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Identification and management of GCK-MODY complicating pregnancy in Chinese patients with gestational diabetes

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Abstract

Precise differentiation of glucokinase (GCK) monogenic diabetes from gestational diabetes mellitus (GDM) is critical for accurate management of the pregnancy outcome. We screened GCK-MODY complicating pregnancies in Chinese GDM patients, explored the pathogenesis of novel GCK mutations, and evaluated the patients’ pregnancy outcome and management. The GCK gene from 411 GDM patients was screened with PCR–direct sequencing and multiplex ligation-dependent probe amplification (MLPA) and 15 GCK mutations were identified. We also retrospectively analyzed a total of 65 pregnancies from 21 GCK-MODY families, wherein 41 were from 15 maternal families and 24 were from six paternal families. Bioinformatic analysis and biochemical functional study were conducted to identify novel GCK mutations. In total, we identified 21 GCK mutations: 15 from the 411 GDM patients and six from 24 fathers. Of th Asp78Asn (GAC → AAC), Met87Arg (ATG → AGG), Leu451Val (CTT → GTT), Leu451Pro (CTG → CCG) and 1019 + 20G > A e mutations, five, i.e., were novel and deleterious, with markedly decreased enzyme activity and thermal stability. The unaffected offspring of GCK mutation-affected mothers were heavier than affected offspring (p < 0.001). Of 21 insulin-treated affected mothers, 10 had maternal hypoglycemia (47.6%) and seven had perinatal complications (33.3%), and the affected offspring of the insulin-treated affected mothers had significantly lower birth weights than that of the 20 diet-control affected mothers (p = 0.031). In this study, the prevalence of GCK-MODY complicating pregnancy in Chinese GDM patients was 3.6% (15/411). The defective GCK may contribute to the hyperglycemia in GCK-MODY. Insulin therapy is not beneficial for GCK-MODY complicating pregnancy and therefore should not be recommended.

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All data generated or analyzed during this study are included in this published article and its supporting materials.

Abbreviations

FPG:

Fasting plasma glucose

FPR:

False-positive rate

G-6-P:

Glucose-6-phosphate

GCK-WT:

GCK-wild type

GCK::

Glucokinase

GDM:

Gestational diabetes mellitus

2hPG:

2-H postprandial glucose

mGCKs:

GCK mutants

OGTT:

Oral glucose tolerance test

TG:

Triglyceride

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Acknowledgements

We thank KX, LH, WJ, SZ, YH and WJ for their assistance. We apologize to many authors whose works could not be cited due to space limitations.

Funding

This work was supported by the National Natural Science Foundation of China (Grant Numbers 81970686, 81770791, 81471012, 82070823, 81270876; to L. Liu.), the Interdisciplinary Program of Shanghai Jiao Tong University (Grant Number YG2019ZDA08; to L. Liu.), the Shanghai Leading Talent (Grant Number SLJ15055; to L. Liu.) and the National Institutes of Health (Grant Number SC1DK104821; to Y. Liu), the TRDRP (Grant Number T31IR1603; to Y. Liu).

Author information

Author notes

  1. Yanyan Jiang, Fusong Jiang and Ming Li contributed equally to this work.

Authors and Affiliations

  1. Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai, 200233, China

    Yanyan Jiang, Fusong Jiang, Ming Li, Rong Zhang, Yating Chen, Juan Zhang & Limei Liu

  2. Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No.600 Yishan Road, Shanghai, 200233, China

    Qingkai Wu

  3. The Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China

    Chenming Xu

  4. Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China

    Chenming Xu

  5. Department of Endocrinology, Weihai Municipal Hospital, No. 70, Heping Road, Weihai, 264200, China

    Mingqiang Song

  6. School of Population Health and Environmental Science, King’s College London, London, UK

    Yanzhong Wang

  7. Department of Pediatrics, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA

    Ying Wang

  8. School of Medicine, Huanghuai University, Zhumadian, 463000, Henan, China

    Juan Zhang

  9. Department of Endocrinology, School of Medicine, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China

    Xiaoxu Ge

  10. Department of Endocrinology, The first affiliated hospital of Wenzhou Medical University, The South of Shangcai Village, Nanbaixiang Town, Ouhai District, Wenzhou, 325000, Zhejiang, China

    Qihan Zhu

  11. Department of Endocrinology, the First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233004, China

    Langen Zhuang

  12. Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, USA

    Di Yang

  13. Department of Endocrinology & Metabolism, Putuo Hospital Attached to Shanghai University of Traditional Chinese Medicine, 164 Lanxi Road, Shanghai, 200000, China

    Ming Lu

  14. Department of Nephrology, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai, 200233, China

    Feng Wang

  15. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA

    Meisheng Jiang

  16. State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dong-Chuan Road, Shanghai, 200240, China

    Xipeng Liu

  17. Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA

    Yanjun Liu

  18. David Geffen School of Medicine at University of California, Los Angeles, USA

    Yanjun Liu

Authors
  1. Yanyan Jiang
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  2. Fusong Jiang
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  3. Ming Li
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  4. Qingkai Wu
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  5. Chenming Xu
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  6. Rong Zhang
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  7. Mingqiang Song
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  8. Yanzhong Wang
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  9. Ying Wang
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  10. Yating Chen
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  11. Juan Zhang
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  15. Di Yang
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  16. Ming Lu
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  17. Feng Wang
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  18. Meisheng Jiang
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  19. Xipeng Liu
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  20. Yanjun Liu
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  21. Limei Liu
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Contributions

LL designed the experiments; LL, YL, XL, CX and QW were responsible for the coordination of the project; LL, YL, YJ, YW, XL and MJ contributed to drafting and revising the manuscript; LL, YL, and XG contributed to the construction of molecular models and bioinformatics study. XL, YJ, ML, and LL contributed to kinetic analysis and thermostability study and data analysis. YW, XG, YW, YC, MJ and DY contributed to statistics and interpretation of data. YJ, FJ, MS, YC, JZ, QZ, LZ, ML, CX and QW contributed to the recruitment of MODY families, blood samples collection, data acquisition, genotyping, and genotype–phenotype analysis. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Limei Liu.

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Conflict of interest

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Jiang, Y., Jiang, F., Li, M. et al. Identification and management of GCK-MODY complicating pregnancy in Chinese patients with gestational diabetes. Mol Cell Biochem 477, 1629–1643 (2022). https://doi.org/10.1007/s11010-022-04374-8

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