The ameliorating effects of mesenchymal stem cells compared to α‐tocopherol on apoptosis and autophagy in streptozotocin‐induced diabetic rats: Implication of PI3K/Akt signaling pathway and entero‐insular axis

Abstract

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are considered a novel regenerative therapy that holds much potential. This study aimed to examine and compare the ameliorative effects of BM-MSCs compared to α-tocopherol (α-Toc) on apoptosis, autophagy, and β-cell function in a rat model of streptozotocin (STZ)-induced diabetes and further analyzed the implications and interrelations of the entero-insular axis, and type I phosphoinositide 3-kinase (PI3K)/Akt signaling. Forty adult male albino rats were categorized into four groups (n = 10, in each): control group, STZ-induced diabetic group (single i.p. injection of STZ 45 mg/kg), diabetic and treated with BM-MSCs injection, diabetic and treatment with α-Toc p.o. The serum glucose, insulin, nitric oxide (NO), and catalase (CAT) were measured. Histopathological examination of the pancreas, the expression levels of insulin, CD44, caspase-3, autophagy markers, P13K/Akt, and pancreas/duodenum homeobox protein 1, in pancreatic tissue, and glucose-dependent insulinotropic polypeptide (GIP) in the duodenum were detected by hematoxylin and eosin staining, immunofluorescence labeling, and by quantitative real-time polymerase chain reaction. The diabetic rats showed reduced insulin, hyperglycemia, nitrosative stress (NO, CAT), augmented apoptosis (caspase 3), impaired autophagy (p62/SQSTM1, LC3), downregulated PI3K/Akt pathway and increased GIP expression, and degeneration of pancreatic islets. Treatment with either BM-MSCs or α-Toc suppressed the nitrosative stress, reduced apoptosis, recovered autophagy, upregulated PI3K/Akt pathway, and subsequently increased insulin levels, decreased blood glucose, and downregulated GIP expression with partial restoration of pancreatic islets. Based on our findings, the cytoprotective effects of BM-MSCs and α-Toc in type 1-induced diabetes appeared to be related to repaired autophagy and recovered PI3K/Akt signaling. Moreover, we reported their novel effects on reversing intestinal GIP expression level. The effect of BM-MSCs was notably superior to that of α-Toc.