Mechanisms of DiseaseGenetic cause of hyperglycaemia and response to treatment in diabetes
Introduction
Type 2 diabetes is an increasing global health burden.1 Control of glycaemia is a treatment priority in type 2 diabetes. Most patients on pharmacological treatment receive sulphonylureas, or metformin, or both. These agents are equally effective, resulting in a similar average improvement in glycaemic control (with a fall in glycated haemoglobin of about 1%).2 However, non-insulin-dependent diabetes is heterogeneous, with many subtypes.3 These subtypes are usually treated as type 2 diabetes either because they are not diagnosed, or because there is insufficient evidence to justify alternative treatment.
One monogenic subtype of diabetes, maturity onset diabetes of the young (mody) is characterised by young onset (usually before the age of 25 years) non-insulin dependent diabetes caused by β-cell dysfunction, with an autosomal dominant inheritance.4 Heterozygous mutations in the hepatocyte nuclear factor (hnf)-1α gene are the most common cause of maturity onset diabetes of the young in most populations investigated and account for 1-2% of all diabetes.5 Patients with HNF-1α diabetes have been described in isolated case reports6, 7, 8, 9 as being more sensitive to the hypoglycaemic effects of sulphonylureas than those with type 2 diabetes. No therapeutic trials have assessed this. The mechanism is uncertain, but in one study10 a glucose-tolerant person with an HNF-1α mutation had an increased insulin secretory response to intravenous tolbutamide compared with healthy controls.
To test the hypothesis that patients with HNF-1α diabetes respond better to sulphonylureas than patients with type 2 diabetes, we did a randomised trial comparing patients' responses to the sulphonylurea gliclazide and the biguanide metformin. We also tested three possible mechanisms for sulphonylurea sensitivity. We postulated that, compared with type 2 diabetes, patients with HNF-1α would secrete more insulin in response to sulphonylureas; produce the same amount of insulin but be more insulin sensitive to the insulin secreted; or have impaired metabolism of sulphonylureas.
Section snippets
Patients
Between February, 2001 and August, 2002, we investigated two groups of white patients with diabetes from the UK who were treated with diet or oral agents. The first group included patients with MODY who had an HNF-1α mutation, and the second included patients with type 2 diabetes (without a known cause of diabetes and when diagnosis had been made when patients were older than 40 years). These groups were matched for body-mass index and fasting plasma glucose 1 week after stopping treatment.
Drug trial
Table 1 shows the baseline characteristics of patients with HNF-1α diabetes and type 2 diabetes. Both groups had a similar body-mass index and fasting plasma glucose after the washout period off hyperglycaemic drugs. Because of the nature of the two different types of diabetes the patients in the type 2 diabetes group were older and had a shorter duration of diabetes than did those in the HNF-1α group. The waist circumference was higher in patients with type 2 diabetes compared with those with
Discussion
We have shown that the cause of diabetes affects the response to treatment and provide evidence for the mechanism of this response. Pateients with diabetes caused by mutations in the HNF-1α gene showed a greater improvement in glycaemia in response to the sulphonylurea gliclazide than patients with type 2 diabetes with similar body-mass index and glycaemia. The large response to gliclazide in patients with HNF-1α diabetes reflects a preserved insulin secretory response to sulphonylureas
GLOSSARY
- hepatocyte nuclear factor-1α (hnf-1α)
- A homoeodomain-containing transcription factor that is widely expressed. An alternative name for its encoding gene is TCF1.
- maturity onset diabetes of the young (mody)
- A young onset, non-insulin-dependent diabetes with an autosomal dominant inheritance.
- sulphonylurea sensitivity
- Sensitivity to the hypoglycaemic effects of the oral hypoglycaemic agents sulphonylureas.
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