Numerous factors can lead to inflammation and enlargement of the colon, posing a serious health risk. This study investigated the protective effects of watercress (Nasturtium officinale) leaf methanolic extract against dextran sodium sulfate (DSS)-induced colonic inflammation in rats. Phytochemical analysis showed high levels of polyphenols, flavonoids, and condensed tannins in the methanolic extract, which exhibited the strongest in vitro anti-diabetic (α-amylase and α-glucosidase enzymes; Inhib.

Background: Paracetamol (PAC) overdose causes acute liver injury through oxidative stress, inflammation, and apoptosis. While N-acetyl cysteine (NAC) is the standard treatment, fucoxanthin (FUC), a carotenoid from brown seaweed, has shown hepatoprotective effects in animal studies, but its role in PAC toxicity is unclear. Objective: Compared to NAC, this study assessed the hepatoprotective potential of oral FUC solution toward PAC-induced injury to the rat's liver. Method: FUC was formulated as a pharmaceutical solution and characterized via UV-VIS spectroscopy. Six groups of male Wistar rats each contain five animal which are in total 30 rats: negative control (NC), positive control (PC, 2 g/kg PAC), NAC (1200 mg/kg), and three oral FUC doses (100, 200, and 500 mg/kg) for seven days, with PAC administered on day-8. Liver tissues were analyzed for oxidative stress, gene expression, and histology. Results: FUC solution was clear with absorbance at 433 nm. PAC caused 30% mortality (p < .01 vs. others). NAC reduced ALT (56%), AST (78%), ALP (28%), and increased TP by 25% (p < .001 vs. PC). FUC at 500 mg/kg (F500) was superior, reducing ALT (82%), AST (93%), ALP (40%), and increasing TP (35%) (p < .001 vs. NAC). PAC increased oxidative stress, CYP2E1/CYP3A2 expression, apoptosis markers, and suppressed Nrf2/AMPK/AKT1. F500 improved antioxidants, reduced oxidative stress, and apoptosis, enhanced the Nrf2/AMPK pathway, and downregulated CYP2E1/CYP3A2 (p < .01). Conclusion: FUC, particularly at 500 mg/kg, offers significant hepatoprotection against PAC-induced liver injury by modulating drug metabolizing enzymes and enhancing antioxidant defenses, warranting further research.

Genetic factors might influence metabolic syndrome (MetS) or any of its components. It was postulated that low density lipoprotein receptor (LDLR) gene variants could play a role in cholesterol hemostasis and the development of MetS. However, the causal-effect relationship between such variants and the development of MetS is not clearly identified or even studied before in Saudi Arabian women. This study aims to identify the variants of LDLR exon-4 in Saudi Arabian women with MetS in comparison to healthy women and to assess the expected effect of amino acids alterations on the structure and functions of the LDLR proteins. A total of 208 female Saudi patients with MetS and 104 controls were included in the study. The exon 4 of LDLR gene was studied by DNA sequencing (Sanger) and structural analysis was performed using Project HOPE software. Four variants were identified; 2 were missense variants (2.4

Multidrug resistance (MDR) is the major complex mechanism that causes the failure of chemotherapy, especially with drugs of natural origin such as doxorubicin (DOX). Intracellular drug accumulation and detoxification are also involved in cancer resistance by reducing the susceptibility of cancer cells to death. This research aims to identify the volatile composition of Cymbopogon citratus (lemon grass; LG) essential oil and compare the ability of LG and its major compound, citral, to modulate MDR in resistant cell lines. The composition of LG essential oil was identified using gas chromatography mass spectrometry (GC-MS). In addition, a comparison of the modulatory effects of LG and citral, performed on breast (MCF-7/ADR), hepatic (HepG-2/ADR), and ovarian (SKOV-3/ADR) MDR cell lines, were compared to their parent sensitive cells using the MTT assay, ABC transporter function assays, and RT-PCR. Oxygenated monoterpenes (53.69%), sesquiterpene hydrocarbons (19.19%), and oxygenated sesquiterpenes (13.79%) made up the yield of LG essential oil. α-citral (18.50%), β-citral (10.15%), geranyl acetate (9.65%), ylangene (5.70), δ-elemene (5.38%), and eugenol (4.77) represent the major constituents of LG oil. LG and citral (20 μg/mL) synergistically increased DOX cytotoxicity and lowered DOX dosage by >3-fold and >1.5-fold, respectively. These combinations showed synergism in the isobologram and CI < 1. DOX accumulation or reversal experiment confirmed that LG and citral modulated the efflux pump function. Both substances significantly increased DOX accumulation in resistant cells compared to untreated cells and verapamil (the positive control). RT-PCR confirmed that LG and citral targeted metabolic molecules in resistant cells and significantly downregulated PXR, CYP3A4, GST, MDR1, MRP1, and PCRP genes. Our results suggest a novel dietary and therapeutic strategy combining LG and citral with DOX to overcome multidrug resistance in cancer cells. However, these results should be confirmed by additional animal experiments before being used in human clinical trials.

