Small-molecule discovery in the pancreatic beta cell

Abstract

The pancreatic beta cell is the only cell type in the body responsible for insulin secretion, and thus plays a unique role in the control of glucose homeostasis. The loss of beta-cell mass and function plays an important role in both type 1 and type 2 diabetes. Thus, using chemical biology to identify small molecules targeting the beta cell could be an important component to developing future therapeutics for diabetes. This strategy provides an attractive path toward increasing beta-cell numbers in vivo. A regenerative strategy involves enhancing proliferation, differentiation, or neogenesis. On the other hand, protecting beta cells from cell death, or improving maturity and function, could preserve beta-cell mass. Here, we discuss the current state of chemical matter available to study beta-cell regeneration, and how they were discovered.

Figure 1

Representative small molecules reported to increase beta-cell proliferation. The mechanism of action for each compound is indicated below the name, and details about the biology of these compounds are included in the text.

Figure 2

Representative small molecules that protect beta cells from death induced by (a) inflammatory cytokines or (b) glucolipotoxicity and ER stress.

Figure 3

(a) Small molecules and mechanisms that enhance beta-cell maturity and function. (b) Emerging strategies to target senescent beta cells (Venetoclax) or to enable selective delivery to beta cells, due to their high levels of zinc, either through compound chelation or prodrug strategies.

Figure 4

Summary of representative pathways affected in the beta cell. Two key pathways modulated by multiple compounds are highlighted: activation and inhibition of calcium influx into the beta cell, and inhibition of the kinase DYRK1A. VDCC, voltage-dependent calcium channel.