Adel Fadi W, Zheng Ye, Wan Siu-Hin, Greason Christie, Pan Shuchong, Ameenuddin Syed, Chen Horng H
Cardiorenal Research Laboratory, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States.
Minneapolis Heart Institute, United Hospital, Saint Paul, MN, United States.
Front Physiol. 2022 Apr 27;13:890907. doi: 10.3389/fphys.2022.890907. eCollection 2022.
The incidence of diabetes mellitus (DM) is rising. DM is a risk factor for developing left ventricular (LV) dysfunction and adverse cardiovascular outcomes. Insulin, commonly used to treat DM, is associated with further worsening of such outcomes. Yet, the pathophysiology of the adverse properties of insulin on the heart remains poorly defined. Therefore, the objective of this study was to determine the biological effects of insulin on the heart in DM, which we tested in a diabetic rat model and on human cardiomyocytes and fibroblasts. Male Wistar rats were divided into 3 groups: controls ( = 17), untreated diabetics (UDM, = 15), and insulin-treated diabetics (IDM, = 9). Diabetes was induced with Streptozotocin. Insulin pumps in IDM and saline pumps in UDM and controls were implanted for 4 weeks before tissue collection. Separately, cultures of human cardiomyocytes (AC16) and human cardiac fibroblasts (HCF) were treated with insulin to assess apoptosis and fibrosis, respectively. In rats, insulin partially rescued the DM-associated weight loss while fully restoring euglycemia. However, IDM had 2 × the rate of LV fibrosis ( < 0.0001) compared to UDM, and triple the rate of cardiomyocyte apoptosis compared to controls ( < 0.05). Similarly, , insulin triggered apoptosis in a dose-dependent fashion in AC16 cells, and it increased fibrosis and upregulated SMAD2 in HCF to levels comparable to Transforming Growth Factor Beta 1. Therefore, we conclude that insulin therapy is associated with increased cardiomyocyte apoptosis and myocardial interstitial fibrosis. Longer studies are needed to explore the long-term effects of insulin on cardiac structure and function.
糖尿病（DM）的发病率正在上升。DM是发生左心室（LV）功能障碍和不良心血管结局的一个危险因素。常用于治疗DM的胰岛素与这些结局的进一步恶化相关。然而，胰岛素对心脏不良作用的病理生理学仍不清楚。因此，本研究的目的是确定胰岛素在DM中对心脏的生物学效应，我们在糖尿病大鼠模型以及人心肌细胞和成纤维细胞中进行了测试。雄性Wistar大鼠分为3组：对照组（n = 17）、未治疗的糖尿病大鼠（UDM，n = 15）和胰岛素治疗的糖尿病大鼠（IDM，n = 9）。用链脲佐菌素诱导糖尿病。在采集组织前4周，给IDM植入胰岛素泵，给UDM和对照组植入生理盐水泵。另外，分别用胰岛素处理人心肌细胞（AC16）和人心脏成纤维细胞（HCF）培养物，以评估细胞凋亡和纤维化。在大鼠中，胰岛素部分挽救了与DM相关的体重减轻，同时完全恢复了血糖正常。然而，与UDM相比，IDM的LV纤维化发生率高出2倍（P < 0.0001），与对照组相比，心肌细胞凋亡率高出3倍（P < 0.05）。同样，胰岛素在AC16细胞中以剂量依赖的方式触发细胞凋亡，并且它增加了HCF中的纤维化并将SMAD2上调至与转化生长因子β1相当的水平。因此，我们得出结论，胰岛素治疗与心肌细胞凋亡增加和心肌间质纤维化有关。需要进行更长时间的研究来探索胰岛素对心脏结构和功能的长期影响。
