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Genotype–phenotype correlations and response to glucose lowering therapy in subjects with HNF1β associated diabetes

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Abstract

Aims

Molecular defects of hepatic nuclear factor 1β (HNF1β) are associated with multiorgan disease (renal disease, pancreatic hypoplasia, and genital tract anomalies) in addition to diabetes. We examined the phenotypic features, insulin secretory response to glucose, and response to treatment in subjects with HNF1β-MODY (MODY 5).

Methods

Twelve subjects with HNF1β-MODY were phenotyped in detail. A 2-h oral glucose tolerance test was performed to establish insulin secretory response with glucose, insulin and C-peptide measurements taken at baseline and 30 min intervals. Clinical follow-up occurred bi-annually.

Results

Ten of 12 subjects had diabetes with mean age of onset of 30.2 ± 15.5 years, fasting glucose of 9.7 ± 4.6 mmol/L and HbA1c of 60.9 ± 17.1 mmol/mol (7.7 ± 1.6%). Renal and/or pancreatic morphological abnormalities were found in 9 subjects. Mean fasting C-peptide (0.5 ± 0.4 nmol/L) and AUC C-peptide (1.5 ± 1.0 nmol/L/120 min) were reduced in our cohort with 4 subjects demonstrating marked insulin deficiency. OGIS was reduced at 290.2 ± 67.0 ml min−1 m−2. 6/10 subjects were on insulin therapy at initial diagnosis and 8/10 at last clinical follow-up. Mean insulin dose at last clinical follow-up was 0.45 ± 0.23units/kg/day. 5 subjects on insulin were trialled on sulphonylurea therapy, and none was successfully weaned off insulin.

Conclusions

Diagnosing HNF1β-MODY in a diabetes clinic is challenging due to its variable phenotype and variable age of onset. β-Cell dysfunction and insulin resistance contribute to diabetes in HNF1β-MODY. No subjects successfully transitioned to sulphonylurea. Early initiation of insulin therapy would be suitable to achieve glycaemic control. This emphasizes the importance of genetic testing for monogenic forms of diabetes to guide personalized treatment.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Code availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors wish to thank the subjects who participated in this study and the Consultant Endocrinologists who referred subjects to the Mater MODY clinic. We would like to acknowledge the laboratory staff in the Mater Misericordiae University hospital with a particular thanks to Ms.Rachel Cullen. We would also like to thank Dr.Kevin Colclough in the Exeter Molecular Genetics laboratory for genetic analysis and advice.

Funding

This study was sponsored by the HRB/MRCG Research Award RP-06/01. J.Kim was supported by an Irish Endocrine Society summer student research bursary, 2019.

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Author notes

  1. Najia Siddique

    Present address: Department of Diabetes and Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland

Authors and Affiliations

  1. Department of Diabetes and Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland

    Nicholas Ng, Matilde Mijares Zamuner, Joon Kim, Marie Burke & Maria Michele Byrne

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Contributions

NN and MB were responsible for the study design. Material preparation, data collection and analysis were performed by NN, MBMZ, NS, JK and MB. The first draft of the manuscript was written by NN, MBMZ and MMB and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Nicholas Ng.

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The authors declare that they have no conflict of interest.

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The study was approved by the Research Ethics Committee of the Mater University hospital (reference number 1/378/1021).

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Ng, N., Mijares Zamuner, M., Siddique, N. et al. Genotype–phenotype correlations and response to glucose lowering therapy in subjects with HNF1β associated diabetes. Acta Diabetol 59, 83–93 (2022). https://doi.org/10.1007/s00592-021-01794-8

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