The GCKR-P446L gene variant predisposes to raised blood cholesterol and lower blood glucose in the P446L mouse-a model for GCKR rs1260326

Ford, Brian E.; Chachra, Shruti S.; Rodgers, Katrina; Moonira, Tabassum; Al‐Oanzi, Ziad H.; Anstee, Quentin M.; Reeves, Helen L.; Schattenberg, Jörn M.; Fairclough, Rebecca J.; Smith, David M.; Tiniakos, Dina; Agius, Loranne

doi:10.1016/j.molmet.2023.101722

Cited by 7 publications

(21 citation statements)

References 80 publications

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“…The effects of HNF4A on insulin action and GGT contribute to the development of both T2DM and GSD. On the other hand, GCKR regulates glucose conversion to glucose-6-phosphate in the liver and pancreas ( 42 , 43 ). It is associated with various metabolites involved in carbohydrate and lipid metabolism ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

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Observational and genetic analyses clarify the relationship between type 2 diabetes mellitus and gallstone disease

Yan,

Zhang,

Yang

et al. 2024

Front. Endocrinol.

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BackgroundThe relationship between type 2 diabetes mellitus (T2DM) and gallstone disease (GSD) have been incompletely understood. We aimed to investigate their phenotypic and genetic associations and evaluate the biological mechanisms underlying these associations.MethodsWe first evaluated the phenotypic association between T2DM and GSD using data from the UK Biobank (n>450,000) using a prospective observational design. We then conducted genetic analyses using summary statistics from a meta-analysis of genome-wide association studies of T2DM, with and without adjusting for body mass index (BMI) (Ncase=74,124, Ncontrol=824,006; T2DMadjBMI: Ncase=50,409, Ncontrol=523,897) and GSD (Ncase=43,639, Ncontrol=506,798).ResultsA unidirectional phenotypic association was observed, where individuals with T2DM exhibited a higher GSD risk (hazard ratio (HR)=1.39, P<0.001), but not in the reverse direction (GSD→T2DM: HR=1.00, P=0.912). The positive T2DM-GSD genetic correlation (rg=0.35, P=7.71×10-23) remained even after adjusting for BMI (T2DMadjBMI: rg=0.22, P=4.48×10-10). Mendelian randomization analyses provided evidence of a unidirectional causal relationship (T2DM→GSD: odds ratio (OR)=1.08, P=4.6×10-8; GSD→T2DM: OR=1.02, P=0.48), even after adjusting for important metabolic confounders (OR=1.02, P=0.02). This association was further corroborated through a comprehensive functional analysis reflected by 23 pleiotropic single nucleotide polymorphisms, as well as multiple neural and motor-enriched tissues.ConclusionThrough comprehensive observational and genetic analyses, our study clarified the causal relationship between T2DM and GSD, but not in the reverse direction. These findings might provide new insights into prevention and treatment strategies for T2DM and GSD.

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Section: Discussionmentioning

confidence: 99%

“…The minor allele of GCKR has been associated with hepatospecific glucokinase activation, reduced plasma insulin levels, and protection against T2DM ( 42 ). Additionally, GCKR enhances hepatic cholesterol availability, leading to elevated bile cholesterol concentration and GSD development ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

Observational and genetic analyses clarify the relationship between type 2 diabetes mellitus and gallstone disease

Yan,

Zhang,

Yang

et al. 2024

Front. Endocrinol.

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“…In homozygote knockout mice (GKRP -/- ), the disruption of regulatory function and the corresponding reduction in GK activity leads to impaired glucose homeostasis, as demonstrated by reduced glycogen levels, elevated expression of PEPCK gene encoding the gluconeogenic enzyme, and impaired glucose disposal under a glucose challenge ( 71 ). Notably, unlike the elevated blood glucose observed in GKRP -/- on a high-sucrose/high-fat diet ( 71 ), the P446L mice showed lower blood glucose levels when fed a sugar containing diet ( 73 ). The discrepancy might be ascribed to the modest retention of GKRP still present in the P446L mice.…”

