Abstract
BackgroundDiabetes Mellitus (DM) is one of the metabolic diseases which leads to fatty tissue injury, and consequently inducing lipotoxicity and cellular senescence. This condition contributes to endothelial dysfunction with chronic inflammation and organ damage. Heparanase which has a role in disrupting endothelial surface layer (glycocalyx) may promote endothelial Nitric oxide synthase (eNOS) reduction and inflammation. However, its relationship with DM and organ injury has not been fully elucidated yet. This study aimed to determine how heparanase from fatty tissue may contribute to endothelial dysfunction and inflammation in patients with hyperglycemia and in a hyperglycemia model in rats.MethodsThis population study with a cross-sectional design was conducted with 28 subjects without diagnosis and medication of DM. Fasting blood glucose levels, lipid profile, heparanase protein, MCP-1 protein and HbA1c were quantified. In vivo study was performed with a diabetic model in Wistar rats induced with streptozotocin 60 mg/kg body weight by single intraperitoneal injection. Rats were euthanized after 1 month (DM1 group, n = 6), 2 months (DM2 group, n = 6) and 4 months (DM4 group, n = 6). White Adipose Tissue (WAT) was harvested from visceral fat. Real Time and Reverse Transcriptase-PCR (RT-PCR) was done to quantify expressions of heparanase, MCP-1, eNOS, IL-6 and p-16 (senescence). Immunostaining was performed to localize MCP-1 and macrophage (CD68). Western blot tests were used to examine eNOS, MCP-1 and heparanase protein expression.ResultsThis study revealed associations between blood glucose levels with higher HbA1c, LDL, cholesterol, heparanase and MCP-1. The in vivo study also revealed lipid levels as the source of Heparanase and MCP-1 mRNA and protein expressions. This finding was associated with inflammation, cellular senescence and macrophage infiltration in fat tissue based on immunostaining and qRT-PCR analysis. RT-PCR revealed significantly lower expression of eNOS and higher expression of IL-6 in DM groups compared to the control group.ConclusionHeparanase upregulation in fat tissue was associated with endothelial injury and inflammation in hyperglycemia conditions.
Highlights
Diabetes Mellitus (DM) is one of the metabolic diseases which leads to fatty tissue injury, and inducing lipotoxicity and cellular senescence
Obese with DM condition associated with higher cholesterol and triglycerides The K1 group represented normal conditions with normal Body Mass Index (BMI) and normal glucose levels
Higher glucose levels associated with increased endothelial dysfunction, heparanase expression and inflammation we examined HbA1c as marker for glycation of endothelial cells, especially in diabetic condition for showing endothelial function and predicting arterial stiffness and endothelial dysfunction [27]
Summary
Diabetes Mellitus (DM) is one of the metabolic diseases which leads to fatty tissue injury, and inducing lipotoxicity and cellular senescence. This condition contributes to endothelial dysfunction with chronic inflammation and organ damage. Adiponectin downregulation and resistin upregulation, which leads to unhealthy metabolism changes. Those alterations include adipocyte hypertrophy which induces increases in free fatty acid levels. All of these phenomena are involved in lipotoxicity [3]
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