Case report: hypoglycemia due to a novel activating glucokinase variant in an adult – a molecular approach
We present a case of an obese 22-year-old man with activating <i>GCK</i> 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 <i>G...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Frontiers Media
2022
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| _version_ | 1797110844898672640 |
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| author | Koneshamoorthy, A Seniveratne-Epa, D Calder, G Sawyer, M Kay, TWH Farrell, S Loudovaris, T Mariana, L McCarthy, D Lyu, R Liu, X Thorn, P Tong, J Chin, LK Zacharin, M Trainer, A Taylor, S MacIsaac, RJ Sachithanandan, N Thomas, HE Krishnamurthy, B |
| author_facet | Koneshamoorthy, A Seniveratne-Epa, D Calder, G Sawyer, M Kay, TWH Farrell, S Loudovaris, T Mariana, L McCarthy, D Lyu, R Liu, X Thorn, P Tong, J Chin, LK Zacharin, M Trainer, A Taylor, S MacIsaac, RJ Sachithanandan, N Thomas, HE Krishnamurthy, B |
| author_sort | Koneshamoorthy, A |
| collection | OXFORD |
| description | We present a case of an obese 22-year-old man with activating <i>GCK</i> 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 <i>GCK</i> 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 <i>GCK</i> 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 <i>INS</i> and <i>CKB</i> genes and downregulated <i>DLK1</i> and <i>NPY</i> 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 <i>GCK</i> mutations. In-depth molecular analyses in the islets have revealed possible mechanisms for hyperplastic islets and insulin hypersecretion. |
| first_indexed | 2024-03-07T08:00:23Z |
| format | Journal article |
| id | oxford-uuid:63c6dc87-9a91-4813-ad6e-e035bc729229 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:00:23Z |
| publishDate | 2022 |
| publisher | Frontiers Media |
| record_format | dspace |
| spelling | oxford-uuid:63c6dc87-9a91-4813-ad6e-e035bc7292292023-09-28T17:33:42ZCase report: hypoglycemia due to a novel activating glucokinase variant in an adult – a molecular approachJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:63c6dc87-9a91-4813-ad6e-e035bc729229EnglishSymplectic ElementsFrontiers Media2022Koneshamoorthy, ASeniveratne-Epa, DCalder, GSawyer, MKay, TWHFarrell, SLoudovaris, TMariana, LMcCarthy, DLyu, RLiu, XThorn, PTong, JChin, LKZacharin, MTrainer, ATaylor, SMacIsaac, RJSachithanandan, NThomas, HEKrishnamurthy, BWe present a case of an obese 22-year-old man with activating <i>GCK</i> 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 <i>GCK</i> 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 <i>GCK</i> 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 <i>INS</i> and <i>CKB</i> genes and downregulated <i>DLK1</i> and <i>NPY</i> 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 <i>GCK</i> mutations. In-depth molecular analyses in the islets have revealed possible mechanisms for hyperplastic islets and insulin hypersecretion. |
| spellingShingle | Koneshamoorthy, A Seniveratne-Epa, D Calder, G Sawyer, M Kay, TWH Farrell, S Loudovaris, T Mariana, L McCarthy, D Lyu, R Liu, X Thorn, P Tong, J Chin, LK Zacharin, M Trainer, A Taylor, S MacIsaac, RJ Sachithanandan, N Thomas, HE Krishnamurthy, B Case report: hypoglycemia due to a novel activating glucokinase variant in an adult – a molecular approach |
| title | Case report: hypoglycemia due to a novel activating glucokinase variant in an adult – a molecular approach |
| title_full | Case report: hypoglycemia due to a novel activating glucokinase variant in an adult – a molecular approach |
| title_fullStr | Case report: hypoglycemia due to a novel activating glucokinase variant in an adult – a molecular approach |
| title_full_unstemmed | Case report: hypoglycemia due to a novel activating glucokinase variant in an adult – a molecular approach |
| title_short | Case report: hypoglycemia due to a novel activating glucokinase variant in an adult – a molecular approach |
| title_sort | case report hypoglycemia due to a novel activating glucokinase variant in an adult a molecular approach |
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