Membrane estrogen receptor-α contributes to female protection against high-fat diet-induced metabolic disorders.

Background: Estrogen Receptor α (ERα) is a significant modulator of energy balance and lipid/glucose metabolisms. Beyond the classical nuclear actions of the receptor, rapid activation of intracellular signaling pathways is mediated by a sub-fraction of ERα localized to the plasma membrane, known as Membrane Initiated Steroid Signaling (MISS). However, whether membrane ERα is involved in the protective metabolic actions of endogenous estrogens in conditions of nutritional challenge, and thus contributes to sex differences in the susceptibility to metabolic diseases, remains to be clarified. Methods: Male and female C451A-ERα mice, harboring a point mutation which results in the abolition of membrane localization and MISS-related effects of the receptor, and their wild-type littermates (WT-ERα) were maintained on a normal chow diet (NCD) or fed a high-fat diet (HFD). Body weight gain, body composition and glucose tolerance were monitored. Insulin sensitivity and energy balance regulation were further investigated in HFD-fed female mice. Results: C451A-ERα genotype had no influence on body weight gain, adipose tissue accumulation and glucose tolerance in NCD-fed mice of both sexes followed up to 7 months of age, nor male mice fed a HFD for 12 weeks. In contrast, compared to WT-ERα littermates, HFD-fed C451A-ERα female mice exhibited: 1) accelerated fat mass accumulation, liver steatosis and impaired glucose tolerance; 2) whole-body insulin resistance, assessed by hyperinsulinemic-euglycemic clamps, and altered insulin-induced signaling in skeletal muscle and liver; 3) significant decrease in energy expenditure associated with histological and functional abnormalities of brown adipose tissue and a defect in thermogenesis regulation in response to cold exposure. Conclusion: Besides the well-characterized role of ERα nuclear actions, membrane-initiated ERα extra-nuclear signaling contributes to female, but not to male, protection against HFD-induced obesity and associated metabolic disorders in mouse.

Ephrin-B1 regulates the adult diastolic function through a late postnatal maturation of cardiomyocyte surface crests.

The rod-shaped adult cardiomyocyte (CM) harbors a unique architecture of its lateral surface with periodic crests, relying on the presence of subsarcolemmal mitochondria (SSM) with unknown role. Here, we investigated the development and functional role of CM crests during the postnatal period. We found in rodents that CM crest maturation occurs late between postnatal day 20 (P20) and P60 through both SSM biogenesis, swelling and crest-crest lateral interactions between adjacent CM, promoting tissue compaction. At the functional level, we showed that the P20-P60 period is dedicated to the improvement of relaxation. Interestingly, crest maturation specifically contributes to an atypical CM hypertrophy of its short axis, without myofibril addition, but relying on CM lateral stretching. Mechanistically, using constitutive and conditional CM-specific knock-out mice, we identified ephrin-B1, a lateral membrane stabilizer, as a molecular determinant of P20-P60 crest maturation, governing both the CM lateral stretch and the diastolic function, thus highly suggesting a link between crest maturity and diastole. Remarkably, while young adult CM-specific Efnb1 KO mice essentially exhibit an impairment of the ventricular diastole with preserved ejection fraction and exercise intolerance, they progressively switch toward systolic heart failure with 100% KO mice dying after 13 months, indicative of a critical role of CM-ephrin-B1 in the adult heart function. This study highlights the molecular determinants and the biological implication of a new late P20-P60 postnatal developmental stage of the heart in rodents during which, in part, ephrin-B1 specifically regulates the maturation of the CM surface crests and of the diastolic function.

Smoking and Diabetes: Sex and Gender Aspects and Their Effect on Vascular Diseases.

