الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Life is the instantaneous encounter of circulating matter and flowing energy (Jean Giaja, Serbian physiologist), This definition can be applied to the relationship between how much we eat and how much we need. Their evolutionary partnership has resulted in an inseparable yet dynamic homeostasis in health, which, when disrupted, leads to disease. This connection is even more important today, in an era of epidemic metabolic diseases such as obesity, metabolic syndrome, and diabetes. Obesity is a medical condition in which excess body fat has accumulated to the point where it may be harmful to one’s health. It has become a worldwide epidemic and a major public health concern. It is now the second most preventable cause of death in the United States. Obesity-Induced Hyperglycemia Pathogenesis Diabetes type II is one of the most common disorders in the overweight and obese population. Type 2 diabetes mellitus (T2DM) is a disease of antiquity characterized by dysregulation of carbohydrate, lipid, and protein metabolism and caused by impaired insulin secretion, insulin resistance, or a combination of the two. Cell dysfunction, insulin resistance followed by hyperglycemia and β-cell death, and chronic inflammation characterize the pathophysiological changes, all of which progressively impair blood glucose control and lead to the development of micro and macrovascular complications. Despite the great progress in therapeutic and diagnostic approaches, human medicine still faces many challenges, and among these challenges is pandemic of diabetes mellitus (DM), especially type 2 diabetes mellitus (T2DM). If diabetes is not treated promptly, the risk of complications has been growing. Despite the availability of numerous anti-diabetic medications, proper treatment of hyperglycemia remains a challenge. As a result, there is a persistent need for drug repurposing is an alternate way to addressing this problem, in which old medications used for different indications are examined for new usage wherein, not only the failure of the antidiabetic drug monotherapy in glycemic control and increasing side effects when large doses of antidiabetic drugs are used to achieve better glycemic control, but also insulin therapy is costly and not preferred due to poor patients’ compliance in parenteral application. Hydroxychloroquine (HCQ) is a specialized medication with pleiotropic effects that is now used to treat patients with autoimmune diseases as a result, it is commonly used in rheumatology and dermatology. It is a cationic-amphiphilic 4-aminoquinine compound with a weakly basic structure that allows free membrane passage and accumulates in acidic vesicles like the lysosomal compartment (an important site of action of this drug) as a result, HCQ inhibits various insulin degrading enzymes and thus inhibits insulin degradation by increasing intracellular pH. Several studies have shown that HCQ is effective in lowering the risk of developing type 2 diabetes and improving metabolic profiles such as fasting blood sugar, insulin sensitivity, hemoglobin A1c (HbA1c), and lipid profiles. These advantages have been reported in patients with autoimmune diseases. Therefore, the current study was designed to investigate the effect of HCQ on hyperglycemia that influences the redox state, inflammation and apoptosis in the liver and pancreas, and diabetic consequences of T2DM-induced rats by using high fat diet (HFD) for 18 weeks that led to obesity which caused insulin resistance leading to T2DM. This work was carried out on 24 male Wistar albino rats with bodyweight 120-150 g. After one week of acclimatization, animals have randomly divided into 4 groups ; 6 rats in each group rats were randomly divided into four groups ; 6 rats in each group. Control (Cont.) group : rats received only a standard diet and tap water daily for 18 weeks. (HCQ) administrated group : rats were orally given HCQ with a gastric tube (40 mg /kg.BW), daily for 18 weeks. High-fat diet (HFD) fed group : rats received pellets of HFD and tap water daily for 18 weeks. HFD + HCQ-treated group : The rats received HFD pellets and tap water along with HCQ oral injection by using a gastric tube (40 mg/kg/BW) together from the first day of the experiment after a week of acclimation daily for 18 weeks. Body weights were recorded on the first day of the experiment then weekly for consecutive 18 weeks (about 4 months) using a digital weighing balance in addition to Weekly glucose levels (mg/dl) which were determined by Accu-Chek blood glucose meter. Biochemical analysis Metabolic parameters Serum glucose levels, serum insulin levels, HOMA-IR, HOMA-B, HOMA-IS, and HbA1c Determination of serum lipid profile ( TC, TG, HDL-C, LDL-C, and VLDL-C ). Determination of oxidative stress marker and antioxidants in liver ( 4-HNE, GPx, GSH ). Determination of pro-inflammatory and anti-inflammatory cytokines (IL6, TNF-α, leptin, IL10, adiponectin). Determination of cardiac parameters (CK-MB, LDH, cTn-T). Determination of thrombotic indicator (D-dimer). All data were statistically performed with GraphPad Prism 8.0 software. Results are presented as mean ± SEM of n = 6. Statistical comparisons were evaluated by one-way analysis of variance (ANOVA) followed by Duncan’s multiple range tests. Percent of changes in treated groups were calculated, comparing to control and hydroxychloroquine groups respectively. The results were summarized as follows : The results showed that eating the rats a high-fat diet for 18 weeks led to an increase in the level of glucose, and at the same time the level of insulin was higher than normal, which indicates that there is a pathological condition known as insulin resistance, which leads to the appearance of diabetes mellitus of the second type, as the measured parameters confirmed this condition. Treatment of high-fat diet fed rats with hydroxychloroquine significantly normalized the levels of blood glucose , serum glucose , HbA1-c , and the lipid profile and improved the insulin level and insulin resistance compared with diabetic rats , affirming its antidiabetic effect in addition to its ameliorative effect on the body weight. Hydroxychloroquine significantly inhibited the development of oxidative stress and sustained the levels of glutathione and activity of glutathione peroxidase in the liver of diabetic rats and lowered the 4-HNE level, a lipid peroxidation product, indicating its antioxidant capacity. Additionally, HCQ limited the increase in pro-inflammatory cytokines (IL-6, TNF-α, leptin) and enhanced the anti-inflammatory cytokine (IL-10, adiponectin) indicating its anti - inflammatory effect. Hydroxychloroquine controlled the levels of cardiac troponin-T (cTn-T), creatine kinase-myocardial band (CK-MB), and lactate dehydrogenase (LDH) activity, indicating that HCQ can sustain the integrity of cardiomyocytes and ameliorate myocardial injury. Hydroxychloroquine significantly ameliorated the elevation of D-dimer levels in diabetic rats, reflecting the efficacy and safety application of hydroxychloroquine especially on the heart. In conclusion, these results indicate that HCQ has an anti-hyperglycemic and anti-lipidemic effect while maintaining liver function. Comparable values of cardiac function parameters (cTn-T, CK-MB, and LDH) were observed in the control group, reflecting the positive effects of HCQ on the heart of obese rats. The effects of HCQ were explained by striking the amelioration of oxidative stress indicated by the lower level of 4-HNE and higher level of GPx and GSH in the liver of HFD+HCQ than in HFD-fed rats. Furthermore, the inflammatory markers in serum of HFD+HCQ-treated rats were normalized to the control levels. By contrast, anti-inflammatory cytokines were elevated when HFD-fed rats received HCQ. Therefore, the stabilization of redox balance and modulation of inflammatory response and their interdependence indicate the ameliorative effect of HCQ on obesity and related metabolic disruption as well as organ functions.