Section: Characteristics and Biological Functions Of Gkrpmentioning

confidence: 95%

“…However, contrary to expectations, with the knockout or knockdown of GKRP, GK expression and activity decrease simultaneously in the liver ( 71 , 72 ). In both mouse and human GKRP, the P446>L substitution has also been observed to reduce GKRP protein expression and lead to decreased hepatic GK levels ( 73 ). This suggests that GKRP has a stabilizing effect on GK, and that any knockdown or mutation of GKRP could dimmish this effect, leading to lower GK expression in hepatocytes.…”

Section: Characteristics and Biological Functions Of Gkrpmentioning

confidence: 99%

“…Without sufficient GK in the nucleus, hepatocytes cannot mobilize enough GK into the cytoplasm in response to changes in glucose levels. Due to the synchronous decrease in both total GK protein levels and nucleus reserves, hepatocytes from P446L mice had lower metabolic rates at elevated glucose concentrations, underscoring the acute regulatory role of GKRP in response to elevated glucose ( 73 ). In homozygote knockout mice (GKRP -/- ), the disruption of regulatory function and the corresponding reduction in GK activity leads to impaired glucose homeostasis, as demonstrated by reduced glycogen levels, elevated expression of PEPCK gene encoding the gluconeogenic enzyme, and impaired glucose disposal under a glucose challenge ( 71 ).…”

Section: Characteristics and Biological Functions Of Gkrpmentioning

confidence: 99%

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Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD

Zhang,

Ji,

2023

Front. Endocrinol.

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Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide, affected by both genetics and environment. Type 2 diabetes (T2D) stands as an independent environmental risk factor that precipitates the onset of hepatic steatosis and accelerates its progression to severe stages of liver damage. Furthermore, the coexistence of T2D and NAFLD magnifies the risk of cardiovascular disease synergistically. However, the association between genetic susceptibility and metabolic risk factors in NAFLD remains incompletely understood. The glucokinase regulator gene (GCKR), responsible for encoding the glucokinase regulatory protein (GKRP), acts as a regulator and protector of the glucose-metabolizing enzyme glucokinase (GK) in the liver. Two common variants (rs1260326 and rs780094) within the GCKR gene have been associated with a lower risk for T2D but a higher risk for NAFLD. Recent studies underscore that T2D presence significantly amplifies the effect of the GCKR gene, thereby increasing the risk of NASH and fibrosis in NAFLD patients. In this review, we focus on the critical roles of GKRP in T2D and NAFLD, drawing upon insights from genetic and biological studies. Notably, prior attempts at drug development targeting GK with glucokinase activators (GKAs) have shown potential risks of augmented plasma triglycerides or NAFLD. Conversely, overexpression of GKRP in diabetic rats improved glucose tolerance without causing NAFLD, suggesting the crucial regulatory role of GKRP in maintaining hepatic glucose and lipid metabolism balance. Collectively, this review sheds new light on the complex interaction between genes and environment in NAFLD, focusing on the GCKR gene. By integrating evidence from genetics, biology, and drug development, we reassess the therapeutic potential of targeting GK or GKRP for metabolic disease treatment. Emerging evidence suggests that selectively activating GK or enhancing GK-GKRP binding may represent a holistic strategy for restoring glucose and lipid metabolic balance.

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Compromised chronic efficacy of a glucokinase activator AZD1656 in mouse models for common human GCKR variants

Ford,

Chachra,

Alshawi

et al. 2024

Biochemical Pharmacology

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The GCKR-P446L gene variant predisposes to raised blood cholesterol and lower blood glucose in the P446L mouse-a model for GCKR rs1260326

Cited by 7 publications

References 80 publications

Observational and genetic analyses clarify the relationship between type 2 diabetes mellitus and gallstone disease

Observational and genetic analyses clarify the relationship between type 2 diabetes mellitus and gallstone disease

Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD

Compromised chronic efficacy of a glucokinase activator AZD1656 in mouse models for common human GCKR variants

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