DB19-0909_Supplemental_Material_for_2nd_revision.pdf (858.91 kB)

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

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posted on 24.04.2020 by Ada Admin, Rosemary Li, Nagesha Guthalu Kondegowda, 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 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.

Funding

This work was supported by grants from the National Institutes of Health (P30 DK020541 and R01 DK113079) to A. Garcia-Ocana; the National Institutes of Health (R01DK102893), the Juvenile Diabetes Research Foundation (17-2012-37) and City of Hope Wanek Family Project to Cure T1D to R. C. Vasavada.

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