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Angiotensin converting enzyme-2 (ACE2) is the cell-surface receptor enabling cellular entry of SARS-CoV-2. ACE2 is highly expressed in adipose tissue (AT), rendering AT a potential SARS-CoV-2 reservoir contributing to massive viral spread in COVID-19 patients with obesity. Although rodent and cell studies suggest that the polyphenol resveratrol alters ACE2, human studies are lacking. Here, we investigated the effects of 30-days resveratrol supplementation on RAS components in AT and skeletal muscle in men with obesity in a placebo-controlled cross-over study. Resveratrol markedly decreased ACE2 (~40%) and leptin (~30%), but did neither alter angiotensinogen, ACE and AT1R expression in AT nor skeletal muscle RAS components. These findings demonstrate that resveratrol supplementation reduces ACE2 in AT, which might dampen SARS-CoV-2 spread in COVID-19. [ABSTRACT FROM AUTHOR]

Objective: Severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) uses the host's angiotensin‐converting enzyme 2 (ACE2) as a cellular entry point. Therefore, modulating ACE2 might impact SARS‐CoV‐2 viral replication, shedding, and coronavirus disease 2019 (COVID‐19) severity. Here, it was investigated whether the angiotensin II type 1 receptor blocker valsartan alters the expression of renin‐angiotensin system (RAS) components, including ACE2, in human adipose tissue (AT) and skeletal muscle. Methods: A randomized, double‐blind, placebo‐controlled clinical trial was performed, in which 36 participants (BMI 31.0 ± 0.8 kg/m2) with impaired glucose metabolism received either valsartan or placebo for 26 weeks. Before and after 26 weeks' treatment, abdominal subcutaneous AT and skeletal muscle biopsies were obtained, and gene expression of RAS components was measured by quantitative reverse transcription polymerase chain reaction. Results: Valsartan treatment did not significantly impact the expression of RAS components, including ACE2, in AT and skeletal muscle. Conclusions: Given the pivotal role of ACE2 in SARS‐CoV‐2 spread and the clinical outcomes in COVID‐19 patients, the data suggest that the putative beneficial effects of angiotensin II type 1 receptor blockers on the clinical outcomes of patients with COVID‐19 may not be mediated through altered ACE2 expression in abdominal subcutaneous AT. [ABSTRACT FROM AUTHOR]

Objective: SGTL2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes. The underlying mechanism may involve caloric restriction-like metabolic effects due to urinary glucose loss. We investigated the effects of dapagliflozin on 24-h energy metabolism and insulin sensitivity in patients with type 2 diabetes.Research Design and Methods: There were 26 patients with type 2 diabetes randomized to a 5-week double-blind, crossover study with a 6- to 8-week washout. Indirect calorimetry was used to measure 24-h energy metabolism and the respiratory exchange ratio (RER), both by whole-room calorimetry and by ventilated hood during a two-step euglycemic-hyperinsulinemic clamp. Results are presented as the differences in least squares mean (95% CI) between treatments.Results: Evaluable patients (n = 24) had a mean (SD) age of 64.2 (4.6) years, BMI of 28.1 (2.4) kg/m2, and HbA1c of 6.9% (0.7) (51.7 [6.8] mmol/mol). Rate of glucose disappearance was unaffected by dapagliflozin, whereas fasting endogenous glucose production (EGP) increased by dapagliflozin (+2.27 [1.39, 3.14] μmol/kg/min, P < 0.0001). Insulin-induced suppression of EGP (-1.71 [-2.75, -0.63] μmol/kg/min, P = 0.0036) and plasma free fatty acids (-21.93% [-39.31, -4.54], P = 0.016) was greater with dapagliflozin. Twenty-four-hour energy expenditure (-0.11 [-0.24, 0.03] MJ/day) remained unaffected by dapagliflozin, but dapagliflozin reduced the RER during daytime and nighttime, resulting in an increased day-to-nighttime difference in the RER (-0.010 [-0.017, -0.002], P = 0.016). Dapagliflozin treatment resulted in a negative 24-h energy and fat balance (-20.51 [-27.90, -13.12] g/day).Conclusions: Dapagliflozin treatment for 5 weeks resulted in major adjustments of metabolism mimicking caloric restriction, increased fat oxidation, improved hepatic and adipose insulin sensitivity, and improved 24-h energy metabolism. [ABSTRACT FROM AUTHOR]

