الفهرس 
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Abstract
Diabetes mellitus isa long-life progressive disease and is one of the oldest non-communicable diseases known to the humanitywith growing prevalence that leads to massive life-threatening complications. The vast majority of diabetes mellitus cases fall under two broad categories, classified as type 1 and type 2 diabetes mellitus. Recently, it is considered as one of the main threats to the human health in the 21stcentury which ranked the 7th of leading causes of death worldwide.
Type 2 diabetes mellitus is a chronic and heterogeneous metabolic disorder which is characterized by hyperglycemia as a common feature with disturbed fats and carbohydrates metabolism that resulted from impaired insulin secretion, insulin action or even both of them. The chronic hyperglycemia is associated with long-term dysfunction of different organs andinsulin resistance is contributed to the interrelated plasma lipid abnormalities which is manifested as diabetic dyslipidemia.
Diabetic dyslipidemia is one of the main risk factors attributed to cardiovascular diseases in type 2 diabetes mellitus. It is manifested as elevated levels of serum total cholesterol, triglycerides and low-density lipoproteins, and reduced levels of high-density lipoproteins. Diabetic dyslipidemia, obesity, and insulin resistance observed in type 2 diabetic patients may lead to accelerated atherosclerosis.
Sterol regulatory element binding-proteins (SREBPs) is the master regulator of lipogenesis that regulates the biosynthesis of fatty acids, cholesterol and triglycerides through regulating crucial genes in lipogenesis. It is mainly regulated by insulin and integrates multiple mechanisms to control lipogenesis. In type 2 diabetic patients,the main isoform of SREBPs in the liver, which is SREBP-1c, is dysregulated resulting in enhanced lipogenesis, leading to central obesity and diabetic dyslipidemia.
The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3, and its receptors, vitamin D receptors (VDR) introducing beneficial pleiotropic effects away from their classical role in bone remodeling and regulating serum calcium and phosphorus homeostasis.Vitamin D receptors are widely distributed in extra musculoskeletal tissuessuch as: the pancreatic β-cells as well as the white and brown adipose tissues. As a result of such distribution, vitamin D ameliorates insulin secretion and insulin sensitivity by several mechanisms and also improves lipidsmetabolism abnormalities associated with type 2 diabetes mellitus.
The aim of this study is to evaluate the possible antidiabetic effects of vitamin D receptor agonist, alfacalcidol, solely or in a combination with the conventional antidiabetic drug, metformin.
This study was conducted on 50 male albino rats, divided into 5 groups each of ten rats. Ten rats were assorted as normal control group. The other 40 rats wereassorted as diabetic rats, and divided as follows: 10 rats wereleft untreated, 10 rats wereassigned for treatment with 200 mg/kg/day metformin solely, 10 rats wereassigned for the treatment with 0.1µg/kg/day alfacalcidol solely, and the last 10 rats wereassigned for a combined treatment of metformin and alfacalcidol.
For the evaluation of the possible antidiabetic effects of alfacalcidol in our study several parameters were evaluated. Routine clinical investigations were performed such as: glucose homeostasis parameters including: fasting blood glucose, fasting serum insulin and homeostatic model assessment of insulin resistance. Also lipid profile was assessed by the determination of total cholesterol, triglycerides, high density lipoprotein-cholesterol and low density lipoprotein-cholesterol. Liver functions including serum alanine aminotransferase and serum aspartate aminotransferase were evaluated. Serum calcium and phosphorusas well as serum 25-hydroxyvitamin D3 levels were also assessed.Besides, the expression level of SREBP-1c in the liver and both white and brown adipose tissues and the expression level of VDR in the pancreas and the white adipose tissue was determined in order to assume new strategies for the management of type 2 diabetes mellitus through the used therapeutic combination.
Results of the current study revealed that the combined treatment of metformin and alfacalcidol significantly lowered blood glucose level, HOMA-IR, and fasting insulin level confirming the antidiabetic effect of vitamin D3 on the pancreatic β-cells via improving both insulin secretion and insulin sensitivity. Moreover, such combination improved the lipid profile suggesting that vitamin D3 exerts beneficial effects on lipid metabolism. The elevated levels of liver enzymes, ALT and AST, indicated hepatocytes inflammation induced by HFD and the treatmentmanifested a protective hepatic effect of both metformin and alfalcacidol. Serum calcium and phosphorus levels are maintained in the normal level via the given alfacalcidol dose in order to provide minimal calcemic effect. Serum 25-hydroxyvitamin D3 showed significant reduction in all diabetic groups confirming that vitamin D3 deficiency is associated with many health problems.
In regard to SREBP-1c mRNA expression that varies widely in different tissues using various treatments indicated that the beneficial effect of vitamin D3is tightly linked to SREBP-1c resulting in reduced synthesis of TG and cholesterol levels. The combined treatment offered synergistic effect as both drugs affect SREBP-1c in the same mechanism.
Vitamin D receptor (VDR) mRNA expression revealed significant downregulationin the pancreas among the treatment groups resulting in improved glucose homeostasis parameters. However, white adipose tissue manifested significant upregulation in vitamin D receptor mRNA expression level that ensures the effect of vitamin D3 on the expression of genes related to lipid metabolism and adipogenesis.
Hence, it is worth saying that the main points discussed in the submitted study are still under investigation and showing many contradictions that permit further evaluation of such parameters and other genes using different doses and therapeutic regimens.