Lower Extremity Arterial Disease in Type 2 Diabetes Mellitus: Metformin Inhibits Femoral Artery Ultrastructural Alterations as well as Vascular Tissue Levels of AGEs/ET-1 Axis-Mediated Inflammation and Modulation of Vascular iNOS and eNOS Expression
Lower extremity arterial disease (LEAD) is a major risk factor for amputation in diabetic patients. The advanced glycation end products (AGEs)/endothelin-1 (ET-1)/nitric oxide synthase (NOS) axis-mediated femoral artery injury with and without metformin has not been previously investigated. Type 2 d...
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MDPI AG
2023-01-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/2/361 |
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| author | Ayed A. Shati Amro Maarouf Amal F. Dawood Nervana M. Bayoumy Youssef A. Alqahtani Refaat A. Eid Saeed M. Alqahtani Mohamed Abd Ellatif Bahjat Al-Ani Alia Albawardi |
| author_facet | Ayed A. Shati Amro Maarouf Amal F. Dawood Nervana M. Bayoumy Youssef A. Alqahtani Refaat A. Eid Saeed M. Alqahtani Mohamed Abd Ellatif Bahjat Al-Ani Alia Albawardi |
| author_sort | Ayed A. Shati |
| collection | DOAJ |
| description | Lower extremity arterial disease (LEAD) is a major risk factor for amputation in diabetic patients. The advanced glycation end products (AGEs)/endothelin-1 (ET-1)/nitric oxide synthase (NOS) axis-mediated femoral artery injury with and without metformin has not been previously investigated. Type 2 diabetes mellitus (T2DM) was established in rats, with another group of rats treated for two weeks with 200 mg/kg metformin, before being induced with T2DM. The latter cohort were continued on metformin until they were sacrificed at week 12. Femoral artery injury was established in the diabetic group as demonstrated by substantial alterations to the femoral artery ultrastructure, which importantly were ameliorated by metformin. In addition, diabetes caused a significant (<i>p</i> < 0.0001) upregulation of vascular tissue levels of AGEs, ET-1, and iNOS, as well as high blood levels of glycated haemoglobin, TNF-α, and dyslipidemia. All of these parameters were also significantly inhibited by metformin. Moreover, metformin treatment augmented arterial eNOS expression which had been inhibited by diabetes progression. Furthermore, a significant correlation was observed between femoral artery endothelial tissue damage and glycemia, AGEs, ET-1, TNF-α, and dyslipidemia. Thus, in a rat model of T2DM-induced LEAD, an association between femoral artery tissue damage and the AGEs/ET-1/inflammation/NOS/dyslipidemia axis was demonstrated, with metformin treatment demonstrating beneficial vascular protective effects. |
| first_indexed | 2024-03-11T09:06:57Z |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T09:06:57Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-6c88a94eca4845c981a60be74ad1abcb2023-11-16T19:17:05ZengMDPI AGBiomedicines2227-90592023-01-0111236110.3390/biomedicines11020361Lower Extremity Arterial Disease in Type 2 Diabetes Mellitus: Metformin Inhibits Femoral Artery Ultrastructural Alterations as well as Vascular Tissue Levels of AGEs/ET-1 Axis-Mediated Inflammation and Modulation of Vascular iNOS and eNOS ExpressionAyed A. Shati0Amro Maarouf1Amal F. Dawood2Nervana M. Bayoumy3Youssef A. Alqahtani4Refaat A. Eid5Saeed M. Alqahtani6Mohamed Abd Ellatif7Bahjat Al-Ani8Alia Albawardi9Department of Child Health, College of Medicine, King Khalid University, Abha 61421, Saudi ArabiaDepartment of Clinical Biochemistry, Birmingham Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham B9 5SS, UKDepartment of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi ArabiaDepartment of Physiology, College of Medicine, King Saud University, Riyadh 11461, Saudi ArabiaDepartment of Child Health, College of Medicine, King Khalid University, Abha 61421, Saudi ArabiaDepartment of Pathology, College of Medicine, King Khalid University, Abha 61421, Saudi ArabiaDepartment of Surgery, College of Medicine, King Khalid University, Abha 61421, Saudi ArabiaDepartment of Clinical Biochemistry, College of Medicine, King