Project Description

There is increasing evidence that Type 1 diabetes (T1D) is caused by the dysfunction of both insulin-producing β cells and glucagon-producing α cells in the islet of the pancreas. While efforts have focused on understanding changes occurring in β cells, little is known about the genetic or molecular factors that regulate α cell activity in T1D, or even under healthy conditions. Notably, in addition to the activation of proteins involved in inflammation, abnormally high lipid levels are also commonly seen in the T1D population. This is called lipotoxicity, and it contributes to β cell dysfunction and likely α cell dysfunction. However, it’s presently unclear how these lipids are normally regulated by human islet α cells, and whether their misregulation contributes to dysfunction in T1D.

Intracellular lipid droplets (LDs) typically serve as an important storage depot for excess lipids. However, no one has studied the impact of LDs in α cells. My research discovered that LDs accumulate in an age- and the diabetes-dependent manner in human islet α and β cells. Interestingly, LD levels were significantly higher in the α cells of long-standing T1D islets. To examine the relationship between LD accumulation and islet cell function, I have used human β cells to obtain experimental and mechanistic insight. I demonstrated that LDs play a critical role in maintaining β cell function and health by protecting against lipotoxicity.

In this study, I will directly examine how LDs influence islet α cell function under both healthy and diabetic lipotoxic conditions. I hypothesize that the genetic/nutritional factors involved in LD formation and/or lipid handling influence α cell activity. These studies will include examining if cellular LD levels impact the inflammation and lipotoxicity associated with T1D islets.