title: Variants of GCKR affect both β-cell and kidney function in patients with newly diagnosed type 2 diabetes: the Verona newly diagnosed type 2 diabetes study 2.
abstract: OBJECTIVE
  In genome-wide association studies, performed mostly in nondiabetic individuals, genetic variability of glucokinase regulatory protein (GCKR) affects type 2 diabetes-related phenotypes, kidney function, and risk of chronic kidney disease (CKD). We tested whether GCKR variability affects type 2 diabetes or kidney-related phenotypes in newly diagnosed type 2 diabetes.
  
  
  METHODS
  In 509 GAD-negative patients with newly diagnosed type 2 diabetes, we 1) genotyped six single nucleotide polymorphisms in GCKR genomic region: rs6717980, rs1049817, rs6547626, rs780094, rs2384628, and rs8731; 2) assessed clinical phenotypes, insulin sensitivity by the euglycemic insulin clamp, and β-cell function by state-of-the-art modeling of glucose/C-peptide curves during an oral glucose tolerance test; and 3) estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease formula.
  
  
  RESULTS
  The major alleles of rs6717980 and rs2384628 were associated with reduced β-cell function (P < 0.05), with mutual additive effects of each variant (P < 0.01). The minor alleles of rs1049817 and rs6547626 and the major allele of rs780094 were associated with reduced eGFR according to a recessive model (P < 0.03), but with no mutual additive effects of the variants. Additional associations were found between rs780094 and 2-h plasma glucose (P < 0.05) and rs8731 and insulin sensitivity (P < 0.05) and triglycerides (P < 0.05).
  
  
  CONCLUSIONS
  Our findings are compatible with the idea that GCKR variability may play a pathogenetic role in both type 2 diabetes and CKD. Genotyping GCKR in patients with newly diagnosed type 2 diabetes might help in identifying patients at high risk for metabolic derangements or CKD.
authors.affiliation: Department ofMedicine,University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bonetti
authors.forename: Maddalena
authors.initials: M
authors.lastname: Trombetta
authors.forename: Maria Linda
authors.initials: ML
authors.lastname: Boselli
authors.forename: Fabiola
authors.initials: F
authors.lastname: Turrini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Malerba
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Trabetti
authors.forename: Pier Franco
authors.initials: PF
authors.lastname: Pignatti
authors.forename: Enzo
authors.initials: E
authors.lastname: Bonora
authors.forename: Riccardo C
authors.initials: RC
authors.lastname: Bonadonna
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485100:GCKR protein, human