title: Recognition and Management of Individuals With Hyperglycemia Because of a Heterozygous Glucokinase Mutation.
abstract: 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.
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K. MacLeod Diabetes and Endocrine Centre, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, U.K. alichakera@nhs.net a.t.hattersley@exeter.ac.uk.
authors.forename: Ali J
authors.initials: AJ
authors.lastname: Chakera
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K. National Institute for Health Research Exeter Clinical Research Facility, Royal Devon and Exeter National Health Service Foundation Trust, and University of Exeter Medical School, Exeter, U.K.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Steele
authors.affiliation: Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, U.K. National Institute for Health Research Oxford Biomedical Research Centre, The Churchill Hospital, Oxford, U.K.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K. National Institute for Health Research Exeter Clinical Research Facility, Royal Devon and Exeter National Health Service Foundation Trust, and University of Exeter Medical School, Exeter, U.K.
authors.forename: Maggie H
authors.initials: MH
authors.lastname: Shepherd
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K.
authors.forename: Beverley
authors.initials: B
authors.lastname: Shields
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K. Department of Molecular Genetics, Royal Devon and Exeter National Health Service Foundation Trust, and University of Exeter Medical School, Exeter, U.K.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K. MacLeod Diabetes and Endocrine Centre, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, U.K. National Institute for Health Research Exeter Clinical Research Facility, Royal Devon and Exeter National Health Service Foundation Trust, and University of Exeter Medical School, Exeter, U.K. alichakera@nhs.net a.t.hattersley@exeter.ac.uk.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D001786:Blood Glucose / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D016640:Diabetes, Gestational / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D005941:Glucokinase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D006943:Hyperglycemia / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy*; D009154:Mutation; D011247:Pregnancy; D015995:Prevalence
chemical_list: D001786:Blood Glucose; D005941:Glucokinase