Function of the voltage-gated Ca2+ channel 2-1 subunit in insulin release and diabetes

Type 2 diabetes occurs when an insufficient amount of insulin is released in the bloodstream, thus failing to maintain normal glycaemia. Pancreatic beta-cells are the main cell type residing in the pancreatic islets and are responsible for the release of insulin. beta-cells are excitable and express several voltage-gated ion channels and among them, voltage-gated Ca2+ channels are critical for the release of insulin. In fact, once a pancreatic beta-cell is depolarized, high voltage-gated Ca2+ channels activate, leading to Ca2+ influx and raise in cytosolic Ca2+ concentrations. The subsequent Ca2+ increase triggers the exocytic machinery and thus the release of insulin. Voltage-gated Ca2+ channels are composed by the pore-forming alpha1 subunit and by auxiliary subunits beta and alpha2delta. alpha2delta subunits regulate the membrane targeting of the alpha1 subunit and its current kinetics and they have shown their importance in a variety of neuronal and non-neuronal cell types. However, the importance of alpha2delta subunits for the release of insulin has never been previously reported. In this thesis, we investigated the role of the alpha2delta-1 subunit in pancreatic beta-cells. We have found that alpha2delta-1 is the main alpha2delta isoform expressed in pancreatic islets. Moreover, mice lacking the alpha2delta-1 subunits develop diabetes in a gender-dependent fashion. alpha2delta-1-/- male mice show a severe glucose intolerance, while alpha2delta-1-/- female mice are pre-diabetic, with a milder glucose intolerance. Pancreatic beta-cells from both alpha2delta-1-/- male and female mice have reduced Ca2+ influx. Nonetheless, only pancreatic islets from male alpha2delta-1-/- mice show reduced and delayed Ca2+ transients, while islets from female alpha2delta-1-/- mice have unaffected Ca2+ increase, however still delayed. Moreover, islets from alpha2delta-1+/+ female mice have reduced Ca2+ increase, compared to islets from alpha2delta-1+/+ male mice. We have shown tha
Type 2 diabetes occurs when an insufficient amount of insulin is released in the bloodstream, thus failing to maintain normal glycaemia. Pancreatic beta-cells are the main cell type residing in the pancreatic islets and are responsible for the release of insulin. beta-cells are excitable and express several voltage-gated ion channels and among them, voltage-gated Ca2+ channels are critical for the release of insulin. In fact, once a pancreatic beta-cell is depolarized, high voltage-gated Ca2+ channels activate, leading to Ca2+ influx and raise in cytosolic Ca2+ concentrations. The subsequent Ca2+ increase triggers the exocytic machinery and thus the release of insulin. Voltage-gated Ca2+ channels are composed by the pore-forming alpha1 subunit and by auxiliary subunits beta and alpha2delta. alpha2delta subunits regulate the membrane targeting of the alpha1 subunit and its current kinetics and they have shown their importance in a variety of neuronal and non-neuronal cell types. However, the importance of alpha2delta subunits for the release of insulin has never been previously reported. In this thesis, we investigated the role of the alpha2delta-1 subunit in pancreatic beta-cells. We have found that alpha2delta-1 is the main alpha2delta isoform expressed in pancreatic islets. Moreover, mice lacking the alpha2delta-1 subunits develop diabetes in a gender-dependent fashion. alpha2delta-1-/- male mice show a severe glucose intolerance, while alpha2delta-1-/- female mice are pre-diabetic, with a milder glucose intolerance. Pancreatic beta-cells from both alpha2delta-1-/- male and female mice have reduced Ca2+ influx. Nonetheless, only pancreatic islets from male alpha2delta-1-/- mice show reduced and delayed Ca2+ transients, while islets from female alpha2delta-1-/- mice have unaffected Ca2+ increase, however
Mag. Vincenzo Mastrolia
Im Titel 2+ hochgestellt und 2 tiefgestellt
Medical University of Innsbruck, Dissertation, 2017
(VLID)1744707