Mechanistic Role of IP3R Calcium Release Channel in Pancreatic Beta-Cell Function

Background: According to the classic paradigm, insulin secretion is triggered by the influx of extracellular Ca2+ via voltage-dependent channels, leading to the fusion of insulin granules. Instead, the mechanisms involved in Ca2+ mobilization from internal stores are less defined. The main intracellular Ca2+ release channels are inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR), whereas Ca2+ is returned to the ER primarily by the activity of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pump. We recently demonstrated the importance of RyR in type 2 diabetes mellitus (T2DM), showing that it is essential in glucose-stimulated insulin secretion (GSIS). Conversely, the exact role of IP3R in GSIS remains not fully understood. Methods and Results: Three isoforms of IP3R have been identified in mammalian cells. Channel opening is stimulated by the binding of second messenger IP3 and by changes in Ca2+ concentrations. Studies in rodent and human samples indicate that β cells express all IP3R isoforms. We demonstrated that the expression of all isoforms is significantly increased in human islets from T2DM cadaveric donors T2DM compared with nondiabetic individuals. These results were also confirmed in diabetic db/db mice and in mice fed high-fat diet. Moreover, pancreatic β cells from T2DM patients exhibited dysmorphic and dysfunctional mitochondria, with markedly altered Ca2+ uptake. Similar features were found in clonal β cells chronically exposed to high glucose. In vitro, overexpression of IP3Rs was associated with impaired GSIS, whereas IP3R silencing improved β cell function, mitochondrial Ca2+ uptake and function, ER stress, and insulin release in response to different secretagogues. Conclusions: Taken together, our data indicate that IP3Rs are upregulated in human islets from T2DM donors, leading to mitochondrial dysfunction and pancreatic β cell failure, identifying in these intracellular Ca2+ release channels a novel therapeutic target to treat T2DM. Disclosure J. Shu: None. J. Gambardella: None. D. Sorriento: None. G. Santulli: None.