GABP is a novel regulator of beta cell metabolism and proliferation
Contact PI: Richard A Cox, PhD, Baylor College of Medicine (R03 DK135458)
Start Date: May 1, 2023
NIH HIRN Gateway Investigator Award Recipient
Reduced beta cell mass underlies insulin deficiency leading to hyperglycemia in type 1 diabetes (T1D). Restoring autonomous glucose control in T1D requires beta cell replacement therapy, which is dependent on strategies to regenerate endogenous beta cells and expand islets ex vivo for transplant. However, there are no current therapeutic approaches to regenerate beta cells for people with T1D. Thus, our long-term goal is to identify targets to expand beta cell mass in order to restore glucose control for patients with T1D. To address this, we established a robust model of beta cell expansion through acute whole-body disruption of the leptin receptor (LepR). We found LepR deletion induces durable and remarkable beta cell expansion, even in ~2-year-old mice. Unbiased approaches nominated the transcription factor GA-binding protein (GABP) as a novel regulator of beta cell metabolism and proliferation. GABP is an ETS transcription factor that forms a heterodimeric complex with GABPa as the obligate DNA binding subunit. However, the function of GABPa in beta cells is unknown. Our preliminary data show glucose induces GABPA expression in human islets. Studies in other cell types demonstrated GABP is required for mitochondrial biogenesis, oxidative phosphorylation, and cell cycle regulation. These cellular functions are essential to generate ATP and synthesize key molecular building blocks to support cell proliferation. Nutrient and mitogenic signals also converge on GABP, providing further evidence that GABP is a rate limiting transcription factor that responds to increases in metabolic demand to stimulate cell proliferation. Thus, we hypothesize that GABP couples expression of metabolism and cell cycle genes to promote beta cell proliferation. In this proposal we will pursue the Aim to define the mechanistic role of GABP in human and mouse beta cell proliferation. To accomplish this, we will leverage beta cell specific Gabpa knockout mice to quantify the in vivo physiologic and proliferation responses to increased metabolic demand. In human islets studies, we will deplete GABPa to assay beta cell function, proliferation, and mitochondrial respiration following nutrient stimulation and pursue mechanistic studies via metabolomics and genome-wide approaches. These experiments will reveal how GABPa drives beta cell proliferation in response to metabolic demand and will direct new strategies to expand beta cells for people with T1D.