Role of calcium channels in the development of diabetes

Role of calcium channels in the development of diabetes

Researchers have deciphered the diabetogenic role of a certain type of calcium channel in insulin-secreting beta cells. The researchers believe that blockade of these channels could be a potential new treatment strategy for diabetes. The study is published in the scientific journal PNAS.

CaV3.1 channels have a marginal role in healthy insulin-secreting beta cells in the endocrine pancreas but become hyperactive along with the occurrence of diabetes. This raises a critical question of whether the hyperactivation of these calcium channels is a cause or consequence of diabetes. Now, researchers have found that increased expression of CaV3.1 leads to excessive calcium influx, impairing the genomic expression of exocytotic proteins in beta cells.

"This leads to a reduced insulin-secretion capacity of beta cells and aberrant glucose homeostasis," explains the first author of the study.

The role of CaV3.1 in the development of diabetes was investigated with a series of approaches, including experiments on rat and human pancreatic islets and diabetic rats. The experimental models used suggest that the results apply to both type 1 and type 2 diabetes, but more studies are needed to verify this.

Authors also show that expression of calcium channels reduced phosphorylated FoxO1 in the cytoplasm of INS-1E cells, elevated FoxO1 nuclear retention, and decreased syntaxin 1A, SNAP-25, and synaptotagmin III. These effects were prevented by inhibiting CaV3.1 channels or the Ca2+-dependent phosphatase calcineurin. Enhanced expression of β cell CaV3.1 channels therefore impairs insulin release and glucose homeostasis by means of initial excessive Ca2+ influx, subsequent activation of calcineurin, consequent dephosphorylation and nuclear retention of FoxO1, and eventual FoxO1-mediated down-regulation of β cell exocytotic proteins.

"Over a long period of time, the pathological role of beta cell CaV3.1 channels in the development of diabetes and its complications has been neglected," says the senior author of the study. "Our work pinpoints an increased expression of these channels as a critical pathogenic mechanism in diabetes, meaning that CaV3.1 channels should not be neglected in diabetes research."

Now, the researchers want to work out if increased expression of CaV3.1 also alter transcriptomic profiles in other types of cells, such as vascular smooth muscle cells and T cells of the immune system to contribute to the development of diabetes and its complications.

"The selective blockade of CaV3.1 channels may have potential as a new mechanism-based treatment strategy," says another senior author of the study. "Clinical trials with CaV3.1 channel blockers in patients with diabetes will be one of our future study priorities."