Saltar al contenido
Merck

Lactogens Reduce Endoplasmic Reticulum Stress-Induced Rodent and Human β-Cell Death and Diabetes Incidence in Akita Mice.

Diabetes (2020-04-26)
Rosemary Li, Nagesha Guthalu Kondegowda, Joanna Filipowska, Rollie F Hampton, Silvia Leblanc, Adolfo Garcia-Ocana, Rupangi C Vasavada
RESUMEN

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 of endoplasmic reticulum (ER) stress. However, whether lactogens modulate the ER stress pathway is unknown. This study examines whether lactogens can protect β-cells against ER stress and mitigate diabetes incidence in Akita (Ak) mice, a rodent model of ER stress-induced diabetes, akin to neonatal diabetes in humans. We show that lactogens protect INS-1 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 proapoptotic molecules in the ER stress pathway that are induced by chronic ER stress in INS-1 cells and rodent islets. Transgenic expression of placental lactogen in β-cells of Ak mice drastically reduces the severe hyperglycemia, diabetes incidence, hypoinsulinemia, β-cell death, and loss of β-cell mass observed in Ak littermates. These are the first studies in any cell type demonstrating that lactogens modulate the ER stress pathway, causing enhanced β-cell survival and reduced diabetes incidence in the face of chronic ER stress.

MATERIALES
Referencia del producto
Marca
Descripción del producto

Sigma-Aldrich
Tunicamycin from Streptomyces sp.
Sigma-Aldrich
Thapsigargin, ≥98% (HPLC), solid film
Sigma-Aldrich
Prolactin human, recombinant, expressed in E. coli, lyophilized powder, BioReagent, suitable for cell culture, >97% (SDS-PAGE)
Sigma-Aldrich
AG 490, A cell-permeable, reversible, substrate competitive, and potent inhibitor of epidermal growth factor receptor kinase autophosphorylation (IC₅₀ = 100 nM).