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The 5′ AMP-activated protein kinase (AMPK) is a potential antidiabetic drug target. Here we show that the pharmacological activation of AMPK by 5-aminoimidazole-1-β-4-carboxamide ribofuranoside (AICAR) leads to inactivation of glycogen synthase (GS) and phosphorylation of GS at Ser 7 (site 2). In muscle of mice with targeted deletion of the α2-AMPK gene, phosphorylation of GS site 2 was decreased under basal conditions and unchanged by AICAR treatment. In contrast, in α1-AMPK knockout mice, the response to AICAR was normal. Fuel surplus (glucose loading) decreased AMPK activation by AICAR, but the phosphorylation of the downstream targets acetyl-CoA carboxylase-β and GS was normal. Fractionation studies suggest that this suppression of AMPK activation was not a direct consequence of AMPK association with membranes or glycogen, because AMPK was phosphorylated to a greater extent in response to AICAR in the membrane/glycogen fraction than in the cytosolic fraction. Thus, the downstream action of AMPK in response to AICAR was unaffected by glucose loading, whereas the action of the kinase upstream of AMPK, as judged by AMPK phosphorylation, was decreased. The fact that α2-AMPK is a GS kinase that inactivates GS while simultaneously activating glucose transport suggests that a balanced view on the suitability for AMPK as an antidiabetic drug target should be taken. Diabetes 53:3074-3081, 2004 [ABSTRACT FROM AUTHOR]

Offers information on a study which investigated the physiological role of adenosine monophosphate-activated protein kinase Methods; Results; Discussion.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20412-9. [ABSTRACT FROM AUTHOR]

Background: Patients with type 2-diabetes mellitus (T2D), are characterized by visceral and ectopic adipose tissue expansion, leading to systemic chronic low-grade inflammation. As visceral adiposity is associated with severe COVID-19 irrespective of obesity, we aimed to evaluate and compare the predictive value for early intensive care or death of three fat depots (cardiac, visceral and subcutaneous) using computed tomography (CT) at admission for COVID-19 in consecutive patients with and without T2D. Methods: Two hundred and two patients admitted for COVID-19 were retrospectively included between February and June 2020 and distributed in two groups: T2D or non-diabetic controls. Chest CT with cardiac (CATi), visceral (VATi) and subcutaneous adipose tissue (SATi) volume measurements were performed at admission. The primary endpoint was a composite outcome criteria including death or ICU admission at day 21 after admission. Threshold values of adipose tissue components predicting adverse outcome were determined. Results: One hundred and eight controls [median age: 76(IQR:59–83), 61% male, median BMI: 24(22–27)] and ninety-four T2D patients [median age: 70(IQR:61–77), 70% male, median BMI: 27(24–31)], were enrolled in this study. At day 21 after admission, 42 patients (21%) had died from COVID-19, 48 (24%) required intensive care and 112 (55%) were admitted to a conventional care unit (CMU). In T2D, CATi was associated with early death or ICU independently from age, sex, BMI, dyslipidemia, CRP and coronary calcium (CAC). (p = 0.005). Concerning T2D patients, the cut-point for CATi was > 100 mL/m2 with a sensitivity of 0.83 and a specificity of 0.50 (AUC = 0.67, p = 0.004) and an OR of 4.71 for early ICU admission or mortality (p = 0.002) in the fully adjusted model. Other adipose tissues SATi or VATi were not significantly associated with early adverse outcomes. In control patients, age and male sex (OR = 1.03, p = 0.04) were the only predictors of ICU or death. Conclusions: Cardiac adipose tissue volume measured in CT at admission was independently predictive of early intensive care or death in T2D patients with COVID-19 but not in non-diabetics. Such automated CT measurement could be used in routine in diabetic patients presenting with moderate to severe COVID-19 illness to optimize individual management and prevent critical evolution. Keypoints: Prognostic value of pericardiac fat tissue assessed using CT to predict adverse outcomes for T2D patients admitted for COVID-19 infection A disctinct phenotypic pattern was found between diabetic patients and controls with respect to adverse outcom:. classicl risk factors such as age or sex adetermine the prognosis in controls whereas the metabolic and inflammatory profile determine outcome in diabetics. Fast and reliable measurement of cardiac adipose tissue using CT. The assessment of this parameter could be useful to better stratify individual risk in diabetic patients with COVID-19 and adapt patient management of patients in routine practice. [ABSTRACT FROM AUTHOR]

