Regrowth of Beta Cells with Small Molecule Therapy
Type 1 diabetes (T1D) results when beta cells are destroyed and the body can no longer produce enough insulin to convert the sugar from the foods we eat into energy. A major focus of our work towards a cure for T1D is on identifying the events that occur in the beta cell on the path towards their destruction and the development of diabetes. The process that leads to destruction of beta cells is not well understood, but seems to progress steadily and predictably. In the early stages, generally only small numbers of beta cells are lost but gradually over time, more and more cells are lost. By the time a person becomes diabetic, there are very few beta cells left and therefore not enough insulin. We think that by identifying new events during the progression towards T1D we may be able to design new interventions that could prevent or even reverse the onset of diabetes.
We have recently found that a beta cell growth pathway, called the mTORC1 pathway, gets switched on in a subset of beta cells during the progression towards and the onset of T1D in mice. Intriguingly, the mTORC1 pathway is normally off in the adult beta cell but is switched on under specific conditions and may help beta cells cope with insults that affect their numbers or function. When the mTORC1 pathway is activated in beta cells, it causes them to grow in size, allowing them to make more insulin and it also can promote their progression towards cell division. Therefore,it seems that beta cells may sense that their numbers are starting to decline and attempt to compensate by turning on the mTORC1 pathway.
The aim is to help beta cells grow (increase in size) and divide (increase in number) using small molecules to stimulate the level of mTORC1 activity in the cells that have already switched it on during the onset of T1D. This could increase insulin production by the remaining beta cells and also encourage cell division to generate new beta cells. To this end we will test known small molecules targeting the mTORC1 pathway and screen to identify new mTORC1-stimulating small molecules. We will test the effects of these small molecules of these on beta cell growth and cell division in culture, in diabetic mouse models and human beta cells.
This approach is completely novel and will give us exciting insights into how beta cells may be trying to compensate for their declining numbers during the onset of T1D. Importantly, this study will show us whether we can increase the mTORC1 pathway to improve beta cell growth and division as a new therapeutic strategy. Depending on what we find, this could constitute a whole new framework for how to augment the insulin production by existing beta cells and replace lost beta cells in a diabetic person’s body. If we can identify and target the right factors in the mTORC1 pathway, we may be able to reverse the progression towards and the onset of diabetes. Ultimately, it would mean that a person with T1D would no longer need insulin injections because they could have sufficient numbers of functioning beta cells to make enough insulin on their own.
“I want to thank you and DRC for all of your efforts in funding my research project. You’ll be happy to know that because of the DRC grant support and the results we’ve obtained, I was successful in securing another T1D-based grant from the Larry L. Hillblom Foundation. It’s a more substantial grant with funds for up to 3 years, allowing me to continue the work started with the DRC grant!”
Final Update 3-1-18
Type 1 diabetes (T1D) results when immune cells mistakenly destroy beta cells, a specialized cell in the body that produces insulin. Insulin is required for storing energy from the foods we eat, and so is essential for our normal bodily functions. Currently, there is no cure for T1D and since people with T1D don’t produce enough insulin they must receive insulin from other sources in order to live. The reasons why beta cells are destroyed in this disease are still a mystery. In this project, we found that a small subset of beta cells turned on a known growth pathway before the disease occurred in a mouse model. This led us to think that this pathway might be a way to compensate for beta cell loss by regrowing or replenishing the pool of beta cells. We hoped to encourage this potential growth of beta cells in such a way that could reverse T1D and restore normal levels of insulin.
As we investigated the changes occurring in beta cells further, we found that rather than activating a growth response, these beta cells were adopting a growth-arrested state called senescence. Thus our initial hypothesis was wrong. Even more remarkable, the senescent beta cells seemed to be promoting the progression of the disease, as they produced signals that encouraged further beta cell death and invasion by immune cells. We also found evidence that beta cells become senescent in humans with T1D and those at high risk for developing T1D by looking at markers for senescence in beta cells from human donors. In order to determine whether senescent beta cells were actually promoting the disease, we thought that if we could selectively kill this small subset of beta cells, it would spare the remaining majority of non-senescent, healthy beta cells. Using drugs that specifically kill off senescent cells, we found that treating our mouse model with these drugs prevented them from becoming diabetic. We also found that the drugs were, in fact, depleting senescent beta cells from these mice, but not killing off the immune cells.
In conclusion, we have identified a new and important factor in the disease process in T1D, where some of the beta cells (the senescent ones) are actually contributing to the destruction process. This represents a radical change in the way T1D has been understood, where beta cells are just passive victims. We have also proved the concept of using drugs that selectively kill senescent cells as therapeutics for preventing T1D in our mouse model. Although it is unclear whether this approach would work in cases of established T1D, in the future, we envision that we may be able to prevent T1D in people, and provide a therapeutic benefit for new T1D patients using a similar approach.
Update on 7-3-17
I am very grateful for the funds that I have received for this project and I am happy to inform you that I began working on it. Recent studies show that patients with diabetes have a much higher likelihood of depression than the general population, and young people with T1D had 11 times the suicide rate. Our goal is to identify genetic signatures in white blood cells that distinguish non-progressor T1D patients and T1D patients that do progress to depression. We have found that several neuronal proteins that are known to be important for brain function show abnormal expression in beta cells from T1D compared to non-diabetic donors. Even though it has been well recognized that abnormal expression or autoantibodies to proteins such as GAD and IA2 are separately associated with risk of T1D OR mental disorders, there are no studies looking for the signature of these genes as a predictor of co-occurrence of mental disorders AND T1D.
In this project, I will be isolating RNA from the blood samples of matched healthy and T1D patients with and without depression. RNAseq will be performed to reveal genetic signature in this unbiased search for changes in gene expression that are shared between depression and T1D. Any identified targets will be verified by qPCR to validate the results. We are hoping to identify markers in the blood that can be used to screen T1D patients for their likelihood to progress to depression. This will allow a better intervention in the at-risk population to prevent comorbidity of depression and T1D.