Context: Patients with type 2 diabetes mellitus (T2DM) have elevated plasma branched-chain amino acid (BCAA) levels. The underlying cause, however, is not known. Low mitochondrial oxidation of BCAA levels could contribute to higher plasma BCAA levels.Objective: We aimed to investigate ex vivo muscle mitochondrial oxidative capacity and in vivo BCAA oxidation measured by whole-body leucine oxidation rates in patients with T2DM, first-degree relatives (FDRs), and control participants (CONs) with overweight or obesity.Design and Setting: An observational, community-based study was conducted.Participants: Fifteen patients with T2DM, 13 FDR, and 17 CONs were included (age, 40-70 years; body mass index, 27-35 kg/m2).Main Outcome Measures: High-resolution respirometry was used to examine ex vivo mitochondrial oxidative capacity in permeabilized muscle fibers. A subgroup of 5 T2DM patients and 5 CONs underwent hyperinsulinemic-euglycemic clamps combined with 1-13C leucine-infusion to determine whole-body leucine oxidation.Results: Total BCAA levels were higher in patients with T2DM compared to CONs, but not in FDRs, and correlated negatively with muscle mitochondrial oxidative capacity (r = -0.44, P < .001). Consistently, whole-body leucine oxidation rate was lower in patients with T2DM vs CON under basal conditions (0.202 ± 0.049 vs 0.275 ± 0.043 μmol kg-1 min-1, P < .05) and tended to be lower during high insulin infusion (0.326 ± 0.024 vs 0.382 ± 0.013 μmol kg-1 min-1, P = .075).Conclusions: In patients with T2DM, a compromised whole-body leucine oxidation rate supports our hypothesis that higher plasma BCAA levels may originate at least partly from a low mitochondrial oxidative capacity. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to investigate the influence of both hypothyroidism and thyroid-stimulating hormone (TSH) suppression on vascular inflammation, as assessed with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT). Methods: Ten thyroid carcinoma patients underwent an 18F-FDG PET/CT during post-thyroidectomy hypothyroidism and during thyrotropin (TSH) suppression after 131I (radioiodine) ablation therapy. We analysed the 18F-FDG uptake in the carotids, aortic arch, ascending, descending, and abdominal aorta to investigate the effects of thyroid hormone status on arterial inflammation. Target-to-background ratios (TBRs) corrected for blood pool activity were established for all arterial territories. Results were further compared to euthyroid historic control subjects. Results: In general, there was a trend towards higher vascular TBRs during TSH suppression than during hypothyroidism (TBRmax all vessels = 1.6 and 1.8, respectively, p = 0.058), suggesting a higher degree of arterial inflammation. In concurrence with this, we found increased C-reactive protein (CRP) levels after levothyroxine treatment (CRP = 2.9 mg/l and 4.8 mg/l, p = 0.005). An exploratory comparison with euthyroid controls showed significant higher TBRs during TSH suppression for the carotids, aortic arch, thoracic descending aorta, and when all vascular territories were combined (TBRmaxp = 0.013, p = 0.016, p = 0.030 and p = 0.018 respectively). Conclusions: Arterial inflammation is increased during TSH suppression. This finding sheds new light on the underlying mechanism of the suspected increased risk of cardiovascular disease in patients with TSH suppression. [ABSTRACT FROM AUTHOR]

Objective: To determine whether resveratrol supplementation can improve insulin sensitivity and promote overall metabolic health on top of standard diabetes care.Research Design and Methods: Seventeen subjects with well-controlled type 2 diabetes (T2D) were treated with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. The main outcome measure was insulin sensitivity by the hyperinsulinemic-euglycemic clamp technique.Results: Hepatic and peripheral insulin sensitivity were not affected by resveratrol treatment. Intrahepatic lipid content also remained unaffected by resveratrol; however, the change in intrahepatic lipid content correlated negatively with plasma resveratrol levels (R = -0.68, P = 0.03). Intramyocellular lipid content increased in type 2 muscle fibers (P = 0.03), and systolic blood pressure tended to decrease (P = 0.09) upon resveratrol treatment. In addition, resveratrol significantly improved ex vivo mitochondrial function (state 3 and state U respiration upon malate with octanoyl-carnitine, P < 0.005). Intriguingly, a correlation was found between plasma levels of a metabolite of resveratrol (dihydroresveratrol) and the metformin dose used by the patients (R = 0.66, P = 0.005), suggesting an interaction between metformin and resveratrol. It could be speculated that the lack of a resveratrol-induced insulin-sensitizing effect is caused by this interaction.Conclusions: Resveratrol supplementation does not improve hepatic or peripheral insulin sensitivity. Our results question the generalized value of resveratrol as an add-on therapy in the treatment of T2D and emphasize the need to perform studies in drug-naive patients with T2D or subjects with prediabetes. [ABSTRACT FROM AUTHOR]

A correction to the article "Effects of the SGLT2 Inhibitor Dapagliflozin on Energy Metabolism in Patients With Type 2 Diabetes: A Randomized, Double-Blind Crossover Trial," that was published in a 2021 issue is presented.

