Abstract
Type 2 diabetes mellitus (T2DM) is a prevalent chronic metabolic disorder accompanied by high blood glucose, insulin resistance, and relative insulin deficiency. Endoplasmic reticulum (ER) stress induced by high glucose and free fatty acids has been suggested as one of the main causes of β-cell dysfunction and death in T2DM. Stem cell-derived insulin-secreting cells were recently suggested as a novel therapy for diabetes. In the present study, we demonstrate the therapeutic potential of tonsil-derived mesenchymal stem cells (TMSCs) to treat high-fat diet (HFD)-induced T2DM. To explore whether TMSC administration can alleviate T2DM, TMSCs were intraperitoneally injected in HFD-induced T2DM mice once every 2 weeks. TMSC injection markedly improved glucose tolerance and glucose-stimulated insulin secretion and prevented HFD-induced pancreatic β-cell hypertrophy and cell death. In addition, TMSC injection relieved the ER-stress response and preserved gene expression related to glucose sensing and insulin secretion. Moreover, administration of TMSC-derived conditioned medium induced similar therapeutic outcomes, suggesting paracrine effects. Finally, proteomic analysis revealed high secretion of insulin-like growth factor-binding protein 5 by TMSCs, and its expression was critical for the protective effects of TMSCs against HFD-induced glucose intolerance and ER-stress response in pancreatic islets. TMSC administration can alleviate HFD-induced-T2DM via preserving pancreatic islets and their function. These results provide novel evidence of TMSCs as an ER-stress modulator that may be a novel, alternative cell therapy for T2DM.
Highlights
Type 2 diabetes mellitus (T2DM) is a heterogeneous metabolic disease characterized by hyperglycaemia due to insulin resistance in adipose tissue, muscle, and liver and/or impaired insulin secretion by pancreatic β-cells [1]
Since tonsil-derived mesenchymal stem cells (TMSCs) exhibit unique properties compared with Mesenchymal stem cells (MSCs) from other sources, we examined the therapeutic efficacy and mechanism of TMSCs in high-fat diet (HFD)-induced T2DM in the present study
As reported previously [17], TMSCs used in the present study were negative for CD34 and positive for CD73, CD90, and CD105 (Supplementary Figure S1A)
Summary
Type 2 diabetes mellitus (T2DM) is a heterogeneous metabolic disease characterized by hyperglycaemia due to insulin resistance in adipose tissue, muscle, and liver and/or impaired insulin secretion by pancreatic β-cells [1]. While currently available T2DM treatments, including oral anti-diabetic drugs and insulin subcutaneous injection, can alleviate hyperglycaemia or temporarily improve insulin sensitivity in target tissues, these can neither reverse insulin resistance nor the progressive β-cell dysfunction; that is, none of these therapies modulate the course of the disease [6]. Mesenchymal stem cells (MSCs) are non-haematopoietic, multi-potent stem cells with the ability to differentiate into mesodermal lineage such as osteocytes, adipocytes, and chondrocytes [7]. They can be isolated from various tissues including adipose tissue, amniotic fluid, umbilical cord, and Wharton’s jelly [7]. TMSCs can be efficiently differentiated into functional insulin-producing cells, and administration of these cells into streptozotocin (STZ)-induced type 1 diabetic mice improved glucose intolerance [14]. A single intravenous infusion of AMSCs could improve glucose tolerance with better-preserved pancreatic β-cell mass in HFD-induced T2DM mice [23]
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