Intermittent hypoxia increases lipid insulin resistance in healthy humans: A randomized crossover trial.

Sympathetic overactivity caused by chronic intermittent hypoxia is a hallmark of obstructive sleep apnea. A high sympathetic tone elicits increases in plasma free fatty acid and insulin. Our objective was to assess the impact of 14 nights of chronic intermittent hypoxia exposure on sympathetic activity, glucose control, lipid profile and subcutaneous fat tissue remodelling in non-obese healthy humans. In this prospective, double-blinded crossover study, 12 healthy subjects were randomized, among them only nine underwent the two phases of exposures of 14 nights chronic intermittent hypoxia versus air. Sympathetic activity was measured by peroneal microneurography (muscle sympathetic nerve activity) before and after each exposure. Fasting glucose, insulin, C-peptide and free fatty acid were assessed at rest and during a multisampling oral glucose tolerance test. We assessed histological remodelling, adrenergic receptors, lipolysis and lipogenesis genes expression and functional changes of the adipose tissue. Two weeks of exposure of chronic intermittent hypoxia versus ambient air significantly increased sympathetic activity (p = 0.04). Muscle sympathetic nerve activity increased from 24.5 [18.9; 26.8] before to 21.7 [13.8; 25.7] after ambient air exposure, and from 20.6 [17.4; 23.9] before to 28.0 [24.4; 31.5] bursts per min after exposure to chronic intermittent hypoxia. After chronic intermittent hypoxia, post-oral glucose tolerance test circulating free fatty acid area under the curve increased (p = 0.05) and free fatty acid sensitivity to insulin decreased (p = 0.028). In adipocyte tissue, intermittent hypoxia increased expression of lipolysis genes (adipocyte triglyceride lipase and hormone-sensitive lipase) and lipogenesis genes (fatty acid synthase; p < 0.05). In this unique experimental setting in healthy humans, chronic intermittent hypoxia induced high sympathetic tone, lipolysis and decreased free fatty acid sensitivity to insulin. This might participate in the trajectory to systemic insulin resistance and diabetes for patients with obstructive sleep apnea.

Impact of sleep and physical activity habits on real-life glycaemic variability in patients with type 2 diabetes.

The aim of this study was to better characterise whether sleep habits, eating schedule and physical activity in real-life are associated with glycaemic control in patients with type 2 diabetes. A total of 28 patients (aged 60 years [58; 66], 54% female) with type 2 diabetes treated with basal-bolus insulin therapy administered by insulin pumps were analysed. Glycaemic data measured by Flash Glucose Monitor System, physical activity and sleep data measured by accelerometer, and meal schedules were simultaneously collated with insulin pump administration data, for 7 days in real-life. Their respective impact on the time spent in target, in hypoglycaemia, in hyperglycaemia and on glycaemic variability was evaluated. Multiple regressions showed that the total daily dose of meal boluses of insulin was inversely associated with the coefficient of variation (CV; coefficient ß = -0.073; 95% confidence interval: -0.130, -0.015; p = 0.016), as well as sleep duration. The higher the sleep duration, the lower the glycaemic variability (coefficient ß = -0.012; 95% confidence interval: -0.023, -0.002; p = 0.027). The mean 7 days physical activity of the subjects was very low and was not associated with glycaemic control on the 7 days mean values. However, days with at least 1 hr spent in physical activity higher than 1.5 METs were associated with less glycaemic variability that same day. This real-life observation highlights the importance of sufficient sleep duration and regular physical activity to lessen the glycaemic variability of patients with type 2 diabetes.

Respiratory effort during sleep and the rate of prevalent type 2 diabetes in obstructive sleep apnoea.

