Skip to main content
Top
Published in: Acta Diabetologica 2/2016

01-04-2016 | Original Article

GCKR polymorphism influences liver fat content in patients with type 2 diabetes

Authors: Jean-Michel Petit, David Masson, Boris Guiu, Fabien Rollot, Laurence Duvillard, Benjamin Bouillet, Marie-Claude Brindisi, Perrine Buffier, Patrick Hillon, Jean-Pierre Cercueil, Bruno Verges

Published in: Acta Diabetologica | Issue 2/2016

Login to get access

Abstract

Aims

It has recently been shown that an allele in the glucokinase regulatory protein (GCKR) gene was associated with increased liver fat content in obese children. In this study, we set out to determine whether GCKR rs1260326 polymorphism was associated with liver fat content in patients with type 2 diabetes.

Methods

Three hundred and eight patients with type 2 diabetes were included in this study. Liver fat content was evaluated using 1H-MR spectroscopy.

Results

In our population, carriers of the rs1260326 minor T allele had a higher liver fat content than did carriers of the C allele homozygote (12.4 ± 9.6 vs. 10.3 ± 9.1 %, p = 0.03). The number of patients with steatosis was significantly higher in minor T allele carriers than in C allele homozygote carriers (70.7 vs. 55.4 %; p = 0.008). In multivariate analysis, the predictive variables for steatosis were BMI [odds ratio (OR) 1.08; 95 % confidence interval (CI) 1.03–1.13; p = 0.002], statin therapy (yes) [OR 0.54; 95 % CI 0.31–0.94; p = 0.03], metformin therapy (yes) [OR 2.67; 95 % CI 1.50–4.75; p < 0.001], and rs1260326 GCKR polymorphism (TT+CT) [OR 1.99; 95 % CI 1.14–3.47; p = 0.01].

