Date of Award

11-2022

Document Type

Thesis

Degree Name

Master of Science in Medical Sciences (MSMS)

Department

Biochemistry & Molecular Biology

First Advisor

Ernest Adeghate

Abstract

Diabetes mellitus (DM) is a chronic endocrine disease affecting millions of people worldwide. In spite of the advances made in the management of DM, poor glycemic control and diabetes complications are still very common. There is a continuous search for new and more effective drugs to treat DM. One of the drugs currently in clinical trials for the treatment of DM is licogliflozin (LIK066), a dual SGLT1/2 inhibitor, which can be used to treat obesity and diabetes. LIK066 inhibits glucose reabsorption in the kidney and small intestine, thereby reducing hyperglycemia. This study aims to investigate the efficacy of licogliflozin on diabetes and cardiac complications in a rodent model of experimental diabetes. DM was induced by streptozotocin in male Wistar rats. This was followed by the administration of LIK066 at a dose of 0.588 mg/Kg given intraperitoneally for 4 weeks. The immunofluorescence technique was used to determine whether SGLT1/2 is found in the pancreas and to determine if it co-localizes with insulin in pancreatic islet cells. Markers of cardiomyopathy (Collage 3, TIMP4, Keap1, fibronectin) and oxidative stress (catalase, superoxide dismutase, glutathione reductase) were also examined using immunofluorescence and Masson staining and enzyme immunoabsorbent essay in heart homogenates and the serum. Moreover, oxidative stress markers were also studied in the pancreas using immunofluorescence techniques and in serum by colorimetric analysis. LIK066 causes slight weight reduction in diabetic rats. SGLT1 and SGLT2 expression were slightly higher after treatment with LIK066 in normal and diabetic rats. TIMP4 result shows a significant elevation in LIK066-treated diabetic rats compared to diabetic untreated causing improvement in diabetic cardiomyopathy. Oxidative stress is a hallmark of the pathogenesis of DM. In the pancreas, treatment DM rats with LIK066 caused a significant elevation of GSH compared to untreated DM rats. Heart muscle catalase shows a significant increase in diabetic rats treated with LIK066 compared to diabetic untreated rats. Also, GSH reductase was significantly increased in diabetics treated with LIK066. In conclusion, LIK066 may exert its beneficial cardiac effects by increasing the endogenous pool of antioxidants.

