Effect of ketotifen in obese patients with type 2 diabetes mellitus.

AIM: Mast cells are found to be an important contributor in obesity induced insulin resistance. We evaluate the effect of ketotifen in obese patient with type 2 diabetes (T2DM) treated with glimepiride. METHOD: In a randomized controlled study we recruited forty-eight obese patients with T2DM from Internal Medicine Department at Tanta University Hospital, Egypt. They were classified into three groups: group 1, those who received glimepiride (GL) 3mg/d alone; group 2, those who received GL 3mg/d+ketotifen 1mg once daily; and group 3, those who received GL 3mg/d+ketotifen 1mg twice daily. Fasting blood samples were obtained before and 12weeks after treatment for biochemical analysis of glycemic and inflammatory biomarkers. Data were statistically analyzed by paired Student's t-test and one way analysis of variance; p<0.05 was considered statistically significant. RESULTS: The obtained data suggested that the addition of ketotifen in twice daily dose has a beneficial effect on all measured parameters except adiponectin. However, glimepiride plus ketotifen once daily only affected the level of inflammatory biomarkers without any significant effect on other parameters. CONCLUSIONS: The co-administration of ketotifen twice daily plus glimepiride improves glycemic and inflammatory process in obese patients with T2DM.

The role of hepatic expression of STAT1, SOCS3 and PIAS1 in the response of chronic hepatitis C patients to therapy.

BACKGROUND: The underlying mechanisms of hepatitis C virus (HCV) resistance to treatment are unknown. Signal transducers and activators of transcription (STAT) proteins play a critical role in antiviral defense. OBJECTIVE: To explore some of the mechanisms of HCV resistance to interferon, the expression of STAT1 and its negative regulators, protein inhibitor of activated STAT (PIAS1) and suppressor of cytokine signalling (SOCS3), in liver tissues of both inteferon responders and nonresponders in chronic HCV patients. METHODS: Sixty patients were divided into the following groups: group 1a comprised 38 treatment-responder chronic HCV patients; group 1b consisted of 22 treatment-nonresponder chronic HCV patients; and group 2 consisted of six control subjects. Liver biopsies were examined for histological scoring; STAT1, SOCS3 and PIAS1 expression was analyzed using Western blotting methods. RESULTS: STAT1 expression in the liver tissue of patients in group 1 was significantly increased compared with group 2 patients (P=0.001), while no significant difference in expression was observed between group 1a and group 1b patients (P=0.747). However, phosphorylated STAT1 protein was expressed at a significantly higher level in liver tissue of patients in group 1a compared with patients in group 1b (P=0.001). Western blot analysis of PIAS1 and SOCS3 protein expression in liver tissues from groups 1 and 2 revealed significantly increased expression in group 1 compared with group 2 (P=0.001). In addition, PIAS1 and SOCS3 protein expression was significantly higher in the liver tissues of patients in group 1b compared with patients in group 1a. CONCLUSION: Levels of STAT1 and/or the protein expression of its negative regulators, PIAS1 and SOCS3, may be a good predictor of response to therapy. These could be used as biomarkers that are easily detected by Western blotting or immunostaining during standard histopathological liver biopsy analysis.

Fibrosis severity and mannan-binding lectin (MBL)/MBL-associated serine protease 1 (MASP-1) complex in HCV-infected patients.

