Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor‐1α gene mutations: evidence for pharmacogenetics in diabetes
Open accessAbstract
SUMMARY Introduction Maturity‐onset diabetes of the young (MODY) is characterized by autosomal dominantly inherited, early‐onset, non‐insulin‐dependent diabetes. Mutations in the hepatocyte nuclear factor (HNF)‐1α gene are the commonest cause of MODY. Individual patients with HNF‐1α mutations have been reported as being unusually sensitive to the hypoglycaemic effects of sulphonylurea therapy. We report three patients, attending a single clinic, with HNF‐1α mutations that show marked hypersensitivity to sulphonylureas. Case reports In cases 1 and 2 there were marked changes in HbA 1c on cessation (4.4% and 5.8%, respectively) and reintroduction (5.0% and 2.6%) of sulphonylureas. Case 3 had severe hypoglycaemic symptoms on the introduction of sulphonylureas despite poor glycaemic control and was shown with a test dose of 2.5 mg glibenclamide to have symptomatic hypoglycaemia (blood glucose 2 mmol/l) after 4 h despite eating. Conclusions HNF‐1α MODY diabetic subjects are more sensitive to sulphonylureas than Type 2 diabetic subjects and this is seen in different families, with different mutations and may continue up to 13 years from diagnosis. This is an example of pharmacogenetics, with the underlying aetiological genetic defect altering the pharmacological response to treatment. The present cases suggest that in HNF‐1α MODY patients: (i) sulphonylureas can dramatically improve glycaemic control and should be considered as initial treatment for patients with poor glycaemic control on an appropriate diet; (ii) hypoglycaemia may complicate the introduction of sulphonylureas and therefore very low doses of short acting sulphonylureas should be used initially; and (iii) cessation of sulphonylureas should be undertaken cautiously as there may be marked deterioration in glycaemic control. Keywords genetics, HNF‐1α, MODY, pharmacogenetics, sulphonylurea sensitivity
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Neonatal diabetes due to Kir6.2 or SUR1 mutations can be treated with high-dose sulfonylureas despite being insulin dependent.
“can be treated with high-dose sulfonylureas despite being insulin dependent also provide a compelling case for genetic evaluation of monogenic diabetes with therapeutic and prognostic implications ( 2 – 6 ).”
From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [4]
The Discussion (page unavailable) supports sulphonylurea treatment for genetically defined diabetes, but the patients studied had HNF-1α MODY, not neonatal diabetes due to Kir6.2 or SUR1 mutations. It recommends starting with very low doses because of hypoglycaemia risk; it does not establish high-dose treatment for insulin-dependent neonatal patients. (LLM, conf=0.85)
Experimental — accuracy not yet measuredNeonatal diabetes is most commonly due to activating mutations in genes encoding the ATP-sensitive potassium channel subunits Kir6.2 or SUR1.
“Findings that neonatal diabetes is most commonly due to activating mutations in genes encoding the ATP-sensitive potassium channel subunits Kir6.2 or SUR1”
From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [4]
The Introduction and Abstract discuss HNF-1α mutations in maturity-onset diabetes of the young, and the Discussion addresses sensitivity to sulphonylureas; no page number is available for these passages. Searches for neonatal diabetes, Kir6.2, SUR1, and their gene names found no passage addressing the claimed cause of neonatal diabetes. (LLM, conf=0.76)
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Cites
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Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young
Fajans, S. S., Bell, G. I., & Polonsky, K. S. (2001) · New England Journal of Medicine · doi:10.1056/nejmra002168 · Cited by 1,123 · see citing works
β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment
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Self-citationNovel insights into genetics and clinics of the HNF1A-MODY
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- Authors
- Pearson, E. R., Liddell, W. G., Shepherd, M., Corrall, R. J., & Hattersley, A. T.
- Affiliations
- University of Exeter (GB)
- Bristol Royal Infirmary (GB)
- Corresponding author
- Hattersley, A. T.
- Venue
- Diabetic Medicine
- Publisher
- Wiley
- Published
- 2000-07
- Volume
- 17
- Issue
- 7
- Pages
- 543-545
- ISSN
- 0742-3071 (ISSN-L)
- 1464-5491
- OpenAlex
- W2109429703
- Cited by
- 259
- References
- 9
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 9 · 2023: 7 · 2022: 16 · 2021: 8 · 2020: 10 · 2019: 10 · 2018: 8 · 2017: 11 · 2016: 13 · 2015: 12 · 2014: 17 · 2013: 10 · 2012: 10
- FWCI
- 9.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetic Medicine (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- maturity-onset diabetes of the young, pharmacogenetics, glibenclamide, hypoglycemia, glycemic control, type 2 diabetes, sulphonylurea therapy
- MeSH terms
- Adult, Chlorpropamide, Diabetes Mellitus, Type 2, DNA Transposable Elements, DNA-Binding Proteins, Female, Glyburide, Humans, Hypoglycemic Agents, Insulin, Metformin, Middle Aged, Nuclear Proteins, Sulfonylurea Compounds, Transcription Factors, Point Mutation, Amino Acid Substitution, Hepatocyte Nuclear Factor 1, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 1-beta
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