BACKGROUND Serum ferritin is an acute-phase protein whose level is increased in several inflammatory diseases. This review describes the structure and function of ferritin as well as its association with the prognosis of patients with COVID-19. METHODS We searched MEDLINE/PubMed databases, Scopus, and Web of Science for prospective and review articles that examined ferritin and its association with COVID-19 severity. Based on all these articles and clinical experience, a review was constructed and full texts of the articles that were retrieved were accessed. RESULTS All COVID-19 related studies conducted in 2020, which performed serum ferritin testing, clearly showed ferritin as a biomarker of COVID-19 severity in hospitalized patients. Ferritin levels in severe patients were significantly increased relative to those in non-severe patients (p < 0.001). Non-survivors had significantly higher ferritin levels than the survivors (p < 0.001). CONCLUSIONS Determination of ferritin levels was specific and sensitive for early disease severity prediction in patients with COVID-19. Serum ferritin can also be used for predicting the response to COVID-19 vaccines.

We evaluated the prevalence and association of Vitamin D deficiency with glycemic control and CVD risk in T2DM patients. Serum 25 (OH)D3, lipid profile, glucose panel, HbA1c, serum insulin, and HOMA-IR were assessed in 93 T2DM patients and 69 controls. 10 years and lifetime ASCVD risk scores were calculated. The levels of 25(OH)D3 were significantly low in T2DM patients compared to the control. T2DM patients with hypovitaminosis D displayed significantly increased FBG, insulin, and HOMA-IR compared to normovitaminosis. Their lifetime and 10-year ASCVD risk scores were significantly higher regardless of vitamin D deficiency levels ( P = 0.006 ; P = 0.023 ) in comparison to patients with sufficient levels of vitamin D. Among patients, the lifetime and 10 years of ASCVD risk showed a significant negative correlation with serum 25(OH)D3 and HDLc ( P = 0.037 ; 0.018) ( P = 0.0001 ), respectively, and significant positive correlation with T2DM duration, serum insulin, and HOMA-IR ( P = 0.018 ; 0.0001) ( P = 0.002 ; 0.001) ( P = 0.005 ; 0.001), respectively. The 10-year ASCVD risk exhibited a significant positive correlation with FBG ( P = 0.003 ) and HbA1c ( P = 0.009 ). T2DM duration was a predictor of vitamin D deficiency among T2DM patients (β = 0.22; CI = 0.002–0.04). There is a considerable association between lifetime and 10 years of ASCVD risk with hypovitaminosis D in T2DM, regardless of the deficiency levels which could be predicted by the diabetes duration.

