Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners.

Objective: Dysregulated glucagon secretion and inadequate functional beta cell mass are hallmark features of diabetes. While glucagon receptor (GCGR) antagonism ameliorates hyperglycemia and elicits beta cell regeneration in pre-clinical models of diabetes, it also promotes alpha and delta cell hyperplasia. We sought to investigate the mechanism by which loss of glucagon action impacts pancreatic islet non-alpha cells, and the relevance of these observations in a human islet context. Methods: We used zebrafish, rodents, and transplanted human islets comprising six different models of interrupted glucagon signaling to examine their impact on delta and beta cell proliferation and mass. We also used models with global deficiency of the cationic amino acid transporter, SLC7A2, and mTORC1 inhibition via rapamycin, to determine whether amino acid-dependent nutrient sensing was required for islet non-alpha cell growth. Results: Inhibition of glucagon signaling stimulated delta cell proliferation in mouse and transplanted human islets, and in mouse islets. This was rapamycin-sensitive and required SLC7A2. Likewise, gcgr deficiency augmented beta cell proliferation via SLC7A2- and mTORC1-dependent mechanisms in zebrafish and promoted cell cycle engagement in rodent beta cells but was insufficient to drive a significant increase in beta cell mass in mice. Conclusion: Our findings demonstrate that interruption of glucagon signaling augments islet non-alpha cell proliferation in zebrafish, rodents, and transplanted human islets in a manner requiring SLC7A2 and mTORC1 activation. An increase in delta cell mass may be leveraged for future beta cell regeneration therapies relying upon delta cell reprogramming.

Modulation of Cytoskeleton, Protein Trafficking, and Signaling Pathways by Metabolites from Cucurbitaceae, Ericaceae, and Rosaceae Plant Families.

One promising frontier within the field of Medical Botany is the study of the bioactivity of plant metabolites on human health. Although plant metabolites are metabolic byproducts that commonly regulate ecological interactions and biochemical processes in plant species, such metabolites also elicit profound effects on the cellular processes of human and other mammalian cells. In this regard, due to their potential as therapeutic agents for a variety of human diseases and induction of toxic cellular responses, further research advances are direly needed to fully understand the molecular mechanisms induced by these agents. Herein, we focus our investigation on metabolites from the Cucurbitaceae, Ericaceae, and Rosaceae plant families, for which several plant species are found within the state of Florida in Hillsborough County. Specifically, we compare the molecular mechanisms by which metabolites and/or plant extracts from these plant families modulate the cytoskeleton, protein trafficking, and cell signaling to mediate functional outcomes, as well as a discussion of current gaps in knowledge. Our efforts to lay the molecular groundwork in this broad manner hold promise in supporting future research efforts in pharmacology and drug discovery.