Mutations in GCK May Lead to MODY2 by Reducing Glycogen Synthesis

Abstract

Dysfunction of glucokinase (GCK) caused by mutations in the GCK gene is the main cause of maturity‐onset diabetes of the young type‐2 (MODY2, also known as GCK‐MODY), which is usually present in adolescence or young adulthood. MODY2 is characterized by mild, stable fasting hyperglycemia that presents at birth, usually 5.4–8.3 mmol L−1, and rarely develops complications from diabetes. The treatment of MODY2 prefers a manageable diet rather than the use of insulin. Previous studies have identified GCK mutations only by online software prediction or enzyme kinetic analysis and thermolability assays which are complicated to be conducted. In this study, six mutations in the GCK gene, including four novel mutations and two mutations that are previously reported, are identified. All the six locations are highly conserved according to the sequencing alignment. Moreover, missense mutations are strongly predicted to be pathogenic using online programs. Functional studies show that mutations in GCK mutation do not affect insulin secretion but affect glycogen synthesis. These findings demonstrate that GCK mutations decrease glycogen synthesis, which leads to hyperglycemia in MODY2. Meanwhile, this study provides a new perspective and methods for identifying pathogenic mutations in GCK.

Changes in metabolites in raw and wine processed Corni Fructus combination metabolomics with network analysis focusing on potential hypoglycemic effects

“…Network analysis revealed that these tested compounds of CF potentially exert a hypoglycemic effect by regulating the core proteins GCK and ADCYs, thereby affecting multiple pathways. According to the literature, glucokinase (GCK) and adenylate cyclases (ADCYs) proteins are considered important targets for diabetes treatment, glucokinase (GCK) serves as the initial and rate-limiting step in pancreatic and hepatic glycolysis ( Li et al, 2022 ), while adenylate cyclases (ADCYs) are involved in the development of diabetes ( Abdel-Halim et al, 2020 ). To elucidate the hypoglycemia molecular mechanism of the active ingredients in HepG2 cells, we investigated the effects of six compounds on the expression of proteins associated with GCK and ADCYs.…”

Expanding the mutational spectrum ofGCKin Turkish pediatric population

“…Consequently, both H50D and R191Q were given PM5 instead of PS3, nevertheless, either variant ensured adequate points to be classified as pathogenic. Other variants with a functional study were Arg36Trp (Osbak et al, 2009), Gly44Ser (Wang et al, 2019), Gly72Arg (Raimondo et al, 2014), Gly223Ser (Valentinova et al, 2012), Glu265Lys (Osbak et al, 2009), Met393Thr (Raimondo et al, 2014), Thr431Lys (Lin et al, 2019), and Gly448Ser (Li et al, 2022).…”