title: A Common Gene Variant in Glucokinase Regulatory Protein Interacts With Glucose Metabolism on Diabetic Dyslipidemia: the Combined CODAM and Hoorn Studies.
abstract: Small molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP) are potential new glucose-lowering targets. They stimulate hepatic glucose disposal by increasing glucokinase activity in the liver. It can, however, be anticipated that increased hepatic glucokinase activity might be accompanied by the development of hypertriglyceridemia, particularly in type 2 diabetes. We examined whether the strength of association between rs1260326, a common, functional gene variant in GKRP, and plasma lipids is affected by glucose metabolism.
  
  
  
  rs1260326 was genotyped in subjects with normal glucose metabolism (n = 497), subjects with impaired glucose metabolism (n = 256), and patients with type 2 diabetes (n = 351) in the combined Hoorn and Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) studies.
  
  
  
  The strength of association between the rs1260326 minor T allele and plasma triglycerides increased from normal glucose metabolism to impaired glucose metabolism to type 2 diabetes (P for interaction = 0.002). The inverse relation between rs1260326 and plasma HDL cholesterol was again most prominent in type 2 diabetes (P for interaction = 0.004). Similar trends were observed when the Hoorn and CODAM cohorts were analyzed separately. Comparable results were obtained when glucose metabolism strata were replaced by continuous indices of glucose metabolism, i.e., HbA1c and fasting plasma glucose.
  
  
  
  These findings illustrate that common gene variants, such as rs1260326, can have substantial effect sizes when they are studied in specific populations, such as type 2 diabetes. Moreover, our results shed light on potential side effects of small molecule disruptors of the GKRP-glucokinase complex, especially when glucose control is suboptimal.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands.
authors.forename: Nynke
authors.initials: N
authors.lastname: Simons
authors.affiliation: Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Dekker
authors.affiliation: Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands.
authors.forename: Marleen M J
authors.initials: MM
authors.lastname: van Greevenbroek
authors.affiliation: Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Giel
authors.initials: G
authors.lastname: Nijpels
authors.affiliation: Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Leen M
authors.initials: LM
authors.lastname: 't Hart
authors.affiliation: Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands.
authors.forename: Carla J H
authors.initials: CJ
authors.lastname: van der Kallen
authors.affiliation: Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands.
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands School for Public Health and Primary Care (CAPHRI), Maastricht, the Netherlands.
authors.forename: Nicolaas C
authors.initials: NC
authors.lastname: Schaper
authors.affiliation: Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands mcgj.brouwers@mumc.nl.
authors.forename: Martijn C G J
authors.initials: MC
authors.lastname: Brouwers
mesh_terms: D000368:Aged; D000483:Alleles; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics*; D001786:Blood Glucose / Q000378:metabolism*; D015992:Body Mass Index; D001835:Body Weight; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D016014:Linear Models; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014280:Triglycerides / Q000097:blood; D055105:Waist Circumference
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005941:Glucokinase; D006442:Glycated Hemoglobin; D014280:Triglycerides; C080906:glucokinase regulatory protein