Smoking and diabetes mellitus (DM) have been identified as 2 major cardiovascular risk factors for many years. In the field of cardiovascular diseases, considering sex differences, or gender differences, or both has become an essential element in moving toward equitable and quality health care. We reviewed the effect of sex or gender on the link between smoking and DM. The risk of type 2 DM due to smoking has been established in both sexes at the same level. As is the case in the general population, the prevalence of smoking in those with DM is higher in men than in women, although the decrease in smoking observed in recent years is more pronounced in men than in women. Regarding chronic DM complications, smoking is an independent risk factor for all-cause mortality, as well as macrovascular and microvascular complications, in both sexes. Nevertheless, in type 2 DM, the burden of smoking appears to be greater in women than in men for coronary heart disease morbidity, with women having a 50% greater risk of fatal coronary event. Women are more dependent to nicotine, cumulate psychosocial barriers to quitting smoking, and are more likely to gain weight, which might make it more difficult for them to quit smoking. Smoking cessation advice and treatments should take into account gender differences to improve the success and long-term maintenance of abstinence in people with and without DM. This might include interventions that address emotions and stress in women or designed to reach specific populations of men.

Initiation of the Fixed Combination IDegLira in Patients with Type 2 Diabetes on Prior Injectable Therapy: Insights from the EASY French Real-World Study.

INTRODUCTION: Combining basal insulin (BI) with glucagon-like peptide-1 receptor agonist (GLP-1RA) is recognized as a relevant option to optimize glucose control in type 2 diabetes (T2D). The EASY real-world study aimed to evaluate the modalities of initiation and the effectiveness of the insulin Degludec plus Liraglutide (IDegLira) fixed-ratio combination in the French health care system. METHODS: A retrospective analysis included all patients with T2D and prior injectable therapy (GLP1-RA and/or insulin) who started treatment with IDegLira from September 2016 to December 2017 in 11 French diabetes centers. Baseline characteristics, reasons for IDegLira initiation, and modes of implementation were collected from the medical records. Changes in HbA1c and body weight were determined in patients with available follow-up data (nearest 6-month visit). RESULTS: IDegLira was initiated in 629 patients previously treated with GLP-1RA alone (11.6%), insulin alone (31.5% including 16.5% with BI and 14.9% with multiple daily injections [MDI]) or a free combination of GLP-1RA and insulin (56.9% including 44.8% with BI and 12.1% with MDI), associated or not with oral agents. IDegLira starting dose (mean of 29 ± 11 dose steps) most often exceeded the recommended dose, and was significantly correlated with prior BI but not GLP-1RA dosage. At initiation, mean age, body mass index (BMI) and HbA1c were 60.1 ± 10.2 years, 33.4 ± 6.2 kg/m2 and 8.8 ± 1.7%, respectively. In 461 patients with available follow-up (median 178 days), HbA1c decreased in all subgroups submitted to treatment intensification (- 1.7 ± 1.8% [p < 0.0001], - 1.2 ± 1.8% [p < 0.001] and - 0.8 ± 1.8% [p = 0.0026] in patients with prior GLP-1RA, BI or MDI therapy, respectively) but also in those switching from BI and GLP-1RA free combination (- 0.2 ± 0.9%, p = 0.0419). Significant body weight gain occurred in patients previously treated with GLP-1RA alone (+ 1.5 ± 5.8 kg, p = 0.0572) or combined to BI (+ 1.0 ± 3.1 kg, p < 0.0001) while those on BI (- 1.4 ± 4.6 kg, p = 0.0139) or MDI (- 1.4 ± 5.0 kg, p = 0.0484) experienced weight loss. CONCLUSIONS: While providing new information on the use of IDegLira in the French healthcare system, these data confirm the effectiveness of this fixed-ratio combination in the management of T2D.

Smoking and diabetes interplay: A comprehensive review and joint statement.

Evidence shows that smoking increases the risk of pre-diabetes and diabetes in the general population. Among persons with diabetes, smoking has been found to increase the risk of all-cause mortality and aggravate chronic diabetic complications and glycemic control. The current paper, which is a joint position statement by the French-Speaking Society on Tobacco (Société Francophone de Tabacologie) and the French-Speaking Society of Diabetes (Société Francophone du Diabète), summarizes the data available on the association between smoking and diabetes and on the impact of smoking and smoking cessation among individuals with type 1, type 2, and gestational diabetes mellitus. It also provides evidence-based information about the pharmacological and behavioral strategies for smoking cessation in these patients.

