Towards a Cure for Diabetes Mellitus

The pancreas is an organ located in the abdomen. It is made up of exocrine cells and endocrine cells. In particular, the endocrine cells include hormone-producing cells that form clusters within the pancreas, called islets of Langerhans. There are five major types of endocrine cells, namely alpha, beta, gamma, pancreatic polypeptide (PP), and epsilon cells. These cells regulate blood glucose levels by releasing hormones into the bloodstream. Among them, beta cells play the most important role in maintaining glucose levels by producing insulin. Insulin helps lower blood sugar levels by promoting the absorption of glucose from the blood to peripheral tissue, such as skeletal muscle, fat, and liver. When the autoimmune system attacks beta cells, it results in type 1 diabetes due to insufficient insulin production. On the other hand, type 2 diabetes results from peripheral tissue that poorly responds to insulin or uptakes less glucose due to insulin resistance. The two major types of diabetes have different causes, but they both result in a significant loss of beta cells. Here, we will discuss the characteristics of beta cells and suggest potential targets and strategies to regenerate them. Chapter 1 provides an overview of pancreatic beta cells, including their general properties, stressors, and biological processes that lead to generate new beta cells. Chapter 2 focuses on NEUROG3+ cells, which were previously considered pancreatic endocrine progenitors during development. We identified these cells in the postnatal human pancreas and discovered their unique genetic signatures and regulatory networks. Chapter 3 investigates the sex differences in the pancreas using single-cell resolution technologies. We found that female endocrine cells have higher secretion capacities than male endocrine cells. Additionally, endocrine cells in male controls exhibited molecular signatures resembling type 2 diabetes. Chapter 4 outlines our CRISPR/Cas9 genetic candidate screen pipeline to investigate beta cell proliferation and presents promising molecular targets. By inhibiting these targets, we found that beta cell proliferation can be promoted. We also assessed how transcriptional changes under knock-out of these promising target genes affect endocrine function and proliferation. Together, this work provides new insights into beta cell regeneration and its molecular characteristics. We believe this will accelerate the development of beta cell regeneration therapies to treat diabetes.