Regrowth of Beta Cells with Small Molecule Therapy

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Project Researcher: Peter Thompson, Ph.D. – University of California, San Francisco

Project Description

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 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.

Project Updates

Update on 9-8-17

Hi! My name is Peter Thompson. I’m a postdoctoral scholar at the UCSF Diabetes Center, and it’s been about 6 months now since we reached our funding goal with your support. I’m very happy to share with you some updates today.

Type 1 diabetes results from an autoimmune disorder in which the immune system kills beta cells. Beta cells are required to make insulin, which is an important hormone that allows us to take the energy from the foods we eat and take it into cells. A person with type 1 diabetes no longer produces enough insulin because they have lost the majority of their beta cells.

Our research project was based on an initial finding in our lab that a growth-promoting pathway in beta cells called the mTORC1 pathway, is dramatically upregulated in a subset of beta cells during the onset of diabetes in mice. Our hypothesis was that this could represent an attempt by the beta cells to somehow restore themselves and replenish themselves, to compensate for their destruction by the immune system. Our goal was to be able to manipulate this pathway using small molecule drugs and then be able to enhance the growth and proliferation of beta cells in order to restore sufficient insulin.

As it turns out, our hypothesis about what the mTORC1 pathway might be doing in beta cells, we thought it would be promoting their growth and enhancing their proliferation, turned out to be false! I guess that’s one of the goals any scientist has, to be able to verify or falsify their original hypothesis. In this case, it seems like our original hypothesis was inaccurate. As it turns out, what the mTORC1 pathway is probably doing in beta cells is activating a conversion to a growth-arrested state, in which cellular growth and proliferation are inhibited.

These findings were very interesting, and as I said, totally unexpected. We started out with one hypothesis to explain what the mTORC1 pathway could be doing, it could be promoting growth and proliferation of beta cells in a context in which they’re being assaulted by the immune system. And as it turns out, it might be doing the exact opposite.

So as you can imagine, there is still a lot we don’t understand and there’s a lot of work to be done. But I’m excited to say that we have some new results that we hope to publish very soon related to this project. So until then, please keep posted for my updates, and I hope to share some more information with you very soon. Once again thank you for your support!

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.