mediated destruction of the beta-cells in the pancreatic islets of Langerhans is the underlying cause of type 1 diabetes (T1D). Despite decades of research, the exact mechanisms involved at the beta-cell level during the development of disease remain poorly understood. This includes the mode(s) of beta-cell death and signaling events implica...

Objective EndoC-βH5 is a newly established human beta-cell model which may be superior to previous model systems. Exposure of beta cells to pro-inflammatory cytokines is widely used when studying immune-mediated beta-cell failure in type 1 diabetes. We therefore performed an in-depth characterization of the effects of cytokines on EndoC-βH5 cells....

Pancreatic β cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in β cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in β cell loss of function and apoptosis a...

Background Heterogeneity in the rate of β-cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease-modifying clinical trials. Integrative analyses of complementary multi-omics data obtained after the diagnosis of T1D may provide mechanistic insight into the diverse rates...

Aims/hypothesis We previously demonstrated that N-glycosylation of plasma proteins and IgGs is different in children with recent-onset type 1 diabetes compared with their healthy siblings. To search for genetic variants contributing to these changes, we undertook a genetic association study of the plasma protein and IgG N-glycome in type 1 diabetes...

Objective: To examine whether iron intake and genetically determined iron overload interact in predisposing to the development of childhood islet autoimmunity (IA) and type 1 diabetes (T1D). Research design and methods: In The Environmental Determinants of Diabetes in the Young (TEDDY) study, 7,770 genetically high-risk children were followed fr...

Objective: EndoC-βH5 is a newly established human beta-cell model which may be superior to previous models of native human beta cells. Exposure of beta cells to proinflammatory cytokines is a widely used in vitro model of immune-mediated beta-cell failure in type 1 diabetes and we therefore performed an in-depth characterisation of the effects of c...

Circular RNAs (circRNAs) have recently been implicated in impaired β-cell function in diabetes. Using microarray-based profiling of circRNAs in human EndoC-βH1 cells treated with pro-inflammatory cytokines, this study aimed to investigate the expression and possible regulatory roles of circRNAs in human β cells. We identified ~5000 β-cell-expressed...

Aims/hypothesis Individual variation in plasma N -glycosylation has mainly been studied in the context of diabetes complications, and its role in type 1 diabetes onset is largely unknown. Our aims were to undertake a detailed characterisation of the plasma and IgG N -glycomes in patients with recent onset type 1 diabetes, and to evaluate their disc...

(1) Autoantibodies to the leucine variant of neuropeptide Y (NPY-LA) have been found in individuals with type 1 diabetes (T1D). We investigated the association between the levels of NPY-LA and single nucleotide polymorphisms (SNP) to better understand the genetic regulatory mechanisms of autoimmunity in T1D and the functional impacts of increased N...

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 potentia...

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...

Background: Development of disease-modifying therapy for type 1 diabetes (T1D) is hampered by the limited understanding of pathogenesis, heterogeneity, lack of disease biomarkers and stratifiers. Using the INNODIA consortium pan-European infrastructure to collect prospective clinical data from newly diagnosed subjects combined with multi-omics data...

The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2 (SKAP2) gene is associated with type 1 diabetes (T1D) suggesting SKAP2 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 diagn...

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 thro...

Type 1 diabetes (T1D) is an autoimmune disease with an unknown cause. It is characterised by the destruction of pancreatic insulin producing beta cells. Glycosylation is a ubiquitous protein modification, but studies of glycosylation changes in T1D are scarce. We studied plasma samples of 1105 children and adolescents (0-18 years), collected within...

Background and aims: Changes in N-glycosylation of plasma proteins have been reported in adult population with type 1 diabetes, as well as was an increase in level of mannose binding lectin that triggers one of the complement activation pathways. However, glycosylation changes have never been studied at the onset of this disease, in children and ad...

Endothelial dysfunction is a key element in cerebral small vessel disease (CSVD), which may cause stroke and cognitive decline. Cyclic nucleotide signaling modulates endothelial function. The cyclic adenosine monophosphate-degrading enzyme phosphodiesterase 3 (PDE3) is an important treatment target which may be modulated by microRNAs (miRNAs) impor...