Khalid University, Abha 61421, Saudi ArabiaDepartment of Physiology, College of Medicine, King Khalid University, Abha 61421, Saudi ArabiaDepartment of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 15551, United Arab EmiratesLower extremity arterial disease (LEAD) is a major risk factor for amputation in diabetic patients. The advanced glycation end products (AGEs)/endothelin-1 (ET-1)/nitric oxide synthase (NOS) axis-mediated femoral artery injury with and without metformin has not been previously investigated. Type 2 diabetes mellitus (T2DM) was established in rats, with another group of rats treated for two weeks with 200 mg/kg metformin, before being induced with T2DM. The latter cohort were continued on metformin until they were sacrificed at week 12. Femoral artery injury was established in the diabetic group as demonstrated by substantial alterations to the femoral artery ultrastructure, which importantly were ameliorated by metformin. In addition, diabetes caused a significant (<i>p</i> < 0.0001) upregulation of vascular tissue levels of AGEs, ET-1, and iNOS, as well as high blood levels of glycated haemoglobin, TNF-α, and dyslipidemia. All of these parameters were also significantly inhibited by metformin. Moreover, metformin treatment augmented arterial eNOS expression which had been inhibited by diabetes progression. Furthermore, a significant correlation was observed between femoral artery endothelial tissue damage and glycemia, AGEs, ET-1, TNF-α, and dyslipidemia. Thus, in a rat model of T2DM-induced LEAD, an association between femoral artery tissue damage and the AGEs/ET-1/inflammation/NOS/dyslipidemia axis was demonstrated, with metformin treatment demonstrating beneficial vascular protective effects.https://www.mdpi.com/2227-9059/11/2/361femoral arterydiabetesAGEsET-1NOSinflammation |
| spellingShingle | Ayed A. Shati Amro Maarouf Amal F. Dawood Nervana M. Bayoumy Youssef A. Alqahtani Refaat A. Eid Saeed M. Alqahtani Mohamed Abd Ellatif Bahjat Al-Ani Alia Albawardi Lower Extremity Arterial Disease in Type 2 Diabetes Mellitus: Metformin Inhibits Femoral Artery Ultrastructural Alterations as well as Vascular Tissue Levels of AGEs/ET-1 Axis-Mediated Inflammation and Modulation of Vascular iNOS and eNOS Expression Biomedicines femoral artery diabetes AGEs ET-1 NOS inflammation |
| title | Lower Extremity Arterial Disease in Type 2 Diabetes Mellitus: Metformin Inhibits Femoral Artery Ultrastructural Alterations as well as Vascular Tissue Levels of AGEs/ET-1 Axis-Mediated Inflammation and Modulation of Vascular iNOS and eNOS Expression |
| title_full | Lower Extremity Arterial Disease in Type 2 Diabetes Mellitus: Metformin Inhibits Femoral Artery Ultrastructural Alterations as well as Vascular Tissue Levels of AGEs/ET-1 Axis-Mediated Inflammation and Modulation of Vascular iNOS and eNOS Expression |
| title_fullStr | Lower Extremity Arterial Disease in Type 2 Diabetes Mellitus: Metformin Inhibits Femoral Artery Ultrastructural Alterations as well as Vascular Tissue Levels of AGEs/ET-1 Axis-Mediated Inflammation and Modulation of Vascular iNOS and eNOS Expression |
| title_full_unstemmed | Lower Extremity Arterial Disease in Type 2 Diabetes Mellitus: Metformin Inhibits Femoral Artery Ultrastructural Alterations as well as Vascular Tissue Levels of AGEs/ET-1 Axis-Mediated Inflammation and Modulation of Vascular iNOS and eNOS Expression |
| title_short | Lower Extremity Arterial Disease in Type 2 Diabetes Mellitus: Metformin Inhibits Femoral Artery Ultrastructural Alterations as well as Vascular Tissue Levels of AGEs/ET-1 Axis-Mediated Inflammation and Modulation of Vascular iNOS and eNOS Expression |
| title_sort | lower extremity arterial disease in type 2 diabetes mellitus metformin inhibits femoral artery ultrastructural alterations as well as vascular tissue levels of ages et 1 axis mediated inflammation and modulation of vascular inos and enos expression |
| topic | femoral artery diabetes AGEs ET-1 NOS inflammation |
| url | https://www.mdpi.com/2227-9059/11/2/361 |
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