Expansion of functional pancreatic beta cell mass is a major therapeutic goal for both Type 1 and Type 2 diabetes. Glucose is a key physiological driver of adaptive beta cell mass expansion, promoting beta cell proliferation both in vitro and in vivo. We have been studying mechanisms of glucose-regulated gene expression for nearly two decades. In 2012 we found that carbohydrate response element binding protein (ChREBP; Mlxipl) is required for glucose-stimulated beta cell proliferation in both rodent and human beta cells. That same year, our co-investigator (Dr. Mark Herman) discovered that ChREBP exists as 2 major isoforms. ChREBP? is the full-length form that is mostly cytoplasmic and repressed in low glucose. ChREBP? is a product of alternative splicing, with the nuclear export signals and the low glucose inhibitory domain removed. Consequently, ChREBP? is mostly nuclear, and is constitutively and potently active. ChREBP? transcription is induced by a powerful carbohydrate response element after activation of the glucose-responsive ChREBP?, creating a vigorous feed-forward loop (Fig. 1). Remarkably, in every system studied in detail, the induction of ChREBP? is the molecular engine that drives the major physiological effects of ChREBP. In adipose tissue or liver, induction of ChREBP? increases de novo lipogenesis and either increases or decreases insulin sensitivity, respectively.. In beta cells, we recently showed that the exponential induction of ChREBP? - from a nearly undetectable level to amounts comparable to ChREBP? - is required for glucose-stimulated proliferation. Strikingly, however, overexpression of ChREBP? in beta cells, as may happen with prolonged hyperglycemia or by ectopic viral expression, results in beta cell apoptosis. In stark contrast, overexpression of ChREBP? amplifies glucose-stimulated beta cell proliferation without cell death. Our overarching hypothesis is that the ratio of ChREBP? to ChREBP? abundance is critically important for beta cell function, both for beta cell mass expansion and, when dysregulated, as a mediator of glucose toxicity. We will test our hypothesis by performing the following Specific Aims: (1) Determine the effects of increasing or decreasing the abundance of ChREBP? specifically in beta cells on beta cell mass and glucose homeostasis; (2) Determine if exogenous expression of ChREBP? or ChREBP? in human islets improves or worsens islet transplantation outcomes; and (3) Determine how the ratio of ChREBP? to ChREBP? controls the fate of beta cells. This application uses novel tools that will provide an essential mechanistic understanding of transcriptional glucose sensing that will inform therapies to expand and protect beta cell mass.
Both major forms of diabetes are a result of not enough beta cells. Our project is to better understand natural versions of a gene product, ChREBP, which is required for glucose-stimulated beta cell expansion, but is also involved in glucose toxicity. Our project will explore the functions of two versions of ChREBP, which may lead to therapies that increase the survival and replication of beta cells, while simultaneously decreasing beta cell death.
|Wang, Peng; Karakose, Esra; Liu, Hongtao et al. (2018) Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells. Cell Metab :|
|Kumar, Anil; Katz, Liora S; Schulz, Anna M et al. (2018) Activation of Nrf2 Is Required for Normal and ChREBP?-Augmented Glucose-Stimulated ?-Cell Proliferation. Diabetes 67:1561-1575|