Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment
Background: Functionally disruptive variants in the glucokinase gene (GCK) cause a form of mild non-progressive hyperglycemia, which does not require pharmacological treatment. A substantial proportion of patients with type 2 diabetes (T2D) carry GCK variants. We aimed to investigate whether carrier...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Molecular Genetics and Metabolism Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426923000186 |
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| author | Anne Cathrine Baun Thuesen Rasmus Tanderup Jensen Henrik Maagensen Maja Refshauge Kristiansen Henrik Toft Sørensen Allan Vaag Henning Beck-Nielsen Oluf B. Pedersen Niels Grarup Jens Steen Nielsen Jørgen Rungby Anette Prior Gjesing Heidi Storgaard Tina Vilsbøll Torben Hansen |
| author_facet | Anne Cathrine Baun Thuesen Rasmus Tanderup Jensen Henrik Maagensen Maja Refshauge Kristiansen Henrik Toft Sørensen Allan Vaag Henning Beck-Nielsen Oluf B. Pedersen Niels Grarup Jens Steen Nielsen Jørgen Rungby Anette Prior Gjesing Heidi Storgaard Tina Vilsbøll Torben Hansen |
| author_sort | Anne Cathrine Baun Thuesen |
| collection | DOAJ |
| description | Background: Functionally disruptive variants in the glucokinase gene (GCK) cause a form of mild non-progressive hyperglycemia, which does not require pharmacological treatment. A substantial proportion of patients with type 2 diabetes (T2D) carry GCK variants. We aimed to investigate whether carriers of rare GCK variants diagnosed with T2D have a glycemic phenotype and treatment response consistent with GCK-diabetes. Methods: Eight patients diagnosed with T2D from the Danish DD2 cohort who had previously undergone sequencing of GCK participated. Clinical examinations at baseline included an oral glucose tolerance test and continuous glucose monitoring. Carriers with a glycemic phenotype consistent with GCK-diabetes took part in a three-month treatment withdrawal. Results: Carriers of pathogenic and likely pathogenic variants had lower median fasting glucose and C-peptide levels compared to carriers of variants of uncertain significance and benign variants (median fasting glucose: 7.3 (interquartile range: 0.4) mmol/l vs. 9.5 (1.6) mmol/l, p = 0.04; median fasting C-peptide 902 (85) pmol/l vs. 1535 (295) pmol/l, p = 0.03). Four participants who discontinued metformin treatment and one diet-treated participant were reevaluated after three months. There was no deterioration of HbA1c or fasting glucose (median baseline HbA1c: 49 (3) vs. 51 (6) mmol/mol after three months, p = 0.4; median baseline fasting glucose: 7.3 (0.4) mmol/l vs. 7.0 (0.6) mmol/l after three months, p = 0.5). Participants did not consistently fulfill best practice guidelines for GCK screening nor clinical criteria for monogenic diabetes. Discussion: Carriers of pathogenic or likely pathogenic GCK variants identified by unselected screening in T2D should be reported, as they have a glycemic phenotype and treatment response consistent with GCK-diabetes. Variants of uncertain significance should be interpreted with care. Systematic genetic screening of patients with common T2D receiving routine care can lead to the identification and precise care of patients with misclassified GCK-diabetes who are not identifiable through common genetic screening criteria. |
| first_indexed | 2024-03-13T10:02:52Z |
| format | Article |
| id | doaj.art-1696d215ff0246ea81cfebf50fdc833b |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-03-13T10:02:52Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-1696d215ff0246ea81cfebf50fdc833b2023-05-23T04:21:49ZengElsevierMolecular Genetics and Metabolism Reports2214-42692023-06-0135100972Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatmentAnne Cathrine Baun Thuesen0Rasmus Tanderup Jensen1Henrik Maagensen2Maja Refshauge Kristiansen3Henrik Toft Sørensen4Allan Vaag5Henning Beck-Nielsen6Oluf B. Pedersen7Niels Grarup8Jens Steen Nielsen9Jørgen Rungby10Anette Prior Gjesing11Heidi Storgaard12Tina Vilsbøll13Torben Hansen14Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Clinical Research, Copenhagen University Hospital – Steno Diabetes Center Copenhagen, Herlev, DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkClinical Research, Copenhagen University Hospital – Steno Diabetes Center Copenhagen, Herlev, DenmarkSteno Diabetes Center Odense, the Danish Centre for Strategic Research in Type 2 Diabetes (DD2), Odense University Hospital, Odense, DenmarkDepartment