AIM: To determine the association between total sleep time (TST) spent in increased respiratory effort (RE) and the prevalence of type 2 diabetes in a large cohort of individuals with suspected obstructive sleep apnoea (OSA) referred for in-laboratory polysomnography (PSG). MATERIALS AND METHODS: We conducted a retrospective cross-sectional study using the clinical data of 1128 patients. Non-invasive measurements of RE were derived from the sleep mandibular jaw movements (MJM) bio-signal. An explainable machine-learning model was built to predict prevalent type 2 diabetes from clinical data, standard PSG indices, and MJM-derived parameters (including the proportion of TST spent with increased respiratory effort [REMOV [%TST]). RESULTS: Original data were randomly assigned to training (n = 853) and validation (n = 275) subsets. The classification model based on 18 input features including REMOV showed good performance for predicting prevalent type 2 diabetes (sensitivity = 0.81, specificity = 0.89). Post hoc interpretation using the Shapley additive explanation method found that a high value of REMOV was the most important risk factor associated with type 2 diabetes after traditional clinical variables (age, sex, body mass index), and ahead of standard PSG metrics including the apnoea-hypopnea and oxygen desaturation indices. CONCLUSIONS: These findings show for the first time that the proportion of sleep time spent in increased RE (assessed through MJM measurements) is an important predictor of the association with type 2 diabetes in individuals with OSA.

Prevalence of sleep apnoea in patients with type 1 diabetes and its association with comorbidities and diabetic complications: A French nationwide prospective study.

AIM: To investigate sleep apnoea prevalence, factors influencing severity, and associations between sleep apnoea severity and micro-/macrovascular complications in a large population of patients with type 1 diabetes. MATERIALS AND METHODS: This French multicentre prospective cohort study was conducted between July 2016 and June 2020. Adults with type 1 diabetes using an insulin pump were eligible. Home care provider nurses collected demographic and clinical data and set up oximetry to determine the oxygen desaturation index (ODI). No, mild-moderate and severe sleep apnoea were defined as ODI <15 events/h, 15 to <30 events/h and ≥30 events/h, respectively. Univariate and multivariate analyses were performed to identify factors associated with sleep apnoea, and associations between sleep apnoea severity and micro-/macrovascular complications were determined using logistic regression. RESULTS: Of 769 participants, 12.4% and 3.4% had mild-to-moderate or severe sleep apnoea, respectively. Factors significantly associated with sleep apnoea on multivariate analysis were age, sex, body mass index (BMI) and hypertension. After adjustment for age, sex and BMI, presence of severe sleep apnoea was significantly associated with macrovascular complications (odds ratio vs. no sleep apnoea: 3.96 [95% confidence interval 1.43-11.11]; P < 0.01), while mild-to-moderate sleep apnoea was significantly associated with presence of diabetic retinopathy (odds ratio 2.09 [95% confidence interval 1.10-3.74]; P < 0.01). CONCLUSION: Sleep apnoea is a significant comorbidity in patients with type 1 diabetes, especially with respect to diabetic complications. This highlights the need for sleep apnoea screening and management in these individuals.

Regional CZT myocardial perfusion reserve for the detection of territories with simultaneously impaired CFR and IMR in patients without obstructive coronary artery disease: a pilot study.

OBJECTIVES: To assess the diagnostic performances of CZT myocardial perfusion reserve (MPR) for the detection of territories with simultaneous impaired coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) in patients without obstructive coronary artery disease. METHODS: Patients were prospectively included before being referred for coronary angiography. All patients underwent CZT MPR before invasive coronary angiography (ICA) and coronary physiology assessment. Rest and dipyridamole-induced stress myocardial blood flow (MBF) and MPR were quantified using 99mTc-SestaMIBI and a CZT camera. Fractional flow reserve (FFR), Thermodilution CFR, and IMR were assessed during ICA. RESULTS: Between December 2016 and July 2019, 36 patients were included. 25/36 patients presented no obstructive coronary artery disease. A complete functional assessment was performed in 32 arteries. No territory presented a significant ischemia on CZT myocardial perfusion imaging. A moderate yet significant correlation was observed between regional CZT MPR and CFR (r = 0.4, P = .03). Sensitivity, specificity, positive and negative predictive value, and accuracy of regional CZT MPR versus the composite invasive criterion (impaired CFR and IMR) were 87 [47% to 99%], 92% [73% to 99%], 78% [47% to 93%], 96% [78% to 99%], and 91% [75% to 98%], respectively. All territories with a regional CZT MPR ≤ 1.8 showed a CFR < 2. Regional CZT MPR values were significantly higher in arteries with CFR ≥ 2 and IMR < 25 (negative composite criterion, n = 14) than in those with CFR < 2 and IMR ≥ 25 (2.6 [2.1 to 3.6] versus 1.6 [1.2 to 1.8]), P < .01). CONCLUSION: Regional CZT MPR presented excellent diagnostic performances for the detection of territories with simultaneously impaired CFR and IMR reflecting a very high cardiovascular risk in patients without obstructive coronary artery disease.

