Genetic cause of hyperglycaemia and response to treatment in diabetes
Abstract
Background Type 2 diabetes shows evidence of underlying heterogeneity. No studies have assessed whether different causes for diabetes change the response to oral hypoglycaemic therapy. In a few cases, patients with diabetes caused by mutations in the hepatocyte nuclear factor 1alpha (HNF-1alpha) gene have been described as sensitive to the hypoglycaemic effects of sulphonylureas. We aimed to see whether the glycaemic response to the sulphonylurea gliclazide and the biguanide metformin differed in HNF-1alpha diabetes and type 2 diabetes, and to investigate the mechanism for differences in sulphonylurea sensitivity. Methods We did a randomised crossover trial of glicazide and metformin in 36 patients, either with diabetes caused by HNF-1alpha mutations or type 2 diabetes, who were matched for body-mass index and fasting plasma glucose. The primary outcome was reduction in fasting plasma glucose. Analysis was by intention to treat. We assessed possible mechanisms for sulphonylurea sensitivity through insulin sensitivity, insulin secretory response to glucose and tolbutamide, and tolbutamide clearance. Findings Patients with HNF-1alpha diabetes had a 5.2-fold greater response to gliclazide than to metformin (fasting plasma glucose reduction 4.7 vs 0.9 mmol/L, p=0.0007) and 3.9-fold greater response to gliclazide than those with type 2 diabetes (p=0.002). Patients with HNF-1alpha diabetes had a strong insulin secretory response to intravenous tolbutamide despite a small response t…
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A diagnosis of monogenic diabetes allows specific treatment with discontinuation of insulin in many cases and has implications for family members and screening for concurrent conditions.
“A diagnosis of monogenic diabetes allows specific treatment with discontinuation of insulin in many cases and has implications for family members and screening for concurrent conditions (19,20).”
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- Authors
- Pearson, E. R., Starkey, B. J., Powell, R. J., Gribble, F. M., Clark, P. M., & Hattersley, A. T.
- Affiliations
- University of Exeter (GB)
- Royal Surrey County Hospital (GB)
- Royal Devon and Exeter Hospital (GB)
- Addenbrooke's Hospital (GB)
- University Hospitals Birmingham NHS Foundation Trust (GB)
- Corresponding author
- Hattersley, Andrew T
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2003-10
- Volume
- 362
- Issue
- 9392
- Pages
- 1275-1281
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2162590815
- Cited by
- 607
- References
- 5
- Citations by year
- 2026: 17 · 2025: 20 · 2024: 23 · 2023: 31 · 2022: 46 · 2021: 29 · 2020: 31 · 2019: 26 · 2018: 29 · 2017: 25 · 2016: 35 · 2015: 27 · 2014: 34 · 2013: 27 · 2012: 22
- FWCI
- 13.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- type 2 diabetes, gliclazide, metformin, pharmacogenetics, insulin secretion, insulin sensitivity, sulfonylurea receptor, fasting blood glucose
- MeSH terms
- Adult, Aged, Blood Glucose, Diabetes Mellitus, Diabetes Mellitus, Type 2, DNA-Binding Proteins, Fasting, Female, Gliclazide, Humans, Hyperglycemia, Hypoglycemic Agents, Male, Metformin, Middle Aged, Nuclear Proteins, Receptors, Drug, Transcription Factors, Potassium Channels, ATP-Binding Cassette Transporters, Potassium Channels, Inwardly Rectifying, Hepatocyte Nuclear Factor 1, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 1-beta, Sulfonylurea Receptors
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