title: CACNA1E variants affect beta cell function in patients with newly diagnosed type 2 diabetes. the Verona newly diagnosed type 2 diabetes study (VNDS) 3.
abstract: BACKGROUND
  Genetic variability of the major subunit (CACNA1E) of the voltage-dependent Ca(2+) channel Ca(V)2.3 is associated to risk of type 2 diabetes, insulin resistance and impaired insulin secretion in nondiabetic subjects. The aim of the study was to test whether CACNA1E common variability affects beta cell function and/or insulin sensitivity in patients with newly diagnosed type 2 diabetes.
  
  
  RESULTS
  In 595 GAD-negative, drug naïve patients (mean ± SD; age: 58.5 ± 10.2 yrs; BMI: 29.9 ± 5 kg/m(2), HbA1c: 7.0±1.3) with newly diagnosed type 2 diabetes we: 1. genotyped 10 tag SNPs in CACNA1E region reportedly covering ∼93% of CACNA1E common variability: rs558994, rs679931, rs2184945, rs10797728, rs3905011, rs12071300, rs175338, rs3753737, rs2253388 and rs4652679; 2. assessed clinical phenotypes, insulin sensitivity by the euglycemic insulin clamp and beta cell function by state-of-art modelling of glucose/C-peptide curves during OGTT. Five CACNA1E tag SNPs (rs10797728, rs175338, rs2184945, rs3905011 and rs4652679) were associated with specific aspects of beta cell function (p<0.05-0.01). Both major alleles of rs2184945 and rs3905011 were each (p<0.01 and p<0.005, respectively) associated to reduced proportional control with a demonstrable additive effect (p<0.005). In contrast, only the major allele of rs2253388 was related weakly to more severe insulin resistance (p<0.05).
  
  
  CONCLUSIONS
  In patients with newly diagnosed type 2 diabetes CACNA1E common variability is strongly associated to beta cell function. Genotyping CACNA1E might be of help to infer the beta cell functional phenotype and to select a personalized treatment.
authors.affiliation: Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Trombetta
authors.forename: Sara
authors.initials: S
authors.lastname: Bonetti
authors.forename: Marialinda
authors.initials: M
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: PierFranco
authors.initials: P
authors.lastname: Pignatti
authors.forename: Enzo
authors.initials: E
authors.lastname: Bonora
authors.forename: Riccardo C
authors.initials: RC
authors.lastname: Bonadonna
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D020908:Calcium Channels, R-Type / Q000235:genetics* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015592:Immunoradiometric Assay; D007333:Insulin Resistance / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D016014:Linear Models; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors; D018709:Statistics, Nonparametric
chemical_list: D001786:Blood Glucose; C423009:CACNA1E protein, human; D020908:Calcium Channels, R-Type; D027682:Cation Transport Proteins