Glucokinase, glucose homeostasis, and diabetes mellitus

Matschinsky, Franz M.

doi:10.1007/s11892-005-0005-4

Cited by 95 publications

(85 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…InserN161 is the second reported MODY2 mutation resulting in the insertion of one extra amino acid in GCK. Previous work revealed that the insertion of an alanine residue at position 454 in the allosteric activator site of GCK activated the enzyme [6]. The novel mutation found in family P33 resulted in the insertion of an asparagine residue between aspartic acid 160 and lysine 161, in the β7 strand, located in the middle of the small domain of GCK (Fig.…”

Section: Discussionmentioning

confidence: 92%

“…GCK plays a role as a beta cell glucose sensor by integrating blood glucose levels and glucose metabolism with insulin secretion [4][5][6]. This specific function of GCK is based on the particular kinetic characteristics of this enzyme, which include a low affinity for glucose, cooperativity with this substrate, and a lack of end-product inhibition at physiological concentrations.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis Glucokinase (GCK) acts as a glucose sensor in the pancreatic beta cell and regulates insulin secretion. In the gene encoding GCK the heterozygous mutations that result in enzyme inactivation cause MODY2. Functional studies of naturally occurring GCK mutations associated with hyperglycaemia provide further insight into the biochemical basis of glucose sensor regulation. Materials and methods Identification of GCK mutations in selected MODY patients was performed by single-strand conformation polymorphism and direct sequencing. The kinetic parameters and thermal stability of recombinant mutant human GCK were determined, and in pull-down assays the effect of these mutations on the association of GCK with glucokinase (hexokinase 4) regulator (GCKR, also known as glucokinase regulatory protein [GKRP]) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB1, also known as PFK2) was tested. Results We identified three novel GCK mutations: the insertion of an asparagine residue at position 161 (inserN161) and two missense mutations (M235V and R308W). We also identified a fourth mutation (R397L) reported in a previous work. Functional characterisation of these mutations revealed that insertion of asparagine residue N161 fully inactivates GCK, whereas the M235V and R308W mutations only partially impair enzymatic activity. In contrast, GCK kinetics was almost unaffected by the R397L mutation. Although none of these mutations affected the interaction of GCK with PFKFB1, we found that the R308W mutation caused protein instability and increased the strength of interaction with GCKR. Conclusions/interpretation Our results show that different MODY2 mutations impair GCK function through different mechanisms such as enzymatic activity, protein stability and increased interaction with GCKR, helping further elucidate the regulation of GCK activity.

show abstract

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity

et al. 2006

View full text Add to dashboard Cite

show abstract

“…GCK also participates in regulating glycogen synthesis and gluconeogenesis in the liver (1). GCK activity is allosterically controlled in hepatocytes by the glucokinase regulatory protein (GCKR), which reversibly binds to GCK and inhibits its activity in the presence of fructose 6-phosphate.…”

mentioning

confidence: 99%

“…Adenoviral-mediated hepatic overexpression of GCKR in mice with high-fat diet-induced diabetes improves fasting and glucoseinduced glycemia and leads to a concomitant increase in insulin sensitivity and triglyceride levels and a decrease in leptin levels (5). Heterozygous mutations in GCK resulting in a reduction of enzymatic activity are responsible for a subtype of monogenic diabetes (maturity-onset diabetes of the young-2) (1,6). Previous genetic studies at the GCKR locus have not reported intragenic mutations associated with type 2 diabetes in humans (7,8).…”

mentioning

confidence: 99%

The Common P446L Polymorphism in GCKR Inversely Modulates Fasting Glucose and Triglyceride Levels and Reduces Type 2 Diabetes Risk in the DESIR Prospective General French Population