Bariatric surgery short-term outcomes in patients with obstructive sleep apnoea: the Severe Obesity Outcome Network prospective cohort.

BACKGROUND/OBJECTIVES: Although the benefits of bariatric surgery have been clearly established, it is not known whether they are as important in patients with obstructive sleep apnoea (OSA). Primary aim: to evaluate whether patients with moderate-to-severe OSA (apnoea-hypopnea index (AHI) ≥ 15 events/h) treated by continuous positive airway pressure/non-invasive ventilation (median [IQR] adherence 6.5 h/night [5; 7.9] at baseline) lose the same amount of body weight 1 year after bariatric surgery as patients with no or mild OSA. Secondary objectives: to compare the evolution of type 2 diabetes and hypertension after bariatric surgery, and surgical complication rates between groups. METHODS/SUBJECTS: Analyses were performed in 371 patients included in a prospective cohort of bariatric surgery, the Severe Obesity Outcome Network cohort. Subjects having moderate-to-severe OSA (n = 210) at baseline were compared with other subjects (n = 161). RESULTS: Excess weight loss (%EWL) at 1 year was lower in patients with moderate-to-severe OSA than in patients without (64.9%EWL [46.9; 79.5] vs. 73.8%EWL [56.6; 89.3], p < 0.01). Multivariable analysis showed that age, initial body mass index and type of surgery, but not OSA status, were associated with 1-year %EWL. Diabetes remitted in 25 (41%) patients with moderate-to-severe OSA and 16 (48%) patients with no or mild OSA (p = 0.48). Hypertension remitted in 28 (32.9%) patients with moderate-to-severe OSA and 9 (40.9%) with no or mild (p = 0.48). Complication rates were 28 (13.3%) in patients with moderate-to-severe OSA and 12 (7.5%) in patients with no or mild OSA (p = 0.07). CONCLUSIONS: Patients with OSA lose less body weight after bariatric surgery. This was related to older age and a higher baseline body mass index. However, the improvements of diabetes and hypertension were similar to that of patients without OSA, and the risk of surgical complications was not higher.

Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes.

Imeglimin is an investigational first-in-class novel oral agent for the treatment of type 2 diabetes (T2D). Several pivotal phase III trials have been completed with evidence of statistically significant glucose lowering and a generally favourable safety and tolerability profile, including the lack of severe hypoglycaemia. Imeglimin's mechanism of action involves dual effects: (a) amplification of glucose-stimulated insulin secretion (GSIS) and preservation of ß-cell mass; and (b) enhanced insulin action, including the potential for inhibition of hepatic glucose output and improvement in insulin signalling in both liver and skeletal muscle. At a cellular and molecular level, Imeglimin's underlying mechanism may involve correction of mitochondrial dysfunction, a common underlying element of T2D pathogenesis. It has been observed to rebalance respiratory chain activity (partial inhibition of Complex I and correction of deficient Complex III activity), resulting in reduced reactive oxygen species formation (decreasing oxidative stress) and prevention of mitochondrial permeability transition pore opening (implicated in preventing cell death). In islets derived from diseased rodents with T2D, Imeglimin also enhances glucose-stimulated ATP generation and induces the synthesis of nicotinamide adenine dinucleotide (NAD+ ) via the 'salvage pathway'. In addition to playing a key role as a mitochondrial co-factor, NAD+ metabolites may contribute to the increase in GSIS (via enhanced Ca++ mobilization). Imeglimin has also been shown to preserve ß-cell mass in rodents with T2D. Overall, Imeglimin appears to target a key root cause of T2D: defective cellular energy metabolism. This potential mode of action is unique and has been shown to differ from that of other major therapeutic classes, including biguanides, sulphonylureas and glucagon-like peptide-1 receptor agonists.

