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

Author:

Li Rosemary1,Kondegowda Nagesha Guthalu123,Filipowska Joanna123,Hampton Rollie F.1,Leblanc Silvia23,Garcia-Ocana Adolfo14,Vasavada Rupangi C.1234ORCID

Affiliation:

1. Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY

2. Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA

3. Department of Translational Research and Cellular Therapeutics, Beckman Research Institute, City of Hope, Duarte, CA

4. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY

Abstract

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.

Funder

National Institute of Diabetes and Digestive and Kidney Diseases

JDRF

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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