TWO OPPOSITE PHENOTYPES OF GLUCOSE DISORDERS IN A FAMILY WITH HETEROZYGOUS P.SER453LEU (C.1358C> T) MUTATION IN THE GLUCOKINASE (GCK) GENE: MATURITY ONSET DIABETES IN YOUNG AND INSULINOMA

M Demiral; H B G Çelebi; S Cander; O Yerci; E Eren; H Demirbilek

doi:10.4183/aeb.2022.458

TWO OPPOSITE PHENOTYPES OF GLUCOSE DISORDERS IN A FAMILY WITH HETEROZYGOUS P.SER453LEU (C.1358C> T) MUTATION IN THE GLUCOKINASE (GCK) GENE: MATURITY ONSET DIABETES IN YOUNG AND INSULINOMA

Acta Endocrinol (Buchar). 2022 Oct-Dec;18(4):458-465. doi: 10.4183/aeb.2022.458.

Authors

M Demiral¹, H B G Çelebi², S Cander³, O Yerci⁴, E Eren⁵, H Demirbilek⁶

Affiliations

¹ Balıkesir Atatürk City Hospital, Department of Paediatric Endocrinology, Balıkesir.
² Balıkesir Atatürk City Hospital, Department of Medical Genetic, Balıkesir.
³ Uludağ University, Department of Endocrinology, Bursa.
⁴ Uludağ University, Department of Pathology, Bursa.
⁵ Uludağ University, Department of Paediatric Endocrinology, Bursa.
⁶ Hacettepe University, Faculty of Medicine, Department of Paediatric Endocrinology, Ankara, Turkey.

Abstract

Background: Heterozygous gain-of-function mutations in the glucokinase (GCK) gene cause hyperinsulinaemic hypoglycaemia (GCK-HI), while loss-of-function mutations lead to a monogenic type of diabetes (GCK-MODY). We, herein, report a heterozygous GCK gene mutation in a large family with GCK-MODY and insulinoma in one individual from the same family.

Patients and methods: The proband, an 11-year-old male, was referred for asymptomatic mild hyperglycemia (fasting glucose:121 mg/dL) and HbA1c of 6.1%. Segregation analysis of the family revealed multiplex members with asymptomatic fasting hyperglycaemia or non-insulin-dependent diabetes and 33-year-old maternal uncle of the proband case had a history of distal pancreatectomy due to the diagnosis of insulinoma. His preoperative investigations were revealed fasting glucose of 31 mg/dL, insulin: 7µU/mL, C-peptide: 2.6 mg/dL, and a low HbA1c(4.0%) which was suggestive for recurring hypoglycaemia episodes. Post-pancreatectomy he developed mild fasting hyperglycemia (115-136 mg/dL).

Results: Genetic analysis revealed heterozygous p.Ser453Leu(c.1358C> T) mutation in the GCK gene in the proband. In segregation analysis, the identical heterozygous p.Ser453Leu(c.1358C> T) GCK gene mutation was detected in all of the other affected family members for whom a DNA analysis was applicable. The maternal uncle was first diagnosed with insulinoma and underwent a pancreatectomy. He also had an identical mutation in a heterozygous state.

Conclusion: We, to the best of our knowledge, firstly identified these two entirely distinct phenotypes of glucose metabolism, GCK-MODY and GCK-HI, due to an identical heterozygous p.Ser453Leu (c.1358C> T) mutation in the GCK. Further studies required to elucidate this new phenomenon and understanding the genotype-phenotype relationship of GCK gene mutations.

Keywords: GCK gene; MODY; hyperinsulinaemic hypoglycaemia; insulinoma.