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.

Research design and 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.

Figure 1

Effects of GCKR score on the curve relating ISR (y-axis) to glucose concentration (x-axis), i.e., the proportional control of β-cell function, in patients with newly diagnosed type 2 diabetes in the VNDS. The GCKR score was computed by counting one per each rs6717980 A allele and one per each rs2384628 C allele carried by each subject. The GCKR score could range from a minimum of 0 (a carrier of neither rs6717980 A alleles nor rs2384628 C alleles) to a maximum of 4 (a carrier of both AA in rs6717980 and CC in rs2384628). The higher the total score, the lower the β-cell insulin secretory response to glucose (unadjusted values were used for the graph; unadjusted P = 0.005; P = 0.012 after adjusting for age, sex, BMI, and eGFR). Data are presented as mean ± SEM.

Figure 2

Relationships between rs1049817, rs6547626, and rs780094 genetic variability and eGFR in patients with newly diagnosed type 2 diabetes in the VNDS. The G allele of rs1049817, the A allele of rs6547626, and the type 2 diabetes risk G allele of rs780094 were associated with reduced renal function (P ≤ 0.01), according to a recessive model. Data are presented as mean ± SEM. GFR, glomerular filtration rate; MDRD, Modification of Diet in Renal Disease.