The Interplay Of Dopamine Receptors In The Pancreatic Islet Regulates Hormone Secretion

The regulated release of hormones from the islets of Langerhans is fundamental to achieve glucose homeostasis. The balance between insulin and glucagon output signals to multiple tissues in the body to uptake or to release glucose. Any acute impairment of this function has dangerous and potentially lethal consequences, such as hyperglycemia, which can lead to diabetic ketoacidosis and coma, or severe hypoglycemia that often leads to seizures, loss of consciousness or death. A chronic imbalance in the insulin/glucagon output is the defining trait of diabetes. This medical condition is characterized by chronic hyperglycemia which in turn leads to damage to the microvasculature in the body. Given the high prevalence of diabetes, the cost of care for diabetic patients is skyrocketing around the globe, and better treatments are constantly needed.One potential treatment target is the neurotransmitter dopamine, which has been shown to exhibit autocrine and paracrine signal between islet cells that can fine tune hormone output via a tonic inhibition on the secretory activity. The dopamine receptors D3 and D2 are present and active in islet cells In particular, and we are characterizing the complex interplay between the dopamine receptors that are active in the various islet cell types. We hypothesize that their signaling cascades are acting on distinct pathways to differentially regulate insulin and glucagon. To test our hypothesis, we use in situ hybridization to test cell specific receptor expression in the islets. We use adeno viruses to deliver genetically encoded fluorescent reporters to mouse and human islets, and confocal microscopy to measure the different responses triggered by selective activation of D2 or D3 receptors. These experiments allow us to define a model for dopaminergic regulation of hormone secretion.