Reduced Expression of PLCXD3 Associates With Disruption of Glucose Sensing and Insulin Signaling in Pancreatic β-Cells

Aljaibeji, Hayat; Mukhopadhyay, Debasmita; Mohammed, Abdul Khader; Dhaiban, Sarah; Hachim, Mahmood Yaseen; Elemam, Noha Mousaad; Sulaiman, Nabil; Salehi, Albert; Taneera, Jalal

doi:10.3389/fendo.2019.00735

Cited by 22 publications

(23 citation statements)

References 44 publications

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“…PLCXD3 is highly expressed in human pancreatic islets [10], significantly downregulated in diabetic islets, correlated positively with insulin secretion and negatively with HbA1c as well as BMI [10]. This is in line with our data showing the homozygous genotype of rs9292806 (CC) and rs319013 (GG) have a significantly higher glycemic profile represented by fasting blood glucose and HbA1c in control subjects.…”

Section: Discussionsupporting

confidence: 91%

“…Recently, we showed that the expression of PLCXD3, a member of the PI-PLC family, is downregulated in human diabetic islets, inversely correlated with HbA1c and positively correlated with insulin secretion [10,11]. Further investigations revealed that PLCXD3 is involved in insulin signaling and glucose sensing, suggesting that PLCXD3 might be regarded as a candidate gene for pre-diabetes and metabolic syndrome.…”

Section: Introductionmentioning

confidence: 99%

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Genetic Variants of the PLCXD3 Gene Are Associated with Risk of Metabolic Syndrome in the Emirati Population

Aljaibeji

Mohammed

Alkayyali

et al. 2020

Genes

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Phosphatidylinositol-specific phospholipase C X domain 3 (PLCXD3) has been shown to influence pancreatic β-cell function by disrupting insulin signaling. Herein, we investigated two genetic variants in the PLCXD3 gene in relation to type 2 diabetes (T2D) or metabolic syndrome (MetS) in the Emirati population. In total, 556 adult Emirati individuals (306 T2D and 256 controls) were genotyped for two PLCXD3 variants (rs319013 and rs9292806) using TaqMan genotyping assays. The frequency distribution of minor homozygous CC genotype of rs9292806 and GG genotype of rs319013 were significantly higher in subjects with MetS compared to Non-MetS (p < 0.01). The minor homozygous rs9292806-CC and rs319013-GG genotypes were significantly associated with increased risk of MetS (adj. OR 2.92; 95% CI 1.61–5.3; p < 0.001) (adj. OR 2.62; 95% CI 1.42–4.83; p = 0.002), respectively. However, no associations were detected with T2D. In healthy participants, the homozygous minor genotypes of both rs9292806 and rs319013 were significantly higher fasting glucose (adj. p < 0.005), HbA1c (adj. p < 0.005) and lower HDL-cholesterol (adj. p < 0.05) levels. Data from T2D Knowledge Portal database disclosed a nominal association of rs319013 and rs9292806 with T2D and components of MetS. Bioinformatics prediction analysis showed a deleterious effect of rs9292806 on the regulatory regions of PLCXD3. In conclusion, this study identifies rs319013 and rs9292806 variants of PLCXD3 as additional risk factors for MetS in the Emirati population.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Genetic Variants of the PLCXD3 Gene Are Associated with Risk of Metabolic Syndrome in the Emirati Population

Aljaibeji

Mohammed

Alkayyali

et al. 2020

Genes

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“…Therefore, we analyzed the microarray expression of the three receptors in human islets. All the studied receptors were found to be expressed in/on human pancreatic islets and their expression was above background control signal, which was calculated based on the mean values of all negative control probesets on the array [ 25 , 26 ] ( Figure 1 A). ADAM17 and TMPRSS2 showed a significantly higher expression level ( p < 0.01) compared to ACE2 in pancreatic islets ( Figure 1 A).…”

Section: Resultsmentioning

confidence: 99%

Expression Profile of SARS-CoV-2 Host Receptors in Human Pancreatic Islets Revealed Upregulation of ACE2 in Diabetic Donors

