Research

Signals controlling insulin secretion

Insulin secretion by pancreatic beta cells is primarily regulated by glucose; however, hormones and additional nutrients, such as long chain fatty acids (LCFAs) also play an important role in adjusting insulin output to physiological needs. With a view to better understanding how β cell respond to their environment in normal and diabetic states, we are studying the fatty acid receptors GPR40 and GPR41 which are activated by LCFAs and short chain fatty acids (SCFAs) respectively. We have shown that GPR40 is essential for full responsiveness of beta cells to LCFAs. More recently, using mouse models of gain and loss of function of GPR41, we demonstrate impaired glucose homeostasis. Thus GPR41 and its ligands SCFAs, may play an important role in fine-tuning of insulin secretion in fed and fasted states.

Gene regulation in developing and mature beta cells

Pancreas development and mature beta cell function are controlled by precisely timed signaling events and tightly regulated gene expression. In turn, this is controlled by key transcription factors, such as the master regulators FoxA2, that is essential for endoderm development and function, and Pdx1 that is essential for pancreas formation and insulin secretion. Our research aims to understand the transcriptional regulatory processes underlying this regulation both during normal development and in the mature beta cell. For example we have recently identified CpG islands in the FoxA2 and Pdx1 genes whose methylation is paradoxically associated with active gene expression. We hypothesize that the demethylated state is associated with binding of repressors to the region contributing to inhibition of expression

Manipulating pancreatic cellular identity

Islet transplantation has been used to treat Type I diabetics. However, this approach is very limited due to shortage of donor cells. Reprogramming of somatic non- β cells into β cells may provide an alternative source of cells. We developed an in vitro system to study and characterize reprogrammed β like cells. Primary mouse pancreatic acinar cells are isolated and transduced with three β cell specific transcription factors. This results in their reprogramming to insulin producing β cells. We use this system to characterize the transcriptional and epigenetic profiles of reprogrammed cells to generate a detailed mechanistic understanding of the reprogramming process.