Involvement of Cdkal1 in the etiology of type 2 diabetes mellitus and microvascular diabetic complications: a review

Ghosh, Chandrachur; Das, Neeladrisingha; Saha, Sarama; Kundu, Tathagata; Sircar, Debabrata; Roy, Partha

doi:10.1007/s40200-021-00953-6

Cited by 9 publications

(5 citation statements)

References 78 publications

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“…Almost all the genes associated with the lead SNPs of S2 are reported associated with T2DM before, including IGF2BP2 and TCF7L2 . For example, GCKR is a hepatocyte-specific inhibitor of the glucose-metabolizing enzyme glucokinase 26 ; IRS1 plays a critical role in insulin-signalling pathways 27 ; A paralog of ELF5A2 is associated with T2DM 28 ; CDKAL1 are involved in misfolded insulin, leading to oxidative and ER stress in the pancreatic β-cells 29 ; DGKB is causally associated with T2DM 30 ; JAZF1 directly and negatively regulates insulin gene transcription 31 ; a loss-of-function of SLC30A8 protects against T2DM 32 ; HHEX are repeatedly associated with T2DM 33 ; KCNQ1 is highly associate with the risk of T2DM 34 ; ARAP1 is located near risk alleles for T2DM 35 ; a variant of CCND2 could reduce risk of T2DM by half 36 ; HMG20A is a key for the functional maturity of islet β cell 37 . The consistence between our results and these reported associations indicates the reliably of our GWASs results for the two subtypes.…”

Section: Resultsmentioning

confidence: 99%

Identification of distinct trajectories in preclinical type 2 diabetes and their associations with outcomes

Huang

2024

Preprint

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Type 2 Diabetes Mellitus (T2DM) is increasingly prevalent and significantly impacts patients' lives. However, the phenotypic and genetic heterogeneity of the preclinical stage of T2DM, along with the subsequent effects on various clinical outcomes, remain unclear, impeding progress in disease screening and prevention. To address this gap, we employed a robust machine learning algorithm (Subtype and Stage Inference, SuStaIn) with cross-sectional clinical data from the UK Biobank (20,305 preclinical-T2DM participants and 20,305 controls) to identify underlying subtypes and their progression trajectories for preclinical-T2DM. Our analysis revealed one subtype distinguished by elevated circulating leptin levels and decreased leptin receptor levels, coupled with increased BMI, diminished lipid metabolism, and heightened susceptibility to psychiatric conditions such as anxiety disorder, depression disorder, and bipolar disorder. Conversely, individuals in the second subtype manifested typical abnormalities in glucose metabolism, including rising glucose and HbA1c levels, with observed correlations with neurodegenerative disorders. Over ten-year follow-up observations of these individuals reveal differential deterioration in brain and heart organs, and statistically significant difference in disease risk and clinical outcomes between the two subtypes. Our findings indicate a heterogenous pathobiological basis underlying the progression of preclinical-T2DM, with clinical implications for understanding human health from a multiorgan perspective, and improving disease risk screening, prediction, and prevention efforts.

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Section: Resultsmentioning

confidence: 99%

Identification of distinct trajectories in preclinical type 2 diabetes and their associations with outcomes

Huang

2024

Preprint

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“…Interestingly, ANO6 deficiency reduces activation of the microglial NLRP3 inflammasome in the brain of AD mouse model (Cui et al, 2023), suggesting the functional link of ANO6 with TREM2 in the regulation of NLRP3 inflammasome (Li et al, 2021; Jiang et al, 2022). CDK5 regulatory subunit Associated protein 1-Like 1 (CDKAL1) has been implicated in the pathogenesis of type2 diabetes (Ghosh et al, 2022) and a family-based GWAS meta-analysis revealed genetic association of two SNPs in the CDKAL1 gene (Herold et al, 2016). ITPRIP gene (The gene encoding inositol 1,4,5-trisphosphate receptor interacting protein) has also been suggested as an AD risk gene (Simino et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Proximity Proteome Analysis Reveals Novel TREM2 Interactors in the ER-Mitochondria Interface of Human Microglia

Kwak

Finan

Park

et al. 2023

Preprint

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Triggering receptor expressed on myeloid cells 2 (TREM2) plays a central role in microglial biology and the pathogenesis of Alzheimer's disease (AD). Besides DNAX-activating protein 12 (DAP12), a communal adaptor for TREM2 and many other receptors, other cellular interactors of TREM2 remain largely elusive. We employed a proximity labeling approach using a biotin ligase, TurboID, and discovered novel TREM2-proximal proteins, many of which localized to the Mitochondria-ER contact sites (MERCs). TREM2 deficiency alters the thickness (inter-organelle distance) of MERCs, a structural parameter of metabolic state, in microglia derived from human induced pluripotent stem cells. Our TurboID-based TREM2 interactome study suggest novel roles for TREM2 in the regulation of MERCs, raising the possibility that dysregulation of MERC-related TREM2 functions contribute to AD pathobiology.

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“…Previous studies have shown that CDKAL1 gene overlaps with identified QTLs associated with cholesterol metabolism, homeostasis, transport and regulation in humans ( Cheon et al, 2018 ) and pigs ( Bovo et al, 2019 ). Polymorphisms in the CDKAL1 gene are reported to be associated with type 2 diabetes mellitus in several human populations ( Hu et al, 2009 ; Han et al, 2010 ; Naser et al, 2021 ; Amin et al, 2022 ; Ghosh et al, 2022 ), and the CDKAL1 gene is involved in the metabolism of insulin that affects glucose mediated mechanisms, crucial for feed-efficiency and other growth and adaptation traits ( Santos et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Lost pigs of Angola: Whole genome sequencing reveals unique regions of selection with emphasis on metabolism and feed efficiency

Sá

Santos²,

Chiaia³

et al. 2022

Front. Genet.

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Angola, in the western coast of Africa, has been through dramatic social events that have led to the near-disappearance of native swine populations, and the recent introduction of European exotic breeds has also contributed to the erosion of this native swine repertoire. In an effort to investigate the genetic basis of native pigs in Angola (ANG) we have generated whole genomes from animals of a remote local pig population in Huambo province, which we have compared with 78 genomes of European and Asian pig breeds as well as European and Asian wild boars that are currently in public domain. Analyses of population structure showed that ANG pigs grouped within the European cluster and were clearly separated from Asian pig breeds. Pairwise FST ranged from 0.14 to 0.26, ANG pigs display lower levels of genetic differentiation towards European breeds. Finally, we have identified candidate regions for selection using a complementary approach based on various methods. All results suggest that selection towards feed efficiency and metabolism has occurred. Moreover, all analysis identified CDKAL1 gene, which is related with insulin and cholesterol metabolism, as a candidate gene overlapping signatures of selection unique to ANG pigs. This study presents the first assessment of the genetic relationship between ANG pigs and other world breeds and uncovers selection signatures that may indicate adaptation features unique to this important genetic resource.

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Involvement of Cdkal1 in the etiology of type 2 diabetes mellitus and microvascular diabetic complications: a review

Cited by 9 publications

References 78 publications

Identification of distinct trajectories in preclinical type 2 diabetes and their associations with outcomes

Identification of distinct trajectories in preclinical type 2 diabetes and their associations with outcomes

Proximity Proteome Analysis Reveals Novel TREM2 Interactors in the ER-Mitochondria Interface of Human Microglia

Lost pigs of Angola: Whole genome sequencing reveals unique regions of selection with emphasis on metabolism and feed efficiency

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