Pancreatic beta-cell CAMKII signaling under physiological and diabetic conditions

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DESCRIPTION (provided by applicant): Pancreatic beta-cell insulin secretion is a calcium dependent process that becomes perturbed during the progression of type-2 diabetes. The calcium/calmodulin-dependent kinase II (CaM kinase II) serves as a signaling intermediate between glucose induced calcium entry and insulin secretion. CaM kinase II may also serve as a signaling conduit for the changes in beta-cell calcium, reactive oxygen species (ROS), and endoplasmic reticulum (ER) stress that occur during the progression of diabetes. Therefore, the overall objective of this proposal is to identify the role(s) of CaM kinase II in modulating beta-cll function under physiological and diabetic conditions. This project will utilize a novel transgenic mouse model with a tetracycline inducible beta-cell CaM kinase II inhibitor. Preliminary studies with this mouse model have determined that glucose activation of CaM kinase II increases beta-cell calcium entry and insulin secretion. Based upon these preliminary observations, we hypothesize that CaM kinase II beta-cell electrical activity and calcium entry influences the glucose dependence of insulin modulation of secretion. Furthermore, we propose that CaM kinase II plays a considerable regulatory role in the type-2 diabetic beta-cell as a signaling mediator for changes in calcium, ROS and ER-stress associated with diabetes. We will these hypotheses with the following specific aims: 1. Determine how beta-cell calcium entry is regulated by CaM kinase II during GSIS and how this influences glucose homeostasis. 2. Determine the influence(s) of beta-cell CaM kinase II on the pathogenesis of type-2 diabetes. These studies will be the first test of how endogenous beta-cell CaM kinase II activity modulates glucose homeostasis. Importantly, this project will make significant insights into mechanisms that modulate insulin secretion and beta-cell dysfunction during the progression of diabetes. This may ultimately lead to new therapeutic targets for treating type-2 diabetes. PUBLIC HEALTH RELEVANCE: Pancreatic beta-cell insulin secretion is dependent on calcium signaling through proteins such as such as CaM kinase II. Uncovering the function(s) of beta-cell CaM kinase II will lead to insights into the mechanisms involved in calcium dependent insulin secretion and how this becomes defective during the progression of diabetes. The results from this project will provide the basis of new therapeutic strategies for treating the bet-cell perturbations associated with type-2 diabetes.