Project Description

The control of blood glucose levels is important for short- and long-term human health. The hormone insulin is the key signal to prevent rises in blood glucose. Insulin is produced and released by specialized cells, called β-cells, that are part of the pancreas. When these cells are destroyed by the immune system, sustained high blood glucose occurs and, eventually gives rise to type 1 diabetes (T1D).

Methods to replenish lost β-cells are considered a major therapeutic strategy to cure T1D. Recently, researchers have developed a method to produce human β-cells from pluripotent stem cells—a type of cell that can transform into all kinds of human tissues when provided with the right environmental cues. Human β-cells produced from stem cells (SC-β-cells) can detect an increased level of glucose and secrete insulin accordingly. Since stem cells can be taken from a person’s own body and have unlimited capacity to expand, SC-β-cells produced from the patient’s own cells would not be rejected like cells coming from another person (which is done for organ transplants and requires the patient to continuously take immunosuppressants).

Recent data from the first-in-human phase 1/2 clinical trial show an increase in insulin levels in T1D patients after SC-β-cell treatment, also called engraftment. However, the amount of graft-derived insulin is insufficient to significantly reduce blood glucose levels. Therefore, further improvement of SC-β-cell development and/or engraftment methods is necessary. Current SC-β-cells lack some important features of healthy human β-cells, including a lower level of insulin secretion in response to high glucose. It has been speculated that this insufficient insulin release is due to the insufficient function of mitochondria. In the cell mitochondria are vital for energy production and play an important role in metabolizing glucose to trigger insulin release. Therefore, defective mitochondria in SC-β-cells make them release less insulin in the presence of glucose, and at the same time hyperactive to another non-glucose energy source. This defect makes SC-β-cells prone to secrete too much insulin during exercise, which can lead to life-threatening bouts of low glucose. Therefore, improving SC-β-cell mitochondrial function is key to ensure both efficacy and safety of an SC-β-cell therapy for T1D. The objective of my proposal is to identify novel regulators of human β-cell mitochondrial activity and to find strategies for promoting SC-β-cell functional maturation.

In my preliminary studies, I have identified factors that regulate human β-cell mitochondrial function and have data which shows that manipulation of these factors in SC-β-cells can improve insulin secretion. In this proposal, I will pursue two goals. First, I will seek to understand how the factors that I have already identified control mitochondrial function and insulin secretion in SC-β-cells. Second, I will utilize novel technologies to identify all possible factors that control mitochondrial function in human β-cells. This approach is predicted to result in the identification of hundreds of candidate factors, which cannot be studied individually. My assumption is that those candidate factors will be interconnected in a network, and that manipulation of some key factors will have effects on the network throughout the cell, leading to significant improvement of SC-β-cell mitochondrial function. By identifying factors that modulate β-cell mitochondrial activity, I anticipate finding novel methods to improve SC-β-cells as a therapeutic for T1D.

Click HERE to view Dr. Zhu’s video.