GABP regulation of beta cell survival and turnover

About This Grant

PROJECT SUMMARY Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic beta cells, causing insulin deficiency and elevated blood glucose levels. Strategies that replace lost beta cells could restore autonomous glucose control in T1D and are in high demand. Patients with type 2 diabetes (T2D) also experience major beta cell loss due to beta cell exhaustion, glucotoxicity and lipotoxicity. Still, there are currently no therapeutic approaches to replace beta cells for people with diabetes. Our long-term goal is to identify durable targets to expand beta cell mass to treat diabetes. The rationale for this project stems from transcriptomic analysis of mouse pancreatic islets during profound beta cell mass expansion that revealed upregulated genes highly enriched with binding sites for the transcription factor GA-binding protein (GABP). Previous studies in other cell types demonstrated GABP is required for mitochondrial biogenesis, oxidative phosphorylation, and cell division1-6. These cellular functions are essential to generate ATP and synthesize key molecular building blocks to support cell division7. Nutrient3 and mitogenic8 signals also converge on GABP, providing further evidence that GABP is a rate limiting transcription factor that responds to increased metabolic demand to ensure cellular energy homeostasis and promote cell division. However, the role of GABP in beta cells is unknown. The goal of this proposal is to define the role of GABP in pancreatic beta cells. To understand the role of GABP in beta cells, we targeted the DNA- binding subunit of GABP (GABPa) to generate beta cell specific Gabpa knockout mice (Ins1-Cre;Gabpa-fl/fl; Gabpabeta-KO) and littermate controls. Unexpectedly, Gabpabeta-KO mice developed polyuria and hyperglycemia, corresponding with reduced serum insulin levels, within the first 2-3 months of life. Pancreatic tissue analysis revealed a dramatic loss of beta cells in Gabpabeta-KO mice at 6 weeks of age compared to controls, likely underlying reduced serum insulin and hyperglycemia. Interestingly, at 3 weeks of age, beta cells were abundant, suggesting a sudden increase in beta cell death soon after weaning. These findings indicate that GABP may play a key role in beta cell survival and turnover in early life. Several studies suggest that beta cell death in diabetes is driven by mitochondrial oxidative stress and dysfunction through cytochrome c release and initiation of caspase-induced apoptosis9-11. GABP is required for mitochondrial function and bioenergetic homeostasis, suggesting that loss of GABP impairs mitochondrial function leading to beta cell death. My central hypothesis is that GABP regulates mitochondrial metabolism to maintain beta cell homeostasis and survival. This hypothesis will be tested using three specific aims: 1) Define the role of GABP in mouse beta cells; 2) Define the role of GABP in human beta cells; 3) Determine the molecular mechanisms of GABP to regulate beta cell mitochondria function. The proposed research is significant, as it will uncover a novel transcriptional mechanism involving GABP regulation of beta cell mitochondrial function integral to cellular energy homeostasis and survival. These findings will direct new therapies to preserve and expand beta cell mass for people with diabetes.