Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor‐1α gene mutations: evidence for pharmacogenetics in diabetes

Pearson, Ewan R.; Liddell, WG; Shepherd, Maggie; Corrall, R. J. M.; Hattersley, Andrew T.

doi:10.1046/j.1464-5491.2000.00305.x

Cited by 251 publications

(182 citation statements)

References 9 publications

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“…Decreased insulin sensitivity also was determined at diagnosis by euglycaemic hyperinsulinaemic clamp method (glucose infusion rate, 4.7 mg·kg -1 ·min -1 ; control subjects, 7.8±0.2 mg·kg -1 ·min -1 ), and was consistent with the increased concentration of fasting plasma insulin (150 pmol/litre). Although many patients with HNF-1α mutations are highly sensitive to the hypoglycaemic effects of sulphonylureas [6], the diabetic state of this subject was refractory to oral drug therapy and is being treated with insulin possibly due to the combined effects of the mutations. Analysis of other family members is necessary to understand the effects of gene interaction on the phenotype.…”

Section: Identification Of Hnf-1α Mutations In Early-onsetmentioning

confidence: 99%

High frequency of mutations in the HNF-1α gene in non-obese patients with diabetes of youth in Japanese and identification of a case of digenic inheritance

et al. 2002

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Aims/hypothesis. There is an emerging epidemic of Type II (non-insulin-dependent) diabetes mellitus of youth in Japan and in many other developed countries. The aim of this study was to determine the prevalence of mutations in the hepatocyte nuclear factor (HNF)-1α gene (TCF1) in a large group of Japanese patients with early-onset non-Type I (insulin-dependent) diabetes mellitus. Since approximately 20% of Caucasian patients with HNF-1α mutations have been shown to be obese or overweight, we also examined the association of genetic variations in TCF1 with body weight in Japanese subjects. Methods. We examined 203 patients with non-Type 1 diabetes who had been diagnosed before they reached 15 years of age. Ten exons and flanking introns of TCF1 of these patients were directly sequenced for mutations. Results. We found 14 different mutations in 18 patients (8.9%), including one that was found to be de novo. The patients with the mutations had lower BMI (20.1±3.0 kg/m 2 ) at diagnosis than the patients without them (24.5±6.0 kg/m 2 ) (p=0.0024). All of the patients with the mutations, except for one, Y120, had normal body weight (BMI<25 kg/m 2 ); the frequency of HNF-1α mutations in the non-obese patients of this study was 17% (17/101). Patient Y120, who had atypical symptoms of mild obesity and insulin resistance at diagnosis, was found to have inherited an additional mutation in an obesity-related gene. Type II diabetes in Caucasians. In contrast, Type II diabetes in Japanese subjects is characterized primarily by pancreatic beta-cell dysfunction, possibly reflecting genetic heterogeneity in the pathogenesis of diabetes between the two populations.Maturity-onset diabetes of the young is an autosomal dominant form of early-onset diabetes. Because MODY is characterized primarily by insulin-secretion defects rather than by impaired insulin action, this form of diabetes could well be a suitable model for examining the pathophysiology of Type II diabetes in Japanese subjects. Six forms of MODY have been identified to date. The third form, MODY3 [1], which is caused by mutations in the hepatocyte nuclear factor (HNF)-1α gene (TCF1), seems to be the most The recent increase in the incidence of Type II (noninsulin-dependent) diabetes mellitus of youth in Japan and in many other developed countries is a result of the interaction of many genetic and non-genetic factors. Obesity and insulin resistance are associated with

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Section: Identification Of Hnf-1α Mutations In Early-onsetmentioning

confidence: 99%

High frequency of mutations in the HNF-1α gene in non-obese patients with diabetes of youth in Japanese and identification of a case of digenic inheritance

et al. 2002

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“…A molecular diagnosis of monogenic diabetes is essential for optimal treatment, prognosis and genetic counselling. Patients with MODY caused by a mutation in the HNF1A or HNF4A genes are sensitive to sulfonylurea treatment, which is associated with improved glycaemic control and quality of life [5][6][7][8][9]. Moreover, patients with a mutation in GCK typically do not require pharmacological intervention [10].…”