Cardiometabolic risk improvement in response to a 3-yr lifestyle modification program in men: contribution of improved cardiorespiratory fitness vs. weight loss.

Our objective was to examine the respective contributions of changes in visceral adiposity, subcutaneous adiposity, liver fat, and cardiorespiratory fitness (CRF) to the improvements in cardiometabolic risk markers in response to a 3-yr healthy eating/physical activity lifestyle intervention. Ninety-four out of 144 viscerally obese healthy men completed a 3-yr lifestyle intervention. Body weight, body composition, and fat distribution were assessed by anthropometry and DEXA/computed tomography. CRF, adipokines, lipoprotein/lipid profile, and 75 g of oral glucose tolerance were assessed. CRF and visceral and subcutaneous adiposity significantly improved over the 3-yr intervention, with a nadir in year 1 and a partial regain in year 3 Liver fat (estimated by insulin hepatic extraction) stabilized from year 1 to year 3, whereas HOMA-IR, ISI-Matsuda index, and adiponectin continued to improve. Multivariate analysis revealed that both visceral adiposity and estimated liver fat reductions contributed to the improved ISI-Matsuda index observed over 3 yr (r2 = 0.28, P < 0.001). Three-year changes in fat mass and CRF were independently associated with changes in visceral fat (adjusted r2 = 0.40, P < 0.001), whereas only changes in CRF were associated with changes in estimated liver fat (adjusted r2 = 0.18, P < 0.001). A long-term (3 yr) healthy eating/physical activity intervention in men improves several cardiometabolic risk markers over the long term (3 yr) despite a partial body weight regain observed between year 1 and year 3 The improvement in CRF contributes to visceral and estimated liver fat losses over the long term, which in turn explain the benefits of the lifestyle intervention on cardiometabolic risk profile.

Outcomes of bariatric surgery in the setting of compensated advanced chronic liver disease associated with clinically significant portal hypertension: a multicenter, retrospective, cohort study on feasibility and safety.

BACKGROUND: The obesity epidemic has led to an increase in the proportion of patients with chronic liver disease due to metabolic associated steatosic liver disease and in the prevalence of obesity in patients with cirrhosis. Metabolic and bariatric surgery (MBS) has been proven to determine weight loss, obesity-related medical problems remission, and liver steatosis, inflammation, and fibrosis improvement. However, cirrhosis and portal hypertension are well-known risk factors for increased morbidity and mortality after surgery. The aim of this study is to evaluate the safety of MBS in patients with compensated advanced chronic liver disease (cALCD) and clinically significant portal hypertension (CSPH). MATERIAL AND METHODS: This is an international, multicentric, retrospective study on 63 individuals affected by obesity with cALCD and CSPH who underwent MBS in tertiary referral centers with experts hepatobiliary surgeons between January 2010 and October 2022. The primary endpoint was postoperative mortality at 90 days. The secondary endpoints included postoperative weight loss at last follow-up and postoperative complication rate. In addition, the authors performed subgroup analyses of Child-Pugh (A vs. B) score, MELD (≤9 vs. >9) score, and type of surgery. RESULTS: One patient (1.6%) experienced gastric leakage and mortality. There were three (5%) reported cases of portal vein thrombosis, two (3%) postoperative acute renal failure, and one (1.6%) postoperative encephalopathy. Child-Pugh score A resulted to be a protective factor for intraoperative bleeding requiring transfusion at univariate analysis (OR: 0.73, 95% CI: 0.55-0.97, P =0.046) but not at multivariate analysis. MELD>9 score and the type of surgery did not result to be a risk factor for any postoperative complication. CONCLUSION: MBS is safe in patients with cALCD and CSPH performed in tertiary bariatric referral centers with hepatobiliary expert surgeons. Larger, prospective studies with longer follow-up periods are needed to confirm these results.

Changes in both global diet quality and physical activity level synergistically reduce visceral adiposity in men with features of metabolic syndrome.

