DB19-0909_Supplemental_Material_for_2nd_revision.pdf (858.91 kB)
Download fileLactogens reduce endoplasmic reticulum stress-induced rodent and human β-cell death and diabetes incidence in Akita mice
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posted on 2020-04-24, 21:29 authored by Ada AdminAda Admin, Rosemary Li, Nagesha Guthalu Kondegowda, Joanna Filipowska, Rollie F. Hampton, Silvia Leblanc, Adolfo Garcia-Ocana, Rupangi C. VasavadaDiabetes occurs
due to a loss of functional β-cells, resulting from β-cell death and
dysfunction. Lactogens protect rodent and human β-cells in vitro and in vivo
against triggers of β-cell cytotoxicity relevant to diabetes, many of which converge
onto a common pathway, endoplasmic reticulum (ER) stress. However, whether
lactogens modulate the ER stress pathway is unknown. This study examines if
lactogens can protect β-cells against ER stress and mitigate diabetes incidence
in Akita mice, a rodent model of ER stress-induced diabetes, akin to neonatal
diabetes in humans. We show that lactogens protect INS1 cells, primary rodent
and human β-cells in vitro against
two distinct ER stressors, tunicamycin and thapsigargin, through activation of the
JAK2/STAT5 pathway. Lactogens mitigate expression of pro-apoptotic molecules in
the ER stress pathway that are induced by chronic ER stress in INS1 cells and
rodent islets. Transgenic expression of placental lactogen in β-cells of Akita
mice drastically reduces the severe hyperglycemia, diabetes incidence,
hypoinsulinemia, β-cell death, and loss of β-cell mass observed in Akita
littermates. These are the first studies in any cell type demonstrating lactogens
modulate the ER stress pathway, causing enhanced β-cell survival and reduced
diabetes incidence in the face of chronic ER stress.