Sharma, Arun J., PhD
Determine if enhancing MafA is sufficient to ameliorate beta cell dysfunction
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Islet Biology, Islet Biology\Beta Cell Growth and Differentiation, Islet Biology\Beta Cell Transcription Regulation
Type of Grant: Basic Science
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
Diabetes results from an inadequate functional amount of pancreatic b-cells: in type 1 diabetes b-cell amount is reduced by autoimmune attack, while in type 2 diabetes the amount of b-cells is insufficient to meet increased demand for insulin. b-cell replacement therapy works but we do not have a reliable method to produce mature b-cells that respond appropriately to glucose. In this proposal we will analyze how b-cells mature/acquire glucose-responsiveness and test if we can overcome inadequate amount of b-cell mass and development of diabetes by increasing the functional capacity of b-cells. Increasing evidence suggests that a regulatory protein, MafA, plays an important role in how early insulin producing cells acquire their glucose-responsiveness and how they become mature b-cells. Other results show that a lack of MafA results in the development of diabetes. Using genetically modified mice in which we can regulate the amount of MafA in their pancreatic b-cells, we will directly test whether increasing MafA in non-responsive b-cells converts them into glucose-responsive b-cells. We will also test whether increasing MafA in b-cells of normal adult mice increases their ability to resist development of diabetes or even reverse preexisting diabetes. This study will evaluate MafA as a potential therapeutic target capable of overcoming b-cell dysfunction and diabetes; this will set the stage for developing novel therapies for diabetes based on enhancing MafA levels/activity in b-cells.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treati or/curing diabetes?
In type 1 diabetes a significant proportion of beta cells are destroyed by autoimmunity, while in type 2 diabetes the beta cells are not sufficient to maintain blood glucose levels in normal range. This study will help both individuals with type 1 or type 2 diabetes by enhancing the ability of their beta cells to normalize their blood glucose levels. However, as the amount of remaining beta cells are higher in individuals with the type 2 diabetes, this study will lead to approaches to prevent the development of diabetes, as well as to treat/cure type 2 diabetes.
If a person with diabetes were to ask you how your project would help in the future, how would you respond?
We identified a regulatory gene called MafA and showed that increasing the amounts of MafA protein in beta cells improve their function. In this study, we will examine whether increasing the amount of MafA protein can prevent the development of diabetes in mice. Additionally, we will determine the ability of this protein to reverse diabetes by increasing the amount of this protein after the beta cells have lost their ability to function properly. Similarly, we will determine if increasing MafA in animal models with small numbers of beta cells will increase their function capacity to match the capacity of a larger number of beta cells, i.e., can we make a small number of beta cells replace the function of larger numbers of beta cells. Such studies are required to establish that increasing MafA levels is a potential therapy for diabetes. A successful demonstration of MafA as a potential therapy for diabetes will lead to development of ways to increase MafA levels in beta cells resulting in novel treatments for diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes is a major health problem in the world today. Current trends indicate that in the developing countries, which constitute a majority of the world population, there is a significant rise in the prevalence of diabetes. Hence, in the absence of concerted efforts to prevent, delay or cure diabetes, the changes in the life style and socioeconomic conditions in the developing countries is resulting in a worldwide epidemic of diabetes. Since, I was born in a developing country, I would like to do my part in this fight against diabetes.
In what direction do you see the future of diabetes research?
From a perspective of a scientist working in the field of basic research, I believe researchers will work towards finding newer therapeutic approaches to treat diabetes. Currently, new findings have led to developing novel strategies for overcoming insulin resistance in type 2 diabetes, and ways to enhance insulin secretion. I presume that in the near future, we will continue to have newer therapies to overcome insulin resistance and circulating glucose levels. However, it will be important to develop new therapies to overcome beta-cell dysfunction while at the same time developing strategies to restore their normal capacity and function. Hence, I think that developing therapies that can restore normal beta cell functional capacity will be a key strategy to cure diabetes.
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