Insulin resistance and diabetic angiopathy group

About

The “Insulin resistance and diabetic angiopathy group” aims to understand the mechanisms underlying the metabolic dysregulation associated with obesity, prediabetes, diabetes and its major vascular complications, in a translational approach from the molecular level to human application. The team is composed by researchers and clinicians, in a truly inter-disciplinary approach to investigate mechanisms, biomarkers and therapeutics for cardiometabolic and cardiorenal diseases. Our involvement in translational projects using imaging biomarkers aims to establish big data approaches to implement more intelligent strategies for the treatment of diabetic complications. Specifically, our main objectives are:

· To understand the role played by perivascular adipose tissue in vascular disorders associated with obesity, insulin resistance and diabetes.

· To dissect the interplay between AGE and nutrient sensing mechanisms in the development of vascular dysfunction and insulin resistance in adipose tissue and liver.

· To develop new strategies for prevention of both metabolic and vascular disorders associated with obesity, metabolic syndrome and diabetes.

· To assess the role of dysbiosis of the gut microbiota in the early stages of diabetes progression.

· To evaluate the impact of therapeutic and nutraceutic options in preventing diabetes and its vascular complications.

· To evaluate the autonomic gastrointestinal dysfunction in animal models of metabolic diseases.

Main achievements

• High sucrose consumption induces a prediabetic condition in rats associated with liver glucose and lipid dysmetabolism without obesity and blood pressure rise. Blueberry juice is able to prevent evolution from prediabetes to diabetes in an HFD-induced animal model due to beneficial effects related with improvement of glucose intolerance, insulin resistance and hepatic steatosis.

• Therapeutic strategies based on the modulation of the incretin GLP-1 are able to improve adipose tissue capillarization and insulin sensitivity, as well as the evolution of microvascular diabetic complications.

• Supplementation of diet-induced obese rats with the AGE precursor methylglyoxal leads to alterations of adipose tissue vascular architecture and blood flow and liver lipidemic profile, causing to insulin resistance. Upregulation of detoxification systems and reduction of glycated products in the adipose tissue by sleeve gastrectomy improves angiogenic ability and insulin sensitivity in adipose tissue, as well as endothelial function.

• Sulforaphane and pyridoxamine in association normalize endothelial dysfunction in type 2 diabetes. Vitamin D in the vasculature is an essential nutrient and its absence leads to endothelial dysfunction in normal rats and to a severe deterioration of NO-dependent vasorelaxation in type 2 diabetes mellitus.

• Adiponectin was able to reduce inflammation in PAT normalizing endothelial function in obese animal models by a mechanism that involved an increment in endothelial nitric oxide synthase phosphorylation.

Scientific interests and ongoing research projects

1. Regulation of GJ-mediated intercellular communication in health and disease

Landmark studies from our lab elucidated the mechanisms whereby ubiquitination/ deubiquitination of Cx43 regulates the fate of gap junctions. Furthermore, we unveiled that autophagy degradation of Cx43 can be either ubiquitin-dependent or -independent.

Additionally, we unraveled how the interactome of Cx43 varies in cardiac ischemia and reperfusion. These unbiased studies paved the way to disclose the mechanisms underlying GJ lateralization and autophagy degradation in myocardial infarction.

We are actively working to unveil the association between Cx43 and the oncogenic process.

2. The impact of cell injury in EV secretion

Groundbreaking studies from our group showed for the first time that the GJ protein Cx43 resides at the extracellular vesicles (EV) surface, mediating the release of vesicle content into target cells. Using a comprehensive translational approach, thanks to the long-lasting collaboration with clinicians, we showed that myocardial infarction alters Cx43 secretion in EV. Furthermore, we unraveled that EV secreted by cardiomyocytes under ischemia impacts on endothelial cells, promoting angiogenesis, and on immune cells, affecting their inflammatory profile. Strikingly, we demonstrated that anti-tumor therapies conveyed in Cx43-containing EV are less cardiotoxic.

3. Biomarkers and innovative therapies in pulmonary arterial hypertension (PAH)

We unveiled a new systemic marker of PAH, the miRNA-424; furthermore, we demonstrated that miRNA-424 released by pulmonary endothelial cells targets SMURF-1 in cardiomyocytes and contribute to right ventricle hypertrophy.

We identified a plant-based therapy targeting the right ventricle that ameliorates cardiac hypertrophy. We are now developing innovative drug delivery platforms based on plant vesicles.

4. Non-canonical functions of Cx43

We demonstrated that Cx43 accumulates in the nucleus where it forms functional channels and modulates gene expression. We are now exploring the pathophysiological impact of nuclear Cx43

We showed that upon lysosomal injury Cx43 promotes the repair and exocytosis of lysosomes through the modulation of cortical actin. We are currently investigating the role of Cx43 in lysosomal homeostasis in cardiovascular diseases.