Leahy Lab Research
Over the past two decades Dr. Leahy's research has focused on understanding how the insulin secreting pancreatic ß-cell functions in health and disease. The ß-cell is at the core of the normal regulation of the blood glucose level: as the demand for insulin rises due to obesity and insulin resistance, it normally compensates through increased secretion of insulin. Failure of this compensation system leads to type 2 diabetes. Our laboratory uses animal models of both successful and failed ß-cell compensation to define the molecular and biochemical events that underlie these processes.
Our current funded projects include
- mechanisms of beta cell compensation in partial pancreatectomized rats (NIH-funded)
A longstanding project of the laboratory is to resolve mechanisms of ß-cell compensation following an acute reduction in ß-cell mass through a partial pancreatectomy in rats. Several years ago we uncovered a novel mechanism for this adaptation that involves an increase in the catalytic activity of glucokinase, a key regulatory enzyme serving as the glucose sensor in ß-cells. Subsequently we found that these animals also undergo a transient burst of both islet neogenesis (newly differentiated cells) and ß-cell hyperplasia following the partial pancreatectomy. Our studies continue to focus on identifying the molecular mechanisms that underlie both aspects of the compensation system, i.e., enhanced ß-cell function and the regeneration of the ß-cell mass. Towards this end, we have found that the nuclear receptor PPAR-gamma plays a pivotal role in regulating ß-cell compensation following partial pancreatectomy.
- ß-cell PPAR-gamma signaling in obesity (American Diabetes Association funded)
This project involves exploring the role of this nuclear receptor/transcription factor in the ß-cell in the context of obesity development, progressive insulin resistance, and the transition to type 2 diabetes. We have found some striking similarities in the complex roles of PPAR-gamma in early ß-cell adaptation in response to insulin resistance and weight gain with those patterns observed in the partial pancreatectomy model.
- effects of PPAR-gamma agonists and DPP-4 inhibitors on ß-cell mass and function (Takeda Pharmaceuticals funded)
Whereas PPAR-gamma has historically been an important and effective drug target to control insulin resistance, the use of DPP-4 inhibitors clinically to improve diabetic outcomes is relatively recent. DPP-4 inhibitors enhance the activity of key gastrointestinal-released hormones that augment ß-cell function. The action of both of these drug classes on ß-cell physiology and growth, both singly and in combination, is being explored.