Arabic Abstract

مرض اﻟﺴﻜﺮي ھﻮ ﻣﺮض ﻣﺰﻣﻦ ﯾﺼﯿﺐ اﻟﻐﺪد اﻟﺼﻤﺎء ﯾﺼﯿﺐ ﻣﻼﯾﯿﻦ اﻷﺷﺨﺎص ﻓﻲ جميع أﻧﺤﺎء اﻟﻌﺎﻟﻢ. ﻋﻠﻰ اﻟﺮﻏﻢ ﻣﻦ اﻟﺘﻘﺪم اﻟﻤﺤﺮز ﻓﻲ إدارة ﻣﺮض اﻟﺴﻜﺮي، إﻻ أن ﻻﯾﺰال ﺷﺎﺋﻊ ﺿﻌﻒ اﻟﺘﺤﻜﻢ ﻓﻲ ﻧﺴﺒﺔ اﻟﺴﻜﺮ ﻓﻲ اﻟﺪم وﻣﻀﺎﻋﻔﺎت ﻣﺮض اﻟﺴﻜﺮي. ھﻨﺎك ﺑﺤﺚ ﻣﺴﺘﻤﺮﻋﻦ أدوﯾﺔ ﺟﺪﯾﺪة أﻛﺜﺮ ﻓﻌﺎﻟﯿﺔ ﻟﻌﻼج ﻣﺮض اﻟﺴﻜﺮي. أﺣﺪ اﻷدوﯾﺔ اﻟﺘﻲ ﺗﺨﻀﻊ ﺣﺎﻟﯿاً ﻟﻠﺘﺠﺎرب اﻟﺴﺮﯾﺮﯾﺔ ﻟﻌﻼج ﻣﺮض اﻟﺴﻜﺮي ھﻮ ﻻﯾﻜﻮﺟﻠﯿﻔﻠﻮزﯾﻦ، ﯾﻌﺘﺒﺮ ﻣﻦ ﻣﺜﺒﻄﺎت ﻧﺎﻗﻠﺔ ﻣﺸﺘﺮﻛﺔ ﻟﻠﺼﻮدﯾﻮم واﻟﺠﻠﻮﻛﻮز ١ و٢ واﻟﺬي ﯾﻤﻜﻦ اﺳﺘﺨﺪاﻣﮫ ﻟﻌﻼج اﻟﺴﻤﻨﺔ وﻣﺮض اﻟﺴﻜﺮي. ﻻﯾﻜﻮﺟﻠﯿﻔﻠﻮزﯾﻦ ﯾﻤﻨﻊ اﻣﺘﺼﺎص اﻟﺠﻠﻮﻛﻮز ﻓﻲ اﻟﻜﻠﻰ واﻷﻣﻌﺎء اﻟﺪﻗﯿﻘﺔ، وﺑﺎﻟﺘﺎﻟﻲ ﺗﻘﻠﯿﻞ ارﺗﻔﺎع اﻟﺴﻜﺮ ﻓﻲ اﻟﺪم. اﻟﮭﺪف ﻣﻦ ھﺬه اﻟﺪراﺳﺔ ھﻮ اﻟﺘﺤﻘﻖ ﻣﻦ ﻓﻌﺎﻟﯿﺔ ﻻﯾﻜﻮﺟﻠﯿﻔﻠﻮزﯾﻦ ﻋﻠﻰ ﻣﺮض اﻟﺴﻜﺮي وﻣﻀﺎﻋﻔﺎت اﻟﻘﻠﺐ ﻓﻲ ﻧﻤﻮذج اﻟﻘﻮارض ﻟﻤﺮض اﻟﺴﻜﺮي اﻟﺘﺠﺮﯾﺒﻲ. ﺗﻢ إﺣﺪاث ﻣﺮض اﻟﺴﻜﺮي ﻓﻲ ذﻛﻮر ﻓﺌﺮان وﯾﺴﺘﺎر ﺑﻮاﺳﻄﺔ اﻟﺴﺘﺮﺑﺘﻮزوﺗﻮﺳﯿﻦ. ﺗﺒﻊ ذﻟﻚ إﻋﻄﺎء ﻟﯿﻜﻮﺟﻠﯿﻔﻠﻮزﯾﻦ ﺑﺠﺮﻋﺔ 0.588 ﻣﺠﻢ / ﻛﺠﻢ داﺧﻞ اﻟﺼﻔﺎق ﻟﻤﺪة 4 أﺳﺎﺑﯿﻊ. ﺗﻢ اﺳﺘﺨﺪام ﺗﻘﻨﯿﺔ اﻟﺘﻮھﺞ اﻟﻤﻨﺎﻋﻲ ﻟﺘﺤﺪﯾﺪ ﻣﺎ إذا ﻛﺎﻧﺖ ﻣﺜﺒﻄﺎت اﻟﺼﻮدﯾﻮم واﻟﺠﻠﻮﻛﻮز ١ و٢ اﻟﻤﺸﺘﺮﻛﺔ ﺗﻮﺟﺪ ﻓﻲ اﻟﺒﻨﻜﺮﯾﺎس وﻟﺘﺤﺪﯾﺪ ﻣﺎ إذا ﻛﺎﻧﺖ ﺗﺘﺘﺸﺎرك ﻣﻊ اﻷﻧﺴﻮﻟﯿﻦ ﻓﻲ ﺧﻼﯾﺎ (اﻟﻜﻮﻻﺟﯿﻦ 3، ﺗﯿﻤﺐ 4، ﻛﯿﺐ ١، اﻟﻔﺒﺮوﻧﻜﺘﯿﻦ) واﻹﺟﮭﺎد اﻟﺘﺄﻛﺴﺪي (اﻟﻜﺎﺗﻠﯿﺰ، ﺳﻮﺑﺮ اوﻛﺴﺎﯾﺪ دﯾﺴﻤﯿﻮﺗﯿﺰ، اﻟﺠﻠﻮﺗﺎﺛﯿﻮن اﻟﻤﺨﺘﺰل) ﺗﻢ ﻓﺤﺼﮭﺎ أﯾﻀًﺎ ﺑﺎﺳﺘﺨﺪام اﻟﺘﻮھﺞ اﻟﻤﻨﺎﻋﻲ وﺻﺒﻎ اﻟﻤﺎﺳﻮن وﻣﻘﺎل إﻧﺰﯾﻢ اﻻﻣﺘﺼﺎص اﻟﻤﻨﺎﻋﻲ ﻓﻲ ﻣﺘﺠﺎﻧﺴﺎت اﻟﻘﻠﺐ واﻟﻤﺼﻞ. ﺑﺎﻹﺿﺎﻓﺔ إﻟﻰ ذﻟﻚ، ﺗﻢ دراﺳﺔ ﻋﻼﻣﺎت اﻹﺟﮭﺎد اﻟﺘﺄﻛﺴﺪي ﻓﻲ اﻟﺒﻨﻜﺮﯾﺎس ﺑﺎﺳﺘﺨﺪام ﺗﻘﻨﯿﺎت اﻟﺘﻮھﺞ اﻟﻤﻨﺎﻋﻲ وﻓﻲ اﻟﻤﺼﻞ ﻋﻦ طﺮﯾﻖ اﻟﺘﺤﻠﯿﻞ اﻟﻠﻮﻧﻲ. ﻻﯾﻜﻮﺟﻠﯿﻔﻠﻮزﯾﻦ ﯾﺴﺒﺐ اﻧﺨﻔﺎﺿاً طﻔﯿﻔاً ﻓﻲ وزن اﻟﻔﺌﺮان اﻟﻤﺼﺎﺑﺔ ﺑﺪاء اﻟﺴﻜﺮي. ﻣﺜﺒﻄﺎت اﻟﺼﻮدﯾﻮم واﻟﺠﻠﻮﻛﻮز ١ و٢ ﯾﺘﻢ اﻟﺘﻌﺒﯿﺮ ﻋﻨﮭﺎ ﻓﻲ ﺧﻼﯾﺎ اﻟﺒﻨﻜﺮﯾﺎس ﺣﯿﺚ ﯾﺘﻢ ﺗﻮاﺟﺪھﺎ ﻣﻊ اﻷﻧﺴﻮﻟﯿﻦ ﻓﻲ اﻟﺠﺮذان اﻟﻌﺎدﯾﺔ واﻟﻤﺼﺎﺑﺔ ﺑﺪاء اﻟﺴﻜﺮي. ﺗﯿﻤﺐ ٤ ﺗﻈﮭﺮ اﻟﻨﺘﯿﺠﺔ ارﺗﻔﺎﻋًﺎ ﻣﻠﺤﻮظًﺎ ﻓﻲ اﻟﻔﺌﺮان اﻟﻤﺼﺎﺑﺔ ﺑﺎﻟﺴﻜﺮي واﻟﻤﻌﺎﻟﺠﺔ ﺑـﺎﻟﻼﯾﻜﻮﺟﻠﯿﻔﻠﻮزﯾﻦ ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻔﺌﺮان اﻟﻤﺼﺎﺑﺔ ﺑﺎﻟﺴﻜﺮي اﻟﻐﯿﺮ ﻣﻌﺎﻟﺠﺔ ﻣﻤﺎ ﯾﺆدي إﻟﻰ ﺗﺤﺴﻦ ﻓﻲ اﻋﺘﻼل ﻋﻀﻠﺔ اﻟﻘﻠﺐ اﻟﺴﻜﺮي. اﻹﺟﮭﺎد اﻟﺘﺄﻛﺴﺪي ھﻮ اﻟﺴﻤﺔ اﻟﻤﻤﯿﺰة ﻟﻤﺮض اﻟﺴﻜﺮي. ﺗﺴﺒﺐ ﻣﻌﺎﻟﺠﺔ اﻟﻔﺌﺮان اﻟﻤﺼﺎﺑﯿﻦ ﺑﺎﻟﺴﻜﺮي ﺑـﺎﻟﻼﯾﻜﻮﺟﻠﯿﻔﻠﻮزﯾﻦ ﻓﻲ ارﺗﻔﺎع ﻛﺒﯿﺮ ﻓﻲ اﻟﺠﻠﻮﺗﺎﺛﯿﻮن اﻟﻤﺨﺘﺰل ﺑﺎﻟﻔﺌﺮان اﻟﻤﺼﺎﺑﺔ ﺑﺎﻟﺴﻜﺮي اﻟﻐﯿﺮ ﻣﻌﺎﻟﺠﺔ. ﯾُﻈﮭﺮ ﻣﺴﺘﻮى اﻟﻜﺎﺗﻠﯿﺰ ﻓﻲ ﻋﻀﻠﺔ اﻟﻘﻠﺐ زﯾﺎدة ﻛﺒﯿﺮة ﻓﻲ اﻟﻔﺌﺮان اﻟﻤﺼﺎﺑﺔ ﺑﺪاء اﻟﺴﻜﺮي ﺑﻌﺪ ﻋﻼﺟﮭﺎ ﺑﺎﻟﻼﯾﻜﻮﺟﻠﯿﻔﻠﻮزﯾﻦ ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻔﺌﺮان اﻟﻤﺼﺎﺑﺔ ﺑﺎﻟﺴﻜﺮي اﻟﻐﯿﺮ ﻣﻌﺎﻟﺠﺔ. أﯾﻀﺎً اﻟﺠﻠﻮﺗﺎﺛﯿﻮن اﻟﻤﺨﺘﺰل زاد ﺑﺸﻜﻞ ﻣﻠﺤﻮظ ﻓﻲ اﻟﻔﺌﺮان اﻟﻤﺼﺎﺑﺔ ﺑﺎﻟﺴﻜﺮي واﻟﻤﻌﺎﻟﺠﺔ ﺑـﺎﻟﻼﯾﻜﻮﺟﻠﯿﻔﻠﻮزﯾﻦ. ﻓﻲ اﻟﺨﺘﺎم، ﻻﯾﻜﻮﺟﻠﯿﻔﻠﻮزﯾﻦ ﻗﺪ ﯾﻤﺎرس آﺛﺎره اﻟﻘﻠﺒﯿﺔ اﻟﻤﻔﯿﺪة ﻋﻦ طﺮﯾﻖ زﯾﺎدة ﻣﺠﻤﻮﻋﺔ ﻣﻀﺎدات اﻷﻛﺴﺪة اﻟﺬاﺗﯿﺔ.

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