Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group of disorders characterised by early onset, lean, non-autoimmunity mediated, non-insulin-dependent diabetes often with autosomal-dominant inheritance and specific pharmaco-genetic response. We describe two siblings with HNF1A-MODY (MODY3) due to a novel germline variant p.(His126Asp) which segregates with diabetes in the family. However, contrary to anticipated therapeutic response, blood glucose in this sib-pair did not respond to sulphonylureas (both low and high dose), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), and glucagon-like peptide-1 receptor agonists (GLP-1RA), also known as incretin mimetics. The unexpected limited pharmaco-therapeutic response could potentially be unique to this specific variant and/or progressive pancreatic β-cell failure associated with long-standing disease duration, higher BMI and glucose-toxicity. Therefore, we report a novel-variant MODY3 sib-pair with atypical pharmaco-therapeutic response i.e. resistant to multiple anti-diabetes agents namely sulphonylurea, DPP-4 inhibitors and GLP-1RA treatment.
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We would like to thank the patients for giving their consent to take part in our study and members of the KTPH Diabetes Centre for their continuing support. The work was supported by NHG-KTPH Small Innovative Grant II/14001 and KTPH STAR17201.
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Tan, C.S.H., Ang, S.F. & Lim, S.C. Response to multiple glucose-lowering agents in a sib-pair with a novel HNF1α (MODY3) variant. Eur J Hum Genet (2019). https://doi.org/10.1038/s41431-019-0561-8