Insulin Therapy is Associated With Increased Myocardial Interstitial Fibrosis and Cardiomyocyte Apoptosis in a Rodent Model of Experimental Diabetes
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 o...
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| Format: | Article |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.890907/full |
| _version_ | 1828342941158998016 |
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| author | Fadi W. Adel Ye Zheng Siu-Hin Wan Christie Greason Shuchong Pan Syed Ameenuddin Horng H. Chen |
| author_facet | Fadi W. Adel Ye Zheng Siu-Hin Wan Christie Greason Shuchong Pan Syed Ameenuddin Horng H. Chen |
| author_sort | Fadi W. Adel |
| collection | DOAJ |
| description | 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 vivo in a diabetic rat model and in vitro on human cardiomyocytes and fibroblasts. Male Wistar rats were divided into 3 groups: controls (n = 17), untreated diabetics (UDM, n = 15), and insulin-treated diabetics (IDM, n = 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 (p < 0.0001) compared to UDM, and triple the rate of cardiomyocyte apoptosis compared to controls (p < 0.05). Similarly, in vitro, 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. |
| first_indexed | 2024-04-13T23:36:03Z |
| format | Article |
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| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-13T23:36:03Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-3d8a6afca12347048bc37c7697bae8072022-12-22T02:24:44ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-04-011310.3389/fphys.2022.890907890907Insulin Therapy is Associated With Increased Myocardial Interstitial Fibrosis and Cardiomyocyte Apoptosis in a Rodent Model of Experimental DiabetesFadi W. Adel0Ye Zheng1Siu-Hin Wan2Christie Greason3Shuchong Pan4Syed Ameenuddin5Horng H. Chen6Cardiorenal Research Laboratory, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United StatesCardiorenal Research Laboratory, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United StatesMinneapolis Heart Institute, United Hospital, Saint Paul, MN, United StatesCollege of Biological Sciences, University of Minnesota, Minneapolis, MN, United StatesCardiorenal Research Laboratory, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United StatesCardiorenal Research Laboratory, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United StatesCardiorenal Research Laboratory, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United StatesThe 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 vivo in a diabetic rat model and in vitro on human cardiomyocytes and fibroblasts. Male Wistar rats were divided into 3 groups: controls (n = 17), untreated diabetics (UDM, n = 15), and insulin-treated diabetics (IDM, n = 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 (p < 0.0001) compared to UDM, and triple the rate of cardiomyocyte apoptosis compared to controls (p < 0.05). Similarly, in vitro, 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.https://www.frontiersin.org/articles/10.3389/fphys.2022.890907/fullinsulindiabetesfibrosisapoptosisrat model |
| spellingShingle | Fadi W. Adel Ye Zheng Siu-Hin Wan Christie Greason Shuchong Pan Syed Ameenuddin Horng H. Chen Insulin Therapy is Associated With Increased Myocardial Interstitial Fibrosis and Cardiomyocyte Apoptosis in a Rodent Model of Experimental Diabetes Frontiers in Physiology insulin diabetes fibrosis apoptosis rat model |
| title | Insulin Therapy is Associated With Increased Myocardial Interstitial Fibrosis and Cardiomyocyte Apoptosis in a Rodent Model of Experimental Diabetes |
| title_full | Insulin Therapy is Associated With Increased Myocardial Interstitial Fibrosis and Cardiomyocyte Apoptosis in a Rodent Model of Experimental Diabetes |
| title_fullStr | Insulin Therapy is Associated With Increased Myocardial Interstitial Fibrosis and Cardiomyocyte Apoptosis in a Rodent Model of Experimental Diabetes |
| title_full_unstemmed | Insulin Therapy is Associated With Increased Myocardial Interstitial Fibrosis and Cardiomyocyte Apoptosis in a Rodent Model of Experimental Diabetes |
| title_short | Insulin Therapy is Associated With Increased Myocardial Interstitial Fibrosis and Cardiomyocyte Apoptosis in a Rodent Model of Experimental Diabetes |
| title_sort | insulin therapy is associated with increased myocardial interstitial fibrosis and cardiomyocyte apoptosis in a rodent model of experimental diabetes |
| topic | insulin diabetes fibrosis apoptosis rat model |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.890907/full |
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