RAGE signalling contributes to oxidative stress and inflammation in knee osteoarthritis patients with metabolic syndrome.

OBJECTIVES: Metabolic factors play significant role in the natural history of knee osteoarthritis (KO). There is a limited understanding of molecular and cellular events that give rise to the disease in patients. This study explored the possible cellular mechanisms by which metabolic syndrome leads to KO. METHODS: This cross-sectional study enrolled 80 subjects with KO who fulfilled the ACR diagnostic criteria and were undergoing total knee replacement surgery. The patients were divided into two groups: KO patients without metabolic syndrome and KO patients with metabolic syndrome. RESULTS: We hypothesised that metabolic syndrome may accelerate pathogenesis of OA by enhanced RAGE axis in articular cartilage and Infrapatellar fat pad of the knee joint. We have found enhanced protein expression of receptor for advanced glycation end products (RAGE) and its ligands AGEs and HMGB-1 in knee joint tissue of KO patients with metabolic syndrome as compared to KO patients without metabolic syndrome. Further downstream, the gene expression of oxidative stress regulators such as NADPH and inflammation, NFĸB were upregulated in KO patients with MetS as compared to KO patients alone. Higher levels of advanced oxidation products and inflammatory marker IL-17 were exhibited in synovial fluid of KO patients with metabolic syndrome. The enhanced levels of these oxidative stress and inflammatory markers were reflected in the serum of KO patients with metabolic syndrome as well. CONCLUSIONS: We conclude that enhanced function of RAGE axis could be one of the mechanisms by which metabolic syndrome leads to KO.

Association of Hepcidin levels in Type 2 Diabetes Mellitus treated with metformin or combined anti-diabetic agents in Pakistani population.

Objective: To evaluate the impact of hepcidin and ferritin in pathogenesis and prognosis of type 2 diabetes mellitus subjects taking only metformin or combined anti-glycaemic agents. METHODS: The observational case-control study was conducted at the Department of Physiology, Baqai Medical University, Karachi, from August 2019 to October 2020, and comprised subjects from both genders who categorised into equal groups as non-diabetic controls, newly-diagnosed type 2 diabetes mellitus patients without any treatment, type 2 diabetes mellitus patients with exposure to metformin only, type 2 diabetes mellitus patients taking oral hypoglycaemic agents along with metformin, type 2 diabetes mellitus patients taking only insulin, and type 2 diabetes mellitus patients taking insulin and oral hypoglycaemic agents. Fasting plasma glucose was determined using glucose oxidase-peroxidase method, glycated haemoglobin by high performance liquid chromatography, high-density lipoprotein and low-density lipoprotein by direct methods, cholesterol by cholesterol oxidase phenol 4-amino antipyrine peroxidase and triglycerides by glycerol phosphate oxidase-phenol 4-amino antipyrine peroxidase method. Serum levels of ferritin, insulin and hepcidin were evaluated using Enzyme-linked immunosorbent assay. Insulin resistance was assessed using homeostasis model assessment for insulin resistance. Data was analysed using SPSS 21. RESULTS: Of the 300 subjects, there were 50(16.66%) in each of the 6 groups. Overall, there were 144(48%) males and 155(51.66%) females. The mean age was significantly lower in the control group 34.72±7.87 compared to all the diabetic groups (p<0.05), and the same was the case with respect to all the parameters (p<0.05) except high-density lipoprotein (p>0.05). Besides, hepcidin level was significantly higher in the control group (p<0.05). Ferritin levels were significantly increased in newly-diagnosed T2DM subjects compared to the controls (p<0.05) while all other groups showed decreased ferritin levels (p<0.05). Hepcidin gave inverse correlation with glycated haemoglobin only in diabetics taking only metformin (r = -0.27, p=0.05). CONCLUSIONS: Anti-diabetes drugs not only addressed type 2 diabetes mellitus, but also reduced levels of ferritin and hepcidin that are found to play a role in diabetes development.

Effects of varying levels of gonadotropins and estrogen in adolescent females having type 1 diabetes with their impact on health-related quality of life in Karachi Pakistan.

The purpose of this study is to evaluate quality of life, the gonadotropins and estrogen levels in type 1 diabetic adolescent females. This cross-sectional study was conducted at Baqai Institute of Diabetology and Endocrinology (BIDE). The Diabetes quality of life for youth questionnaire (DQOLY) was used to evaluate quality of life. FSH was found to be significantly lower in Type 1 Diabetes. HbA1c had a significant inverse moderate correlation with FSH(-0.300*).In Type 1 Diabetes, FSH had a positive moderate correlation with LH(0.415*), (P-value<0.05). LH and estradiol levels were almost similar in both groups. Overall mean percentage score of DQOLY questionnaire for Type 1 Diabetes was 26.94±1.36. Low QOL score was observed on the basis of impact on activities. Adolescent females with Type 1 Diabetes were found to be shorter and underweight than non-diabetic adolescent females. Lower height and weight of the diabetes as compared to controls cannot be attributed to only metabolic control, suggesting other mechanisms for short stature. Control on metabolism has always been the target for diabetes treatment for ensuring the improved prognosis of disease but also for the quality of life in Type 1 diabetes.

Association of fibrinogen and plasminogen activator inhibitor-1 with diabetes mellitus.

As the state of hyperfibrinogenemia in diabetes patients occurs due to hyperglycemia which also activates the coagulative cascade ultimately stimulating hepatic fibrinogen synthesis and thus increases clotting factors and PAI-1 levels in the blood. Therefore, in present study our aim is to correlate between type of diabetes and plasma fibrinogen level and plasminogen activator inhibitor-1. This cross sectional study was conducted at Baqai Medical University (BMU) with the collaboration of Baqai Institute of Diabetology and Endocrinology, Karachi. Data was collected from 161 subjects, out of which 51 were control and 55 were subjects in each type 1 diabetes, type 2 diabetes simultaneously. Anthropometric measurements included measurement of weight, height, BMI and blood pressure which were done for each participant. Blood sugar levels and glycated hemoglobin, lipid profile, PAI-1 and fibrinogen were measured in cases and controls. Out of 161 subjects, 80 (49.7%) were male and 81 (50.3%) were female with mean age of 37.75±1.25 years. Fibrinogen level was significantly decreased in healthy subjects as compared to type 1 and type 2 diabetes subjects P-value<0.0001, however no significant difference was observed in fibrinogen level of type 1 diabetes subjects and type 2 diabetes subjects. Plasminogen activator inhibitor-1 of type 2 diabetes subjects was significantly increased as compared to type 1 diabetes subjects (P-value<0.05) but not significantly different to healthy subjects (P-value>0.05). Since, fibrinogen and plasminogen activator inhibitor type 1 was increased in diabetes patients this predisposed them to increased risk of coronary artery disease, our study further supports the clinical observation that diabetes is a thrombophillic condition.