Lactogens reduce endoplasmic reticulum stress-induced rodent and human β-cell death and diabetes incidence in Akita mice

• DOI: 10.2337/figshare.12168477
• Publication Date: 2020-04-24T21:29:13Z
• Authors: Ada Admin; Rosemary Li; Nagesha Guthalu K...; Joanna Filipowska; Rollie F. Hampton; Silvia Leblanc; Adolfo Garcia-Ocana; Rupangi C. Vasavada

Diabetes occurs due to a loss of functional β-cells, resulting from β-cell death and dysfunction. Lactogens protect rodent and human β-cells <i>in vitro</i> and<i> in vivo</i> 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 <i>in vitro</i> 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.