Sepsis-related mortality and morbidity are major health care problems worldwide. More effort is required to identify factors associated with adverse outcome. Evaluate the prognostic capacity of tumor necrosis factor (TNF), kidney injury molecule (KIM), and lactate and TNF-α-308 G > A gene polymorphism for prediction of 28 days-intensive care unit (ICU) mortality. TNF-α-308 G > A single nucleotide polymorphisms was detected by real-time-PCR on 112 had septic shock and 88 were septic. Serum TNF-α and urinary KIM were assessed by enzyme-linked immunosorbent assay. This study included 200 critically ill patients, 125 (62.5%) of them died within 28 days in ICU (nonsurvivors). Frequencies of TNF-308 G > A was (70.7) GG, (28) GA and (1.3) AA in survivors versus (85.6) GG, (12) GA and (2.4) AA for nonsurvivors, revealed significant association with ICU mortality but not sepsis severity (p = 0.15) or sepsis-induced acute kidney injury (AKI). In contrast, urinary KIM-1 revealed significant association with sepsis severity (p = 0.036) and AKI (p = 0.0001), but not 28-days ICU mortality. The relative risk of death in patients with GG genotype was 2.5 mainly in ICU younger male patients (odds ratios 24 and 4.9, p = 0.001). The genotype GG and GA were significantly associated with [increased urinary KIM-1 (0.29 ± 0.1) (p = 0.0001), terminal creatinine (1.67 ± 0.8) (p = 0.0001)] and [increased terminal urea (109 ± 0.001) (p = 0.001) and basal serum TNF (60 ± 0.001) (p = 0.0001)], respectively. In linear regression analysis, AKI 0.0001 (0.4-0.67), basal serum TNF 0.04 (0.0001-0.04), and TNF-308 GG 0.007 (0.05-0.33) were associated with 28 days ICU mortality [p value (95% confidence interval)]. The same results were observed for initial urea 0.024 (0.0001-0.003) and lack of diuretic usage 0.0001 (0.35-0.7) mainly in septic patients. Major frequency of TNF-308 G > A polymorphism (mainly in young age male patients), AKI and serum TNF were associated with increased risk for 28 days-ICU mortality. Furthermore, sepsis severity was influenced by TNF and urinary KIM-1, which reflects in AKI.

The title of the original article has been corrected to: Assessment of tumor necrosis factor alpha polymorphism TNF-α-238 (rs 361525) as a risk factor for development of acute kidney injury in critically ill patients. The original article has been corrected to reflect the correct title.

Background: High serum total testosterone is associated with metabolic syndrome (MS). This study aimed to identify possible alterations in total testosterone and their relationship with plasma glucose, blood pressure, and serum lipid profile. Methods: One hundred forty-two female subjects were selected to participate in this study, and they were recruited by consultant physicians from the Clinic and Medical Out-Patient, King Abdulaziz Hospital, Kingdom of Saudi Arabia. The anthropometric characteristics were obtained from questionnaires by using standard methods. Blood samples were obtained for the determination of glucose, triglycerides, total cholesterol, low-density lipoprotein, and high-density lipoprotein by using enzymatic methods. Total testosterone was determined by enzyme-linked immunosorbent assay for the quantitative measurement of testosterone in human serum. Results: Significantly higher concentrations of total testosterone, low-density lipoprotein, and glucose, but lower concentrations of high-density lipoprotein, were observed in subjects with MS compared with women without MS (P<0.05). Conclusion: This study suggests that high levels of total testosterone and disturbance in lipid profile were associated with MS in Saudi women.

Aim To evaluate the effect of different anti-diabetic treatment strategy on oxidative stress markers in patients with type 2 diabetes mellitus (T2DM). Subject and methods A total of 93 patients with T2DM treated with metformin (G1 = 25), OHA (G2 = 22), OA and insulin (G3 = 26) and insulin alone (G4 = 20). In all patients, lipid profile and glycemic indices were assessed using routine laboratory tests. MDA and Oxidized LDL were assessed using commercially available ELISA kits. Laboratory tests were performed at baseline and at a control visit after 24 weeks of treatment. Results A significant decrease in the levels of MDA with improvement of glycemic control was observed in the group receiving OHA in combination with insulin therapy. A similar decrease of oxLDL was observed in all diabetic subgroups with borderline significance in those receiving metformin alone. The remaining clinical and biochemical parameters were not changed during follow-up in any of the involved groups. Conclusion A combination therapy with insulin was more effective in glycemic control and MDA reduction in T2DM. Whereas, a significant oxLDLc reduction was observed in T2DM irrespective of categories of antidiabetic treatment or glycemic control.