Impact of diabetes on COVID-19 prognosis beyond comorbidity burden: the CORONADO initiative.

AIMS/HYPOTHESIS: Diabetes has been recognised as a pejorative prognostic factor in coronavirus disease 2019 (COVID-19). Since diabetes is typically a disease of advanced age, it remains unclear whether diabetes remains a COVID-19 risk factor beyond advanced age and associated comorbidities. We designed a cohort study that considered age and comorbidities to address this question. METHODS: The Coronavirus SARS-CoV-2 and Diabetes Outcomes (CORONADO) initiative is a French, multicentric, cohort study of individuals with (exposed) and without diabetes (non-exposed) admitted to hospital with COVID-19, with a 1:1 matching on sex, age (±5 years), centre and admission date (10 March 2020 to 10 April 2020). Comorbidity burden was assessed by calculating the updated Charlson comorbidity index (uCCi). A predefined composite primary endpoint combining death and/or invasive mechanical ventilation (IMV), as well as these two components separately, was assessed within 7 and 28 days following hospital admission. We performed multivariable analyses to compare clinical outcomes between patients with and without diabetes. RESULTS: A total of 2210 pairs of participants (diabetes/no-diabetes) were matched on age (mean±SD 69.4±13.2/69.5±13.2 years) and sex (36.3% women). The uCCi was higher in individuals with diabetes. In unadjusted analysis, the primary composite endpoint occurred more frequently in the diabetes group by day 7 (29.0% vs 21.6% in the no-diabetes group; HR 1.43 [95% CI 1.19, 1.72], p<0.001). After multiple adjustments for age, BMI, uCCi, clinical (time between onset of COVID-19 symptoms and dyspnoea) and biological variables (eGFR, aspartate aminotransferase, white cell count, platelet count, C-reactive protein) on admission to hospital, diabetes remained associated with a higher risk of primary composite endpoint within 7 days (adjusted HR 1.42 [95% CI 1.17, 1.72], p<0.001) and 28 days (adjusted HR 1.30 [95% CI 1.09, 1.55], p=0.003), compared with individuals without diabetes. Using the same adjustment model, diabetes was associated with the risk of IMV, but not with risk of death, within 28 days of admission to hospital. CONCLUSIONS/INTERPRETATION: Our results demonstrate that diabetes status was associated with a deleterious COVID-19 prognosis irrespective of age and comorbidity status. TRIAL REGISTRATION: ClinicalTrials.gov NCT04324736.

ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity.

In hepatocytes, peroxisome proliferator-activated receptor α (PPARα) orchestrates a genomic and metabolic response required for homeostasis during fasting. This includes the biosynthesis of ketone bodies and of fibroblast growth factor 21 (FGF21). Here we show that in the absence of adipose triglyceride lipase (ATGL) in adipocytes, ketone body and FGF21 production is impaired upon fasting. Liver gene expression analysis highlights a set of fasting-induced genes sensitive to both ATGL deletion in adipocytes and PPARα deletion in hepatocytes. Adipose tissue lipolysis induced by activation of the ß3-adrenergic receptor also triggers such PPARα-dependent responses not only in the liver but also in brown adipose tissue (BAT). Intact PPARα activity in hepatocytes is required for the cross-talk between adipose tissues and the liver during fat mobilization.

The hepatocyte insulin receptor is required to program the liver clock and rhythmic gene expression.

Liver physiology is circadian and sensitive to feeding and insulin. Food intake regulates insulin secretion and is a dominant signal for the liver clock. However, how much insulin contributes to the effect of feeding on the liver clock and rhythmic gene expression remains to be investigated. Insulin action partly depends on changes in insulin receptor (IR)-dependent gene expression. Here, we use hepatocyte-restricted gene deletion of IR to evaluate its role in the regulation and oscillation of gene expression as well as in the programming of the circadian clock in the adult mouse liver. We find that, in the absence of IR, the rhythmicity of core-clock gene expression is altered in response to day-restricted feeding. This change in core-clock gene expression is associated with defective reprogramming of liver gene expression. Our data show that an intact hepatocyte insulin receptor is required to program the liver clock and associated rhythmic gene expression.

COVID-19 and Diabetes Outcomes: Rationale for and Updates from the CORONADO Study.

PURPOSE OF REVIEW: In France, in order to describe the phenotypic characteristics of patients with diabetes hospitalized for coronavirus disease-2019 (COVID-19) and to identify the prognostic factors in this specific population, the CORONADO (CORONAvirus and Diabetes Outcomes) study was launched. This review will summarize the key findings from the CORONADO study and put them in perspectives with others studies published on the subject. RECENT FINDINGS: For almost 2 years, the new SARS-CoV-2 (Severe Acute Respiratory Syndrome-CoronaVirus-2), which causes COVID-19, has spread all around the world leading to a pandemic. From the first epidemiological reports, diabetes mellitus has rapidly emerged as a major risk factor associated with severe forms of COVID-19 but few data were available about diabetes characteristics in hospitalized people with COVID-19. Between March 10 and April 10, 2020, 2951 patients were included in 68 centers throughout the national territory, including overseas territories. In the CORONADO study, the primary outcome was a composite endpoint combining invasive mechanical ventilation (IMV) and/or death within day 7 (D7). Secondary outcomes included death, IMV, intensive care unit (ICU) admission, and hospital discharge, all considered within D7 and day 28 (D28). The primary outcome occurred in 29.0% participants within D7 following hospital admission. Within D28, the end of the follow-up period, the mortality rate was 20.6%, while 50.2% of patients were discharged. In multivariable analysis, advanced age, microvascular complications, treatment with insulin or statin prior to admission, dyspnea on admission, as well as biological markers reflecting the severity of the infection (high levels of transaminases, leukocytes and CRP, and low platelet levels) were associated with an increased risk of death. Several exploratory analyses were performed to clarify the influence of some parameters such as weight status, sex, type of diabetes, and some routine drugs, including metformin or statins.

Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target.

OBJECTIVE: We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans. DESIGN: Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver. RESULTS: The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα. CONCLUSIONS: These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target. TRIAL REGISTRATION NUMBER: NCT02390232.

History of bariatric surgery and COVID-19 outcomes in patients with type 2 diabetes: Results from the CORONADO study.

OBJECTIVE: This study assessed the impact of a history of metabolic and bariatric surgery (MBS) on the clinical outcomes in patients with type 2 diabetes (T2D) and severe obesity hospitalized for COVID-19. METHODS: In this post hoc analysis from the nationwide observational CORONADO (Coronavirus SARS-CoV2 and Diabetes Outcomes) study, patients with T2D and a history of MBS were matched with patients without MBS for age, sex, and BMI either at the time of MBS or on admission for COVID-19. The composite primary outcome (CPO) combined invasive mechanical ventilation and/or death within 7 and 28 days following admission. RESULTS: Out of 2,398 CORONADO participants, 20 had a history of MBS. When matching for BMI at the time of MBS and after adjustment for diabetes duration, the CPO occurred less frequently within 7 days (3 vs. 17 events, OR: 0.15 [0.01 to 0.94], p = 0.03) and 28 days (3 vs. 19 events, OR: 0.11 [0.01 to 0.71], p = 0.02) in patients with MBS (n = 16) vs. controls (n = 44). There was no difference in CPO rate between patients with MBS and controls when matching for BMI on admission. CONCLUSIONS: These data are reassuring regarding COVID-19 prognosis in patients with diabetes and a history of MBS compared with those without MBS.

Roles of Estrogens in the Healthy and Diseased Oviparous Vertebrate Liver.

