title: Effects of activin A on survival, function and gene expression of pancreatic islets from non-diabetic and diabetic human donors.
abstract: Emerging evidence suggests that activin with its associated receptors, second messengers, and antagonists would be excellent targets for therapeutic drug development in the treatment of diabetes. We undertook the current study to investigate the ability to extrapolate findings from rodent studies to human islets in which data thus far has been scarce. We tested the hypothesis that human islets synthesize activin and that activin participates in the regulation of islet β-cells. Human islets from 33 separate isolations were categorized based on functional status, culture status and diabetic status. Statistical comparisons were made by ANOVA with Tukey post-hoc adjustment for multiple comparisons. Experiments investigating activin utilized qPCR, FACS cell sorting, immunofluorescent antibody staining, functionality assays, viability assays and protein secretion assays. We have defined the transcript expression patterns of activin and the TGFβ superfamily in human islets. We found INHBA (the gene encoding activin A) to be the most highly expressed of the superfamily in normal, cultured islets. We elucidated a link between the islet microenvironment and activin A. We found differential ligand expression based on diabetic, culture and functional status. Further, this is also the first report that links direct effects of activin A with the ability to restore glucose-stimulated insulin secretion in human islets from type 2 diabetic donors thereby establishing the relevance of targeting activin for therapeutic drug development.
authors.affiliation: a University of Massachusetts Amherst ; Amherst , MA USA.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Brown
authors.forename: Nathan
authors.initials: N
authors.lastname: Ungerleider
authors.forename: Lara
authors.initials: L
authors.lastname: Bonomi
authors.forename: Danielle
authors.initials: D
authors.lastname: Andrzejewski
authors.forename: Amy
authors.initials: A
authors.lastname: Burnside
authors.forename: Alan
authors.initials: A
authors.lastname: Schneyer
mesh_terms: D028341:Activins / Q000096:biosynthesis / Q000502:physiology*; D000328:Adult; D000368:Aged; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000502:physiology; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000096:biosynthesis; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000502:physiology; D055815:Young Adult
chemical_list: D007328:Insulin; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins
keywords: activin; diabetes; human islets
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