The calcium-sensing receptor and insulin secretion: a role outside systemic control 15 years on

Hodgkin, Matthew N.; Hills, Claire E.; Squires, Paul E.

doi:10.1677/joe-08-0261

Cited by 17 publications

(10 citation statements)

References 34 publications

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“…However, since the identi�ication and characterisation of the receptor [2], it has become increasingly apparent that this cationic ion binding receptor is found on many tissues not associated with the control of plasma [Ca 2+ ] including; oesophageal [3] and colonic epithelia [4], the cardiovascular system (reviewed in [5]), hypothalamic neurons [6], pancreatic ducts [7] and pancreatic α-and β-cells [8][9][10]. The functional signi�icance of the CaR in tissue not involved in the control of systemic Ca 2+ is not fully understood [11,12]. In exocrine pancreas it has been suggested that the CaR monitors extracellular Ca 2+ in pancreatic juice to limit the risk of Ca 2+ carbonate stone formation [13], whilst the receptor may detect changes in levels of dietary Ca 2+ in gastrin secreting cells of the human antrum [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Calcium-Sensing Receptor Activation Increases Cell-Cell Adhesion and ß-Cell Function

Hills¹,

Younis²,

Bennett³

et al. 2012

Cell Physiol Biochem

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Background/Aims: The extracellular calcium-sensing receptor (CaR) is expressed in pancreatic β-cells where it is thought to facilitate cell-to-cell communication and augment insulin secretion. However, it is unknown how CaR activation improves β-cell function. Methods: Immunocytochemistry and western blotting confirmed the expression of CaR in MIN6 β-cell line. The calcimimetic R568 (1µM) was used to increase the affinity of the CaR and specifically activate the receptor at a physiologically appropriate extracellular calcium concentration. Incorporation of 5-bromo-2’-deoxyuridine (BrdU) was used to measure cell proliferation, whilst changes in non-nutrient-evoked cytosolic calcium were assessed using fura-2-microfluorimetry. AFM-single-cell-force spectroscopy related CaR-evoked changes in epithelial (E)-cadherin expression to improved functional tethering between coupled cells. Results: Activation of the CaR over 48hr doubled the expression of E-cadherin (206±41%) and increased L-type voltage-dependent calcium channel expression by 70% compared to control. These changes produced a 30% increase in cell-cell tethering and elevated the basal-to-peak amplitude of ATP (50µM) and tolbutamide (100µM)-evoked changes in cytosolic calcium. Activation of the receptor also increased PD98059 (1-100µM) and SU1498 (1-100µM)-dependent β-cell proliferation. Conclusion: Our data suggest that activation of the CaR increases E-cadherin mediated functional tethering between β-cells and increases expression of L-type VDCC and secretagogue-evoked changes in [Ca²⁺]_i. These findings could explain how local changes in calcium, co-released with insulin, activate the CaR on neighbouring cells to help ensure efficient and appropriate secretory function.

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Section: Introductionmentioning

confidence: 99%

Calcium-Sensing Receptor Activation Increases Cell-Cell Adhesion and ß-Cell Function

Hills¹,

Younis²,

Bennett³

et al. 2012

Cell Physiol Biochem

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“…A majority of the pathways identified from this study, such as calcium signaling, PPAR signaling, N-glycan biosynthesis, TGF-b signaling, and cell communication, have been implicated as important T2D pathways in the literature. For example, calcium signaling is crucial for insulin secretion in pancreatic b-cells 34,35 as well as insulin-mediated glucose uptake in skeletal muscle. [36][37][38] PPAR signaling plays a critical role in glucose homeostasis and insulin sensitivity, and PPAR-gamma agonists such as thiazolidinediones have been used to treat T2D.…”

mentioning

confidence: 99%

Integrating Pathway Analysis and Genetics of Gene Expression for Genome-wide Association Studies