The liver is a vital organ that sustains multiple functions beneficial for the whole organism. It is sexually dimorphic, presenting sex-biased gene expression with implications for the phenotypic differences between males and females. Estrogens are involved in this sex dimorphism and their actions in the liver of several reptiles, fishes, amphibians, and birds are discussed. The liver participates in reproduction by producing vitellogenins (yolk proteins) and eggshell proteins under the control of estrogens that act via two types of receptors active either mainly in the cell nucleus (ESR) or the cell membrane (GPER1). Estrogens also control hepatic lipid and lipoprotein metabolisms, with a triglyceride carrier role for VLDL from the liver to the ovaries during oogenesis. Moreover, the activation of the vitellogenin genes is used as a robust biomarker for exposure to xenoestrogens. In the context of liver diseases, high plasma estrogen levels are observed in fatty liver hemorrhagic syndrome (FLHS) in chicken implicating estrogens in the disease progression. Fishes are also used to investigate liver diseases, including models generated by mutation and transgenesis. In conclusion, studies on the roles of estrogens in the non-mammalian oviparous vertebrate liver have contributed enormously to unveil hormone-dependent physiological and physiopathological processes.

Sex disparities in COVID-19 outcomes of inpatients with diabetes: insights from the CORONADO study.

OBJECTIVE: Male sex is one of the determinants of severe coronavirus diseas-e-2019 (COVID-19). We aimed to characterize sex differences in severe outcomes in adults with diabetes hospitalized for COVID-19. METHODS: We performed a sex-stratified analysis of clinical and biological features and outcomes (i.e. invasive mechanical ventilation (IMV), death, intensive care unit (ICU) admission and home discharge at day 7 (D7) or day 28 (D28)) in 2380 patients with diabetes hospitalized for COVID-19 and included in the nationwide CORONADO observational study (NCT04324736). RESULTS: The study population was predominantly male (63.5%). After multiple adjustments, female sex was negatively associated with the primary outcome (IMV and/or death, OR: 0.66 (0.49-0.88)), death (OR: 0.49 (0.30-0.79)) and ICU admission (OR: 0.57 (0.43-0.77)) at D7 but only with ICU admission (OR: 0.58 (0.43-0.77)) at D28. Older age and a history of microvascular complications were predictors of death at D28 in both sexes, while chronic obstructive pulmonary disease (COPD) was predictive of death in women only. At admission, C-reactive protein (CRP), aspartate amino transferase (AST) and estimated glomerular filtration rate (eGFR), according to the CKD-EPI formula predicted death in both sexes. Lymphocytopenia was an independent predictor of death in women only, while thrombocytopenia and elevated plasma glucose concentration were predictors of death in men only. CONCLUSIONS: In patients with diabetes admitted for COVID-19, female sex was associated with lower incidence of early severe outcomes, but did not influence the overall in-hospital mortality, suggesting that diabetes mitigates the female protection from COVID-19 severity. Sex-associated biological determinants may be useful to optimize COVID-19 prevention and management in women and men.

Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study.

AIMS/HYPOTHESIS: This is an update of the results from the previous report of the CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study, which aims to describe the outcomes and prognostic factors in patients with diabetes hospitalised for coronavirus disease-2019 (COVID-19). METHODS: The CORONADO initiative is a French nationwide multicentre study of patients with diabetes hospitalised for COVID-19 with a 28-day follow-up. The patients were screened after hospital admission from 10 March to 10 April 2020. We mainly focused on hospital discharge and death within 28 days. RESULTS: We included 2796 participants: 63.7% men, mean age 69.7 ± 13.2 years, median BMI (25th-75th percentile) 28.4 (25.0-32.4) kg/m2. Microvascular and macrovascular diabetic complications were found in 44.2% and 38.6% of participants, respectively. Within 28 days, 1404 (50.2%; 95% CI 48.3%, 52.1%) were discharged from hospital with a median duration of hospital stay of 9 (5-14) days, while 577 participants died (20.6%; 95% CI 19.2%, 22.2%). In multivariable models, younger age, routine metformin therapy and longer symptom duration on admission were positively associated with discharge. History of microvascular complications, anticoagulant routine therapy, dyspnoea on admission, and higher aspartate aminotransferase, white cell count and C-reactive protein levels were associated with a reduced chance of discharge. Factors associated with death within 28 days mirrored those associated with discharge, and also included routine treatment by insulin and statin as deleterious factors. CONCLUSIONS/INTERPRETATION: In patients with diabetes hospitalised for COVID-19, we established prognostic factors for hospital discharge and death that could help clinicians in this pandemic period. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04324736.