Taneera

El‐Huneidi

Hamad

et al. 2020

Biology

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Cellular entry of SARS-CoV-2 is thought to occur through the binding of viral spike S1 protein to ACE2. The entry process involves priming of the S protein by TMPRSS2 and ADAM17, which collectively mediate the binding and promote ACE2 shedding. In this study, microarray and RNA-sequencing (RNA-seq) expression data were utilized to profile the expression pattern of ACE2, ADAM17, and TMPRSS2 in type 2 diabetic (T2D) and non-diabetic human pancreatic islets. Our data show that pancreatic islets express all three receptors irrespective of diabetes status. The expression of ACE2 was significantly increased in diabetic/hyperglycemic islets compared to non-diabetic/normoglycemic. Islets from female donors showed higher ACE2 expression compared to males; the expression of ADAM17 and TMPRSS2 was not affected by gender. The expression of the three receptors was statistically similar in young (≤40 years old) versus old (≥60 years old) donors. Obese (BMI > 30) donors have significantly higher expression levels of ADAM17 and TMPRSS2 relative to those from non-obese donors (BMI < 25). TMPRSS2 expression correlated positively with HbA1c and negatively with age, while ADAM17 and TMPRSS2 correlated positively with BMI. The expression of the three receptors was statistically similar in muscle and subcutaneous adipose tissues obtained from diabetic and nondiabetic donors. Lastly, ACE2 expression was higher in sorted pancreatic β-cell relative to other endocrine cells. In conclusion, ACE2 expression is increased in diabetic human islets. More studies are required to investigate whether variations of ACE2 expression could explain the severity of COVID-19 infection-related symptoms between diabetics and non-diabetic patients.

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“…4 a). The functions of those genes were dispersed in the heat stress ( DNAJC18 [ 34 ]), lipid and ATP metabolic process ( PLCXD3 [ 35 ]: GO:0006629, lipid metabolic process; MUSK [ 36 ]: GO:0005524, ATP binding; PKN2 [ 37 ]: GO:0005524, ATP binding;) and muscle development ( CTNNA1 [ 38 , 39 ]: GO:0051149, positive regulation of muscle cell differentiation; MUSK [ 40 ]: GO:0071340, skeletal muscle acetylcholine-gated channel clustering; PKN2 [ 41 ]). It is of note that all significant CNV segments showed high ratio of deletion in Bos indicus , while no change or normal in Bos taurus (Fig.…”

Section: Resultsmentioning

confidence: 99%

Comparative analyses of copy number variations between Bos taurus and Bos indicus

Xia

et al. 2020

BMC Genomics

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Background Bos taurus and Bos indicus are two main sub-species of cattle. However, the differential copy number variations (CNVs) between them are not yet well studied. Results Based on the new high-quality cattle reference genome ARS-UCD1.2, we identified 13,234 non-redundant CNV regions (CNVRs) from 73 animals of 10 cattle breeds (4 Bos taurus and 6 Bos indicus), by integrating three detection strategies. While 6990 CNVRs (52.82%) were shared by Bos taurus and Bos indicus, large CNV differences were discovered between them and these differences could be used to successfully separate animals into two subspecies. We found that 2212 and 538 genes uniquely overlapped with either indicine-specific CNVRs and or taurine-specific CNVRs, respectively. Based on FST, we detected 16 candidate lineage-differential CNV segments (top 0.1%) under selection, which overlapped with eight genes (CTNNA1, ENSBTAG00000004415, PKN2, BMPER, PDE1C, DNAJC18, MUSK, and PLCXD3). Moreover, we obtained 1.74 Mbp indicine-specific sequences, which could only be mapped on the Bos indicus reference genome UOA_Brahman_1. We found these sequences and their associated genes were related to heat resistance, lipid and ATP metabolic process, and muscle development under selection. We further analyzed and validated the top significant lineage-differential CNV. This CNV overlapped genes related to muscle cell differentiation, which might be generated from a retropseudogene of CTH but was deleted along Bos indicus lineage. Conclusions This study presents a genome wide CNV comparison between Bos taurus and Bos indicus. It supplied essential genome diversity information for understanding of adaptation and phenotype differences between the Bos taurus and Bos indicus populations.

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Reduced Expression of PLCXD3 Associates With Disruption of Glucose Sensing and Insulin Signaling in Pancreatic β-Cells

Cited by 22 publications

References 44 publications

Genetic Variants of the PLCXD3 Gene Are Associated with Risk of Metabolic Syndrome in the Emirati Population

Genetic Variants of the PLCXD3 Gene Are Associated with Risk of Metabolic Syndrome in the Emirati Population

Expression Profile of SARS-CoV-2 Host Receptors in Human Pancreatic Islets Revealed Upregulation of ACE2 in Diabetic Donors

Comparative analyses of copy number variations between Bos taurus and Bos indicus

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