Background: Alterations of trace elements, could induce metabolic disorders as they forthwith participating in the metabolic pathways and play different roles modulating it as well as many enzymes require trace elements for their activation and functions. Of these elements, selenium (Se), zinc (Zn), copper (Cu) and manganese (Mn) have been recognized as essentials for metabolism. Hyperglycemia and diabetes mellitus are important causes of mortality and morbidity worldwide, and their global prevalence are growing from 2.8% in 2000 projecting to be 4.4% in 2030. Diabetes is prevalent in Saudi Arabia with high incidence in urbanized areas and its prevalence is estimated to expand 3 times by 2030. Patients and Methods: In total, 75 diabetic women and 80 aberrantly healthy women were recruited. Clinical and familial history was recorded. Hair Se, Zn, Cu and Mn levels were analyzed as well as fasting blood sugar (FBS), glycated hemoglobin (HbA1c). Results: Our findings revealed a marked decrease of Zn and Mn levels in diabetic women hair compared to control group (p < 0.05, p <0.005 respectively). Otherwise, Se and Cu levels were significantly elevated in hair of diabetic patients (p < 0.005, p <0.05 respectively). Conclusion: Diabetes may disrupt the trace elements balance as well as their alterations can affect glucose metabolism and insulin action. Chronic hyperglycemia can cause disturbance of some trace elements which, in turn, can modulate glucose homeostasis. The metabolic dysregulation occurring in hyperglycemia may influence trace element status by increasing excretion, diminishing availability or redistribution of trace elements among different body pools. Hair trace elements can be useful long-term markers for metabolic disturbance; however, larger prospective studies are required to validate their role in diagnosis and follow up applications.

Particulate matter may comprise toxic trace elements with carcinogenic effects. Of these trace elements, Cadmium (Cd), Chromium (Cr), Arsenic (As), Beryllium (Be) and Nickel (Ni) are classified as probable human carcinogens. During the annual Hajj pilgrimage, 2.3 million pilgrims stay in Makkah, Saudi Arabia; the increased vehicle traffic contributes to elevated concentrations of particulate matter. We aimed to determine the excess cancer risk (ECR) associated with inhalation exposure in the Makkah population. This study was conducted in the Arafat area, which is a highly-crowded area during Hajj. Inductively coupled plasma-mass spectrometry (ICP-MS) was used for trace element analysis. ECR resulting from inhalation exposure to each metal was calculated in accordance with the unit risk suggested by the Integrated Risk Information System. In summer, including Hajj, mean Cd, Cr, As, Be, and Ni atmospheric concentrations were 0.098, 0.008, 0.26, 0.03, and 0.012 μg/m3, respectively; in autumn, values were 0.06, 0.006, 0.16, 0.002, and 0.01 μg/m3, respectively. ECRs were 1.08 × 10𕒸, 7.21 × 10𕒸, 4.0 × 10𕒺, 4.6 × 10𕒺, and 2.4 × 10𕒺, respectively, exceeding the acceptable inhalation risk level (1.0 × 10𕒺) set by the US Environmental Protection Agency for each element. Higher atmospheric trace element concentrations in summer were due to high temperatures that increased atmospheric turbulence, leading to a greater amount of re-suspended dust from roads and blowing sand particles. These findings can be used by relevant authorities while developing regulations and strategies for developing air quality management to improve the health of pilgrims; however, larger prospective studies are required to estimate ECR in different seasons.

