Elsevier

The Lancet

Volume 362, Issue 9392, 18 October 2003, Pages 1275-1281
The Lancet

Mechanisms of Disease
Genetic cause of hyperglycaemia and response to treatment in diabetes

https://doi.org/10.1016/S0140-6736(03)14571-0Get rights and content

Summary

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 1α (HNF-1α) 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-1α 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-1α 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-1α 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-1α diabetes had a strong insulin secretory response to intravenous tolbutamide despite a small response to intravenous glucose, and were more insulin sensitive than those with type 2 diabetes. Sulphonylurea metabolism was similar in both patient groups.

Interpretation

The cause of hyperglycaemia changes the response to hypoglycaemic drugs; HNF-1α diabetes has marked sulphonylurea sensitivity. This pharmacogenetic effect is consistent with models of HNF-1α deficiency, which show that the β-cell defect is upstream of the sulphonylurea receptor. Definition of the genetic basis of hyperglycaemia has implications for patient management.

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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