{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T19:47:56Z","timestamp":1782157676458,"version":"3.54.5"},"reference-count":25,"publisher":"American Diabetes Association","issue":"7","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["T32CA285265"],"award-info":[{"award-number":["T32CA285265"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Egyptian","award":["GM 1109"],"award-info":[{"award-number":["GM 1109"]}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK066485"],"award-info":[{"award-number":["R01DK066485"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>Glucokinase and ATP-sensitive potassium (KATP) channels in pancreatic \u03b2-cells control insulin secretion in response to glucose stimulation to maintain glucose homeostasis. It is well established that loss-of-function (LOF) variants in GCK, which encodes glucokinase, are diabetogenic, whereas LOF variants in KATP channel genes lead to congenital hyperinsulinism (HI) and hypoglycemia. However, how the co-occurrence of GCK and KATP channel variants manifests in glycemic phenotypes is unknown. This study presents a multiplex pedigree with a heterozygous GCK deletion along with a heterozygous ABCC8 variant that results in the E1209K missense variant in the regulatory subunit of the KATP channel sulfonylurea receptor 1 (SUR1). The three-generation pedigree exhibits a complex spectrum of dysglycemia depending on genotype and age at referral. Individuals harboring the heterozygous GCK deletion alone present with maturity-onset diabetes; those harboring the heterozygous ABCC8 E1209K variant alone exhibit HI resulting from the LOF of KATP channels, with some developing diabetes later in life; and those harboring both GCK and ABCC8 variants escape HI but not diabetes. This unique pedigree offers insights into the complex interplay between LOF genetic variants of glucokinase and KATP channels in age-dependent dysglycemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>Genetic variants causing loss of function (LOF) of glucokinase or ATP-sensitive potassium (KATP) channels underlie diabetes or congenital hyperinsulinism, respectively, but how the co-occurrence of such variants affects glucose control is unknown. This study presents genotypes and clinical phenotypes in a pedigree with LOF variants in both GCK and the pancreatic KATP channel. Heterozygous glucokinase deletion masked infantile hyperinsulinemia and hypoglycemia caused by a heterozygous LOF KATP channel variant. Carriers of the LOF KATP variant exhibited a shift from hypoglycemia to diabetes, as has been reported previously in some carriers of KATP LOF variants.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-1098","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T16:58:59Z","timestamp":1776445139000},"page":"1323-1328","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["Co-occurrence of Loss-of-Function\n                    <i>GCK<\/i>\n                    and\n                    <i>ABCC8<\/i>\n                    Variants in a Pedigree With a Spectrum of Dysglycemia"],"prefix":"10.2337","volume":"75","author":[{"given":"C\u00e9cile","family":"Saint-Martin","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Sorbonne University 1 , Assistance Publique\u2013H\u00f4pitaux de Paris (AP-HP), Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Assmaa","family":"ElSheikh","sequence":"additional","affiliation":[{"name":"Department of Chemical Physiology and Biochemistry, Oregon Health & Science University 2 , Portland, OR"},{"name":"Department of Medical Biochemistry, Tanta University 3 , Tanta, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Jacqueminet","sequence":"additional","affiliation":[{"name":"Diabetology Department, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Sorbonne University 4 , AP-HP, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Baptiste","family":"Arnoux","sequence":"additional","affiliation":[{"name":"Department of Inherited Metabolic Disease, Necker-Enfants Malades University Hospital 5 , AP-HP, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Ciangura","sequence":"additional","affiliation":[{"name":"Diabetology Department, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Sorbonne University 4 , AP-HP, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8415-6771","authenticated-orcid":false,"given":"Christine","family":"Bellann\u00e9-Chantelot","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Sorbonne University 1 , Assistance Publique\u2013H\u00f4pitaux de Paris (AP-HP), Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8230-8820","authenticated-orcid":false,"given":"Show-Ling","family":"Shyng","sequence":"additional","affiliation":[{"name":"Department of Chemical Physiology and Biochemistry, Oregon Health & Science University 2 , Portland, OR"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"2026062214515523700_B1","doi-asserted-by":"crossref","first-page":"S394","DOI":"10.2337\/diabetes.51.2007.S394","article-title":"Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics","volume":"51","author":"Matschinsky","year":"2002","journal-title":"Diabetes"},{"key":"2026062214515523700_B2","doi-asserted-by":"crossref","first-page":"693","DOI":"10.2337\/dbi22-0030","article-title":"KATP channels and the metabolic regulation of insulin secretion in health and disease: the 2022 Banting Medal for Scientific Achievement Award Lecture","volume":"72","author":"Ashcroft","year":"2023","journal-title":"Diabetes"},{"key":"2026062214515523700_B3","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.tibs.2024.12.007","article-title":"Glucokinase: from allosteric glucose sensing to disease variants","volume":"50","author":"Gersing","year":"2025","journal-title":"Trends Biochem Sci"},{"key":"2026062214515523700_B4","doi-asserted-by":"crossref","first-page":"995","DOI":"10.33549\/physiolres.934487","article-title":"Clinical implications of the glucokinase impaired function - GCK MODY today","volume":"69","author":"Hul\u00edn","year":"2020","journal-title":"Physiol Res"},{"key":"2026062214515523700_B5","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1002\/humu.23995","article-title":"Update of variants identified in the pancreatic \u03b2-cell KATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes","volume":"41","author":"De Franco","year":"2020","journal-title":"Hum