Zhong

Yang

Kaplan

et al. 2010

The American Journal of Human Genetics

224

222

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Genome-wide association studies (GWAS) have achieved great success identifying common genetic variants associated with common human diseases. However, to date, the massive amounts of data generated from GWAS have not been maximally leveraged and integrated with other types of data to identify associations beyond those associations that meet the stringent genome-wide significance threshold. Here, we present a novel approach that leverages information from genetics of gene expression studies to identify biological pathways enriched for expression-associated genetic loci associated with disease in publicly available GWAS results. Specifically, we first identify SNPs in population-based human cohorts that associate with the expression of genes (eSNPs) in the metabolically active tissues liver, subcutaneous adipose, and omental adipose. We then use this functionally annotated set of SNPs to investigate pathways enriched for eSNPs associated with disease in publicly available GWAS data. As an example, we tested 110 pathways from the Kyoto Encylopedia of Genes and Genomes (KEGG) database and identified 16 pathways enriched for genes corresponding to eSNPs that show evidence of association with type 2 diabetes (T2D) in the Wellcome Trust Case Control Consortium (WTCCC) T2D GWAS. We then replicated these findings in the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) study. Many of the pathways identified have been proposed as important candidate pathways for T2D, including the calcium signaling pathway, the PPAR signaling pathway, and TGF-beta signaling. Importantly, we identified other pathways not previously associated with T2D, including the tight junction, complement and coagulation pathway, and antigen processing and presentation pathway. The integration of pathways and eSNPs provides putative functional bridges between GWAS and candidate genes or pathways, thus serving as a potential powerful approach to identifying biological mechanisms underlying GWAS findings.

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“…For T2D analysis, HisCoM-PCA successfully identified several well-known pathways biologically related to T2D. For example, pathways such as calcium signaling, the renin-angiotensin system, and phosphatidylinositol signaling, are known to be related to insulin resistance or insulin sensitivity [24][25][26][27]. Of these, calcium signaling is crucial for insulin secretion in pancreatic β-cells [24,25], while phosphatidylinositol signaling is known to play an important role in an insulin-stimulated glucose metabolism pathway associated with obesity and T2D [27].…”

Section: Real Data Analysis Of Common Variants From Karementioning

confidence: 99%

“…For example, pathways such as calcium signaling, the renin-angiotensin system, and phosphatidylinositol signaling, are known to be related to insulin resistance or insulin sensitivity [24][25][26][27]. Of these, calcium signaling is crucial for insulin secretion in pancreatic β-cells [24,25], while phosphatidylinositol signaling is known to play an important role in an insulin-stimulated glucose metabolism pathway associated with obesity and T2D [27]. Moreover, some diseases, such as Alzheimer's disease (AD), asthma, and dilated cardiomyopathy have been reported to share molecular pathways or risk factors with T2D [28][29][30][31], and several studies have shown that insulin resistance is related to risk of AD, as well as T2D [28].…”

Section: Real Data Analysis Of Common Variants From Karementioning

confidence: 99%

Hierarchical structural component model for pathway analysis of common variants

2020

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Background: Genome-wide association studies (GWAS) have been widely used to identify phenotype-related genetic variants using many statistical methods, such as logistic and linear regression. However, GWAS-identified SNPs, as identified with stringent statistical significance, explain just a small portion of the overall estimated genetic heritability. To address this 'missing heritability' issue, gene-and pathway-based analysis, and biological mechanisms, have been used for many GWAS studies. However, many of these methods often neglect the correlation between genes and between pathways. Methods: We constructed a hierarchical component model that considers correlations both between genes and between pathways. Based on this model, we propose a novel pathway analysis method for GWAS datasets, Hierarchical structural Component Model for Pathway analysis of Common vAriants (HisCoM-PCA). HisCoM-PCA first summarizes the common variants of each gene, first at the gene-level, and then analyzes all pathways simultaneously by ridge-type penalization of both the gene and pathway effects on the phenotype. Statistical significance of the gene and pathway coefficients can be examined by permutation tests. Results: Using the simulation data set of Genetic Analysis Workshop 17 (GAW17), for both binary and continuous phenotypes, we showed that HisCoM-PCA well-controlled type I error, and had a higher empirical power compared to several other methods. In addition, we applied our method to a SNP chip dataset of KARE for four human physiologic traits: (1) type 2 diabetes; (2) hypertension; (3) systolic blood pressure; and (4) diastolic blood pressure. Those results showed that HisCoM-PCA could successfully identify signal pathways with superior statistical and biological significance. Conclusions: Our approach has the advantage of providing an intuitive biological interpretation for associations between common variants and phenotypes, via pathway information, potentially addressing the missing heritability conundrum.

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The calcium-sensing receptor and insulin secretion: a role outside systemic control 15 years on

Cited by 17 publications

References 34 publications

Calcium-Sensing Receptor Activation Increases Cell-Cell Adhesion and ß-Cell Function

Calcium-Sensing Receptor Activation Increases Cell-Cell Adhesion and ß-Cell Function

Integrating Pathway Analysis and Genetics of Gene Expression for Genome-wide Association Studies

Hierarchical structural component model for pathway analysis of common variants

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