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UC.PT

IBILI

Diabetic endothelial dysfunction

Raquel Seiça, Goup Leader

Physiology

Objectives

Diabetes exerts its greatest impact throughout the vascular system. The mechanisms that lead to endothelial dysfunction are still unclear but are likely to be multifactorial. Our main goal is to understand the mechanisms and the different players involved in such deregulation in order to design new pharmacological or gene-based therapies to prevent or treat endothelial dysfunction associated with diabetes.

Adipocytes have the ability to store large amounts of fatty acids and glucose in the form of triglycerides. As well, they produce a series of hormonal factors which inform other organs about the nutritional state of the organism. In states of excessive fat mass, adipocytes usually become dysfunctional, developing higher rates of lipolysis and impaired secretory function. Our previous data suggest that glycation may contribute to the impairment of adipose tissue microvasculature leading to decreased adipocyte’s ability to adapt its metabolism. These mechanisms may lead to tissue dysfunction and thus contribute to accelerated progression of metabolic syndrome and type 2 diabetes. Our main interests rely on the factors that lead to incorrect adipose tissue irrigation and therefore to adipose tissue dysfunction that in turn contributes to the pathogenesis of several diseases, such as hepatic and muscular steatosis, causing insulin-resistance, macrovascular disease (cerebro and cardio), pancreatic dysfunction, dementia and even cancer.

Main Achievements

In the past, our group showed that the AGE precursor methylglyoxal (MG) imbalance the ratio between vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), leading to an impairment of angiogenesis and to the formation of aberrant capillaries in the retina and in adipose tissue (Bento, 2010, Matafome, 2012). More, MG also caused vascular alterations in kidney and aorta and in heart response to ischemia (Rodrigues, 2014; Sena, 2012, Crisóstomo, 2013).

In adipose tissue and heart, we were able to demonstrate that these effects are time-dependent and specifically caused by the MG, as they were reverted by the treatment with the dicarbonyl scavenger drug pyridoxamine (Rodrigues, 2013a, Almeida, 2013). Later, we performed a shorter period of MG administration in order to induce AGE accumulation without major vascular damages. We then evaluated adipocyte’s pathways of lipid and glucose metabolism after a surgery-induced reduction of blood supply (~55-60% of normal irrigation) to the left epididymal adipose tissue during 48 hours). We observed that a decrease of blood supply in a single fat depot of normal rats causes a systemic overload that leads to hyperglycemia and hyperinsulinemia, besides increased circulating lipid levels and decreased adiponectinemia. MG administration caused an increased degradation of Perilipin A (marker of adipocyte dysfunction and death), what was accompanied by lower levels of PPAR and activated Akt (Rodrigues, 2013b. More recently, we were able to produce synthetic adiponectin and evaluate its therapeutic effectiveness in a model of high-fat diet-induced obesity. We observed that adiponectin treatment resulted in decreased body weight and fasting glycemia and glucose intolerance. In adipose tissue, adiponectin prevented high-fat diet-induced inactivation of IRS-1 and downregulation of PPARgamma, suggesting a role in improving glucose and lipid storage in adipocytes, and thus contributing to better systemic metabolism (unpublished data).

We have previously shown that endothelial dysfunction is present in diabetic, obese and ageing animal models and we have also demonstrated that several therapeutic interventions including alpha-lipoic acid, caloric restriction and metformin prevent major complications associated with type 2 diabetes (Sena, 2008; Sena, 2011). Therapeutic approaches such as berberine or pyridoxamine were tested in diet-induced obesity (DIO) and diabetic Goto-Kakizaki rats and vascular endothelial dysfunction and the underlying mechanisms were evaluated. Our results showed that berberine normalized endothelium-dependent relaxation in DIO rats and ameliorated this parameter in GK rats. The present study provides evidence for berberine as one of the potential useful agents in the treatment of macrovascular complications associated with diabetes and metabolic syndrome. Additionally, pyridoxamine improved endothelial dysfunction in Wistar and GK rats treated with methylglyoxal. The mechanism is at least in part by inhibiting oxidative stress and/or AGEs formation with a concomitant decrement of inflammation.

Group Members

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Antonio Pires

PhD - Investigator

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Cristina Sena

PhD - Investigator

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Fernanda Carrilho

PhD - Student

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Hans Eickhoff
PhD - Investigator

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Joana Crisóstomo

PhD - Investigtor

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Liliana Letra

PhD - Student

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Paulo Matafome

PhD - Investigator

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Tiago Rodrigues

PhD - Student