Role of Ca2+-channel β3 subunit in Ca2+ dynamics and insulin secretion from diabetic islets

Abstract

Diabetes is one of the life-threatening disease of human being and accompanies many complications including nerve damage, kidney failure, microcirculatory impairment, and stroke. There have been many efforts to understand the development of diabetes mellitus for the treatment, but still research on the treatment of diabetes mellitus is needed. Pancreatic islets are dispersed throughout the pancreatic exocrine tissue and receive a rich vascular supply. Pancreatic islets are composed of α, β, and δ cells that secrete unique sets of hormones in response to various stimuli. The β cells are abundant, and have been well studied for their roles in secreting insulin and regulating the cytosolic Ca2+ ([Ca2+]i) concentration to maintain glucose homeostasis. Insulin secreted from the β cells is a critically important regulator of whole body energy metabolism. When insulin secretion is absent or reduced, or when peripheral tissues fail to respond to insulin, the result is hyperglycaemia leading ultimately to diabetes. Voltage-gated Ca2+ channels (Cav) are essential for pancreatic beta-cell function as they mainly mediate Ca2+ influx, which leads to insulin exocytosis. Cav is composed of α1, α2/δ, β and γ subunit. Cav expression and function are critically dependent on the β subunit, which transports α1 to the surface membrane and regulates diverse channel properties. The β3 subunit of Cav (Cavβ3) has been suggested to regulate cytosolic Ca2+ ([Ca2+]i) oscillation frequency and insulin secretion under physiological conditions. However, there is lack of information about function of how Cavβ works in Ca2+ dynamics and insulin secretion in diabetes. Therefore, I focused on function of Cavβ in the diabetes model. Here, I report that islets from diabetic mice show Cavβ3 overexpression, altered [Ca2+]i dynamics, and impaired insulin secretion upon glucose stimulation. After Cavβ3 was overexpressed in the islets, I found alteration of [Ca2+]i dynamics and insulin secretion. Moreover, in high fat diet (HFD) induced diabetes, Cavβ3-deficient (Cavβ3–/–) mice showed improved islet function and enhanced glucose tolerance. Therefore, I suggest that overexpression of Cavβ3 can cause islet dysfunction in diabetes development. Normalization of Cavβ3 expression in ob/ob islets by an antisense oligonucleotide (ASO) rescued the altered [Ca2+]i dynamics and impaired insulin secretion. Therefore, regulation of the Cavβ3 level could lead to an improvement of islet function and glucose homeostasis. Importantly, transplantation of Cavβ3–/– islets into the anterior chamber of the eye improved glucose tolerance in HFD-fed mice. These results suggest that suppression of Cavβ3 after the time of onset of diabetes can significantly improve the diabetes phenotype in mice. Collectively, I suggest that Cavβ3 is responsible for dysfunction of pancreatic islets in diabetes and this was important for progression of T2DM. Based on these findings, targeting strategy for this subunit such as reducing Cavβ3 level by ASO might have beneficial effect not only on Ca2+ handling but also on insulin release in the islets and thereby resulting in improved glucose homeostasis. I therefore propose Cavβ3 as a novel target for diabetes treatment.