Relationship between obesity and severe COVID-19 outcomes in patients with type 2 diabetes: Results from the CORONADO study.

AIM: To assess the relationship between body mass index (BMI) classes and early COVID-19 prognosis in inpatients with type 2 diabetes (T2D). METHODS: From the CORONAvirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study, we conducted an analysis in patients with T2D categorized by four BMI subgroups according to the World Health Organization classification. Clinical characteristics and COVID-19-related outcomes (i.e. intubation for mechanical ventilation [IMV], death and discharge by day 7 [D7]) were analysed according to BMI status. RESULTS: Among 1965 patients with T2D, 434 (22.1%) normal weight (18.5-24.9 kg/m2 , reference group), 726 (36.9%) overweight (25-29.9 kg/m2 ) and 805 (41.0%) obese subjects were analysed, including 491 (25.0%) with class I obesity (30-34.9 kg/m2 ) and 314 (16.0%) with class II/III obesity (≥35 kg/m2 ). In a multivariable-adjusted model, the primary outcome (i.e. IMV and/or death by D7) was significantly associated with overweight (OR 1.65 [1.05-2.59]), class I (OR 1.93 [1.19-3.14]) and class II/III obesity (OR 1.98 [1.11-3.52]). After multivariable adjustment, primary outcome by D7 was significantly associated with obesity in patients aged younger than 75 years, while such an association was no longer found in those aged older than 75 years. CONCLUSIONS: Overweight and obesity are associated with poor early prognosis in patients with T2D hospitalized for COVID-19. Importantly, the deleterious impact of obesity on COVID-19 prognosis was no longer observed in the elderly, highlighting the need for specific management in this population.

Routine use of statins and increased COVID-19 related mortality in inpatients with type 2 diabetes: Results from the CORONADO study.

AIM: Patients with type 2 diabetes mellitus (T2DM) represent a high-risk population for both cardiovascular diseases and severe coronavirus disease 2019 (COVID-19). Recent studies have reported interactions between statin treatment and COVID-19-related outcomes. The study reported here specifically assessed the association between routine statin use and COVID-19-related outcomes in inpatients with T2DM. METHODS: The Coronavirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study was a nationwide observational study aiming to describe the phenotypic characteristics and prognosis of T2DM patients with COVID-19 admitted to 68 French hospitals between 10 March and 10 April 2020. The composite primary outcome comprised tracheal intubation and/or death within 7 and 28 days of admission. The association between statin use and outcomes was estimated by logistic regression analysis after applying inverse probability of treatment weighting (IPTW) using a propensity score-weighting approach. RESULTS: Of the 2449 patients with T2DM (881 women, 1568 men; aged 70.9 ± 12.5 years) suitable for analysis, 1192 (49%) were using statin treatment before admission. In unadjusted analyses, patients using statins had rates of the primary outcome similar to those of non-users within both 7 (29.8% vs 27.0%, respectively; P = 0.1338) and 28 days (36.2% vs 33.8%, respectively; P = 0.2191) of admission. However, mortality rates were significantly higher in statin users within 7 (12.8% vs 9.8%, respectively; P = 0.02) and 28 days (23.9% vs 18.2%, respectively; P < 0.001). After applying IPTW, significant associations were observed with statin use and the primary outcome within 7 days (OR [95% CI]: 1.38 [1.04-1.83]) and with death within both 7 (OR [95% CI]: 1.74 [1.13-2.65]) and 28 days (OR [95% CI]: 1.46 [1.08-1.95]). CONCLUSION: Routine statin treatment is significantly associated with increased mortality in T2DM patients hospitalized for COVID-19.

Correction to: Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study.

The authors regret a mistake in Table 1.

Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study.

