Type 1 and type 2 diabetes and its metabolic consequences continue to be among the most significant biomedical challenges worldwide today. In addition to morbidities specifically related to diabetes the disease is associated with complications such as dyslipidemia, cardiovascular disease and several types of cancer and is a leading cause of death in the US and worldwide. These observations highlight the urgent need for more research into factors that can safely and selectively enhance proliferation of beta cells to plan for therapeutic approaches to combat the disease. Several mammalian models of insulin resistance indicate that beta cell have a remarkable capacity to enhance their mass to counter and/or delay the onset of overt diabetes. The source of potential factors that promote proliferation of beta cells in these models is not fully explored and is a timely area of research. Our preliminary data using parabiosis and transplantation approaches indicates that the liver is a potential source of growth factors that can enhance beta cell proliferation. Using proteomics and affymetrix approaches we have identified this factor as serpinB1. SerpinB1 is able to directly promote the proliferation of beta cells in vitro in mouse islets and human islets. The goa of this proposal is to investigate the role of serpinB1 in the regulation of islet biology. We will address the following Aims in this proposal: 1) Determine the ability of serpinB1 to regulate beta cell mass. We will test the hypothesis that SerpinB1 modulates beta cell mass in vivo using models that lack sepinB1 globally or in a liver-specific manner. We will also test the ability of serpinB1 to reverse the effects hyperglycemia in a model of diabetes. 2) We will explore the mechanisms by which serpinB1 regulates beta cell proliferation using in vitro studies that include effects of recombinant serpinB1 and serpinB1 variants on mouse and human islet proliferation. We will define the signaling pathways that mediate the effects of serpinB1 and coupled our approach with affymetrix and proteomics analyses of islet treated with serpinB1;and, finally 3) We will examine the translational and therapeutic significance of serpinB1 by investigating the effects of recombinant serpinB1 in human islets in vitro and in a humanized mouse model that is made diabetic. Together these studies will provide a novel perspective on human beta cell proliferation.
Identification of novel growth factors that promote proliferation of glucose responsive insulin secreting beta cells is an important area of research to plan therapeutic approaches to limit the growing incidence of diabetes and its attendant complications. The studies proposed in this application will allow us to determine the mechanism of action of the novel factor serpinB1, identify the proteins that it interacts with in order to impact downstream targets in beta cells with the long term goal of developing approaches to enhance beta cell mass in patients with type 1 and type 2 diabetes.
|Kahraman, Sevim; Dirice, Ercument; De Jesus, Dario F et al. (2014) Maternal insulin resistance and transient hyperglycemia impact the metabolic and endocrine phenotypes of offspring. Am J Physiol Endocrinol Metab 307:E906-18|