Obesity-related changes in the vascular actions of insulin

Abstract Over the past 2 to 3 decades, research has focused on the changes in the vascular effects of insulin occurring in insulin resistant states like obesity. Consistent evidence indicates that obesity results in reduced endothelial release of nitric oxide in response to insulin, associated with concomitant enhancement in the production of endothelin-1. More recent work has pointed toward reduced vascular permeability and changes in the physical-chemical characteristics of the perivascular extracellular matrix as additional mechanisms of impaired insulin sensitivity in obesity. All these perturbations are important, because they contribute to impaired delivery of insulin itself and metabolic substrates to the target tissues and may play a role in the development of both diabetes and vascular damage. This review will describe the physiological vascular actions of insulin and their changes in obesity, focusing on some established pathophysiological determinants of the derangement of vascular insulin signaling, such as the lipid overflow from expanded fat depots and signals originating from inflamed obese adipose tissue (both distant and perivascular). Also, it will outline novel evidence underscoring the contribution of dysregulated adipokine secretion and changes in intestinal permeability and gut microbiome. Finally, it will touch upon some unresolved issues, such as the potential role of vascular insulin resistance in obesity-driven adipose tissue remodeling, and will discuss perspectives for future studies, regarding in particular possible therapeutic strategies with translational implications for the patients care

Metabolic and Cardiovascular Effects of Ghrelin

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is synthesized as a preprohormone and then proteolytically processed to yield a 28-amino acid peptide. This peptide was originally reported to induce growth hormone release; large evidence, however, has indicated many other physiological activities of ghrelin, including regulation of food intake and energy balance, as well as of lipid and glucose metabolism. Ghrelin receptors have been detected in the hypothalamus and the pituitary, but also in the cardiovascular system, where ghrelin exerts beneficial hemodynamic activities. Ghrelin administration acutely improves endothelial dysfunction by increasing nitric oxide bioavailability and normalizes the altered balance between endothelin-1 and nitric oxide within the vasculature of patients with metabolic syndrome. Other cardiovascular effects of ghrelin include improvement of left ventricular contractility and cardiac output, as well as reduction of arterial pressure and systemic vascular resistance. In addition, antinflammatory and antiapoptotic actions of ghrelin have been reported both in vivo and in vitro. This review summarizes the most recent findings on the metabolic and cardiovascular effects of ghrelin through GH-dependent and -independent mechanisms and the possible role of ghrelin as a therapeutic molecule for treating cardiovascular diseases

Endothelin-dependent vasoconstrictor activity in metabolically healthy and unhealthy obese patients

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Circulating MicroRNAs in Elderly Type 2 Diabetic Patients

The circulating microRNAs (miRNAs) associated with type 2 diabetes (T2D) in elderly patients are still being defined. To identify novel miRNA biomarker candidates for monitoring responses to sitagliptin in such patients, we prospectively studied 40 T2D patients (age > 65) with HbA1c levels of 7.5–9.0% on metformin. After collection of baseline blood samples (t0), the dipeptidyl peptidase-IV (DPP-IV) inhibitor (DPP-IVi) sitagliptin was added to the metformin regimen, and patients were followed for 15 months. Patients with HbA1c0.5% after 3 and 15 months of therapy were classified as “responders” (group R, n = 34); all others were classified as “nonresponders” (group NR, n = 6). Circulating miRNA profiling was performed on plasma collected in each group before and after 15 months of therapy (t0 and t15). Intra- and intergroup comparison of miRNA profiles pinpointed three miRNAs that correlated with responses to sitagliptin: miR-378, which is a candidate biomarker of resistance to this DPP-IVi, and miR-126-3p and miR-223, which are associated with positive responses to the drug. The translational implications are as immediate as evident, with the possibility to develop noninvasive diagnostic tools to predict drug response and development of chronic complications

Metabolic Syndrome, Chronic Kidney, and Cardiovascular Diseases: Role of Adipokines

