Genotype-phenotype discrepancy among family members carrying a novel glucokinase mutation: insights into the interplay of GCK-MODY and insulin resistance
Authors: Ji Shuhui , Shu Hua , Zhao Hongqiang , Ye Yuanyuan , Liu Xuan , Chen Shanshan , Yang Ying , Feng Wenli , Qiao Jingting , Zhen Jinyang , Yang Xiong , Zhang Ziyue , Fan Yu , Huang Yadi , He Qing , Wang Minxian , Wang Kunlin , Liu Ming 
Published: August 2024

AbstractAims/HypothesisHeterozygous inactivating mutations in the glucokinase (GCK) gene are known to cause maturity-onset diabetes of the young (GCK-MODY). We identified a novel variant of uncertain significance (VUS) GCK mutation (c.77A>T, p.Q26L) in two family members presenting markedly different severities of diabetic phenotypes. This study aimed to elucidate the potential diabetogenic effect of GCK-Q26L and to explore the mono- and poly-genetic background attributing to different diabetes phenotypes.MethodsWhole-exome sequencing (WES) and genetic analyses, including polygenic risk score (PRS) assessments, were performed in three members of a family with early-onset diabetes. To elucidate the impact of the GCK-Q26L mutation on glucose homeostasis, a global knock-in mouse model harboring this mutation in both heterozygous and homozygous states was generated. Insulin content and insulin secretion response to glucose and potassium were evaluated in isolated islets. Furthermore, the effects of dorzagliatin (a glucokinase activator, GKA) and liraglutide (a glucagon like peptide 1 receptor agonist, GLP-1RA) on glucose tolerance and insulin secretion were assessed in GCK-Q26L mutant mice.ResultsThe proband, who inherited the GCK-Q26L mutation from her father (presenting with non-progressive, mildly elevated blood glucose), exhibited severe diabetic phenotypes including polydipsia, polyuria, polyphagia, weight loss, and ketosis, accompanied by significant dyslipidemia. Genetic analyses revealed that the proband’s severe phenotypes and metabolic profiles were associated with a high polygenic risk score (PRS) for insulin resistance that was inherited from her mother. Global heterozygous GCK-Q26L knock-in mice showed a mild increased fasting blood glucose, impaired glucose tolerance (IGT), and decreased serum insulin. Homozygous GCK-Q26L mice presented more severe phenotypes compared to their heterozygous counterparts, confirming the diabetogenic nature of the GCK-Q26L mutation. Further analyses indicated that GCK-Q26L did not affect insulin sensitivity and islet insulin content. However, GCK-Q26L blunted islet responsiveness to different glucose concentrations and markedly impaired glucose-stimulated insulin secretion (GSIS) without affecting potassium chloride-stimulated insulin secretion (KSIS) and glucose inhibitory effects on glucagon secretion. Both GKA and GLP-1RA enhanced insulin secretion and improved glucose tolerance in mutant mice.Conclusions/InterpretationThis study demonstrates that GCK-Q26L is a GCK-MODY causing mutation. The interplay of GCK-Q26L with a high PRS for insulin resistance contributes to severe diabetic phenotypes. The findings not only expend the list of GCK-MODY causing mutations originally classified as VUS mutations, but also provides insights into interactions of GCK-MODY with polygenic risks of type 2 diabetes, highlighting the importance of considering polygenic backgrounds in the assessment and management of monogenic diabetes.Research in ContextWhat is already known about this subject?Heterozygous inactivating mutations in the GCK gene cause GCK-MODY, an autosomal dominant disorder characterized by mild hyperglycemia present from birth.Insulin resistance can be influenced by multiple genetic polymorphisms, contributing to varying diabetes phenotypes.What is the key question?Is the newly discovered GCK mutation pathogenic?Do the interactions between the GCK mutation and PRS for insulin resistance influence the phenotypic variability in patients carrying GCK-MODY?What are the new findings?The study demonstrates GCK-Q26L impairs GSIS and causes diabetes, establishing it as a novel GCK-MODY causing mutation originally classified as a VUS mutation.The GCK-Q26L knock-in mouse line replicates phenotypes of GCK-MODY in humans, establishing it as an excellent model for GCK-MODY.The phenotypic variability in patients with GCK-MODY can be significantly influenced by high-risk genetic predisposition of type 2 diabetes.Both GKA and GLP-1RA enhance insulin secretion and improve glucose tolerance in GCK-Q26L mutant mice, suggesting that they are favorite options for treatment of patients with GCK-MODY and insulin resistance.How might this impact clinical practice in the foreseeable future?Recognizing atypical presentations of monogenic diabetes influenced by polygenic factors can enhance diagnostic accuracy and personalized management.Genetic testing and polygenic risk score assessments can help identify patients at higher risk of severe phenotypes, allowing for earlier and more targeted interventions.