Section: Introductionmentioning

confidence: 99%

Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry

et al. 2016

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Aims/hypothesis MODY can be wrongly diagnosed as type 1 diabetes in children. We aimed to find the prevalence of MODY in a nationwide population-based registry of childhood diabetes. Methods Using next-generation sequencing, we screened the HNF1A, HNF4A, HNF1B, GCK and INS genes in all 469 children (12.1%) negative for both GAD and IA-2 autoantibodies and 469 antibody-positive matched controls selected from the Norwegian Childhood Diabetes Registry (3882 children). Variants were classified using clinical diagnostic criteria for pathogenicity ranging from class 1 (neutral) to class 5 (pathogenic). Results We identified 58 rare exonic and splice variants in cases and controls. Among antibody-negative patients, 6.5% had genetic variants of classes 3-5 (vs 2.4% in controls; p = 0.002). For the stricter classification (classes 4 and 5), the corresponding number was 4.1% (vs 0.2% in controls; p = 1.6 × 10 −5 ). HNF1A showed the strongest enrichment of class 3-5 variants, with 3.9% among antibody-negative patients (vs 0.4% in controls; p = 0.0002). Antibody-negative carriers of variants in class 3 had a similar phenotype to those carrying variants in classes 4 and 5. Conclusions/interpretation This is the first study screening for MODY in all antibody-negative children in a nationwide population-based registry. Our results suggest that the prevalence of MODY in antibody-negative childhood diabetes may reach 6.5%. One-third of these MODY cases had not been recognised by clinicians. Since a precise diagnosis is important Henrik U. Irgens, Janne Molnes and Paweł Sztromwasser contributed equally to the study. Stefan Johansson and Pål R. Njølstad share joint senior authorship.Electronic supplementary material The online version of this article

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“…Patients can be initially treated with diet, but the majority will eventually need glucose-lowering agents 7. Low-dose oral sulfonylureas (SU) have been shown to be at least as effective as insulin in adults with HNF-a; MODY 89. However, experience with their use in children is limited.…”

mentioning

confidence: 99%

Response to oral gliclazide in a pre-pubertal child with hepatic nuclear factor-1 alpha maturity onset diabetes of the young

Habeb

George

Hattersley

2011

Annals of Saudi Medicine

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The term “maturity onset diabetes of the young” (MODY) describes a heterogeneous group of monogenic diabetes of which hepatic nuclear factor-1 alpha (HNF-1α) MODY is the most common. Patients with HNF-1α mutations typically present after puberty, and oral sulfonylureas (SU) have been shown to be effective in adults with this condition. A 7-year-old boy presented with asymptomatic hyperglycemia ranging between 6.2 and 10.1 mmol/L and glycosuria for nearly a year. The child's initial HbA1c was 6.9% and the pancreatic Islet cell autoantibodies were negative. His response to the oral glucose tolerance test (OGTT) showed a large increment of glucose from basal level of 7.7 to 21.1 mmol/L in 120 min. The mild presentation, family history, and negative autoantibodies were suggestive of HNF-1α MODY, which was confirmed by mutation analysis. Initial management with diet alone was not sufficient, but he responded well to 20 mg oral gliclazide once a day with an improvement of HbA1C from 7.2% to 6.5% within 3 months of treatment. The case is an illustration of the clinical utility of molecular genetic tests in the management of childhood diabetes.

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Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor‐1α gene mutations: evidence for pharmacogenetics in diabetes

Cited by 251 publications

References 9 publications

High frequency of mutations in the HNF-1α gene in non-obese patients with diabetes of youth in Japanese and identification of a case of digenic inheritance

High frequency of mutations in the HNF-1α gene in non-obese patients with diabetes of youth in Japanese and identification of a case of digenic inheritance

Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry

Response to oral gliclazide in a pre-pubertal child with hepatic nuclear factor-1 alpha maturity onset diabetes of the young

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