T2DM is one of the leading causes of morbidity and mortality due its complication like nephropathy and other cardiovascular diseases, accounting for at least 10 % of total health care expenditure in many countries .
Ischemic heart disease (IHD) remains the leading cause of death in the patients with T2DM. It seems apparent, therefore, that current pharmacotherapy of the patients with both IHD and T2DM should be aimed not only at glucose lowering but also at prevention of cardiovascular complications
DN is one of the major microvascular complication of T2DM and is the major cause of end-stage renal disease (ESRD) worldwide and causes premature death in diabetic patients. It is found that between 20 to 40 % of all diabetic patients are prone to developing renal failure.
NAFLD is the most common cause of chronic liver disease. It includes a broad spectrum of liver alterations, ranging from pure steatosis to cirrhosis through NASH .NAFLD is the most common liver disorder worldwide. Its prevalence ranges 10–24% in the general population, reaching 60–95% in obese and 28–55% inpatient with T2DM.
Clinical data suggests that glycemic control with monotherapy cannot be maintained ,Only ~ 25% of adult diabetic patients achieve adequate glycemic control on monotherapy and the majority of diabetic patients will eventually require the addition of a second drug to achieve acceptable glycemic control .Therefore T2DM patients are often treated with a combination of antidiabetics with different and complimentary mechanism of actions to achieve and maintain the optimal glycemic control.
vildagliptin is one of a new class of oral anti-hyperglycemic drugs for the treatment of T2DM. It is a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of vildagliptin to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic β-cell mass and function due to oxidative stress induced inflammation . It regulates not only glucose and lipid metabolism, but also exhibits several systemic effects at different site levels. It improves endothelial function, reduces the pro-oxidative and the pro-inflammatory state .
Metformin, an oral antidiabetic drug in the biguanide class is a widely prescribed drug to treat high blood glucose in individuals with T2DM.Various investigations show that metformin decreases intracellular ROS. It modulates several oxidative stress markers and pro-inflammatory cytokines at the biochemical and gene expression levels.
The present study was designed to explore the potential prophylactic effect of vildagliptin and or metformin on experimentally induced AMI induced by ischemic reperfusion injury and on development and progression of experimentally induced DN in NA-STZ type 2 diabetic rats model .Also to explore the potential prophylactic effect of vildagliptin and or metformin on development and progression of experimentally induced diabetic NASH in HFSD-STZ type 2 diabetic rats model.
To study the potential prophylactic effect of vildagliptin and or metformin on experimentally induced AMI induced by I-R injury in NA-STZ type 2 diabetic rats model,30 adult male albino rats, weighing about 250 -300 gmdivided into 5 equal groups (6 rats in each ):1stgroup is normal control group. Induction of T2DM by a single I.P injection of STZ 60 mg/kg after 15 min of a single I.P injection of NA120 mg/kg of experimental rats resulted in hyperglycemia at 72 h which was confirmed by the elevated blood glucose level then on day 7 after injection, Only rats confirmed to have permanent NIDDM with blood glucose concentration more than 250mg/dl were used in the study. Induction of AMI by LCA ligation for ischemia for 30 min and reperfusion for120 min in these experimentally NA-STZ type 2 diabetic rats after development of diabetes.2nd group diabetic infracted non treated group receive no treatment prior to induction of AMI, 3rd group:vildagliptin treated diabetic infarcted group :diabetic rats are given single dose of vildagliptin 2mg IV 30 min prior to induction of AMI 4th group: metformin treated diabetic infracted group:diabetic rats are given metformin 200 mg/kg/day I.P for 3 days prior to induction of AMI and 5th group: vildagliptin and metformin treated diabetic infarcted group: diabetic rats are given a single dose of vildagliptin 2mg IV 30-min prior to induction of AMI in combination with metformin 200 mg/kg/day I.P for 3 days prior to induction of AMI and after development of NC-STZ type 2 DM. All these groups were subjected to measure FBG level, serum CPK-MB level, serum troponin-1 level , HR,ST segment elevation, infarcted size, total serum cholesterol, serum TG , serum LDL-C and serum HDL-C.