Background: Hypertension is one of the primary modifiable risk factors for cardiovascular disease. Adequate vitamin D (vit D) levels have been shown to reduce vascular smooth muscle contraction and to increase arterial compliance, which may be beneficial in hypertension. Further, coenzyme Q10 (COQ10) through its action to lower oxidative stress has been reported to have beneficial effects on hypertension and heart failure. This study examined the possible cardiac and renal protective effects of vit D and COQ10 both separately and in combination with an angiotensin II receptor blocker, valsartan (vals) in L-NAME hypertensive rats.Materials and Methods: Hypertension was induced in rats by L-NAME administration. Following induction of hypertension, the rats were assigned into the following 6 subgroups: an L-NAME alone group and treated groups receiving the following drugs intraperitoneally for 6 weeks; vals, vit D, COQ10 and combination of vals with either vit D or COQ10. A group of normotensive rats were used as negative controls. At the end of the treatment period, blood pressure, serum creatinine, blood urea nitrogen, lipids and serum, cardiac and renal parameters of oxidative stress were measured.Results: Compared to the L-NAME only group, all treatments lowered systolic, diastolic, mean arterial pressure, total cholesterol, low-density lipoprotein cholesterol, and creatinine levels as well as TNF-alpha and malondialdehyde. Further, the agents increased serum, cardiac and renal total antioxidant capacity. Interestingly, the combination of agents had further effects on all the parameters compared to treatment with each single agent.Conclusions: The study suggests that the additive protective effects of vit D and COQ10 when used alone or concurrent with vals treatment in hypertensive rats may be due to their effects as antioxidants, anticytokines and blood pressure conservers.

Alterations in the trace element content can induce metabolic disorders as these elements are involved in the regulation of metabolism. Obesity increases the likelihood of various diseases, particularly cardiovascular disease and type 2 diabetes, and is more prevalent in Saudi Arabia, especially in women. This study explored the potential of alterations in hair trace elements as long-term markers in diabetic and/or obese Saudi females. In total, 65 diabetic obese women, 47 non-diabetic obese women, and 70 normal-weight women were recruited. Clinical and familial history and anthropometric variables were recorded. Hair Se, Zn, Cu, Mn, and Fe levels were analyzed. Fasting blood sugar (FBS), glycated hemoglobin (HbA1c), and lipid profile were analyzed. Our findings revealed a marked decrease of hair Zn, Mn, and Fe and elevated Se and Cu levels in obese women. In addition, Zn and Fe levels were decreased in diabetic women. Thus, the metabolic distress occurring in obesity and hyperglycemia may affect trace element status by increasing the excretion and decreasing the bioavailability of trace elements or redistributing them among various pools. Hair trace elements can serve as important long-term markers for metabolic disorders; however, larger prospective studies are warranted to validate their diagnostic and follow-up utilities.

Hepatic fibrosis detection is considered as a major independent predictor of treatment response in patients with chronic hepatitis C virus (HCV). Liver biopsy wasrepresented as the gold standard method for evaluating liver fibrosis and has prone sampling errors and completions.Right now, usages of non-invasive predictors of fibrosis are considered less accurate than liver biopsy.We are aiming to reduce the use of the liver biopsy and instead evaluate the performance value of serum hyaluronic acid (HA), Collagen type IV (Coll-IV), and aspartate aminotransferase (AST) to platelet ratio index (APRI) as non-invasive diagnostic and stratification markers for hepatic fibrosis.In this study, we have recruited 104 subjects from Saudi population effected with chronic hepatitis C genotype 4. The enzyme-linked immunosorbent assay (ELISA) method was implemented for Liver histopathological staging (F), serum hyaluronic acid and Collagen-IV.APRI was calculated from serum AST activity and platelet count.The results of our current study indicated both Collagen-IV and APRI significantly distinguished fibrotic patients from non-fibrotic group.The HA, APRI, and Coll-IV results discriminate early F0/F1 from F2/ F3 (p<0.001).A combination of direct and indirect tests (Coll-IV and APRI) improved the performance with sensitivity and specificity.The combination of APRI and Collagen-IV has a high diagnostic value in predicting moderate and severe fibrotic stages and could be clinically used as a diagnostic test especially for those HCV patients who could not be submitted for liver biopsy.Key words: Hepatic fibrosis, chronic hepatitis C, HCV genotype 4, serum hyaluronic acid (HA), serum Collagen type IV (Coll-IV), AST to platelet ratio index (APRI) and Receiver operating characteristicsHepatitis C is a global socio-medical health problem and the Hepatitis C virus genotype 4 (HCV-4), most dominant genotype in Saudi Arabia 1-4 .Despite the reported declines in HCV prevalence, the disease continue to represent a major public health problem in the country with a significant morbidity and mortality as well as a great burden on the country's healthcare system 5 .Chronic infection with HCV induces the progression of liver fibrosis.HCV infection of the

