ChREBP Isoforms in Pancreatic Beta Cells

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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. ChREBPα is the full-length form that is mostly cytoplasmic and repressed in low glucose. ChREBPβ is a product of alternative splicing, with the nuclear export signals and the low glucose inhibitory domain removed. Consequently, ChREBPβ is mostly nuclear, and is constitutively and potently active. ChREBPβ transcription is induced by a powerful carbohydrate response element after activation of the glucose-responsive ChREBPα, creating a vigorous feed-forward loop (Fig. 1). Remarkably, in every system studied in detail, the induction of ChREBPβ is the molecular engine that drives the major physiological effects of ChREBP. In adipose tissue or liver, induction of ChREBPβ increases de novo lipogenesis and either increases or decreases insulin sensitivity, respectively.. In beta cells, we recently showed that the exponential induction of ChREBPβ - from a nearly undetectable level to amounts comparable to ChREBPα - is required for glucose-stimulated proliferation. Strikingly, however, overexpression of ChREBPβ in beta cells, as may happen with prolonged hyperglycemia or by ectopic viral expression, results in beta cell apoptosis. In stark contrast, overexpression of ChREBPα amplifies glucose-stimulated beta cell proliferation without cell death. Our overarching hypothesis is that the ratio of ChREBPα to ChREBPβ 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 ChREBPβ specifically in beta cells on beta cell mass and glucose homeostasis; (2) Determine if exogenous expression of ChREBPα or ChREBPβ in human islets improves or worsens islet transplantation outcomes; and (3) Determine how the ratio of ChREBPα to ChREBPβ 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.