Studying long noncoding RNAs (lncRNAs) may improve diagnosis and treatment of inflammatory bowel disease (IBD). These RNAs are found between genes in DNA regions previously thought to be “junk,” and have recently been shown to be important in development of various diseases. IBD, which includes both Crohn’s disease and ulcerative colitis, damages t...

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...

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 a...

The objective of this study was to identify circulating miRNAs affected by disease duration in newly diagnosed children with 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...

Inflammatory β-cell failure contributes to type 1 and type 2 diabetes pathogenesis. Pro-inflammatory cytokines cause β-cell dysfunction and apoptosis, and lysine deacetylase inhibitors (KDACi) prevent β-cell failure in vitro and in vivo, in part by reducing NF-κB transcriptional activity. We investigated the hypothesis that the protective effect of...

KDACi reduced cytokine-induced apoptosis and NO accumulation in INS1 cells. INS1 cells were left untreated (-), treated with 1 μM CI994 or 125 nM Givinostat (Giv.) 1 h prior to addition of 0.1 ng/mL IFN-γ plus 37–150 pg/mL IL-1β (as indicated) or no cytokines (Ctrl) for 24 h. (A) Apoptosis as % of control measured with the Cell Death Detection ELIS...

Cytokine-induced miR-146a-5p expression in rat islets. (A) The miR-146a-5p expression was analyzed by qRT-PCR analysis in isolated rat islets exposed to IL-1β (160 pg/ml) or a combination of IL-1β (160 pg/ml) and IFN-γ (5 ng/ml). The data is presented as the mean of two experiments. The miR-146a-5p data was normalized to the internal control, let-7...

Two-way ANOVA test statistics of qRT-PCR, apoptosis and NO results. (DOCX)

Functional annotation clustering of miR-targets from the selected four groups. The clustering of gene ontology (GO) biological process (BP) terms was performed in DAVID. Representative biological terms associated for each enriched cluster (group enrichment score > 1.3) are shown along with total number of genes in each cluster (Count) and gene name...

Target prediction and regulatory interaction networks of identified miR groups. The figure depicts regulatory interaction networks (RINs) of miR-targets for group A (S2A), group B (S2B) and group’s c and d (S2C). Each RIN includes two types of nodes: the miRs (cyan) and their predicted targets (pink) as identified from miRTarBase and TargetScan dat...

miR-146a-5p targets TRAF6 and IRAK1 in INS1 cells. (A) Representative Western blot of iNOS, TRAF6, IRAK1 and β-actin (n = 4). INS1 cells were transiently transfected with a control oligo, miR-146a-5p, or anti-anti-miR-146a-5p oligo for 48 h, and exposed to media with or without IL-1β (160 pg/ml) for 6 h. (B) The luciferase assay was performed in IN...

Aims/hypothesis: Sphingolipids play important roles in beta cell physiology, by regulating proinsulin folding and insulin secretion and in controlling apoptosis, as studied in animal models and cell cultures. Here we investigate whether sphingolipid metabolism may contribute to the pathogenesis of human type 1 diabetes and whether increasing the l...

Hepatitis B virus (HBV) infection is a major global health burden as chronic hepatitis B (CHB) is associated with the development of liver diseases including hepatocellular carcinoma (HCC). To gain insight into the mechanisms causing HBV-related HCC, we investigated the effects of HBV replication on global host cell gene expression using human HepG...

Introduction: Alkaloids are a diverse group of naturally occurring phytochemical compounds that exhibit a wide range of therapeutic effects such as anticancer, anti-inflammatory, anti-diabetic, anti-Alzheimer’s disease, antiviral, antibacterial, antifungal, etc. Plant alkaloids showed to have inhibitory effect against carbohydrate digestive enzymes...

Aims/hypothesisWe aimed to identify circulating microRNA (miRNA) that predicts clinical progression in a cohort of 123 children with new-onset type 1 diabetes mellitus. Methods Plasma samples were prospectively obtained at 1, 3, 6, 12 and 60 months after diagnosis from a subset of 40 children from the Danish Remission Phase Cohort, and profiled for...

