糖尿病（DM）是一种代谢性疾病，其特点是由胰岛素分泌缺陷和/或胰岛素作用缺陷导致的高血糖。本研究旨在评估来自骨髓来源的间充质干细胞（BM-MSCs）单独或与吡格列酮（Pz）或艾塞那肽（Ex）联合治疗高脂饮食/链脲佐菌素（HFD/STZ）诱导的大鼠糖尿病的治疗潜力。大鼠在注射单一剂量STZ（35 mg/kg bw）前经过3周高脂饮食处理。确认2型糖尿病（T2DM）诱导后，将动物分配到不同的治疗组。未经治疗的HFD/STZ T2DM大鼠中验证了严重胰岛素抗性现象，同时还发现了脂肪组织中氧化应激、炎症、凋亡和自噬抑制的加剧。用BM-MSCs和Pz或Ex单独治疗HFD/T2DM大鼠通过增加胰岛素敏感性、降低凋亡和炎症（表现为降低血清肿瘤坏死因子-α、半胱氨酸天冬酶-3和核转录因子κB（NF-κB）基因表达，以及Janus激酶（JNK）蛋白表达）、增强自噬（表现为升调beclin和LC3，以及过氧化物酶增殖物激活受体-γ共激活因子-1 alpha（PGC-1α）基因表达在脂肪组织中）减轻了糖尿病并发症。联合治疗显示出增强的改善效果。通过胰腺组织的组织学检查证实了生化和分子结果。将Pz或Ex与BM-MSCs联合使用是一种协同治疗选择，通过多种分子机制减轻T2DM中的胰岛素抵抗和随之而来的并发症。

Diabetes mellitus (DM) is a metabolic disease, characterized by hyperglycemia resulting from defects in insulin secretion and/or insulin action. The current study was designed to assess the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) alone and in combination with pioglitazone (Pz) or exendin-4 (Ex) in high-fat diet/streptozotocin (HFD/STZ)-induced diabetes in rats.The rats were subjected to the HFD for three weeks before being injected with a single low dosage of STZ (35 mg/kg bw). The animals were assigned to different treatment groups after type II diabetes mellitus (T2DM) induction was confirmed.Severe insulin resistance was verified in untreated HFD/STZ T2DM rats, along with the exaggeration of oxidative stress, inflammation, apoptosis, and autophagy suppression in the adipose tissues. Monotherapy of HFD/T2DM rats with BM-MSCs and Pz or Ex alleviated diabetic complications by increasing insulin sensitivity, decreasing apoptosis and inflammation as evidenced by a decrease in serum tumor necrosis factor-alpha, caspase-3, and nuclear factor-kappa B (NF-κB) genes expression and Janus kinase (JNK) protein expression, and enhancing autophagy as revealed by upregulation in beclin and LC3, as well as peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α) genes expression in the adipose tissues. An augmented ameliorative efficacy was recorded in combined treatments. The biochemical and molecular results were confirmed by histological investigation of pancreatic tissues.Combining Pz or Ex with BM-MSCs is a synergistic therapeutic option that reduces insulin resistance and subsequent complications in T2DM via multiple molecular mechanisms.