Genome-wide Association Studies (GWAS) have identified several SNPs in human chromosome 15 at the C2CD4A/C2CD4B/VPS13C locus associated with increased proinsulin levels and type 2 diabetes (T2D) risk. A recent in vivo study has shown that murine Vpc13c has a minor role in glucose homeostasis. Therefore, in this study, I sought to investigate the roles of C2CD4A and C2CD4B in glucose homeostasis and insulin secretion.
C2CD4A and C2CD4B have been predicted to encode nucleus-localised calcium-binding proteins in endothelial cells. To investigate the role of these genes in pancreatic β-cells, we first addressed their subcellular localisation. Our results suggested a novel role for these genes products since they showed localisation at the plasma membrane in addition to the nucleus as shown previously in endothelial cells. We also found that C2CD4A translocates from the cytoplasm to the plasma membrane in response to an elevation in intracellular free calcium. This suggests that the C2 domain of this protein binds to calcium and membrane phospholipids.
We also studied the role of C2cd4b in vivo. Our data showed that a lack of C2cd4b in female mice leads to impaired glucose tolerance, caused by a significantly decreased plasma insulin level. In these mice, we also observed a significant reduction of follicle-stimulating hormone (FSH). In contrast to the latter data, C2cd4a null mice did not present any glucose intolerance phenotype, suggesting a minor role for this gene in glucose homeostasis. However, in humans, deletion of this gene from human pancreas-derived β-cells caused an impairment in insulin secretion.
Taken together, our data demonstrate a novel role for these genes in the control of insulin secretion and glucose homeostasis. Further studies investigating the structures, their specific functions and interacting partners may demonstrate the mechanisms of action of the nearby T2D variants and open new avenues for the treatment of T2D.