With regard to the beneficial impact of lifestyle interventions on weight and abdominal obesity management, our objective was to identify which components of a lifestyle-intervention program [physical activity (PA), energy and macronutrient intake, diet quality] had an influence on visceral adipose tissue (VAT) loss. The present lifestyle intervention targeted a daily energy deficit (500 kcal), coupled with a PA program (160 min/wk). From the 144 participants initially recruited, 93 viscerally obese men (age: 49 ± 1 y; waist circumference: 108 ± 9 cm; plasma triglyceride concentration: 2.46 ± 0.09 mmol/L) who completed a 3-d dietary journal both at baseline and after 1 y of intervention and a daily PA journal for 1 y were considered in the present analyses. Body composition and fat distribution were assessed by using dual-energy X-ray absorptiometry and computed tomography. After 1 y, abdominally obese men significantly improved their diet quality, as assessed by the Dietary Approaches to Stop Hypertension (DASH)-derived diet quality (DQ) score (P < 0.0001). Improved DQ and higher levels of PA were both independently and significantly associated with reductions in body weight, fat mass, VAT, and thigh muscle fat content, beyond reported energy intake or diet macronutrient composition. When stratified according to the level of PA and DQ [PA- (low PA), DQ- (low DQ), PA+ (high PA), DQ+ (high DQ)], the PA+/DQ+ group showed reductions in VAT that were 20% greater than in the PA-/DQ+ group, 28% greater than in the PA+/DQ- group, and 50% (P < 0.05) greater than in the PA-/DQ- group. Our results highlight the strong contribution of DQ beyond macronutrient and energy content to changes in body composition and suggest that synergistic changes in both DQ and PA levels optimally reduce VAT in men with features of metabolic syndrome.

Effect of a lifestyle intervention to prevent weight gain at initiation of insulin pump therapy in type 2 diabetes: A randomized, controlled, multicentre trial.

Insulin pump therapy improves glycaemic control in individuals with type 2 diabetes. However, it may be associated with weight gain. AIM: To test the effectiveness of a six-month dietary and physical activity intervention, compared to usual care, on weight gain prevention after initiation of insulin pump. METHODS: Multicentre randomized, controlled trial of 54 individuals. Primary endpoint was between group difference in weight gain at six-months. RESULTS: Weight gain after 6 months of insulin pump treatment did not differ between groups: mean 3.2 (3.9) kg in the control group and 3.9 (3.8) kg in the intervention group, (p = 0.56). HbA1c improved without difference between groups. Post-hoc multivariate analysis of all participants found that weight gain was independently associated with younger age, active smoking, and the magnitude of HbA1c reduction. A 1 % decrease in HbA1c was associated with an increase of 0.94 kg [95 % Confidence Interval 0.47; 1.41], p < 0.001. CONCLUSIONS: Treatment intensification by insulin pump therapy in patients with type 2 diabetes is effective to improve glycaemic control. A gain of about 1 kg per 1 % drop in HbA1c can be expected after insulin treatment intensification. This weight gain was not prevented by a home-base, individualized, 6-months lifestyle intervention program.

Sleep apnoea attenuates the effects of a lifestyle intervention programme in men with visceral obesity.

BACKGROUND: Excess visceral adiposity and sleep apnoea are two conditions independently associated with cardiovascular diseases. The two conditions are often combined and are believed to interact in a vicious circle. OBJECTIVES: To compare the response of men with visceral obesity with or without sleep apnoea syndrome to a 1-year healthy eating, physical activity/exercise intervention programme. METHODS: 77 men, selected on the basis of increased waist circumference (≥90 cm) and dyslipidaemia (triglycerides ≥1.69 and/or high-density lipoprotein (HDL) cholesterol <1.03 mmol/litre), participated in this study. Body composition and fat distribution were assessed by dual-emission X-ray absorptiometry or CT and sleep breathing disorders by home-based polygraphic recording. Cardiorespiratory fitness, plasma adipokines, plasma inflammatory markers, fasting lipoprotein-lipid profile and oral glucose tolerance test were assessed. RESULTS: After the 1-year lifestyle intervention, the mean oxygen desaturation index (ODI) of the whole sample decreased (-3±13 events/h, p<0.05). Men with sleep apnoea syndrome at baseline (ODI ≥10 events/h, n=28) showed smaller reductions in body mass index, waist circumference, triglycerides and smaller increases in HDL cholesterol and adiponectin than men without sleep apnoea (ODI <10 events/h, n=49), despite similar compliance to the programme. The higher the baseline ODI and the time spent under 90% saturation, the lower the reductions in fat mass and visceral adiposity, and the smaller the improvement in glucose/insulin homeostasis indices after 1 year. CONCLUSIONS: Men with sleep apnoea syndrome at baseline had smaller reduction in body weight and less metabolic improvements associated with the lifestyle intervention programme than men without sleep apnoea syndrome.

