الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Diabetes mellitus is one of the most important public health problems with future estimates are even more alarming. Type 2 diabetes mellitus is the major form of DM, accounting for 90-95% of all cases of DM and has reached epidemic proportions. The burden of T2D microvascular complications is rising substantially with high impact on the quality of life and overall life expectancy. Diabetic kidney disease (DKD) is a common microvascular complication of DM, affecting approximately 25% of the diabetic population. Moreover, it is considered a major cause of end-stage renal disease (ESRD).
In fact, dyslipidemia in association with DM is the major cause of morbidity and mortality due to the high rate of severe cardiovascular diseases. It has been considered as the most significant factor in the development of diabetic complications by stimulating the beginning of the other pathogenic cascades. There are different effects for the anti-diabetic drugs on the arms of these complications and it is still a challenge to control DM without side effects, therefore new strategies need to be examined.
In view of such consideration, the present study was designed to examine and compare the effect of metformin, dapagliflozin, liraglutide and atorvastatin alone or in combinations on the lipid derangements associated with DM and their vascular impact in diabetic rats.
The study was conducted on 72 male albino rats of body weight ranging from 150- 200 grams. Initially, animals were randomly divided into 2 main groups:
I. group A: (normal control group) (8 rats)
Animals in this group were fed normal rat chow throughout the study. They received a single i.p. injection of 1 mL of 0.1 molar citrate buffer after 15 min of normal saline injection (1 mL i.p.) at the beginning of the study, followed by administration of 2.0 mL of 2% gum acacia orally daily for 8 weeks.
II. group B: (Type 2 Diabetic group) (STZ-NA-induced diabetic rats); (64 rats)
All animals in this group received a single dose of streptozotocin (STZ) (65 mg/kg, i.p.) after 15 min of nicotinamide (NA) injection (230 mg/kg, i.p.). Induction of diabetes was confirmed after 72 hours by fasting blood glucose (FBG) ≥ 250 mg/dl.
Finally, diabetic animals were further subdivided into 8 groups each of 8 rats:
• group B-1(diabetic control group): Animals received 2.0 ml of 2% gum acacia orally daily for 8 weeks following induction of DM.
• group B-2 (metformin-treated diabetic group): Animals received metformin (200 mg/kg) suspended in 2.0 mL of 2% gum acacia orally daily for 8 weeks following induction of DM.
• group B-3(dapagliflozin-treated diabetic group): Animals received dapagliflozin (1 mg/kg) suspended in 2.0 mL of 2% gum acacia orally daily for 8 weeks following induction of DM.
• group B-4 (liraglutide-treated diabetic group): Animals received liraglutide (0.8 mg/kg/s.c.), (0.2ml/kg/ s.c.) daily for 8 weeks following induction of DM.
• group B-5 (atorvastatin-treated diabetic group): Animals received atorvastatin (10 mg/kg) suspended in 2.0 mL of 2% gum acacia orally daily for 8 weeks following induction of DM.
Combinations groups:
• group B-6 (metformin + atorvastatin-treated diabetic group): Animals received metformin & atorvastatin as previously mentioned in B-2 and B-5.
• group B-7 (dapagliflozin + atorvastatin-treated diabetic group): Animals received dapagliflozin & atorvastatin as previously mentioned in B-3 and B-5.
• group B-8 (liraglutide + atorvastatin-treated diabetic group): Animals received liraglutide & atorvastatin as previously mentioned in B-4 and B-5.
At the end of the study period (8 weeks), urine samples were collected for (24 hours) to assess UACR. Under ketamine anesthesia, blood samples were collected first from the retro-orbital vein for assessment of glycosylated hemoglobin (HbA1C%) then via a laparotomy, blood was collected from the abdominal aorta for separation of serum for assessment the following parameters: fasting serum glucose (FSG), serum LDL-C, HDL-C, TGs, using colorimetric methods & serum thyrotropin (TSH), serum lipoprotein(a)( Lp (a)), serum highly sensitive C-reactive protein (hs-CRP) and serum advanced glycation end products (AGEs) levels using ELISA kits. Following sacrificing the rats, both kidneys were immediately removed, fixed in 10% formalin, stained with hematoxylin and eosin (H&E) stain and Periodic Acid Schiff (PAS) stain, and then they were examined under the light microscope for histological changes. The histological examination was focused mainly on renal corpuscles and its glomerular capillaries as an example of microvasculature. The histomorphometric analysis of renal cortices was performed using the image processing & analysis software (ImageJ).
Results of the present work revealed that, the STZ-NA model simulated both metabolic and renal derangements observed in T2D.There was a statistically significant increase in the levels of FSG, HbA1C%, LDL-C, Lp (a), TGs, TSH, AGEs and hs-CRP &UACR with a significant decrease in serum HDL-C level, in diabetic control group as compared to the normal control group.
Treatment of diabetic rats with metformin (group B-2) or liraglutide (group B-4) resulted in significant decrease in the levels of FSG, HbA1C%, LDL-C, Lp (a),TGs, TSH, AGEs and hs-CRP &UACR with a significant increase in serum HDL-C level, when compared to the diabetic control group.
Treatment with dapagliflozin (group B-3) showed significant decrease in the levels of FSG, HbA1C%, TGs with a significant increase in serum HDL-C level & insignificant increase in both LDL-C and Lp (a) & insignificant decrease in AGEs, TSH and hs-CRP & significant increase in UACR, when compared to the diabetic control group.
Treatment with atorvastatin (group B-5) resulted in insignificant increase in the levels of FSG, HbA1C% & significant decrease in serum levels of LDL-C, Lp (a),TGs, TSH, AGEs and hs-CRP & UACR with a significant increase in serum HDL-C level, when compared to the diabetic control group.