Lactogens Reduce Endoplasmic Reticulum Stress‚ÄìInduced Rodent and Human Œ≤-Cell Death and Diabetes Incidence in Akita Mice
Authors: Joanna Filipowska
Adolfo Garcia-Ocana
Rupangi C Vasavada
Rollie F Hampton
Rosemary Li
Nagesha Guthalu Kondegowda
Silvia Leblanc
Journal: Diabetes (2020)
Discipline: CLINICAL MEDICINE
Keywords: Diabetes; Œ≤-cells; Lactogens; ER stress; JAK2/STAT5 pathway
Affiliations: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY., Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA., Department of Translational Research and Cellular Therapeutics, Beckman Research Institute, City of Hope, Duarte, CA., Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY., Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY .

Abstract:  Diabetes occurs due to a loss of functional Œ≤-cells, resulting from Œ≤-cell death and dysfunction. Lactogens protect rodent and human Œ≤-cells in vitro and in vivo against triggers of Œ≤-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 Œ≤-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 Œ≤-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 Œ≤-cells of Ak mice drastically reduces the severe hyperglycemia, diabetes incidence, hypoinsulinemia, Œ≤-cell death, and loss of Œ≤-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 Œ≤-cell survival and reduced diabetes incidence in the face of chronic ER stress. 

Retracted: No

PubPeer comments:
 In this article, Dr. Rupangi Vasavadau2019s group claim that Prolactin (PRL) and placental lactogen (PL) blocks apoptosis induced ER stress caused by tunicamycin in human pancreatic beta cells. PRL and PL have been shown to induce proliferation and anti-apoptotic effects in pancreatic beta cells. PR and PRL mediate their biological effects by binding to prolactin receptor (PRLR), which leads to activation of Jak2 STAT5 signaling. However, a recent work (Diabetes. 2015 Nov; 64(11): 3784u20133797) from Dr. Andrew Stewartu2019s lab has shown that human beta cells lack PRLR and STAT5, thus unresponsive to PR and PRL stimulation. To support their claim, Dr. Vasavadau2019s group show immnoblot for PRLR that shows a fuzzy band that can be seen only in lane corresponding to tunicamycin + PRL treated human islet extract (Fig.1E). Since they do not show the whole immunoblot labelled with molecular weight marker positions, it questions the authenticity of the authorsu2019 PRLR band. Because higher beta actin (loading control) level can be seen in tunicamycin+PRL lane (Fig.1E), the induction of PRLR protein in this situation is less believable. Additionally, PRLR detected in MCF7 cell extract is shown in this figure appears to be not from same immunoblot. Therefore, authors should provide uncropped images of all the PRLR and beta actin immunoblots shown in Fig.1E and F (all the 3 immunoblots quantified for this figure). According the paper by Dr. Stewartu2019s group (Diabetes. 2015 Nov; 64(11): 3784u20133797), PRLR transcript was undetectable in human islets. In contrast, Dr. Vasavadau2019s paper shows the expression of PRLR mRNA expression in untreated human islets. They should provide the qRT-PCR data files as that would help the readers clarify discrepancy regarding PRLR expression in human islets. PL overexpression in pancreatic beta cells of Akita mice (Ak+PL) did not block induction of diabetes (Fig. 3 I and J), but authors claim significantly reduced diabetes incidence in these animals (Fig. 3 C-D). Authors claim that beta cell-specific PL overexpression in Akita mice corrects ER stress in beta cells. However, there was no significant difference in islet ER maker expression between Akita versus Akita+PL groups (Fig. 5 C-F). Akita mouse has a mutation in Ins2 gene that leads to insulin misfolding and ER stress. Since PRL or PL cannot correct the mutation in Ins2 gene, how it can block the ER stress and consequent diabetes in these animals? ,