Mutat"},{"key":"2026062214515523700_B6","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1159\/000531766","article-title":"International guidelines for the diagnosis and management of hyperinsulinism","volume":"97","author":"De Leon","year":"2024","journal-title":"Horm Res Paediatr"},{"key":"2026062214515523700_B7","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.2337\/db08-0159","article-title":"Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence","volume":"57","author":"Abdulhadi-Atwan","year":"2008","journal-title":"Diabetes"},{"key":"2026062214515523700_B8","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0140-6736(03)12325-2","article-title":"A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1","volume":"361","author":"Huopio","year":"2003","journal-title":"Lancet"},{"key":"2026062214515523700_B9","doi-asserted-by":"crossref","first-page":"82","DOI":"10.4274\/jcrpe.galenos.2018.2018.0077","article-title":"Congenital hyperinsulinism and evolution to sulfonylurearesponsive diabetes later in life due to a novel homozygous p.L171F ABCC8 mutation","volume":"11","author":"I\u015f\u0131k","year":"2019","journal-title":"J Clin Res Pediatr Endocrinol"},{"key":"2026062214515523700_B10","doi-asserted-by":"crossref","first-page":"180","DOI":"10.2337\/db25-0110","article-title":"Paradoxical maturity-onset diabetes of the young arising from loss-of-function mutations in ATP-sensitive potassium channels","volume":"75","author":"Scala","year":"2026","journal-title":"Diabetes"},{"key":"2026062214515523700_B11","doi-asserted-by":"crossref","first-page":"2575","DOI":"10.1007\/s00125-011-2207-4","article-title":"Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8\/KCNJ11 mutations","volume":"54","author":"Kapoor","year":"2011","journal-title":"Diabetologia"},{"key":"2026062214515523700_B12","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.2337\/db07-0043","article-title":"Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood","volume":"56","author":"Flanagan","year":"2007","journal-title":"Diabetes"},{"key":"2026062214515523700_B13","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1056\/NEJMoa032922","article-title":"Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes","volume":"350","author":"Gloyn","year":"2004","journal-title":"N Engl J Med"},{"key":"2026062214515523700_B14","doi-asserted-by":"crossref","first-page":"568","DOI":"10.2337\/diabetes.52.2.568","article-title":"Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes","volume":"52","author":"Gloyn","year":"2003","journal-title":"Diabetes"},{"key":"2026062214515523700_B15","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"2026062214515523700_B16","doi-asserted-by":"crossref","first-page":"110779","DOI":"10.1016\/j.jbc.2025.110779","article-title":"Identification and rescue of congenital hyperinsulinism-associated ABCC8 mutations that impair KATP channel trafficking","volume":"301","author":"ElSheikh","year":"2025","journal-title":"J Biol Chem"},{"key":"2026062214515523700_B17","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2337\/dbi25-0029","article-title":"ABCC8 missense variants and disease: loss or gain? This is the question","volume":"75","author":"Barbetti","year":"2026","journal-title":"Diabetes"},{"key":"2026062214515523700_B18","doi-asserted-by":"crossref","first-page":"802423","DOI":"10.3389\/fendo.2021.802423","article-title":"Pregnancy in women with monogenic diabetes due to pathogenic variants of the glucokinase gene: lessons and challenges","volume":"12","author":"Timsit","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2026062214515523700_B19","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1111\/j.1365-2265.2008.03214.x","article-title":"Haploinsufficiency at GCK gene is not a frequent event in MODY2 patients","volume":"68","author":"Garin","year":"2008","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2026062214515523700_B20","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s11892-024-01547-1","article-title":"The elusive nature of ABCC8-related maturity-onset diabetes of the young (ABCC8-MODY). A review of the literature and case discussion","volume":"24","author":"Marassi","year":"2024","journal-title":"Curr Diab Rep"},{"key":"2026062214515523700_B21","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/978-1-0716-3818-7_12","article-title":"Non-radioactive Rb(+) efflux assay for screening K(ATP) channel modulators","volume":"2796","author":"ElSheikh","year":"2024","journal-title":"Methods Mol Biol"},{"key":"2026062214515523700_B22","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.2337\/db10-1631","article-title":"Diazoxide-unresponsive congenital hyperinsulinism in children with dominant mutations of the \u03b2-cell sulfonylurea receptor SUR1","volume":"60","author":"Macmullen","year":"2011","journal-title":"Diabetes"},{"key":"2026062214515523700_B23","doi-asserted-by":"crossref","first-page":"917","DOI":"10.2337\/db20-0881","article-title":"Glucokinase inactivation paradoxically ameliorates glucose intolerance by increasing \u03b2-cell mass in db\/db mice","volume":"70","author":"Omori","year":"2021","journal-title":"Diabetes"},{"key":"2026062214515523700_B24","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.2337\/db21-0992","article-title":"Genetic reduction of glucose metabolism preserves functional \u03b2-cell mass in KATP-induced neonatal diabetes","volume":"71","author":"Yan","year":"2022","journal-title":"Diabetes"},{"key":"2026062214515523700_B25","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.2337\/diabetes.54.10.2925","article-title":"ATP-sensitive K+ channel signaling in glucokinase-deficient diabetes","volume":"54","author":"Remedi","year":"2005","journal-title":"Diabetes"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/75\/7\/1323\/862637\/db251098.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/75\/7\/1323\/862637\/db251098.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T18:52:05Z","timestamp":1782154325000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/75\/7\/1323\/164751\/Co-occurrence-of-Loss-of-Function-GCK-and-ABCC8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,17]]},"references-count":25,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4,17]]},"published-print":{"date-parts":[[2026,7,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db25-1098","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,17]]}}}