Obesity hypoventilation syndrome: from sleep-disordered breathing to systemic comorbidities and the need to offer combined treatment strategies.

Obesity hypoventilation syndrome (OHS) is defined as a combination of obesity (body mass index ≥ 30 kg/m(2)), daytime hypercapnia (partial arterial carbon dioxide concentration ≥45 mm Hg) and sleep-disordered breathing after ruling out other disorders that may cause alveolar hypoventilation. Through the prism of the International Classification of Functioning, OHS is a chronic condition associated with respiratory, metabolic, hormonal and cardiovascular impairments, leading to a decrease in daily life activities, a lack of social participation and high risk of hospitalization and death. Despite its severity, OHS is largely underdiagnosed and the health-related costs are higher than those of apnoeic or obese eucapnic patients. The present review discusses the definition, epidemiology, physiopathology and treatment modalities of OHS. Although nocturnal positive airway pressure therapies represent first-line treatment and are effective in improving patient outcomes, there is a need to offer combined treatment strategies and to assess the effect of multimodal therapeutic strategies on morbidity and mortality.

Intermittent Hypoxia Rewires the Liver Transcriptome and Fires up Fatty Acids Usage for Mitochondrial Respiration.

Sleep Apnea Syndrome (SAS) is one of the most common chronic diseases, affecting nearly one billion people worldwide. The repetitive occurrence of abnormal respiratory events generates cyclical desaturation-reoxygenation sequences known as intermittent hypoxia (IH). Among SAS metabolic sequelae, it has been established by experimental and clinical studies that SAS is an independent risk factor for the development and progression of non-alcoholic fatty liver disease (NAFLD). The principal goal of this study was to decrypt the molecular mechanisms at the onset of IH-mediated liver injury. To address this question, we used a unique mouse model of SAS exposed to IH, employed unbiased high-throughput transcriptomics and computed network analysis. This led us to examine hepatic mitochondrial ultrastructure and function using electron microscopy, high-resolution respirometry and flux analysis in isolated mitochondria. Transcriptomics and network analysis revealed that IH reprograms Nuclear Respiratory Factor- (NRF-) dependent gene expression and showed that mitochondria play a central role. We thus demonstrated that IH boosts the oxidative capacity from fatty acids of liver mitochondria. Lastly, the unbalance between oxidative stress and antioxidant defense is tied to an increase in hepatic ROS production and DNA damage during IH. We provide a comprehensive analysis of liver metabolism during IH and reveal the key role of the mitochondria at the origin of development of liver disease. These findings contribute to the understanding of the mechanisms underlying NAFLD development and progression during SAS and provide a rationale for novel therapeutic targets and biomarker discovery.

Impact of Bariatric Surgery on Medication Efficacy: an Analysis of World Health Organization Pharmacovigilance Data.

Bariatric surgery is the most effective treatment of severe obesity. However, this surgery can have an impact on the bioavailability and metabolism of oral drugs as it modifies absorption, intestinal, and hepatic metabolism, and efflux transporter activity. The clinical impact of such modifications often remains unknown. To investigate, we extracted and summarized all reports of changes in drug efficacy associated with bariatric surgery registered in the WHO pharmacovigilance database. We identified 165 drug reports affecting 128 patients. The majority involved gastric bypass surgery (77.3%). Most reports concerned drug ineffectiveness (74.7%). The most frequent modifications concerned psychotropic drugs with a reduction in efficacy. This study underlines the urgent need for more research to better characterize the impact of bariatric surgery on drug pharmacokinetics and clinical efficacy.

