Variants of GCKR Affect Both β-Cell and Kidney Function in Patients With Newly Diagnosed Type 2 Diabetes

Abstract

OBJECTIVEIn 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 METHODSIn 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.RESULTSThe 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).CONCLUSIONSOur 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.

CACNA1E Variants Affect Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 3

“…Furthermore, our finding that homozygous carriers of “poor” beta cell function alleles at both SNPs had a ∼30% reduction in the insulin secretory response to glucose, compares well with the 20–30% reduction of second phase insulin secretion reported in perfused pancreata from Ca V 2.3 −/− mice [3]. It is noteworthy that the p value of the CACNA1E score was virtually unaffected (p = 0.001) by the inclusion in a multivariate model also of the genetic variants previously reported by us to be associated to beta cell function in the VNDS (rs7901695 or rs7903146 in TCF7L2 and rs6717980 or rs2384628 in GCKR ) [9], [10]. Furthermore, the associations of these two SNPs with indicators of glucose control, such as plasma glucose and HbA1c, are consistent with a potentially relevant role in glucose homeostasis of patients with newly diagnosed type 2 diabetes (Supporting Information S1 Tables S5 and S7).…”

Metabolic Effects of Aerobic Training and Resistance Training in Type 2 Diabetic Subjects

“…The analysis of the glucose and C-peptide curves was performed as previously described (16,17). Further details can be found in the Supplementary Materials and Methods.…”

A Novel Insulin/Glucose Model after a Mixed-Meal Test in Patients with Type 1 Diabetes on Insulin Pump Therapy

“…A standard HEC was carried out to assess insulin sensitivity, which was computed with standard formulae351, and expressed as the amount of glucose metabolized during the last 60 min of the clamp.…”

“…Interstitial glucose monitoring was performed by the CGM device throughout the entire duration of insulin clamp for a companion experiment. Serum insulin concentrations were measured by ELISA (Mercodia, Sweden)51, which can detect also lispro, aspart and glulisine insulin. Standard curves for each analog were used to measure accurately circulating insulin levels.…”