The authors respond to comments on their article which examined whether resveratrol can be beneficial for the treatment or prevention of type 2 diabetes. Topics covered include their defense on the use of low-dose resveratrol to examine whether the drug could improve glucose homeostasis via the improvement of mitochondrial function, and their explanation on not finding significant effects on insulin sensitivity in the type of medication used by the patients.

Purpose: Resveratrol has shown promising anti-inflammatory effects in in vitro and animal studies. We aimed to investigate this effect on arterial inflammation in vivo., Methods: This was an additional analysis of a double-blind randomized crossover trial which included eight male subjects with decreased insulin sensitivity who underwent an 18 F-fluoroxyglucose ( 18 F-FDG) PET/CT after 34 days of placebo and resveratrol treatment (150 mg/day). 18 F-FDG uptake was analyzed in the carotid arteries and the aorta, adipose tissue regions, spleen, and bone marrow as measures for arterial and systemic inflammation. Maximum target-to-background ratios (TBR max ) were compared between resveratrol and placebo treatment with the non-parametric Wilcoxon signed-rank test. Median values are shown with their interquartile range., Results: Arterial 18 F-FDG uptake was non-significantly higher after resveratrol treatment (TBR max all vessels 1.7 (1.6-1.7)) in comparison to placebo treatment (1.5 (1.4-1.6); p=0.050). Only in visceral adipose tissue, the increase in 18 F-FDG uptake after resveratrol reached statistical significance (p=0.024). Furthermore, CRP-levels were not significantly affected by resveratrol treatment (p=0.091)., Conclusions: Resveratrol failed to attenuate arterial or systemic inflammation as measured with 18 F-FDG PET in subjects at risk of developing type 2 diabetes. However, validation of these findings in larger human studies is needed., Competing Interests: Disclosures: Joachim E. Wildberger receives institutional grants from Agfa, Morstel, Belgium; Bayer Healthcare, Berlin, Germany; GE, Chicago, Illinois; Optimed, Ettlingen, Germany; Philips Healthcare, Best, the Netherlands; Siemens Healthineers, Forchheim, Germany, and personal fees from the speaker’s bureau of Bayer Healthcare, Berlin, Germany and Siemens Healthineers, Forchheim, Germany. Ellen Boswijk, Marlies de Ligt, Marie-Fleur J. Habets, Alma M.A. Mingels, Wouter D. van Marken Lichtenbelt, Felix M. Mottaghy, Patrick Schrauwen and Jan Bucerius, have no relationships with industry currently or within the last two years. Conflicts of interest: All authors declare that they have no conflict of interest regarding the research presented in this manuscript., (Thieme. All rights reserved.)

In non-athletes, insulin sensitivity correlates negatively with intramyocellular lipid (IMCL) content. In athletes, however, a pattern of benign IMCL storage exists, which is characterized by lipid storage in type I muscle fibres, in small and numerous lipid droplets (LDs) preferable coated with PLIN5, without affecting insulin sensitivity. Administration of resveratrol has been promoted for its beneficial effects on glucose homeostasis. We observed that 30 days of oral resveratrol administration (150 mg/day) in metabolically compromised individuals showed a 33% increase in IMCL (placebo vs. resveratrol; 0.86 ± 0.090 AU vs. 1.14 ± 0.11 AU, p = 0.003) without impeding insulin sensitivity. Thus, the aim of the present study was to examine if a resveratrol-mediated increase in IMCL content, in metabolically compromised individuals, changes the LD phenotype towards the phenotype we previously observed in athletes. For this, we studied IMCL, LD number, LD size, subcellular distribution and PLIN5 coating in different fibre types using high-resolution confocal microscopy. As proof of concept, we observed a 2.3-fold increase (p = 0.038) in lipid accumulation after 48 h of resveratrol incubation in cultured human primary muscle cells. In vivo analysis showed that resveratrol-induced increase in IMCL is predominantly in type I muscle fibres (placebo vs. resveratrol; 0.97 ± 0.16% vs. 1.26 ± 0.09%; p = 0.030) in both the subsarcolemmal (p = 0.016) and intermyofibrillar region (p = 0.026) and particularly in PLIN5-coated LDs (p = 0.024). These data indicate that administration of resveratrol augments IMCL content in metabolically compromised individuals towards a LD phenotype that mimics an 'athlete like phenotype'., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)