P2Y1 RECEPTOR IN PANCREATIC BETA CELLS AND ITS ROLE IN INSULIN SECRETION

• Author / Creator

  Khan, Shara

• Type 2 diabetes mellitus (T2DM) is characterized by peripheral insulin resistance and an insufficiency of insulin secretion from the pancreatic β cell. The incidence of T2DM is rising worldwide at an alarming rate. Increased prevalence of obesity is a major contributor to this rise in T2DM incidence as it is estimated that about 90% of T2DM is attributable to excess weight. The economic burden of this disease is increasing globally; but more importantly, despite numerous treatment options, many patients with type 2 diabetes still suffer from a decreased life expectancy.The mechanisms that regulate insulin secretion from the pancreatic β cell are still not fully understood. Thus, in order to understand β cell dysfunction in the disease state, it is essential to fully understand the mechanisms that regulate insulin secretion from the healthy pancreatic β cell. The present thesis thus investigates the role of the P2Y1 receptor in the regulation of insulin secretionThere was considerable controversy regarding the dominant purinergic receptor subtype present and the proposed mechanisms involved in the human pancreatic β cells. The present work resolves this issue. It shows that, in human β cells, ATP acts as a positive autocrine signal by activating P2Y1 receptors, stimulating electrical activity and coupling Ca2+ influx to Ca2+ release from endoplasmic reticulum stores. Positive autocrine signalling via P2Y1 also activates PKD1 via the PLC/DAG pathway in mouse and human β cells which becomes more important in obesity. Both the pathways enhance exocytosis and increase insulin secretion. Findings of the current thesis shed light on the understudied P2Y1 and PKD1 signalling in pancreatic β cells and provide insights into the potential mechanisms responsible for regulation of insulin secretion. A promising P2Y1 receptor agonist has already been reported and may emerge as an effective drug in the treatment of T2DM.

• Subjects / Keywords

  • Pharmacology

• Graduation date

  Spring 2019

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-y47j-jd72

• License

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