Obesity is a chronic disease, whose incidence is alarmingly growing. It is associated with metabolic abnormalities and cardiovascular complications. These complications are clustered in the metabolic syndrome (MetS) leading to high cardiovascular morbidity and mortality. Obesity predisposes to diabetic nephropathy, hypertensive nephrosclerosis, and focal and segmental glomerular sclerosis and represents an independent risk factor for the development and progression of chronic kidney disease (CKD). Albuminuria is a major risk factor for cardiovascular diseases (CVDs). Microalbuminuria has been described as early manifestation of MetS-associated kidney damage and diabetic nephropathy. Obesity and MetS affect renal physiology and metabolism through mechanisms which include altered levels of adipokines such as leptin and adiponectin, oxidative stress, and inflammation. Secretory products of adipose tissue also deeply and negatively influence endothelial function. A better understanding of these interactions will help in designing more effective treatments aimed to protect both renal and cardiovascular systems

Obesity and common pathways of cancer and cardiovascular disease

Abstract Obesity is constantly increasing worldwide due to the progressive globalization of sedentary lifestyle and diet rich in lipids and processed food. Cardiovascular complications and cancer are the two most fearsome long-term sequelae of obesity that justify the recent definition of this threaten as 'obesity epidemic'. Shared biological pathways can be recognized for obesity-induced cardiovascular and oncological complications that might prompt targeted interventions with potentially double beneficial effect. The present review aims at summarizing main common biological pathways linking obesity with cardiovascular diseases and cancer in order to provide a research framework within which therapeutic strategies might have at the same time cardiovascular-protective and cancer-preventive effects

Mirabegron relaxes arteries from human visceral adipose tissue through antagonism of α1-adrenergic receptors

Aim: As inadequate perfusion has emerged as a key determinant of adipose tissue dysfunction in obesity, interest has grown regarding possible pharmacological interventions to prevent this process. Mirabegron has proved to improve insulin sensitivity and glucose homeostasis in obese humans via stimulation of β3-adrenoceptors which also seem to mediate endothelium-dependent vasodilation in disparate human vascular beds. We characterized, therefore, the vasomotor function of mirabegron in human adipose tissue arteries and the underlying mechanisms. Methods: Small arteries (116-734 μm) isolated from visceral adipose tissue were studied ex vivo in a wire myograph. After vessels had been contracted, changes in vascular tone in response to mirabegron were determined under different conditions. Results: Mirabegron did not elicit vasorelaxation in vessels contracted with U46619 or high-K+ (both P > 0.05). Notably, mirabegron markedly blunted the contractile effect of the α1-adrenergic receptor agonist phenylephrine (P < 0.001) either in presence or absence of the vascular endothelium. The anti-contractile action of mirabegron on phenylephrine-induced vasoconstriction was not influenced by the presence of the selective β3-adrenoceptor blocker L-748,337 (P < 0.05); lack of involvement of β3-adrenoceptors was further supported by absent vascular staining for them at immunohistochemistry. Conclusions: Mirabegron induces endothelium-independent vasorelaxation in arteries from visceral adipose tissue, likely through antagonism of α1-adrenoceptors

Preoperative Immunonutrition vs. Standard Dietary Advice in Normo-Nourished Patients Undergoing Fast-Track Laparoscopic Colorectal Surgery

Immunonutrition (IN) appears to reduce infective complications and in-hospital length of stay (LOS) after major gastrointestinal surgery, but its use in normo-nourished patients is still controversial. The primary aim of this comparative observational study was to evaluate if pre-operative IN reduces in-hospital stay in patients undergoing laparoscopic colorectal resection for cancer under an enhanced recovery after surgery (ERAS) program. The influence of IN on time to first bowel movements, time to full oral diet tolerance, number and type of complications, reasons of prolonged LOS and readmission rate was evaluated as secondary outcome. Patients undergoing ERAS laparoscopic colorectal resection between December 2016 and December 2019 were reviewed. Patients who have received preoperative IN (group A) were compared to those receiving standard dietary advice (group B). Mean in-hospital LOS was significantly shorter in patients receiving preoperative IN than standard dietary advice (4.85 ± 2.25 days vs. 6.06 ± 3.95 days; p < 0.0492). No differences in secondary outcomes were observed. Preoperative IN associated with ERAS protocol in normo-nourished patients undergoing laparoscopic colorectal cancer resection seems to reduce LOS