Metabolomics is the snapshot of all detectable metabolites and lipids in biological materials and has potential in reflecting genetic and environmental factors contributing to the development of complex diseases, such as type 1 diabetes. The progression to seroconversion to development of type 1 diabetes has been studied using this technique, altho...

Type 1 diabetes (T1DM) is a complex disease, arising through the interaction of an incompletely defined combination of genetic susceptibility and environmental factors. It is well accepted that T1DM results from selective immune-mediated destruction of the insulin-producing β cells in the islets of langerhans. Genetic studies of T1DM have identifie...

Genome-wide association studies (GWAS) have identified over 40 type 1 diabetes risk loci. The clinical impact of these loci on β -cell function during disease progression is unknown. We aimed at testing whether a genetic risk score could predict glycemic control and residual β -cell function in type 1 diabetes (T1D). As gene expression may represen...

Supplementary Table 1: The risk allele distribution of the 11 T1D candidate genes. Supplementary Table 2.: Variance explained by regression models for HbA1c and IDAA1c with and without genetic risk score (GRS).

Type 1 diabetes (T1D) is a multifactorial disease resulting from an immune-mediated destruction of the insulin-producing pancreatic β cells. Several environmental and genetic risk factors predispose to the disease. Genome-wide association studies (GWAS) have identified around 50 genetic regions that affect the risk of developing T1D, but the diseas...

Despite numerous studies implicating Alu repeat elements in various diseases, there is sparse information available with respect to the potential functional and biological roles of the repeat elements in Type 1 diabetes (T1D). Therefore, we performed a genome-wide sequence analysis of T1D candidate genes to identify embedded Alu elements within the...

Long non-coding RNAs are a new class of non-coding RNAs that are at the crosshairs in many human diseases such as cancers, cardiovascular disorders, inflammatory and autoimmune disease like Inflammatory Bowel Disease (IBD) and Type 1 Diabetes (T1D). Nearly 90% of the phenotype-associated single-nucleotide polymorphisms (SNPs) identified by genome-w...

This unit describes how to use Foldalign and FoldalignM to make structural alignments of non-protein-coding-RNA (ncRNA). These tools can be used to find new ncRNAs, to find the structure of novel ncRNAs, and to improve alignments for known ncRNAs. Curr. Protoc. Bioinform. 39:12.11.1-12.11.15. © 2012 by John Wiley & Sons, Inc.

Some polyamine derivatives, namely the bisnaphthalimidopropyl polyamines (BNIPPs) may have potential as anticancer drugs. Indeed, previous work from some of us had shown that the ability of these molecules to bind to DNA may contribute to their cytotoxicity. However, their precise mode of action has not been fully understood. In the present work, w...

The cytoskeletal protein, FtsZ plays a pivotal role in prokaryotic cell division and is present in majority of the bacterial species. In recent years, inhibitors of FtsZ have been identified that may function as lead compounds for the development of novel antimicrobials. It has been found that curcumin, the main bioactive component of Curcuma longa...

Histidinol dehydrogenase, the product of the HisD gene, mediates the final step in the histidine biosynthetic pathway. This enzyme has captured attention for drug discovery studies in past few years. Recently, our group cloned and expressed Geotrichum candidum histidinol dehydrogenase and successful screening of substrate analog inhibitors of histi...

The NAD(+)-dependent deacetylases, namely sirtuins, are involved in the regulation of a variety of biological processes such as gene silencing, DNA repair, longevity, metabolism, apoptosis, and development. An enzyme from the parasite Leishmania infantum that belongs to this family, LiSIR2RP1, is a NAD(+)-dependent tubulin deacetylase and an ADP-ri...

The infectious disease burden imposed by trypanosomatidae family continues to create burden in countries that are least equipped to bring new medicines to the clinic. For sickness caused by this family of parasites (African trypanosomiasis, Chagas disease, and leishmaniasis) no vaccines are available, and currently available drugs suffer from insuf...

Three-dimensional (3D) protein structures are of great importance for the rational design and structure-based discovery of specific inhibitors. Homology models of proteins play a significant role when no experimental three dimensional structures are available. LeishBase is a database of 347 Leishmania major proteins whose structures have been model...