الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Diabetes mellitus (DM) is one of the most important public health problems. The prevalence of DM is increasing worldwide. T2DM is the most common type of diabetes. Previous studies have documented that T2DM patients have a significantly higher fracture risk than age-matched persons without diabetes regardless of normal or even high BMD. This condition is now referred to as diabetic bone disease (DBD). This may be due to several factors including diabetes related micro-vascular complications, fall risk and alterations associated with chronic hyperglycemia and increased obesity rates. Anti-diabetic drugs have different effects on bone homeostasis due to, in part, their anti-diabetic action, as well as to drug related effects not related to the diabetic control and unfortunately some of these drugs have negative side effects that compound the health issues already seen with diabetic bone.
In view of such a consideration, the present study was designed to evaluate and compare the bone effects of dapaglifozin as a monotherapy and as combined with metformin, pioglitazone or alfacalcidol in a rat model of T2DM induced by high fat diet (HFD) and low dose streptozotocin (STZ).
The study was conducted on 48 male albino rats of body weight ranging from 150–180 g. Initially, animals were randomly divided into 2 main groups:
group A: Normal control group (8 rats): Animals in this group were fed normal rat chow throughout the study. They received a single intraperitoneal (i.p.) injection of 1.0 mL of 0.1 Molar citrate buffer 2 weeks after the beginning of the study, followed by administration of 2.0 mL of 2% gum acacia orally daily for 9 weeks.
group B: Diabetic group (40 rats): Animals were fed by in-house prepared HFD; 58% calories from fat. At the end of the 2nd week, animals were injected i.p. by a low dose STZ (35mg/kg). Induction of experimental T2DM was confirmed by measuring serum glucose levels one week after STZ injection.
Finally, Diabetic animals were further subdivided into 5 groups of 8 rats each:
• group B-1 (diabetic control group): Animals in this group received 2.0 mL of 2% gum acacia orally daily for 9 weeks following induction of DM.
• group B-2 (dapagliflozin-treated diabetic group): Animals in this group received dapagliflozin (1 mg/kg) suspended in 2.0 mL of 2% gum acacia orally daily for 9 weeks following induction of DM.
• group B-3 (dapagliflozin + metformin-treated diabetic group): Animals in this group received dapagliflozin (1 mg/kg) suspended in 1.0 mL of 2% gum acacia and metformin (100 mg/kg) suspended in 1.0 mL of 2% gum acacia orally daily for 9 weeks following induction of DM.
• group B-4 (dapagliflozin + pioglitazone-treated diabetic group): Animals in this group received dapagliflozin (1 mg/kg) suspended in 1.0 mL of 2% gum acacia and pioglitazone (30 mg/kg) suspended in 1.0 mL of 2% gum acacia orally daily for 9 weeks following induction of DM.
• group B-5 (dapagliflozin + alfacalcidol-treated diabetic group): Animals in this group received dapagliflozin (1mg/kg) suspended in 1.0 mL of 2% gum acacia orally daily and alfacalcidol (0.2 μg/kg) suspended in 1.0 mL of 2% gum acacia orally five times a week for 9 weeks following induction of DM.
By the end of the 12th week, animals were weighed then samples were collected. 24-hour urine samples were collected for assessment of urine calcium/creatinine ratio (UCCR) and urine phosphate/creatinine ratio (UPCR). Under ketamine anesthesia, blood samples were collected for assessment of glycosylated hemoglobin level (HbA1C) ,fasting serum glucose level (FSG), serum procollagen type I N-terminal propeptide (P1NP), a marker of bone formation and serum C-terminal telopeptide of type I collagen (CTX1), a marker of bone resorption. Following sacrificing the rats, their lumbar vertebrae and both femurs were excised and fixed in 10% formalin, routinely processed and embedded in paraffin. Bone tissue sections were subsequently stained with hematoxylin and eosin (H&E) stain and Masson’s trichrome stain then microscopically examined. The histomorphometric analysis was performed using the image processing & analysis software (ImageJ), version 1.49