The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells.

Aims: To understand the mechanism by which imeglimin (a new oral hypoglycemic agent whose phase 3 development program in Japan has now been completed) decreases hepatic glucose production. Materials and methods: We compared the effect of imeglimin and metformin on glucose production, ATP/ADP ratio, oxygen consumption rate, mitochondrial redox potential and membrane potential in primary rat hepatocytes. Results: We found that both imeglimin and metformin dose-dependently decreased glucose production and the ATP/ADP ratio. Moreover, they both increased mitochondrial redox potential (assessed by mitochondrial NAD(P)H fluorescence) and decreased membrane potential (assessed by TMRM fluorescence). However, contrary to metformin, which inhibits mitochondrial Complex I, imeglimin did not decrease the oxygen consumption rate in intact cells. By measuring the oxygen consumption of in situ respiratory chain as a function of the concentration of NADH, we observed that imeglimin decreased the affinity of NADH for the respiratory chain but did not affect its Vmax (ie competitive inhibition) whereas metformin decreased both the Vmax and the affinity (ie uncompetitive inhibition). Conclusions: We conclude that imeglimin induces a kinetic constraint on the respiratory chain that does not affect its maximal activity. This kinetic constraint is offset by a decrease in the mitochondrial membrane potential, which induces a thermodynamic constraint on the ATPase responsible for a decrease in the ATP/ADP ratio.

COVID-19: Underlying Adipokine Storm and Angiotensin 1-7 Umbrella.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third coronavirus leading to a global health outbreak. Despite the high mortality rates from SARS-CoV-1 and Middle-East respiratory syndrome (MERS)-CoV infections, which both sparked the interest of the scientific community, the underlying physiopathology of the SARS-CoV-2 infection, remains partially unclear. SARS-CoV-2 shares similar features with SARS-CoV-1, notably the use of the angiotensin conversion enzyme 2 (ACE2) as a receptor to enter the host cells. However, some features of the SARS-CoV-2 pandemic are unique. In this work, we focus on the association between obesity, metabolic syndrome, and type 2 diabetes on the one hand, and the severity of COVID-19 infection on the other, as it seems greater in these patients. We discuss how adipocyte dysfunction leads to a specific immune environment that predisposes obese patients to respiratory failure during COVID-19. We also hypothesize that an ACE2-cleaved protein, angiotensin 1-7, has a beneficial action on immune deregulation and that its low expression during the SARS-CoV-2 infection could explain the severity of infection. This introduces angiotensin 1-7 as a potential candidate of interest in therapeutic research on CoV infections.

Effectiveness and Safety of Bariatric Surgery in Patients with End-Stage Chronic Kidney Disease or Kidney Transplant.

OBJECTIVE: This study aimed to evaluate (1) the effectiveness, complications, and postoperative access to transplantation in end-stage chronic kidney disease (ECKD) and (2) the effectiveness and complications of bariatric surgery in patients who had already undergone kidney transplant. METHODS: A systematic review and meta-analysis of mortality and complications rates were performed. Thirty studies were reviewed. RESULTS: After bariatric surgery, patients with ECKD had similar postoperative weight loss to patients from the general population. Meta-analysis showed post-bariatric surgery rates of 2% (95% CI: 0%-3%) for mortality and 7% (95% CI: 2%-14%) for complications. Approximately one-fifth of the patients had access to a transplant. This rate may be underestimated because of the short duration of follow-up. The lack of control groups did not allow for a conclusion on the role of bariatric surgery in facilitating access to kidney transplantation. In patients who had received a kidney transplant, bariatric surgery seemed to improve renal function but increased graft-rejection risk, possibly because of changes in the bioavailability of immunosuppressant drugs. CONCLUSIONS: Bariatric surgery yields significant weight loss in patients with ECKD that improves patients' chances of accessing a transplant but does not guarantee it; however, the risk for complications and death is higher than in other patients. After transplantation, bariatric surgery-induced weight loss appeared to positively impact the function of the grafted kidney, but careful monitoring of immunosuppressant medications is required.