TY - JOUR
T1 - Case Report
T2 - Hypoglycemia Due to a Novel Activating Glucokinase Variant in an Adult – a Molecular Approach
AU - Koneshamoorthy, Anojian
AU - Seniveratne-Epa, Dilan
AU - Calder, Genevieve
AU - Sawyer, Matthew
AU - Kay, Thomas W.H.
AU - Farrell, Stephen
AU - Loudovaris, Thomas
AU - Mariana, Lina
AU - McCarthy, Davis
AU - Lyu, Ruqian
AU - Liu, Xin
AU - Thorn, Peter
AU - Tong, Jason
AU - Chin, Lit Kim
AU - Zacharin, Margaret
AU - Trainer, Alison
AU - Taylor, Shelby
AU - MacIsaac, Richard J.
AU - Sachithanandan, Nirupa
AU - Thomas, Helen E.
AU - Krishnamurthy, Balasubramanian
N1 - Publisher Copyright:
Copyright © 2022 Koneshamoorthy, Seniveratne-Epa, Calder, Sawyer, Kay, Farrell, Loudovaris, Mariana, McCarthy, Lyu, Liu, Thorn, Tong, Chin, Zacharin, Trainer, Taylor, MacIsaac, Sachithanandan, Thomas and Krishnamurthy.
PY - 2022/3/17
Y1 - 2022/3/17
N2 - We present a case of an obese 22-year-old man with activating GCK variant who had neonatal hypoglycemia, re-emerging with hypoglycemia later in life. We investigated him for asymptomatic hypoglycemia with a family history of hypoglycemia. Genetic testing yielded a novel GCK missense class 3 variant that was subsequently found in his mother, sister and nephew and reclassified as a class 4 likely pathogenic variant. Glucokinase enables phosphorylation of glucose, the rate-limiting step of glycolysis in the liver and pancreatic β cells. It plays a crucial role in the regulation of insulin secretion. Inactivating variants in GCK cause hyperglycemia and activating variants cause hypoglycemia. Spleen-preserving distal pancreatectomy revealed diffuse hyperplastic islets, nuclear pleomorphism and periductular islets. Glucose stimulated insulin secretion revealed increased insulin secretion in response to glucose. Cytoplasmic calcium, which triggers exocytosis of insulin-containing granules, revealed normal basal but increased glucose-stimulated level. Unbiased gene expression analysis using 10X single cell sequencing revealed upregulated INS and CKB genes and downregulated DLK1 and NPY genes in β-cells. Further studies are required to see if alteration in expression of these genes plays a role in the metabolic and histological phenotype associated with glucokinase pathogenic variant. There were more large islets in the patient’s pancreas than in control subjects but there was no difference in the proportion of β cells in the islets. His hypoglycemia was persistent after pancreatectomy, was refractory to diazoxide and improved with pasireotide. This case highlights the variable phenotype of GCK mutations. In-depth molecular analyses in the islets have revealed possible mechanisms for hyperplastic islets and insulin hypersecretion.
AB - We present a case of an obese 22-year-old man with activating GCK variant who had neonatal hypoglycemia, re-emerging with hypoglycemia later in life. We investigated him for asymptomatic hypoglycemia with a family history of hypoglycemia. Genetic testing yielded a novel GCK missense class 3 variant that was subsequently found in his mother, sister and nephew and reclassified as a class 4 likely pathogenic variant. Glucokinase enables phosphorylation of glucose, the rate-limiting step of glycolysis in the liver and pancreatic β cells. It plays a crucial role in the regulation of insulin secretion. Inactivating variants in GCK cause hyperglycemia and activating variants cause hypoglycemia. Spleen-preserving distal pancreatectomy revealed diffuse hyperplastic islets, nuclear pleomorphism and periductular islets. Glucose stimulated insulin secretion revealed increased insulin secretion in response to glucose. Cytoplasmic calcium, which triggers exocytosis of insulin-containing granules, revealed normal basal but increased glucose-stimulated level. Unbiased gene expression analysis using 10X single cell sequencing revealed upregulated INS and CKB genes and downregulated DLK1 and NPY genes in β-cells. Further studies are required to see if alteration in expression of these genes plays a role in the metabolic and histological phenotype associated with glucokinase pathogenic variant. There were more large islets in the patient’s pancreas than in control subjects but there was no difference in the proportion of β cells in the islets. His hypoglycemia was persistent after pancreatectomy, was refractory to diazoxide and improved with pasireotide. This case highlights the variable phenotype of GCK mutations. In-depth molecular analyses in the islets have revealed possible mechanisms for hyperplastic islets and insulin hypersecretion.
KW - MODY
KW - congenital hyperinsulinism
KW - glucokinase
KW - hyperplastic islets
KW - hypoglycemia
UR - http://www.scopus.com/inward/record.url?scp=85127938223&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127938223&partnerID=8YFLogxK
U2 - 10.3389/fendo.2022.842937
DO - 10.3389/fendo.2022.842937
M3 - Article
AN - SCOPUS:85127938223
SN - 1664-2392
VL - 13
JO - Frontiers in Endocrinology
JF - Frontiers in Endocrinology
M1 - 842937
ER -