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Frequency and spectrum of glucokinase mutations in an adult Maltese population

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Abstract

Aim

To investigate the frequency and spectrum of glucokinase (GCK) mutations in a cohort of adults from an island population having a high prevalence of diabetes mellitus (DM).

Methods

A single-centre cohort study was conducted, including 145 non-obese adults of Maltese-Caucasian ethnicity with impaired fasting glycaemia (IFG) or non-autoimmune diabetes diagnosed before the age of 40 years. Bidirectional sequencing of the GCK coding regions was performed. Genotype–phenotype associations and familial segregation were explored and the effects of missense variants on protein structure were evaluated using computational analysis.

Results

Three probands with pathogenic/likely pathogenic GCK variants in the heterozygous state having clinical features consistent with GCK-diabetes were detected. The missense variants have structurally destabilising effects on protein structure. GCK variant carriers exhibited a significantly lower body mass index and serum triglyceride levels when compared to GCK variant non-carriers.

Conclusions

The frequency of GCK-diabetes is approximately 2% in non-obese Maltese adults with diabetes or prediabetes. This study broadens the mutational spectrum of GCK and highlights clinical features that could be useful in discriminating GCK-DM from type 2 DM or prediabetes. It reinforces the need for increased molecular testing in young adults with diabetes having a suspected monogenic aetiology.

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Availability of data and material

The datasets generated during and/or analysed during the current study are available in the Mendeley Data repository, https://data.mendeley.com/datasets/w8mrxkvcwt/draft?a=7c4492d5-f81e-4ba1-808f-337d95a29c8b.

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Funding

This work was supported by the University of Malta Research Excellence Grant.

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Authors and Affiliations

  1. Centre for Molecular Medicine and Biobanking, Faculty of Medicine and Surgery, University of Malta, Nikolai Paul Pace, Room 325, Msida, 2080, MSD, Malta

    Nikolai Paul Pace, Celine Ann Grech & Barbara Vella

  2. Department of Medicine, Faculty of Medicine and Surgery, University of Malta, Msida, MSD2080, Malta

    Ruth Caruana & Josanne Vassallo

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  1. Nikolai Paul Pace
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  2. Celine Ann Grech
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  3. Barbara Vella
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  4. Ruth Caruana
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Contributions

NPP and RC collected data. CAG, BV, and NPP performed the analyses. NPP and JV drafted the manuscript. All authors contributed to study conception and design and have read and approved the submitted manuscript.

Corresponding author

Correspondence to Nikolai Paul Pace.

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The authors declare that they have no conflict of interest.

Ethics approval

The study was approved by the institutional ethics review board of the University of Malta (71/2013 and 53/2009) and the study protocol was in compliance with the Declaration of Helsinki.

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All subjects gave written informed consent for their participation in the study and for genetic analysis.

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Pace, N.P., Grech, C.A., Vella, B. et al. Frequency and spectrum of glucokinase mutations in an adult Maltese population. Acta Diabetol 59, 339–348 (2022). https://doi.org/10.1007/s00592-021-01814-7

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  • DOI: https://doi.org/10.1007/s00592-021-01814-7

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