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Apolipoprotein A-I (ApoA-I), the primary component of high-density lipoprotein (HDL) cholesterol primes β-cells to increase insulin secretion, however, the mechanisms involved are not fully defined. Here, we aimed to confirm ApoA-I receptors in β-cells and delineate ApoA-I-receptor pathways in β-cell insulin output. An LRC-TriCEPS experiment was performed using the INS-1E rat β-cell model and ApoA-I for unbiased identification of ApoA-I receptors. Identified targets, alongside ATP binding cassette transporter A1 (ABCA1) (included control) were silenced in the same cells, and insulin secretion (ELISA) and mitochondrial metabolism (seahorse) were assessed with/without ApoA-I priming. Human β-cell expression data was used to investigate ApoA-I receptor pathways in type 2 diabetes (T2D). Scavenger receptor B1 (SR-BI) and regulator of microtubule dynamics 1 were identified as ApoA-I targets. SR-BI or ABCA1 silencing abolished ApoA-I induced increases in insulin secretion. ApoA-I priming increased mitochondrial OXPHOS, however this was greatly attenuated with SR-BI or ABCA1 silencing. Supporting this, human β-cell expression data investigations found SR-BI and ABCA1 to be correlated with genes associated with mitochondrial pathways. In all, SR-BI and ABCA1 correlated with 73 and 3 genes differentially expressed in T2D, respectively. We confirm that SR-BI and ABCA1 are the primary β-cell ApoA-I receptors and demonstrate that ApoA-I priming enhances β-cell insulin secretion via the upregulation of mitochondrial metabolism through ApoA-I-SR-BI and ApoA-I-ABCA1 pathways. We propose that SR-BI relies on mitochondrial and exocytotic pathways, while ABCA1 depends solely on mitochondrial pathways. Our findings uncover new targets in ApoA-I β-cell mechanism for T2D therapies. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic [beta] cells. To identify candidate genes contributing to T2D pathophysiology, we studied human pancreatic islets from approximately 300 individuals. We found 395 differentially expressed genes (DEGs) in islets from individuals with T2D, including, to our knowledge, novel (OPRD1, PAX5, TET1) and previously identified (CHL1, GLRA1, IAPP) candidates. A third of the identified expression changes in islets may predispose to diabetes, as expression of these genes associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human [beta] cells, based on single-cell RNA-Seq data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D SNPs. Mouse KO strains demonstrated that the identified T2D-associated candidate genes regulate glucose homeostasis and body composition in vivo. Functional validation showed that mimicking T2D-associated changes for OPRD1, PAX5, and SLC2A2 impaired insulin secretion. Impairments in Pax5-overexpressing [beta] cells were due to severe mitochondrial dysfunction. Finally, we discovered PAX5 as a potential transcriptional regulator of many T2D-associated DEGs in human islets. Overall, we have identified molecular alterations in human pancreatic islets that contribute to [beta] cell dysfunction in T2D pathophysiology., Introduction Type 2 diabetes (T2D) is characterized by chronic hyperglycemia due to insufficient insulin secretion from pancreatic islets, often in combination with insulin resistance in target cells. The number of [...]

Changes in society and government have increased concerns of low participation and involvement by people, especially the young, in the political process and decision-making. As a result, citizenship has become a focus of recent curriculum developments in many countries. In Scotland, "Values and Citizenship" has been made one of the Scottish Executive's national priorities for education and is linked to the major national initiative, "Education for Citizenship". This is seen as encouraging pupils to make informed choices and decisions and to take action, individually and as part of the community. More recently, "A curriculum for excellence 3-18" (SEED 2004) placed promoting responsible citizenship at the heart of the curriculum. This article reports on the extent to which a sample of Scottish schools was making progress towards developing education for citizenship, the strategies they developed and the barriers encountered in this implementation. It compares progress and developments in Scotland to the model devised in a longitudinal study for citizenship in England (Ireland et al. 2004, 2006). (Contains 1 figure.)

Drawing on the principles of formative assessment identified by the Assessment Reform Group in England, Assessment is for Learning was a major Scottish initiative to improve children's learning. This paper surveys the implementation of formative assessment strategies during school placements by three cohorts of final-year Bachelor of Education students (BEd4) at one Scottish university. Also, use of formative assessment by one cohort of Professional Graduate Diploma in Education (Secondary) students at the university is compared with that of the most recent BEd4 cohort. Factors students identified that supported or inhibited implementation of formative assessment are reviewed. The importance of positive support on campus and placements is discussed. (Contains 9 tables and 2 figures.)

Differential expression of microRNAs (miRNAs) is observed in many diseases including type 2 diabetes (T2D). Insulin secretion from pancreatic beta cells is central for the regulation of blood glucose levels and failure to release enough insulin results in hyperglycemia and T2D. The importance in T2D pathogenesis of single miRNAs in beta cells has been described; however, to get the full picture, high-throughput miRNA sequencing is necessary. Here we describe a method using small RNA sequencing, from sample preparation to expression analysis using bioinformatic tools. In the end, a tutorial on differential expression analysis is presented in R using publicly available data., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Voltage-gated Ca 2+ (Ca V ) channel dysfunction leads to impaired glucose-stimulated insulin secretion in pancreatic β-cells and contributes to the development of type-2 diabetes (T2D). The role of the low-voltage gated T-type Ca V channels in β-cells remains obscure. Here we have measured the global expression of T-type Ca V 3.2 channels in human islets and found that gene expression of CACNA1H, encoding Ca V 3.2, is negatively correlated with HbA1c in human donors, and positively correlated with islet insulin gene expression as well as secretion capacity in isolated human islets. Silencing or pharmacological blockade of Ca V 3.2 attenuates glucose-stimulated cytosolic Ca 2+ signaling, membrane potential, and insulin release. Moreover, the endoplasmic reticulum (ER) Ca 2+ store depletion is also impaired in Ca V 3.2-silenced β-cells. The linkage between T-type (Ca V 3.2) and L-type Ca V channels is further identified by the finding that the intracellular Ca 2+ signaling conducted by Ca V 3.2 is highly dependent on the activation of L-type Ca V channels. In addition, CACNA1H expression is significantly associated with the islet predominant L-type CACNA1C (Ca V 1.2) and CACNA1D (Ca V 1.3) genes in human pancreatic islets. In conclusion, our data suggest the essential functions of the T-type Ca V 3.2 subunit as a mediator of β-cell Ca 2+ signaling and membrane potential needed for insulin secretion, and in connection with L-type Ca V channels., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)