Aim: To describe baseline characteristics and follow‐up data in patients with lipodystrophy syndromes treated with metreleptin in a national reference network, in a real‐life setting. Patients and Methods: Clinical and metabolic data from patients receiving metreleptin in France were retrospectively collected, at baseline, at 1 year and at the latest follow‐up during treatment. Results: Forty‐seven patients with lipodystrophy including generalized lipodystrophy (GLD; n = 28) and partial lipodystrophy (PLD; n = 19) received metreleptin over the last decade. At baseline, the median (interquartile range [IQR]) patient age was 29.3 (16.6‐47.6) years, body mass index was 23.8 (21.2‐25.7) kg/m2 and serum leptin was 3.2 (1.0‐4.9) ng/mL, 94% of patients had diabetes (66% insulin‐treated), 53% had hypertension and 87% had dyslipidaemia. Metreleptin therapy, administered for a median (IQR) of 31.7 (14.2‐76.0) months, was ongoing in 77% of patients at the latest follow‐up. In patients with GLD, glycated haemoglobin (HbA1c) and fasting triglyceride levels significantly decreased from baseline to 1 year of metreleptin treatment, from 8.4 (6.5‐9.9)% [68 (48‐85) mmol/mol] to 6.8 (5.6‐7.4)% [51(38‐57) mmol/mol], and 3.6 (1.7‐8.5) mmol/L to 2.2 (1.1‐3.7) mmol/L, respectively (P < 0.001), with sustained efficacy thereafter. In patients with PLD, HbA1c was not significantly modified (7.7 [7.1‐9.1]% [61 (54‐76) mmol/mol] at baseline vs. 7.7 [7.4‐9.5]% [61(57‐80) mmol/mol] at 1 year), and the decrease in fasting triglycerides (from 3.3 [1.9‐9.9] mmol/L to 2.5 [1.6‐5.3] mmol/L; P < 0.01) was not confirmed at the latest assessment (5.2 [2.2‐11.3] mmol/L). However, among PLD patients, at 1 year, 61% were responders regarding glucose homeostasis, with lower baseline leptin levels compared to nonresponders, and 61% were responders regarding triglyceridaemia. Liver enzymes significantly decreased only in the GLD group. Conclusions: In this real‐life setting study, metabolic outcomes are improved by metreleptin therapy in patients with GLD. The therapeutic indication for metreleptin needs to be clarified in patients with PLD. [ABSTRACT FROM AUTHOR]

Changes in dietary habits have occurred concomitantly with a rise of type 2 diabetes (T2D) and obesity. Intestine is the first organ facing nutrient ingestion and has to adapt its metabolism with these dietary changes. HNF-4γ, a transcription factor member of the nuclear receptor superfamily and mainly expressed in intestine, has been suggested to be involved in susceptibility to T2D. Our aim was to investigate the role of HNF-4γ in metabolic disorders and related mechanisms. Hnf4g-/- mice were fed high-fat/highfructose (HF-HF) diet for 6 weeks to induce obesity and T2D. Glucose homeostasis, energy homeostasis in metabolic cages, body composition and stool energy composition, as well as gene expression analysis in the jejunum were analyzed. Despite an absence of decrease in calorie intake, of increase in locomotor activity or energy expenditure, Hnf4g-/- mice fed with HF-HF are protected against weight gain after 6 weeks of HF-HF diet. We showed that Hnf4g-/- mice fed HF-HF display an increase in fecal calorie loss, mainly due to intestinal lipid malabsorption. Gene expression of lipid transporters, Fatp4 and Scarb1 and of triglyceride-rich lipoprotein secretion proteins, Mttp and ApoB are decreased in gut epithelium of Hnf4g-/- mice fed HF-HF, showing the HNF-4γ role in intestine lipid absorption. Furthermore, plasma GLP-1 and jejunal GLP-1 content are increased in Hnf4g-/- mice fed HF-HF, which could contribute to the glucose intolerance protection. The loss of HNF-4γ leads to a protection against a diet-induced weight gain and to a deregulated glucose homeostasis, associated with lipid malabsorption. [ABSTRACT FROM AUTHOR]

Carbohydrates and sweeteners are detected by the sweet taste receptor in enteroendocrine cells (EECs). This receptor is coupled to the gustducin G-protein, which a-subunit is encoded by GNAT3 gene. In intestine, the activation of sweet taste receptor triggers a signaling pathway leading to GLP-1 secretion, an incretin hormone. In metabolic diseases, GLP-1 concentration and incretin effect are reduced while partly restored after Roux-en-Y gastric bypass (RYGB). We wondered if the decreased GLP-1 secretion in metabolic diseases is caused by an intestinal defect in sweet taste transduction pathway. In our RNA-sequencing of EECs, GNAT3 expression is decreased in patients with obesity and type 2 diabetes compared with normoglycemic obese patients. This prompted us to explore sweet taste signaling pathway in mice with metabolic deteriorations. During obesity onset in mice, Gnat3 expression was downregulated in EECs. After metabolic improvement with enterogastro anastomosis surgery in mice (a surrogate of the RYGB in humans), the expression of Gnat3 increased in the new alimentary tract and glucose-induced GLP-1 secretion was improved. To evaluate if high-fat diet-induced dysbiotic intestinal microbiota could explain the changes in the expression of sweet taste a-subunit G-protein, we performed a fecal microbiota transfer in mice. However, we could not conclude if dysbiotic microbiota impacted or not intestinal Gnat3 expression. Our data highlight that metabolic disorders were associated with altered gene expression of sweet taste signaling in intestine. This could contribute to impaired GLP-1 secretion that is partly rescued after metabolic improvement. [ABSTRACT FROM AUTHOR]

Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans. [ABSTRACT FROM AUTHOR]

Metformin is widely used to treat hyperglycemia in individuals with type 2 diabetes. Recently the LKB1/AMP-activated protein kinase (LKB1/AMPK) pathway was proposed to mediate the action of metformin on hepatic gluconeogenesis. However, the molecular mechanism by which this pathway operates had remained elusive. Surprisingly, here we have found that in mice lacking AMPK in the liver, blood glucose levels were comparable to those in wild-type mice, and the hypoglycemic effect of metformin was maintained. Hepatocytes lacking AMPK displayed normal glucose production and gluconeogenic gene expression compared with wild-type hepatocytes. In contrast, gluconeogenesis was upregulated in LKB1-deficient hepatocytes. Metformin decreased expression of the gene encoding the catalytic subunit of glucose-6-phosphatase (G6Pase), while cytosolic phosphoenolpyruvate carboxykinase (Pepck) gene expression was unaffected in wild-type, AMPK-deficient, and LKB1-deficient hepatocytes. Surprisingly, metformin-induced inhibition of glucose production was amplified in both AMPK- and LKB1-deficient compared with wild-type hepatocytes. This inhibition correlated in a dose-dependent manner with a reduction in intracellular ATP content, which is crucial for glucose production. Moreover, metformin-induced inhibition of glucose production was preserved under forced expression of gluconeogenic genes through PPARgamma coactivator 1alpha (PGC-1alpha) overexpression, indicating that metformin suppresses gluconeogenesis via a transcription-independent process. In conclusion, we demonstrate that metformin inhibits hepatic gluconeogenesis in an LKB1- and AMPK-independent manner via a decrease in hepatic energy state. [ABSTRACT FROM AUTHOR]

The concept of treating diabetes with gut hormones was proposed in the early days of endocrinology (1902), but was not put into practice until the early 2000s. The discovery of the incretin effect (potentiation of insulin secretion when glucose is taken orally compared to intravenously) led to the discovery of the two main gut hormones responsible for this effect: GIP and GLP-1. The reduction of the incretin effect is directly involved in the pathogenesis of type 2 diabetes, which has led to the development of a series of innovative therapies such as GLP-1 analogues, GLP-1 receptor agonists, GIP/GLP-1 co-agonists and GIP/GLP-1/glucagon tri-agonists. These therapies, with their potent hypoglycaemic and weight-lowering effects, promote optimal control of excess weight and hyperglycaemia, avoiding the escalation of treatment that was once considered inevitable., (© 2024 médecine/sciences – Inserm.)

Aims: The growing interest in epicardial adipose tissue (EAT) as a biomarker of atrial fibrillation is limited by the difficulties in isolating EAT from other paracardial adipose tissues. We tested the feasibility and value of measuring the pure EAT contained in the atrioventricular groove (GEAT) using cardiovascular magnetic resonance (CMR) imaging in patients with distinct metabolic disorders., Methods and Results: CMR was performed on 100 patients from the MetaCardis cohort: obese ( n = 18), metabolic syndrome (MSD) ( n = 25), type-2 diabetes (T2D) ( n = 42), and age- and gender-matched healthy controls ( n = 15). GEAT volume measured from long-axis views was obtained in all patients with a strong correlation between GEAT and atrial EAT ( r = 0.95; P < 0.0001). GEAT volume was higher in the three groups of patients with metabolic disorders and highest in the MSD group compared with controls. GEAT volume, as well as body mass and body fat, allowed obese, T2D, and MSD patients to be distinguished from controls. GEAT T1 relaxation and peak longitudinal left atrial (LA) strain in CMR were decreased in T2D patients. Logistic regression and random forest machine learning methods were used to create an algorithm combining GEAT volume, GEAT T1, and peak LA strain to identify T2D patients from other groups with an area under curve (AUC) of 0.81 (Se: 77%, Spe: 80%; 95% confidence interval 0.72-0.91, P < 0.0001)., Conclusion: Atrioventricular groove adipose tissue characteristics measured during routine CMR can be used as a proxy of atrial EAT and integrated in a multi-parametric CMR biomarker for early identification of atrial cardiomyopathy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Although bariatric surgery (BS) is recommended for patients with type 2 diabetes (T2D) and moderate to severe obesity, only approximately 2% of patients undergo surgery., Objective: To compare the knowledge and perception of BS with that of other treatments for diabetes among patients with diabetes., Setting: French social media platforms., Methods: A self-administered questionnaire was distributed from May 13 to June 3, 2020, via different French social media, including patients with T2D (main target), and patients with type 1 diabetes (control population). Different profiles of reluctance to BS were identified using a factorial analysis., Results: Of the 4481 responders (50.4% women, 33.9% aged over 65), 60% had T2D. Of the 1736 patients who had heard of BS (38.7%), 1493 declared they never addressed it with their physician. Among T2D patients, BS is the treatment that elicits the most negative response, with more than 10% showing reluctance. Four reluctance profiles were identified: (1) cluster 1 (43.4%), fear of consequences on their eating habits and irreversibility of the procedure; (2) cluster 2 (34.9%), fear of poorer diabetes control; (3) cluster 3 (9.3%), fear of surgical risk; and (4) cluster 4 (12.4%), fear of side effects. In all clusters, the opinion of their physician would be the most important factor to change their mind., Conclusion: Bariatric surgery for T2D is rarely addressed in routine medical visits. Fear of operative risks and irreversibility of the procedure largely explains the reluctance to BS. Information and education campaigns on the benefit of metabolic surgery for patients with T2D remain necessary., (Copyright © 2023 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk., (© 2023. Springer Nature Limited.)

