Similar Datasets
Project description:RNAseq of pancreatic islets of db/db mice treated with AAV- Adipsin vs AAV-GFP 4 weeks post AAV injection
2020-02-04 | GSE144575 | GEO
Project description:Diabetes is a complex genetic disease affecting millions of people worldwide. A common monogenic form of diabetes is glucokinase (GCK) maturity-onset diabetes of the young (GCK-MODY), which is caused by heterozygous inactivating variants in the gene encoding GCK. GCK catalyzes the phosphorylation of glucose and is known as the pancreatic glucose sensor. Patients with GCK-MODY, in contrast to other diabetics, often do not require treatment but are frequently misdiagnosed and treated unnecessarily. Genetic testing can prevent this, but is hampered by the challenge of interpreting genetic variants. To address this challenge, we generated a comprehensive map of human GCK variant activity. The activity map includes 97% of the possible missense and nonsense variants and correlate with in vitro catalytic efficiency, fasting glucose levels in patients and evolutionary conservation analysis. Activity scores include both hyper- and hypoactive variants.
2022-06-16 | GSE198878 | GEO
Project description:Amino acid substitutions can perturb protein activity in multiple ways. Understanding their mechanistic basis may pinpoint how residues contribute to protein function. Here, we characterize the mechanisms of human glucokinase (GCK) variants, building on our previous comprehensive study on GCK variant activity. We assayed the abundance of 95\% GCK missense and nonsense variants, and found that 59\% of hypoactive variants have a decreased cellular abundance. By combining our abundance scores with predictions of protein thermodynamic stability, we identify residues important for GCK metabolic stability and conformational dynamics. These residues could be targeted to modulate GCK activity, and thereby affect glucose homeostasis.
2023-05-22 | GSE226732 | GEO
Project description:C57BL/6J mice were subjected to 30 Gy liver irradiation (5 Gy × 6 fractions). METTL14 overexpression was achieved via AAV-METTL14 tail-vein injection. Liver tissues were collected for RNA-seq analysis to identify differentially expressed genes (DEGs) related to cell death pathways.
2026-05-04 | E-MTAB-16163 | biostudies-arrayexpress
Project description:Beta cell-targeted glucokinase overexpression
| PRJNA413133 | ENA
Project description:Analysis of genes from glucokinase-expressing cells following immunoprecipitation of hypothalamic EGFP-tagged L10 ribosomal protein from Glucokinase-cre/Elongation factor 1 alpha 1 - lox stop lox - EGFPL10 mice mRNA obtained by immunoprecipitation in adult Gck-cre/EF1A1-LSL-EGFPL10 mice
2013-09-13 | E-GEOD-49868 | biostudies-arrayexpress
Project description:Objective: Glucokinase Regulatory Protein (GKRP) controls the activity of Glucokinase (GCK) to regulate liver glucose uptake and storage. Coding variants in GCKR, the gene encoding GKRP, strongly associate with fatty liver disease, hypertriglyceridemia, and hypercholesterolemia. Here, we sought to investigate the mechanisms by which a common GKRP variant affects hepatic lipid and cholesterol metabolism. Methods: We developed mouse models to examine how the human GKRP P446L variant influences liver and systemic metabolism. Endogenous Gckr expression was ablated in adult mouse hepatocytes, together with re-expression of either human GKRP-P446L or the reference GKRP protein. We assessed body weight, adiposity, systemic glucose homeostasis, and hepatic metabolites in mice expressing reference GKRP or GKRP P446L under multiple metabolic conditions. To determine whether the effects of GKRP P446L may result from reduced GCK activity, we analyzed mice with liver-specific deletion of Gck. Results: Hepatic expression of GKRP P446L resulted in reduced GKRP and GCK protein levels and elevated serum cholesterol. Hepatic deletion of Gck in mice recapitulated several effects of GKRP-P446L, including increased hepatic cholesterol and triglyceride content. The elevated cholesterol was associated with increased cholesterogenic gene expression and cholesterol synthesis. Hepatic expression of an alternative hexokinase (HKII) normalized the effects of GCK-deficiency, suggesting that impaired glucose phosphorylation underlies the phenotype. Conclusions: The GKRP P446L variant reduced GKRP protein abundance, and diminished GCK activity while increasing cholesterol levels. Loss of GCK elevated cholesterol and hepatic triglyceride levels. Collectively, these findings demonstrate that GCK suppresses hepatic cholesterol synthesis and lipid accumulation, suggesting that reduced GCK activity underlies the metabolic abnormalities associated with the GKRP P446L variant.
2026-06-11 | GSE334975 | GEO
Project description:We compared RNA expression profiles of wild type of mice maintained on high fat diet or Irs1/2:foxo1-LTKO mice infected with Fst288 AAV-TBG virus Fst288-AAV-TBG infection modestly up- or down-regulated the expression of many genes, including several related to hepatic glucose metabolism (Pck1, G6pc and Gck) (Fig. S8a); qPCR confirmed that Fst288AAV•TBG affected the expression of these and other genes during both fasting (Pck1, G6pc and Gck) and feeding (Foxo1, Igfbp1, Pck1, and Ppargc1a)
2018-03-14 | GSE111745 | GEO
Project description:Hypoxia frequently occurs during rapid tumour growth. However, how tumour cells adapt to hypoxic stress by remodeling central cellular pathways remains largely unclear. Here, we demonstrated that hypoxia induces casein kinase 2 (CK2)-mediated glucokinase (GCK) S398 phosphorylation, which exposes its nuclear localization signal (NLS) for importin 1 binding and nuclear translocation. Importantly, nuclear GCK interacts with TAZ and functions as a protein kinase that phosphorylates TAZ T346. Phosphorylated TAZ recruits PIN1 for cis–trans isomerization of TAZ, which inhibits the binding of -TrCP to TAZ and -TrCP-mediated TAZ degradation. Activated TAZ-TEAD induces the expression of downstream target genes to promote tumour growth. These findings reveal an instrumental mechanism by which a glycolytic enzyme regulates the Hippo pathway under hypoxic conditions and highlight the moonlighting function of GCK as a protein kinase in modulating TAZ activity and tumour growth.
2025-07-14 | PXD061668 | Pride
Project description:Diabetes is a disorder characterized by loss of beta cell mass and/or beta cell function, leading to deficiency of insulin relative to metabolic need. To determine whether stem cell derived-beta cells faithfully reflect the phenotypes of a diabetic subject, we generated induced pluripotent stem cells from diabetic subjects (MODY2) with heterozygous loss-of-function of the gene encoding glucokinase (GCK). These stem cells differentiated into beta cells with an efficiency comparable to controls, and expressed markers of mature beta cells, urocotin-3 and zinc transporter 8 upon transplantation into mice. While insulin secretion in response to arginine or other secretagogues was identical to cells from healthy controls, GCK mutant beta cells required higher glucose levels to stimulate insulin secretion. Importantly this glucose-specific phenotype was fully reverted upon gene sequence correction by homologous recombination. Our results demonstrate that stem cell-derived beta cells reflect beta cell-autonomous phenotypes of MODY2 subjects, providing a platform for mechanistic analysis of specific genotypes on beta cell function.
2013-04-05 | GSE45777 | GEO