BCL-XL Overexpression Protects Pancreatic β-Cells against Cytokine- and Palmitate-Induced Apoptosis

Abstract

Diabetes is a chronic disease that affects glucose metabolism, either by autoimmune-driven β-cell loss or by the progressive loss of β-cell function, due to continued metabolic stresses. Although both α- and β-cells are exposed to the same stressors, such as proinflammatory cytokines and saturated free fatty acids (e.g., palmitate), only α-cells survive. We previously reported that the abundant expression of BCL-XL, an anti-apoptotic member of the BCL-2 family of proteins, is part of the α-cell defense mechanism against palmitate-induced cell death. Here, we investigated whether BCL-XL overexpression could protect β-cells against the apoptosis induced by proinflammatory and metabolic insults. For this purpose, BCL-XL was overexpressed in two β-cell lines—namely, rat insulinoma-derived INS-1E and human insulin-producing EndoC-βH1 cells—using adenoviral vectors. We observed that the BCL-XL overexpression in INS-1E cells was slightly reduced in intracellular Ca2+ responses and glucose-stimulated insulin secretion, whereas these effects were not observed in the human EndoC-βH1 cells. In INS-1E cells, BCL-XL overexpression partially decreased cytokine- and palmitate-induced β-cell apoptosis (around 40% protection). On the other hand, the overexpression of BCL-XL markedly protected EndoC-βH1 cells against the apoptosis triggered by these insults (>80% protection). Analysis of the expression of endoplasmic reticulum (ER) stress markers suggests that resistance to the cytokine and palmitate conferred by BCL-XL overexpression might be, at least in part, due to the alleviation of ER stress. Altogether, our data indicate that BCL-XL plays a dual role in β-cells, participating both in cellular processes related to β-cell physiology and in fostering survival against pro-apoptotic insults.

Deucravacitinib, a tyrosine kinase 2 pseudokinase inhibitor, protects human EndoC-βH1 β-cells against proinflammatory insults

“…Immunofluorescence was carried out as described ( 21 , 33 ). First, cells were washed with cold PBS and fixed with 4% paraformaldehyde.…”

A Supportive Role of Mesenchymal Stem Cells on Insulin-Producing Langerhans Islets with a Specific Emphasis on The Secretome

“…The cytokines also down-regulate the expression of the anti-apoptotic Mcl-1 [ 160 ]. Overexpression of Bcl-xL or Mcl-1 protects β-cells from cytokine-induced apoptosis [ 160 , 211 ]. Other factors that can protect β-cells from cytokine-induced cell death include islet neogenesis-associated protein (INGAP) and its active pentadecapeptide core [ 212 ], n-3 polyunsaturated fatty acids (n-3 PUFAs) [ 213 ], insulin [ 214 ], insulin-like growth factor 1 (IGF1) [ 215 ], IGF2 [ 216 , 217 ], hepatocyte growth factor [ 218 ], osteopontin [ 219 ], stromal cell-derived factor 1 (SDF-1) [ 220 ], and neutral ceramidase [ 221 ] ( Table 1 ).…”