AIMS/HYPOTHESIS: Coronavirus disease-2019 (COVID-19) is a life-threatening infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. Diabetes has rapidly emerged as a major comorbidity for COVID-19 severity. However, the phenotypic characteristics of diabetes in COVID-19 patients are unknown. METHODS: We conducted a nationwide multicentre observational study in people with diabetes hospitalised for COVID-19 in 53 French centres in the period 10-31 March 2020. The primary outcome combined tracheal intubation for mechanical ventilation and/or death within 7 days of admission. Age- and sex-adjusted multivariable logistic regressions were performed to assess the prognostic value of clinical and biological features with the endpoint. ORs are reported for a 1 SD increase after standardisation. RESULTS: The current analysis focused on 1317 participants: 64.9% men, mean age 69.8 ± 13.0 years, median BMI 28.4 (25th-75th percentile: 25.0-32.7) kg/m2; with a predominance of type 2 diabetes (88.5%). Microvascular and macrovascular diabetic complications were found in 46.8% and 40.8% of cases, respectively. The primary outcome was encountered in 29.0% (95% CI 26.6, 31.5) of participants, while 10.6% (9.0, 12.4) died and 18.0% (16.0, 20.2) were discharged on day 7. In univariate analysis, characteristics prior to admission significantly associated with the primary outcome were sex, BMI and previous treatment with renin-angiotensin-aldosterone system (RAAS) blockers, but not age, type of diabetes, HbA1c, diabetic complications or glucose-lowering therapies. In multivariable analyses with covariates prior to admission, only BMI remained positively associated with the primary outcome (OR 1.28 [1.10, 1.47]). On admission, dyspnoea (OR 2.10 [1.31, 3.35]), as well as lymphocyte count (OR 0.67 [0.50, 0.88]), C-reactive protein (OR 1.93 [1.43, 2.59]) and AST (OR 2.23 [1.70, 2.93]) levels were independent predictors of the primary outcome. Finally, age (OR 2.48 [1.74, 3.53]), treated obstructive sleep apnoea (OR 2.80 [1.46, 5.38]), and microvascular (OR 2.14 [1.16, 3.94]) and macrovascular complications (OR 2.54 [1.44, 4.50]) were independently associated with the risk of death on day 7. CONCLUSIONS/INTERPRETATIONS: In people with diabetes hospitalised for COVID-19, BMI, but not long-term glucose control, was positively and independently associated with tracheal intubation and/or death within 7 days. TRIAL REGISTRATION: clinicaltrials.gov NCT04324736.

Sex differences in metabolic regulation and diabetes susceptibility.

Gender and biological sex impact the pathogenesis of numerous diseases, including metabolic disorders such as diabetes. In most parts of the world, diabetes is more prevalent in men than in women, especially in middle-aged populations. In line with this, considering almost all animal models, males are more likely to develop obesity, insulin resistance and hyperglycaemia than females in response to nutritional challenges. As summarised in this review, it is now obvious that many aspects of energy balance and glucose metabolism are regulated differently in males and females and influence their predisposition to type 2 diabetes. During their reproductive life, women exhibit specificities in energy partitioning as compared with men, with carbohydrate and lipid utilisation as fuel sources that favour energy storage in subcutaneous adipose tissues and preserve them from visceral and ectopic fat accumulation. Insulin sensitivity is higher in women, who are also characterised by higher capacities for insulin secretion and incretin responses than men; although, these sex advantages all disappear when glucose tolerance deteriorates towards diabetes. Clinical and experimental observations evidence the protective actions of endogenous oestrogens, mainly through oestrogen receptor α activation in various tissues, including the brain, the liver, skeletal muscle, adipose tissue and pancreatic beta cells. However, beside sex steroids, underlying mechanisms need to be further investigated, especially the role of sex chromosomes, fetal/neonatal programming and epigenetic modifications. On the path to precision medicine, further deciphering sex-specific traits in energy balance and glucose homeostasis is indeed a priority topic to optimise individual approaches in type 2 diabetes prevention and treatment.