Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia

Stride, Amanda; Shields, Beverley M.; Gill-Carey, Olivia; Chakera, Ali J.; Colclough, Kevin; Ellard, Sian; Hattersley, Andrew T.

doi:10.1007/s00125-013-3075-x

Cited by 178 publications

(145 citation statements)

References 9 publications

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“…Patients with pathogenic GCK variants usually need no pharmacological treatment, except during pregnancy when close monitoring is needed since the relative insulin resistance often leads to more severe diabetes with a need for insulin [24]. It should, however, be noted that some patients might have double diabetes (i.e.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Second, many cases of GCK-MODY are misclassified as type 1 or type 2 diabetes or impaired fasting glucose (24). It is important to diagnose these patients correctly, as they may be taking unnecessary treatment and have been given the wrong advice about their condition (25). Finally, there are barriers to genetic testing: both a lack of knowledge of the condition by health care professionals and the cost of the genetic testing (£350 for GCK gene testing [Exeter Molecular Genetics Laboratory]).…”

Section: Population Prevalencementioning

confidence: 99%

“…The low risk of cardiovascular disease may be augmented by the cardioprotective lipid profile seen in GCK-MODY (74). (25). The lack of response reflects that glycemia is tightly regulated by homeostatic mechanisms in GCK-MODY that counteract the glucose-lowering effect of treatment (e.g., when subreplacement exogenous insulin doses are given, endogenous insulin secretion is reduced and glycemia is not altered).…”

Section: Macrovascular Complicationsmentioning

confidence: 99%

Recognition and Management of Individuals With Hyperglycemia Because of a Heterozygous Glucokinase Mutation

et al. 2015

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Glucokinase–maturity-onset diabetes of the young (GCK-MODY), also known as MODY2, is caused by heterozygous inactivating mutations in the GCK gene. GCK gene mutations are present in ∼1 in 1,000 of the population, but most are not diagnosed. They are common causes of MODY (10–60%): persistent incidental childhood hyperglycemia (10–60%) and gestational diabetes mellitus (1–2%). GCK-MODY has a unique pathophysiology and clinical characteristics, so it is best considered as a discrete genetic subgroup. People with GCK-MODY have a defect in glucose sensing; hence, glucose homeostasis is maintained at a higher set point resulting in mild, asymptomatic fasting hyperglycemia (5.4–8.3 mmol/L, HbA1c range 5.8–7.6% [40–60 mmol/mol]), which is present from birth and shows slight deterioration with age. Even after 50 years of mild hyperglycemia, people with GCK-MODY do not develop significant microvascular complications, and the prevalence of macrovascular complications is probably similar to that in the general population. Treatment is not recommended outside pregnancy because glucose-lowering therapy is ineffective in people with GCK-MODY and there is a lack of long-term complications. In pregnancy, fetal growth is primarily determined by whether the fetus inherits the GCK gene mutation from their mother. Insulin treatment of the mother is only appropriate when increased fetal abdominal growth on scanning suggests the fetus is unaffected. The impact on outcome of maternal insulin treatment is limited owing to the difficulty in altering maternal glycemia in these patients. Making the diagnosis of GCK-MODY through genetic testing is essential to avoid unnecessary treatment and investigations, especially when patients are misdiagnosed with type 1 or type 2 diabetes.

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“…36 Therefore, in the absence of concomitant type 1 or 2 diabetes, glucose-lowering therapy can be stopped. The only exception is during a pregnancy where fetal macrosomia is suspected and insulin treatment may be administered in an attempt to control fetal growth.…”

Section: Yesmentioning

confidence: 99%

Clinical utility gene card for: Maturity-onset diabetes of the young

et al. 2014

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Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia

Cited by 178 publications

References 9 publications

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

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

Recognition and Management of Individuals With Hyperglycemia Because of a Heterozygous Glucokinase Mutation

Clinical utility gene card for: Maturity-onset diabetes of the young

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