Vaxillaire

Cavalcanti-Proença²,

Dechaume³

et al. 2008

Diabetes

176

159

View full text Add to dashboard Cite

,9 for the DESIR Study Group OBJECTIVE-Hepatic glucokinase (GCK) is a key regulator of glucose storage and disposal in the liver, where its activity is competitively modulated, with respect to glucose, by binding to glucokinase regulatory protein (GCKR) in the presence of fructose 6-phosphate. Genome-wide association studies for type 2 diabetes identified GCKR as a potential locus for modulating triglyceride levels. We evaluated, in a general French population, the contribution of the GCKR rs1260326-P446L polymorphism to quantitative metabolic parameters and to dyslipidemia and hyperglycemia risk.RESEARCH DESIGN AND METHODS-Genotype effects of rs1260326 were studied in 4,833 participants from the prospective DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) cohort both at inclusion and using the measurements at follow-up. RESULTS-The minor T-allele of rs1260326 was strongly associated with lower fasting glucose (Ϫ1.43% per T-allele; P ϭ 8 ϫ 10 Ϫ13 ) and fasting insulin levels (Ϫ4.23%; P ϭ 3 ϫ 10 Ϫ7 ), lower homeostasis model assessment of insulin resistance index (Ϫ5.69%; P ϭ 1 ϫ 10 Ϫ8 ), and, conversely, higher triglyceride levels (3.41%; P ϭ 1 ϫ 10 Ϫ4 ) during the 9-year study. These effects relate to a lower risk of hyperglycemia (odds ratio [OR] 0.79 [95% CI 0.70 -0.88]; P ϭ 4 ϫ 10 Ϫ5 ) and of incident cases during the study (hazard ratio ; P ϭ 0.005). Moreover, an additive effect of GCKR rs1260326(T) and GCK (Ϫ30G) alleles conferred lower fasting glycemia (P ϭ 1 ϫ 10 Ϫ13 ), insulinemia (P ϭ 5 ϫ 10 Ϫ6 ), and hyperglycemia risk (P ϭ 1 ϫ 10 Ϫ6 ). CONCLUSIONS-GCKR-L446carriers are protected against type 2 diabetes despite higher triglyceride levels and risk of dyslipidemia, which suggests a potential molecular mechanism by which these two components of the metabolic syndrome can be dissociated.

show abstract

“…In the pancreatic ␤-cells, GCK controls insulin secretion and biosynthesis (1). In the liver, GCK regulates glycogen synthesis and gluconeogenesis, and its activity is competitively inhibited by glucokinase regulatory protein (GCKR) (1,2).…”

mentioning

confidence: 99%

Interaction Effect of Genetic Polymorphisms in Glucokinase (GCK) and Glucokinase Regulatory Protein (GCKR) on Metabolic Traits in Healthy Chinese Adults and Adolescents

Tam

et al. 2009

Diabetes

View full text Add to dashboard Cite

OBJECTIVE-Recent studies in European populations have reported a reciprocal association of glucokinase regulatory protein (GCKR) gene with triglyceride versus fasting plasma glucose (FPG) levels and type 2 diabetes risk. GCKR is a rate-limiting factor of glucokinase (GCK), which functions as a key glycolytic enzyme for maintaining glucose homeostasis. We examined the associations of two common genetic polymorphisms of GCKR and GCK with metabolic traits in healthy Chinese adults and adolescents.RESEARCH DESIGN AND METHODS-Two single nucleotide polymorphisms (SNPs), rs780094 at GCKR and rs1799884 at GCK, were genotyped in 600 healthy adults and 986 healthy adolescents. The associations of these SNPs with metabolic traits were assessed by linear regression adjusted for age, sex, and/or BMI. We also tested for the epistasis between these two SNPs and performed a meta-analysis among European and Asian populations. RESULTS-The T-allele of GCKR rs780094 was associated with increased triglycerides (P ϭ 5.4 ϫ 10 Ϫ7 ), while the A-allele of GCK rs1799884 was associated with higher FPG (P ϭ 3.1 ϫ 10 Ϫ7 ). A novel interaction effect between the two SNPs on FPG was also observed (P ϭ 0.0025). Meta-analyses strongly supported the additive effects of the two SNPs on FPG and triglycerides, respectively. CONCLUSIONS-In support of the intimate relationship between glucose and lipid metabolisms, GCKR and GCK genetic polymorphisms interact to increase FPG in healthy adults and adolescents. These risk alleles may contribute to increased diabetes risk in subjects who harbor other genetic or environmental/lifestyle risk factors. Diabetes 58:765-769, 2009

show abstract

Glucokinase, glucose homeostasis, and diabetes mellitus

Cited by 95 publications

References 39 publications

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity

The Common P446L Polymorphism in GCKR Inversely Modulates Fasting Glucose and Triglyceride Levels and Reduces Type 2 Diabetes Risk in the DESIR Prospective General French Population

Interaction Effect of Genetic Polymorphisms in Glucokinase (GCK) and Glucokinase Regulatory Protein (GCKR) on Metabolic Traits in Healthy Chinese Adults and Adolescents

Contact Info

Product

Resources

About