Abstract
BackgroundGenetic variability of the major subunit (CACNA1E) of the voltage-dependent Ca2+ channel CaV2.3 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.Methodology/Principal FindingsIn 595 GAD-negative, drug naïve patients (mean±SD; age: 58.5±10.2 yrs; BMI: 29.9±5 kg/m2, 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/SignificanceIn 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.
Highlights
CaV2.3 is one non–L-type high-voltage-activated (HVA) channel belonging to the voltage-gated Ca2+ channel family, whose members mediate Ca2+ entry into cells in response to membrane depolarization [1].CaV2.3, which is expressed primarily in neuronal cells [2] and in pancreatic beta cells [1], plays a key role in second-phase insulin release [3]
Effects of CACNA1E variants on derivative and proportional control of beta cell function Both major alleles of rs10797728 (A) and rs175338 (G), which are in modest linkage disequilibrium with each other (D9: 0.9, r2: 0.43), were associated to a significant impairment in the derivative control of beta cell function, i.e. the response of beta cell to the rate of glucose increase (p = 0.01 and p = 0.03 respectively by Kruskal-Wallis) (Table 2)
This study explored the potential role(s) of ten CACNA1E variants, purposely selected to capture,93% of common CACNA1E variability, in determining pathophysiological phenotypes in patients with newly diagnosed type 2 diabetes of the Verona Newly Diagnosed Type Diabetes Study (VNDS)
Summary
CaV2.3 is one non–L-type high-voltage-activated (HVA) channel belonging to the voltage-gated Ca2+ channel family, whose members mediate Ca2+ entry into cells in response to membrane depolarization [1].CaV2.3, which is expressed primarily in neuronal cells [2] and in pancreatic beta cells [1], plays a key role in second-phase insulin release [3]. Two earlier studies, performed in two different ethnic groups, reported that CACNA1E variants are associated to type 2 diabetes risk [7,8] Their findings differed because in one study the metabolic phenotype associated to CACNA1E variability was insulin secretion [8], in the other study it was insulin sensitivity [7]. In the latter study [7], only acute insulin response after i.v. glucose challenge was measured, i.e. a facet of beta cell function in which CaV2.3 should play a nonsignificant role [3] In both studies, associations between CACNA1E variability and metabolic phenotypes were investigated in nondiabetic individuals [7,8]. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