BACKGROUND AND STUDY AIMS: Mannan-binding lectin (MBL) is a collectin synthesised in the liver and secreted into the bloodstream. It binds micro-organisms via interactions with glycans on the target surface. Bound MBL subsequently activates MBL-associated serine protease proenzymes (MASPs). Several studies have investigated the possible role for MBL in hepatitis C virus (HCV) infection by examining MBL levels and polymorphisms in relation to disease progression and in response to treatment. The aim of this study was to investigate the relation of the activity of MBL and MBL/MASP-1 complex in sera of patients with mild and severe chronic HCV infection and outcome of HCV infection. PATIENTS AND METHODS: Serum level of MBL and functional assays for MBL/MASP-1 complex activity were assayed in sera of 80 patients with chronic HCV infection. Patients were divided into two groups according to the results of the liver biopsy, group I (40 HCV patients had mild hepatic fibrosis, Ishak fibrosis stages 0-1) and group II (40 HCV patients had severe hepatic fibrosis, Ishak fibrosis stages 5-6), in addition to 20 control subjects as group III. The analysis of the MBL/MASP-1 complex activity at 0, 3 and 6 months was performed in all patients. RESULTS: Serum levels of MBL and MBL/MASP-1 complex activity were higher in sera of patients with chronic HCV liver disease compared to those in control subjects. There was a correlation between the activity of the MBL/MASP-1 complex and the severity of fibrosis (P=0.003). MBL/MASP-1 complex activity was associated more significantly with severe fibrosis in comparison to MBL concentration. CONCLUSION: MBL and MBL/MASP-1 complex activities play a key role in first-line host defence mechanism against certain infectious agents including HCV infection. However, it is also likely that the role of MBL and MBL/MASP-1 complex activity extends beyond this restricted infection-related view in that it appears to be a key regulator of inflammation.

Angiotensin II type 1 receptor gene polymorphism and telomere shortening in essential hypertension.

Several genetic studies were carried out among hypertensive patients to assess allelic association at the 1166 position of the 3' untranslated region of angiotensin II type 1 receptor gene. In addition, attempts have also been made to find out whether telomere length attrition is associated with hypertension. The main aim of this study was to examine the association of A1166C polymorphism of angiotensin II type 1 receptor and telomere length with essential hypertension in Egyptian people. Angiotensin II type 1 genotyping and relative telomere length were investigated by PCR in 40 patients of essential hypertension and 15 healthy controls. The homozygous AA1166 allele frequency was 92.8% among the studied subjects. There was no intergroup variation in A allele frequency in normotensive group. The frequency of homozygous A allele was significantly higher in hypertensive than normotensive subjects (97.5 and 80%, respectively) with higher frequencies in male patients. The average telomere length ratio was significantly shorter in hypertensive than in normal subjects (1.08 ± 0.3 and 1.54 ± 0.18, respectively). No correlation was observed between telomere length ratio and body mass index. This study suggests that the homozygous A1166 allele of angiotensin II type 1 and short telomeres may be predisposing factors for essential hypertension in Egyptians and may be involved in the pathogenesis of the disease. Further strategies for treating high-risk patients could result in prevention or delay of end organ damage.

Association of the C242T polymorphism of the p22 phox gene with advanced carotid atherosclerosis in type 2 diabetes.

Reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase is an important source of superoxide (O2-) in human blood vessels. A critical component of this oxidase is the p22phox protein, which is encoded by the cytochrome b-245 α (CYBA) gene. Studies have suggested a possible association between polymorphisms of the CYBA gene and susceptibility to atherosclerosis in diabetes mellitus (DM). To address this hypothesis, we examined the relationship between the C242T polymorphism of the p22 phox gene and carotid intima/media thickness (IMT) as a factor of atherosclerosis in a group of type 2 DM patients. The study included 40 type 2 diabetic patients and 20 healthy individuals as controls. All patients and controls were matched in terms of age, gender, lipid profile, blood pressure and body mass index (BMI) The C242T p22 phox polymorphism was investigated by RFLP-PCR, and carotid IMT was measured by color duplex scanning. Diabetic subjects with the T242C and T242T genotypes displayed a significantly lower average of carotid IMT (mean 1.033±0.143 mm, range 0.85-1.25, P<0.0001) than did those with the C242C genotype (mean 1.36±0.177 mm, range 0.98-1.63) despite no differences in other risk factors. The average carotid IMT of both diabetic groups was significantly higher than that of the controls (mean 0.828±0.072 mm, range 0.72-0.86, P<0.0001). In non-diabetic subjects, the average carotid IMT of the TC+TT group did not differ from that of the CC group (0.81±0.08 vs. 0.84±0.069 mm, P>0.05). There was a significant positive correlation between carotid IMT and blood glucose level and duration. Our findings demonstrate that the CC genotype of the p22 phox gene is a risk factor for the progression of atherosclerosis in diabetic patients.