Aims/hypothesis We recently described that carotid body (CB) over-activation is involved in the aetiology of insulin resistance and arterial hypertension in animal models of the metabolic syndrome. Additionally, we have demonstrated that CB activity is increased in animal models of insulin resistance, and that carotid sinus nerve (CSN) resection prevents the development of insulin resistance and arterial hypertension induced by highenergy diets. Here, we tested whether the functional abolition of CB by CSN transection would reverse pre-established insulin resistance, dyslipidaemia, obesity, autonomic dysfunction and hypertension in animal models of the metabolic syndrome. The effect of CSN resection on insulin signalling pathways and tissue-specific glucose uptake was evaluated in skeletal muscle, adipose tissue and liver. Methods Experiments were performed in male Wistar rats submitted to two high-energy diets: a high-fat diet, representing a model of insulin resistance, hypertension and obesity, and a high-sucrose diet, representing a lean model of insulin resistance and hypertension. Half of each group was submitted to chronic bilateral resection of the CSN. Age-matched control rats were also used. Results CSN resection normalised systemic sympathetic nervous system activity and reversed weight gain induced by high-energy diets. It also normalised plasma glucose and insulin levels, insulin sensitivity lipid profile, arterial pressure and endothelial function by improving glucose uptake by the liver and perienteric adipose tissue. Conclusions/interpretation We concluded that functional abolition of CB activity restores insulin sensitivity and glucose homeostasis by positively affecting insulin signalling pathways in visceral adipose tissue and liver.

Glucose and fructose metabolism originates the highly reactive byproduct methylglyoxal (MG), which is a strong precursor of advanced glycation end products (AGE). The MG has been implicated in classical diabetic complications such as retinopathy, nephropathy, and neuropathy, but has also been recently associated with cardiovascular diseases and central nervous system disorders such as cerebrovascular diseases and dementia. Recent studies even suggested its involvement in insulin resistance and beta-cell dysfunction, contributing to the early development of type 2 diabetes and creating a vicious circle between glycation and hyperglycemia. Despite several drugs and natural compounds have been identified in the last years in order to scavenge MG and inhibit AGE formation, we are still far from having an effective strategy to prevent MG-induced mechanisms. This review summarizes the endogenous and exogenous sources of MG, also addressing the current controversy about the importance of exogenous MG sources. The mechanisms by which MG changes cell behavior and its involvement in type 2 diabetes development and complications and the pathophysiological implication are also summarized. Particular emphasis will be given to pathophysiological relevance of studies using higher MG doses, which may have produced biased results. Finally, we also overview the current knowledge about detoxification strategies, including modulation of endogenous enzymatic systems and exogenous compounds able to inhibit MG effects on biological systems.

Sprouting angiogenesis, where new blood vessels grow from pre-existing ones, is a complex process where biochemical and mechanical signals regulate endothelial cell proliferation and movement. Therefore, a mathematical description of sprouting angiogenesis has to take into consideration biological signals as well as relevant physical processes, in particular the mechanical interplay between adjacent endothelial cells and the extracellular microenvironment. In this work, we introduce the first phase-field continuous model of sprouting angiogenesis capable of predicting sprout morphology as a function of the elastic properties of the tissues and the traction forces exerted by the cells. The model is very compact, only consisting of three coupled partial differential equations, and has the clear advantage of a reduced number of parameters. This model allows us to describe sprout growth as a function of the cell-cell adhesion forces and the traction force exerted by the sprout tip cell. In the absence of proliferation, we observe that the sprout either achieves a maximum length or, when the traction and adhesion are very large, it breaks. Endothelial cell proliferation alters significantly sprout morphology, and we explore how different types of endothelial cell proliferation regulation are able to determine the shape of the growing sprout. The largest region in parameter space with well formed long and straight sprouts is obtained always when the proliferation is triggered by endothelial cell strain and its rate grows with angiogenic factor concentration. We conclude that in this scenario the tip cell has the role of creating a tension in the cells that follow its lead. On those first stalk cells, this tension produces strain and/or empty spaces, inevitably triggering cell proliferation. The new cells occupy the space behind the tip, the tension decreases, and the process restarts. Our results highlight the ability of mathematical models to suggest relevant hypotheses with respect to the role of forces in sprouting, hence underlining the necessary collaboration between modelling and molecular biology techniques to improve the current state-of-the-art.

MG contributes to dysfunction of adipose tissue during type 2 diabetes progression.