Leveraging glucagon to treat diabetes mellitus

About This Grant

Project Summary Background and Innovation: Glucagon has long been recognized as an insulin counterregulatory hormone. However, more recent studies have revealed that it also activates glucagon-like peptide-1 receptors (GLP1R) on beta cells to enhance glucose-dependent insulin secretion. Harnessing glucagon for diabetes therapy has been challenging because of its opposing hyperglycemic and hypoglycemic effects in the liver and islet. Remarkably, we have discovered a transcriptional network controlled by BCL6 in the liver which causes a unique form of selective glucagon resistance and confers favorable anti-diabetic effects in both the liver and islet. Our first aim will elucidate the impact of BCL6 on glucagon action and metabolism in the liver. Our second aim will determine the inter-organ ramifications of this liver pathway on islet signaling and insulin secretion. Finally, in our third aim we will test a liver specific Bcl6 knockdown as a therapeutic for type 2 diabetes mellitus. Our study will elucidate this previously unknown liver pathway using a broad combination of biochemical assays, epigenetic and gene expression analysis, and physiologic testing with unique mouse models and primary cells, including both gain- and combinatorial loss-of-function genetic strategies to reveal interorgan communication. Further, we will use state-of-the-art hepatocyte-directed antisense oligonucleotides (ASOs) for preclinical testing to establish the benefits of targeting BCL6 for diabetes and obesity therapy. Collectively, these experiments will provide deep mechanistic and physiologic understanding of glucagon and therapeutic manipulation of glucagon signaling, setting the stage for clinical development and testing of analogous hepatocyte-directed therapy for humans. Significance and Impact to Veterans Healthcare: Type 2 diabetes mellitus afflicts 25% of Veterans, and hyperglycemia and diabetes-related complications remain inadequately controlled with current therapies. Our findings will elucidate a new target for treating type 2 diabetes mellitus and obesity-related disease. Exploiting this target will enable therapies to leverage both the benefits of glucagon blockade in the liver and glucagon agonism in the islet to improve glycemic control. Moreover, we will establish the efficacy of targeted nucleic acid-based therapy to specifically exploit the liver BCL6 pathway for therapy of type 2 diabetes mellitus in pre-clinical models. Path to translation/implementation: The work in this proposal will be foundational in establishing BCL6 as a new target for diabetes. We will test antisense oligonucleotides targeted specifically to hepatocyte BCL6 in mice. Success in our pre-clinical model can then be advanced for human translation by adapting the antisense oligonucleotides to knockdown the human BCL6 ortholog for future clinical testing in humans with type 2 diabetes mellitus.