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Exploiting Delta Cell Paracrine Interactions to Curb Glucagon Hypersecretion in Diabetes
Author(s) -
Noguchi Glyn M,
Donaldson Cynthia J,
Mawla Alex M,
Saghatelian Alan,
Huising Mark O
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb716
Subject(s) - delta cell , alpha cell , glucagon , somatostatin , endocrinology , medicine , glucose homeostasis , paracrine signalling , insulin , islet , pancreatic islets , enteroendocrine cell , beta cell , diabetes mellitus , secretion , hormone , biology , insulin resistance , receptor , endocrine system
Diabetes is first and foremost a disease of insulin impairment, but is often accompanied by aberrant glucagon secretion. Uncontrolled alpha cell activity leads to further complications such as diabetic hyperglycemia, and we currently lack good options to manage this aspect of the disease. Within healthy pancreatic islets, delta cells exert an inhibitory influence over the alpha and beta cells via somatostatin; thus, they are uniquely positioned as the principal source of local inhibitory control preventing hormone signaling from going awry. Recent studies from our lab and others have identified local signals (such as Urocortin3 from the beta cells) and external factors (such as ghrelin from the GI tract) that act to directly stimulate somatostatin secretion. These observations cast delta cells as central hubs that are essential to maintain homeostatic control of insulin and glucagon. The objective of this study is to test if the negative feedback from pancreatic delta cells can be targeted to restore control over excess glucagon release in diabetes. Methods We have combined transcriptomics, chemicogenetics, and functional imaging of alpha, beta and delta cells in intact islets to help showcase the role of the delta cell within the islet. Results Our results indicate that Urocortin3 transiently silences alpha cell activity by activating delta cell‐dependent negative feedback. Conclusion By targeting the delta cells, we can take advantage of the local feedback mechanism and restore inhibition of alpha cells. Our findings suggest that the pancreatic delta cell is a viable target to normalize the excess glucagon secretion that is partially responsible for hyperglycemia in diabetes. Support or Funding Information Glyn Noguchi is supported by a NIGMS‐funded Pharmacology Training Program (T32GM099608). The Huising Lab is funded by awards from the Juvenile Diabetes Research Foundation (JDRF) and a Hartwell Individual Biomedical Research Award.