the obtained data revealed that NC -STZ diabetic non treated rats showed significant elevation of serum CPK-MB level, serum troponin-1 level, HR,ST segment elevation, infarcted size ,total serum cholesterol, serum TG ,LDL-C and significant decrease of HDL-C. Treatment of diabetic rats with vildagliptin as monotherapy in experimentally induced AMI model resulted in significant reduction of FBG level, serum CPK-MB level, serum troponin-1 level , ST segment elevation and infarcted size with non significant changes of HR compared to diabetic infarcted non treated rats but treatment of diabetic rats with metformin as monotherapy in this model resulted in same results with significant decrease of HR while co-adminstration of (vildagliptin +metformin) with same previous doses to diabetic rats in experimentally induced AMI model resulted in normalization of FBG level with significant reduction of serum CPK-MB level,serum troponin-1 level, HR, ST segment elevation and infarcted size if compared to vildagliptin treated, metformin treated and diabetic infarcted non treated group. Also in this study, as regarding total lipid profile ,the obtained data revealed that treatment of diabetic rats with vildagliptin in this model resulted in significant reduction of serum TG level with non significant changes of total serum cholesterol level ,serum HDL-C and serum LDL-C level compared to diabetic infarcted non treated rats but treatment of diabetic rats with metformin as monotherapy in this model resulted in significant reduction of serum LDL-C level , significant elevation of serum HDL-C level, with non significant changes of total serum cholesterol level and serum TG compared to diabetic infarcted non treated group while co-adminstration of (vildagliptin + metformin) to resulted in significant reduction of serum TG level and serum LDL-C ,significant elevation of HDL-C with non significant changes of total serum cholesterol level if compared to monotherapy vildagliptin treated, metformin treated and diabetic infarcted non treated group.
To study the potential prophylactic effect of vildagliptin and or metformin on experimentally induced DN, 30 adult male albino rats, weighing about 250 -300 gm divided into 5 equal groups (6 rats in each ):1stgroup is normal control group. Induction of NA –STZ T2DM by a single I.P injection of STZ 65 mg/kg after 15 min of a single I.P injection of NA110 mg/kg of expiremental rats resulted in hyperglycemia determined at 72 h and was confirmed by the elevated glucose levels in plasma, then on day 7after injection, rats with FBG level concentration more than 200 mg/dl were considered as diabetic and development of NA-STZ T2DM. 2nd group diabetic non treated group receive no treatment, 3rd group: vildagliptin treated diabetic group :diabetic rats are given 8.76 mg/kg/day orally for 8weeks study after development T2DM. 4th group: metformin treated diabetic group: diabetic rats are given metformin 100 mg/kg/day orally for 8weeks study after development of T2DM and 5th group: vildagliptin and metformin treated diabetic group: diabetic rats are given vildagliptin 8.76 mg/kg/day orally in combination with metformin 100mg/kg/day orally for 8weeks study after development of T2DM.all these groups were subjected to measure FBG level, 24h UAE,serum urea level, serum creatinine level ,CR-CL and RBF. Histopathological examinationof kidneys at end of study.
These experimentally induced diabetic untreated rats were allowed to developed DN for the next 4weeks and show significant increase in FBG level, 24h UAE, serum urea level, serum creatinine level with significant decrease in CR-CL and RBF. Histopathological findings at 8wks study also have demonstrated glomerulosclerosis, atrophy, tubular vacuolization, interstitial fibrosis, and thickening of GBM. These findings indicate that end-organ injuries occurred in NA-STZ- induced type 2 DN in non treated rats used in the study .Treatment of diabetic rats with vildagliptin or with metformin orally just after development of T 2DM for 8 weeks study resulted in significant decrease in FBG level, 24h UAE, serum urea level ,serum creatinine level with significant increase in CR-CL level and in RBF level compared with diabetic non treated rats. While co-administration of (vildagliptin + metformin) orally daily with same previous doses to diabetic rats just after development of T2DM for 8 weeks study in experimentally induced DN resulted in normalization of FBG level with significant decrease in 24h UAE, serum urea level ,serum creatinine level and significant increase in CR-CL level and in RBF level compared with monotherapy either vildagliptin or metformin treated and diabetic non treated rats.