Conclusions

This study shows that in patients with type 2 diabetes who were not selected for liver abnormalities, liver fat content was related to GCKR rs1260326 polymorphism independent of BMI, triglyceride levels, and age.
Literature
1.
go back to reference Cusi K (2009) Nonalcoholic fatty liver disease in type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes 16:141–149CrossRefPubMed Cusi K (2009) Nonalcoholic fatty liver disease in type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes 16:141–149CrossRefPubMed
2.
go back to reference Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L et al (2007) Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 30:1212–1218CrossRefPubMed Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L et al (2007) Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 30:1212–1218CrossRefPubMed
3.
go back to reference Kotronen A, Juurinen L, Hakkarainen A, Westerbacka J, Cornér A, Bergholm R et al (2008) Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care 31:165–169CrossRefPubMed Kotronen A, Juurinen L, Hakkarainen A, Westerbacka J, Cornér A, Bergholm R et al (2008) Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care 31:165–169CrossRefPubMed
4.
go back to reference Petit JM, Guiu B, Terriat B, Loffroy R, Robin I, Petit V et al (2009) Non-alcoholic fatty liver is not associated with carotid intima-media thickness in type 2 diabetic patients. J Clin Endocrinol Metab 94:4103–4106CrossRefPubMed Petit JM, Guiu B, Terriat B, Loffroy R, Robin I, Petit V et al (2009) Non-alcoholic fatty liver is not associated with carotid intima-media thickness in type 2 diabetic patients. J Clin Endocrinol Metab 94:4103–4106CrossRefPubMed
5.
go back to reference Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA et al (2008) Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40:1461–1465CrossRefPubMedPubMedCentral Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA et al (2008) Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40:1461–1465CrossRefPubMedPubMedCentral
6.
go back to reference Petit JM, Guiu B, Masson D, Duvillard L, Jooste V, Buffier P et al (2010) Specifically-PNPLA3-mediated accumulation of liver fat in obese patients with type 2 diabetes. J Clin Endocrinol Metab 95:E430–E436CrossRefPubMed Petit JM, Guiu B, Masson D, Duvillard L, Jooste V, Buffier P et al (2010) Specifically-PNPLA3-mediated accumulation of liver fat in obese patients with type 2 diabetes. J Clin Endocrinol Metab 95:E430–E436CrossRefPubMed
7.
go back to reference Speliotes EK, Yerges-Armstrong L, Wu J, Hernaez R, Kim L, Palmer C, Gudnason V et al (2011) Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 7:e1001324CrossRefPubMedPubMedCentral Speliotes EK, Yerges-Armstrong L, Wu J, Hernaez R, Kim L, Palmer C, Gudnason V et al (2011) Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 7:e1001324CrossRefPubMedPubMedCentral
8.
go back to reference Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R et al (2012) Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 55:781–789CrossRefPubMedPubMedCentral Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R et al (2012) Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 55:781–789CrossRefPubMedPubMedCentral
9.
go back to reference Petta S, Miele L, Bugianesi E, Cammà C, Rosso C, Boccia S et al (2014) Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic fatty liver disease. PLoS One 9:e87523CrossRefPubMedPubMedCentral Petta S, Miele L, Bugianesi E, Cammà C, Rosso C, Boccia S et al (2014) Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic fatty liver disease. PLoS One 9:e87523CrossRefPubMedPubMedCentral
10.
go back to reference Rees MG, Wincovitch S, Schultz J, Waterstradt R, Beer NL, Baltrusch S et al (2012) Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk. Diabetologia 55:114–122CrossRefPubMedPubMedCentral Rees MG, Wincovitch S, Schultz J, Waterstradt R, Beer NL, Baltrusch S et al (2012) Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk. Diabetologia 55:114–122CrossRefPubMedPubMedCentral
11.
go back to reference Orho-Melander M, Melander O, Guiducci C, Perez-Martinez P, Corella D, Roos C et al (2008) Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations. Diabetes 57:3112–3121CrossRefPubMedPubMedCentral Orho-Melander M, Melander O, Guiducci C, Perez-Martinez P, Corella D, Roos C et al (2008) Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations. Diabetes 57:3112–3121CrossRefPubMedPubMedCentral
12.
go back to reference Guiu B, Petit JM, Loffroy R, Ben Salem D, Aho S, Masson D et al (2009) Quantification of liver fat content: comparison of triple-echo chemical shift gradient-echo imaging and in vivo proton MR spectroscopy. Radiology 250:95–102CrossRefPubMed Guiu B, Petit JM, Loffroy R, Ben Salem D, Aho S, Masson D et al (2009) Quantification of liver fat content: comparison of triple-echo chemical shift gradient-echo imaging and in vivo proton MR spectroscopy. Radiology 250:95–102CrossRefPubMed
13.
go back to reference Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC et al (2004) Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40:1387–1395CrossRefPubMed Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC et al (2004) Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40:1387–1395CrossRefPubMed
14.
go back to reference Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S et al (2005) Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288:E462–E468CrossRefPubMed Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S et al (2005) Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288:E462–E468CrossRefPubMed
15.
go back to reference Adams LA, Harmsen S, St Sauver JL, Charatcharoenwitthaya P, Enders FB, Therneau T et al (2010) Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study. Am J Gastroenterol 105:1567–1573CrossRefPubMedPubMedCentral Adams LA, Harmsen S, St Sauver JL, Charatcharoenwitthaya P, Enders FB, Therneau T et al (2010) Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study. Am J Gastroenterol 105:1567–1573CrossRefPubMedPubMedCentral
16.
go back to reference de Marco R, Locatelli F, Zoppini G, Verlato G, Bonora E, Muggeo M (1999) Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care 22:756–761CrossRefPubMed de Marco R, Locatelli F, Zoppini G, Verlato G, Bonora E, Muggeo M (1999) Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care 22:756–761CrossRefPubMed
17.
go back to reference Lynedjian PB (2009) Molecular physiology of mammalian glucokinase. Cell Mol Life Sci 66:27–42CrossRef Lynedjian PB (2009) Molecular physiology of mammalian glucokinase. Cell Mol Life Sci 66:27–42CrossRef
18.
go back to reference Beer NL, Tribble ND, McCulloch LJ, Roos C, Johnson PR, Orho-Melander M et al (2009) The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet 18:4081–4088CrossRefPubMedPubMedCentral Beer NL, Tribble ND, McCulloch LJ, Roos C, Johnson PR, Orho-Melander M et al (2009) The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet 18:4081–4088CrossRefPubMedPubMedCentral
19.
go back to reference Sparsø T, Andersen G, Nielsen T, Burgdorf KS, Gjesing AP, Nielsen AL et al (2008) The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes. Diabetologia 51:70–75CrossRefPubMed Sparsø T, Andersen G, Nielsen T, Burgdorf KS, Gjesing AP, Nielsen AL et al (2008) The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes. Diabetologia 51:70–75CrossRefPubMed
20.
go back to reference Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU et al (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42:105–116CrossRefPubMedPubMedCentral Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU et al (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42:105–116CrossRefPubMedPubMedCentral
21.
go back to reference Peter A, Stefan N, Cegan A, Walenta M, Wagner S, Königsrainer A et al (2011) Hepatic glucokinase expression is associated with lipogenesis and fatty liver in humans. J Clin Endocrinol Metab 96:E1126–E1130CrossRefPubMed Peter A, Stefan N, Cegan A, Walenta M, Wagner S, Königsrainer A et al (2011) Hepatic glucokinase expression is associated with lipogenesis and fatty liver in humans. J Clin Endocrinol Metab 96:E1126–E1130CrossRefPubMed
22.
go back to reference Williamson RM, Price JF, Glancy S, Perry E, Nee LD, Hayes PC et al (2011) Edinburgh Type 2 Diabetes Study Investigators. Prevalence of and risk factors for hepatic steatosis and nonalcoholic Fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care 34:1139–1144CrossRefPubMedPubMedCentral Williamson RM, Price JF, Glancy S, Perry E, Nee LD, Hayes PC et al (2011) Edinburgh Type 2 Diabetes Study Investigators. Prevalence of and risk factors for hepatic steatosis and nonalcoholic Fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care 34:1139–1144CrossRefPubMedPubMedCentral
Metadata
Title
GCKR polymorphism influences liver fat content in patients with type 2 diabetes
Authors
Jean-Michel Petit
David Masson
Boris Guiu
Fabien Rollot
Laurence Duvillard
Benjamin Bouillet
Marie-Claude Brindisi
Perrine Buffier
Patrick Hillon
Jean-Pierre Cercueil
Bruno Verges
Publication date
01-04-2016
Publisher
Springer Milan
Published in
Acta Diabetologica / Issue 2/2016
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI
https://doi.org/10.1007/s00592-015-0766-4

Other articles of this Issue 2/2016

Acta Diabetologica 2/2016 Go to the issue