Introduction: Gastric cancer (GC) remains a major public health problem worldwide being the third commonest cause of cancer death worldwide. Many recent studies focus on the immunohistochemical evaluation of Bcl-2 expression and its serum expression and its prognostic significance in gastric cancer each one separately. We conducted our study to determine the correlation between serum Bcl-2 antigen and gastric carcinoma, to investigate whether serum Bcl-2 concentrations can be used as marker for immunohistochemical determination of Bcl-2 alterations in gastric cancer patients and examine the association between its expression and other clinicopathological parameters. Methods: Our study conducted in Forty-five consecutive patients with gastric cancer underwent gastrectomy in Mansoura Gastroenterology Center. ELISA was used for the estimation of serum Bcl-2 levels in patients with different stages of gastric cancer. Immunohistochemical localization of Bcl-2 antigen was performed on formalinfixed, paraffin-embedded tissue block; Bcl-2 expression was detected from mild to moderate apoptotic index (AI). Results: Positive serum Bcl-2 expression was found in 13/45 patients (28.9%). Bcl-2 protein was immunohistochemically localized in the cytoplasm of 45% (18/40) of gastric cancer patients. Total apoptosis positivity in Bcl2 detected immunohistochemicaly was detected in 45% (18/ 40) of cases; while total apoptosis positivity in serum expression of Bcl-2 was detected in 28.9% (13/ 45). Conclusion: our current study demonstrated that the formation and growth of cancer is a complex process that requires further research in correlation with the results assessed between serum and immunohistochemical expression of Bcl-2 and with its role in the process of apoptosis.

Dysregulation of maternal circulating adipocytokines has been implicated in several obstetrical syndromes including preeclampsia (PE). It has been suggested that adipocytokines provide a molecular link between metabolic derangements and inflammatory response in complicated pregnancies. We aimed in this study to evaluate the relationship between serum levels of Retinol binding protein-4 (RBP-4) and Resistin with clinical, anthropometric and metabolic parameters of PE. This study included 3 groups: group 1 included 50 pregnant females with PE, group 2 included 50 healthy pregnant females and group 3 included 50 healthy non-pregnant female as a control group. For all groups anthropometric and clinical measurements were performed. Serum RBP-4, resistin, insulin were measured by ELISA and Insulin resistance was calculated by Hemostasis model assessment index (HOMA-IR). Our results showed that serum RBP-4 and resistin concentrations were elevated in PE [39(33.25-40.87) ug/ml] & [61(23.5-91.87) ng/ml] compared to normal pregnancy [18.5(8-27.87) ug/ml] & [25.5(12.7-49.12) ng/ml). Moreover, RBP4 but not resistin levels were elevated in severe cases relative to mild cases of PE. Serum levels of RBP4 showed positive significant correlation with [SBP (r=0.38, p= 0.001) & DBP (r=0.32, p=0.01)] which are markers of severity. Fasting insulin was positively correlated with RBP-4 (p=0.04). By multiple linear regression analysis, serum RBP-4 levels were significantly and positively correlated with SBP (P=0.01), while markers of adiposity were not independently associated with resistin. Conclusion: RBP-4 and resistin were up-regulated in PE, furthermore RBP-4 not resistin levels were independently associated with markers of severity of PE. However no clear relationship were observed between HOMA-IR with both RBP-4 and resistin and the role of Insulin resistance in PE was not clearly proved.