In the present work, as regard histopathological data among treated diabetic rats, it was found that vildigliptin treated and metformin treated diabetic rats at 8wks study demonstrated moderate changes of glomerulosclerosis,atrophy,tubular vacuolization, and thickening of GBM compared to diabetic non treated rats ,while combined therapy (vildagliptin + metformin) for 8wks study demonstrated mild changes of glomerulosclerosis and atrophy that started to be appeared with no tubular vacuolization and no thickening of GBM compared to monotherapy and diabetic non treated rats in experimentally induced DN.
To study the potential prophylactic effect of vildagliptin and or metformin on experimentally induced HFSD –STZ induced type 2 diabetic NASH model,30 adult male albino rats, weighing about 250 -300 gm divided into 5 equal groups (6 rats in each ):1stgroup is normal control group was fed with standard diet. Induction of this model by feeding of rats with HFSD (83.25% basic feed + 10% lard + 5% sugar + 1.5% cholesterol )for 4wk combined with a single dose of STZ 40 mg/kg IP(to induce late stage of T2DM) , 72 hours post-injection, resulted in increase in blood glucose level. Rats which become diabetic with a blood glucose concentration >350 mg/dl would be used in the study then continue to be fed the same HFSD component for the next 8 wk. Diabetic rats will developed diabetic NASH at 6th wk of 12wks study .2nd group diabetic non treated group, receive HFSD with the same component as above for 8 weeks study after development of T2DM with no treatment, 3rd group: vildagliptin treated diabetic group :diabetic rats were given vildagliptin (15 mg/kg/day orally )+HFSD for 8weeks duration of 12wks study after development T2DM. 4th group: metformin treated diabetic group: diabetic rats are given metformin (50 mg/kg/day orally) )+HFSD for 8 weeks study after development of T2DM and 5th group: vildagliptin and metformin treated diabetic group: diabetic rats are given vildagliptin (15 mg/kg/day orally) in combination with metformin (50mg/kg/day orally ) )+HFSD for 8weeks study after development of T2DM.all these groups were subjected to measure FBG level, level, serum ALT level, serum AST level, total serum cholesterol level, serum TG level ,serum HDL-C and serum LDL-C .
The obtained data in the current work revealed that these experimentally induced diabetic untreated rats were developed type 2 diabetic NASH at 6th wks of 12wks study and show significant increase in FBG level, serum ALT level,serum AST level, total serum cholesterol level ,serum TG level and serum LDL-C with significant reduction of serum HDL-C. Histopathological findings at 12wks study also have developed severe degree of macrovesicular steatosis, hydropic degeneration (hepatocyte ballooning) and steatohepatitis. These findings indicate that occurred in HFSD-STZ induced diabetic NASH model in non treated diabetic rats used in the study. Treatment of diabetic rats with vildagliptin or with metformin with same previous doses daily orally + HFSD just after development of T2DM for 8weeks in this model resulted in significant decrease of FBG level, serum ALT level,serum AST level, total serum cholesterol level, serum TG level and serum LDL-C with significant elevation of serum HDL-C compared with diabetic non treated rats,while co-administration of (vildagliptin+metformin) with same previous doses daily orally + HFSD for 8 weeks after development of diabetic NASH model resulted in normalization in FBG level with significant decrease in serum ALT level,serum AST level, total serum cholesterol level ,serum TG level and serum LDL-C with significant elevation of serum HDL-C compared to monotheray either with vildagliptin alone or metformin alone and diabetic non treated rats.
Further more in the present work, as regard histopathological data among treated diabetic rats, it was found that vildigliptin treated and metformin treated diabetic rats at 12wks study demonstrated moderate changes of macrovesicular steatosis, hydropic degeneration (hepatocyte ballooning) and steatohepatitis started to be appeared if compared to diabetic non treated rats ,while combined therapy (vildagliptin +metformin) at 12wks study demonstrated mild changes of macrovesicular steatosis , hydropic degeneration (hepatocyte ballooning) started to be appeared of lesser degree if compared to monotherapy and diabetic non treated rats in experimentally HFSD-STZ induced diabetic NASH model.
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