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

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.

FTO Inhibits Insulin Secretion and Promotes NF-κB Activation through Positively Regulating ROS Production in Pancreatic β cells

“…PRKCQ belongs to Protein kinase C family which is required for the activation of NF-κB pathway. Upregulated gene Cacna1e is involved in the regulation of second-phase insulin release and the polymorphism of Cacna1e is associated with type 2 diabates [ 23 – 25 ]. The expression pattern of these upregulated genes were confirmed by the QPCR analysis using the samples from the MIN6 cells with FTO overexpression ( Fig 8A ).…”

“…CACNA1E, one of the upregulated genes, encodes the voltage-dependent Ca(2+) channel Ca(V) 2.3. It has been reported this gene is involved in the regulation of second-phase insulin secretion and its polymorphism contributes to an increased risk of the development of type 2 diabetes [ 23 – 25 ]. Another upregulated gene, Ptpre, encoding protein tyrosine phosphatases, is a negative regulator of insulin receptor (IR) signaling and involved in the insulin-induced glucose metabolism through inactivation of IR [ 31 , 32 ].…”

Diethyldithiocarbamate-mediated zinc ion chelation reveals role of Cav2.3 channels in glucagon secretion

“…These findings are somewhat difficult to interpret, since mice of various ages (12-50 weeks) were used without appropriate age-matching or discrimination between male and female animals. The concept is nevertheless intriguing, as several studies have since linked variants in the gene encoding Ca v 2.3 channels to impaired glucose homeostasis in human T2DM patients [66][67][68]. Most notably, the region on chromosome 1q21-25, where the human Ca v 2.3 gene is located, has been linked to young-onset T2DM in Pima Indians [67].…”

Chemical genetic-based phenotypic screen reveals novel regulators of gluconeogenesis in human primary hepatocytes

“…Ca V 2.3 is found to be highly expressed in neuronal cells and pancreatic beta cells. So far, three studies in different ethnic groups reported association of CACNA1E variants with type 2 diabetes 15 – 17 and investigation of molecular functions of the gene has been focused on pancreatic beta cells. 18 , 19 Our data for the first time suggest that Ca V 2.3 also plays a role in hepatocytes.…”