Background: Paracetamol (APAP) is the most famous drug used in the world to relieve of pain and used as an antipyretic. Paracetamol overdose induces liver damage and is a well known hepatotoxic drug. This study was aimed to determine the incidence of acidosis in acetaminophen overdose with the time of N! Acetyl C ystiene (NAC) administration and correlation of late acidosis and death in acetaminophen overdose. Materials and methods: The data were obtained from the patients' files admitted to AL!Noor Hospital due to the ingestion of Paracetamol overdose. The Data on Paracetamol levels, liver transaminases (AST, and ALT), arterial blood gases, lactate levels and serum electrolyte levels had been collected from files. Results: Fifty five cases were divided into three groups: Group I (33 cases) had early acidosis with toxic APAP dose; Group II (9 cases) had late acidosis with toxic APAP dose; and Group III (13 cases) with non toxic APAP ingestion or developed acidosis. In 65.45% of cases, the age was between 14!30 years. Most of the cases were females (74.5%), and the adult was 78.77% while 21.23% were children. There was a positive significant relation (P 0.05) between serum transaminases and toxic APAP level or prognosis. Conclusion: Metabolic acidosis are a specific indicator for APAP heptotoxicity than serum transaminases

The prevalence of diet-induced obesity is increasing amongst adults and children worldwide, predisposing millions of people to an array of health problems that include metabolic syndrome, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. In this study we used experimental animals to investigate the effects of dietary obesity on markers of hepatic insulin signaling as well as structural changes in hepatocytes. Adult male Wistar rats were randomized and assigned to either a control group or a test group. Controls were fed standard laboratory pelleted diet (chow-fed), while the test group had free access to a highly-palatable diet (HPD). After eight weeks, the HPD-fed animals were subdivided into three subgroups and their diets altered as follows: HPD-to-chow, HPD with the addition of fenofibrate given by oral gavage for a further seven weeks, or HPD with vehicle (1% carboxymethylcellulose at 1 mL/kg body weight) given by oral gavage for a further seven weeks, respectively. Untreated diet-fed animals had significantly higher body weight, liver weight, and all measured metabolic profiles compared with chow-fed and treated diet-fed groups. Expression of kinases IRβ, IRS-1, AKt, eNOS, Shc and ERK1/2 were unaffected by obesity, while IRS-2 and P I3 kinase levels were significantly reduced in untreated HPD animals. Compared with chow-fed animals, steatosis and steatohepatitis were almost doubled in animals from untreated HPD, while removal of HPD and fenofibrate-treatment reduced steatosis by 40% and 80% respectively. These data suggest that diet-induced obesity affects intracellular insulin signaling mechanisms, namely IRS-2 and PI 3-kinase, leading to hepatic insulin resistance. Moreover, diet-induced obesity induces fatty liver, an effect which can be reversed by either removal of the source of obesity or treatment with fenofibrate, a peroxisome proliferator-activated receptor alpha agonist.

Background: The prevalence of diet-induced obesity is increasing globally, and posing significant health problems for millions of people worldwide. Diet-induced obesity is a major contributor to the global pandemic of type 2 diabetes mellitus. The reduced ability of muscle tissue to regulate glucose homeostasis plays a major role in the development and prognosis of type 2 diabetes. In this study, an animal model of diet-induced obesity was used to elucidate changes in skeletal muscle insulin signaling in obesity-induced diabetes. Methods: Adult male Wistar rats were randomized and assigned to either a control group or to a test group. Controls were fed a standard laboratory pellet diet (chow-fed), while the test group had free access to a highly palatable diet (diet-fed). After 8 weeks, the diet-fed animals were subdivided into three subgroups and their diets were altered as follows: diet-to-chow, diet-fed with addition of fenofibrate given by oral gavage for a further 7 weeks, or diet-fed with vehicle given by oral gavage for a further 7 weeks, respectively. Results: Untreated diet-fed animals had a significantly higher body weight and metabolic profile than the control chow-fed animals. Intramuscular triacylglyceride levels in the untreated obese animals were significantly higher than those in the control chow-fed group. Expression of protein kinase C beta, phosphatidylinositol 3, Shc, insulin receptor substrate 1, ERK1/2, and endothelial nitric oxide synthase was significantly increased by dietary obesity, while that of insulin receptor beta, insulin receptor substrate 1, and protein kinase B (Akt) were not affected by obesity. Conclusion: These data suggest that diet-induced obesity affects insulin signaling mechanisms, leading to insulin resistance in muscle.