Phenotypic Characterization of Congenital Hyperinsulinism Due to Novel Activating Glucokinase Mutations.

Autor:	Li C; Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA.; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.; Nanjing AscendRare Pharmaceutical Technology Co., Nanjing, China., Juliana CA; Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA., Yuan Y; Nanjing AscendRare Pharmaceutical Technology Co., Nanjing, China., Li M; Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China., Lu M; Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA., Chen P; Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA., Boodhansingh KE; Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA., Doliba NM; Institute of Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Bhatti TR; Department of Pathology, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Adzick NS; Department of Surgery, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Stanley CA; Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA.; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., De León DD; Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA.; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2023 Dec 01; Vol. 72 (12), pp. 1809-1819.
DOI:	10.2337/db23-0465
Abstrakt:	The importance of glucokinase (GK) in the regulation of insulin secretion has been highlighted by the phenotypes of individuals with activating and inactivating mutations in the glucokinase gene (GCK). Here we report 10 individuals with congenital hyperinsulinism (HI) caused by eight unique activating mutations of GCK. Six are novel and located near previously identified activating mutations sites. The first recognized episode of hypoglycemia in these patients occurred between birth and 24 years, and the severity of the phenotype was also variable. Mutant enzymes were expressed and purified for enzyme kinetics in vitro. Mutant enzymes had low glucose half-saturation concentration values and an increased enzyme activity index compared with wild-type GK. We performed functional evaluation of islets from the pancreata of three children with GCK-HI who required pancreatectomy. Basal insulin secretion in perifused GCK-HI islets was normal, and the response to glyburide was preserved. However, the threshold for glucose-stimulated insulin secretion in perifused glucokinase hyperinsulinism (GCK-HI) islets was decreased, and glucagon secretion was greatly suppressed. Our evaluation of novel GCK disease-associated mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. Article Highlights: Our evaluation of six novel and two previously published activating GCK mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. These studies provide insights into the pathophysiology of GCK-hyperinsulinism and the dual role of glucokinase in β-cells and α-cells to regulate glucose homeostasis. (© 2023 by the American Diabetes Association.)
Databáze:	MEDLINE
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