of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, DenmarkClinical Research, Copenhagen University Hospital – Steno Diabetes Center Copenhagen, Herlev, Denmark; Department for Translational Type 2 Diabetes Research, Lund University Diabetes Center, Lund University, SwedenSteno Diabetes Center Odense, the Danish Centre for Strategic Research in Type 2 Diabetes (DD2), Odense University Hospital, Odense, DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkSteno Diabetes Center Odense, the Danish Centre for Strategic Research in Type 2 Diabetes (DD2), Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, DenmarkClinical Research, Copenhagen University Hospital – Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkClinical Research, Copenhagen University Hospital – Steno Diabetes Center Copenhagen, Herlev, DenmarkClinical Research, Copenhagen University Hospital – Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Corresponding author at: Blegdamsvej 3B, 07-8, 2200 København N, Denmark.Background: Functionally disruptive variants in the glucokinase gene (GCK) cause a form of mild non-progressive hyperglycemia, which does not require pharmacological treatment. A substantial proportion of patients with type 2 diabetes (T2D) carry GCK variants. We aimed to investigate whether carriers of rare GCK variants diagnosed with T2D have a glycemic phenotype and treatment response consistent with GCK-diabetes. Methods: Eight patients diagnosed with T2D from the Danish DD2 cohort who had previously undergone sequencing of GCK participated. Clinical examinations at baseline included an oral glucose tolerance test and continuous glucose monitoring. Carriers with a glycemic phenotype consistent with GCK-diabetes took part in a three-month treatment withdrawal. Results: Carriers of pathogenic and likely pathogenic variants had lower median fasting glucose and C-peptide levels compared to carriers of variants of uncertain significance and benign variants (median fasting glucose: 7.3 (interquartile range: 0.4) mmol/l vs. 9.5 (1.6) mmol/l, p = 0.04; median fasting C-peptide 902 (85) pmol/l vs. 1535 (295) pmol/l, p = 0.03). Four participants who discontinued metformin treatment and one diet-treated participant were reevaluated after three months. There was no deterioration of HbA1c or fasting glucose (median baseline HbA1c: 49 (3) vs. 51 (6) mmol/mol after three months, p = 0.4; median baseline fasting glucose: 7.3 (0.4) mmol/l vs. 7.0 (0.6) mmol/l after three months, p = 0.5). Participants did not consistently fulfill best practice guidelines for GCK screening nor clinical criteria for monogenic diabetes. Discussion: Carriers of pathogenic or likely pathogenic GCK variants identified by unselected screening in T2D should be reported, as they have a glycemic phenotype and treatment response consistent with GCK-diabetes. Variants of uncertain significance should be interpreted with care. Systematic genetic screening of patients with common T2D receiving routine care can lead to the identification and precise care of patients with misclassified GCK-diabetes who are not identifiable through common genetic screening criteria.http://www.sciencedirect.com/science/article/pii/S2214426923000186T2D (type 2 diabetes)MODY (maturity-onset diabetes of the young)DiagnosisTreatment |
| spellingShingle | Anne Cathrine Baun Thuesen Rasmus Tanderup Jensen Henrik Maagensen Maja Refshauge Kristiansen Henrik Toft Sørensen Allan Vaag Henning Beck-Nielsen Oluf B. Pedersen Niels Grarup Jens Steen Nielsen Jørgen Rungby Anette Prior Gjesing Heidi Storgaard Tina Vilsbøll Torben Hansen Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment Molecular Genetics and Metabolism Reports T2D (type 2 diabetes) MODY (maturity-onset diabetes of the young) Diagnosis Treatment |
| title | Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment |
| title_full | Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment |
| title_fullStr | Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment |
| title_full_unstemmed | Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment |
| title_short | Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment |
| title_sort | identification of pathogenic gck variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment |
| topic | T2D (type 2 diabetes) MODY (maturity-onset diabetes of the young) Diagnosis Treatment |
| url | http://www.sciencedirect.com/science/article/pii/S2214426923000186 |
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