Objective
Islet beta cells play an essential role in glucose homeostasis by releasing insulin to lower the blood glucose level. In type 1 diabetes (T1D), beta cells are lost from autoimmune attack. There have been great interests in developing new therapeutics to preserve beta cell mass by reducing cell death, and to enhance beta cell regeneration by promoting proliferation. Currently there are no anti-diabetic drugs that selectively target beta cells to preserve beta cell mass. Our objective is to develop therapeutic products to slow, halt or reverse the course of T1D, focusing on devising novel targeted delivery of beta cell regenerative or anti-apoptotic therapy.
Background Rationale
Adiponectin is a secretory factor originating in adipose tissue. Adiponectin has pleiotropic favorable effects on a number of organs, and protects various organs from metabolic damage, such as the accumulation of toxic lipids and also enhances the recovery from a number of metabolic insults. These beneficial effects are mediated by adiponectin receptors (AdipoRs). There is a substantial presence of AdipoRs in pancreatic beta cells from both human and mouse, and numerous studies have provided a body of indisputable evidences demonstrating the robust antiapoptotic activity of adiponectin when beta cells are stressed with fatty acids or cytotoxic cytokines. In addition, elevated adiponectin levels enhance proliferation of pancreatic beta cells. With our recent success of developing a small molecule adiponectin agonist with good safety profile and favorable pharmacokinetics in vivo, the stage is set to explore the targeted delivery of AdipoR agonists triggering enhanced activation of AdipoRs in pancreatic islets to protect these cells from insults such as seen in the context of T1D.
Description of Project
slet beta cells play an essential role in glucose homeostasis by releasing insulin to lower the blood glucose level. In type 1 diabetes, loss of beta cells from autoimmune attack represents a primary event leading to high blood glucose and the associated complications. Research over the past decade has reached the conclusion that a two-pronged approach must be undertaken to treat or even cure T1D: The first is to curtail or eliminate autoimmune attack on islet -cells. The second is to improve beta cell robustness and its regenerative capacity to restore beta cell mass (either from endogenous residual beta cells, or from implanted engineered beta cells). This proposal focuses on the second aspect of this two-pronged campaign, and is responsive to the Disease Modifying Therapies outlined in the Cures Mission set forth by JDRF. We aim to develop a novel class of fusion molecules that exert protective and regenerative actions on beta cells of the pancreas. After preparing these compounds by chemical syntheses, the research team will first evaluate their activity in cultured beta cells. Based on the in vitro biochemical assays, we will optimize the structure of these molecules to improve their activity in beta cell preservation. Once obtaining compounds with the desired properties, we plan to assay them further in a diabetic mouse model to examine their ability in vivo to target and to protect beta cells and to restore the glucose level back to the normal. Finally, the team plans to evaluate the activity of these molecules in preserving human islets after transplantation. If successful, the study will produce novel compounds with the therapeutic potential for treating type 1 diabetes.
Anticipated Outcome
Despite the recognition that maintaining functional beta cell mass is pivotal for maintaining euglycemia and for preventing diabetes, few studies have attempted to systematically examine the benefits of beta-cytotrophic agents in vivo through targeted delivery. If successful, our approach in targeted drug delivery to islet beta cells will enable localized drug enrichment in the islets to enhance therapeutic efficacy, and to minimize the potential side effects of systematic, wide-spread activation of AdipoRs, hence improving the therapeutic index of the beta-cytotrophic agents for treating T1D.
Relevance to T1D
This proposal aim to develop a novel class of fusion molecules that exert protective and regenerative actions on beta cells of the pancreas, and to develop targeted delivery strategy to enhance therapeutic efficacy. The proposal is responsive to the Disease Modifying Therapies outlined in the Cures Mission set forth by JDRF.