Variants of GCKR affect both beta cell and kidney function in patients with newly diagnosed type 2 diabetes. The Verona Newly diagnosed type diabets study (VNDS). 2.

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. 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 b-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. The major alleles of rs6717980 and rs2384628 were associated with reduced b-cell function (P<0.05), with mutual additive effects of each variant (P<0.01). The minoralleles 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). 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.