Background: It has been shown that increased aortic stiffness is related to type-2 diabetes (T2D) which is considered as a risk factor for cardiovascular disease. Among other risk factors is epicardial adipose tissue (EAT) which is increased in T2D and is a relevant biomarker of metabolic severity and adverse outcome., Purpose: To assess aortic flow parameters in T2D patients as compared to healthy individuals and to evaluate their associations with EAT accumulation as an index of cardiometabolic severity in T2D patients., Materials and Methods: Thirty-six T2D patients as well as 29 healthy controls matched by age and sex were included in this study. Participants had cardiac and aortic MRI exams at 1.5 T. Imaging sequences included cine SSFP for left ventricle (LV) function and EAT assessment and aortic cine and phase-contrast imaging for strain and flow parameters quantification., Results: In this study, we found LV phenotype to be characterized by concentric remodeling with decreased stroke volume index despite global LV mass within a normal range. EAT was increased in T2D patients compared to controls (p<0.0001). Moreover, EAT, a biomarker of metabolic severity, was negatively correlated to ascending aortic (AA) distensibility (p=0.048) and positively to the normalized backward flow volume (p=0.001). These relationships remained significant after further adjustment for age, sex and central mean blood pressure. In a multivariate model, presence/absence of T2D and AA normalized backward flow (BF) to forward flow (FF) volumes ratio are both significant and independent correlates of EAT., Conclusion: In our study, aortic stiffness as depicted by an increased backward flow volume and decreased distensibility seems to be related to EAT volume in T2D patients. This observation should be confirmed in the future on a larger population while considering additional biomarkers specific to inflammation and using a longitudinal prospective study design., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bouazizi, Zarai, Noufaily, Prigent, Dietenbeck, Bollache, Nguyen, Della Valle, Blondiaux, Clément, Aron-Wisnewsky, Andreelli, Redheuil and Kachenoura.)

Diabetic foot ulcers are one of the complications of diabetes. Malnutrition is one of the risk factors for wounds but, on the other hand, diabetic foot ulceration may promote malnutrition. In this single-centre retrospective study we evaluated the frequency of malnutrition at first admission and the severity of foot ulceration. We demonstrated that malnutrition at admission correlated with duration of hospitalisation and with death rate rather than with the risk of amputation. Our data challenged the concept that protein-energy deficiency may worsen the prognosis of diabetic foot ulcers. Nevertheless, it is still important to screen nutritional status at baseline and during the follow-up in order to start specific nutritional support therapy as soon as possible in order to reduce morbidity/mortality related to malnutrition.

Objectives: Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation., Design: We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice., Results: Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration., Conclusion: Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity., Trial Registration Number: NCT02059538., Competing Interests: Competing interests: KC is a consultant for Danone Research, Ysopia and CONFO therapeutics for work not associated with this study. KC held a collaborative research contract with Danone Research in the context of MetaCardis project. FB is a shareholder of Implexion pharma AB. MB received lecture and/or consultancy fees from AstraZeneca, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis and Sanofi., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim of our study was to test the hypothesis that administration of Regenerating islet-derived protein 3α (Reg3α), a protein described as having protective effects against oxidative stress and anti-inflammatory activity, could participate in the control of glucose homeostasis and potentially be a new target of interest in the treatment of type 2 diabetes. To that end the recombinant human Reg3α protein was administered for one month in insulin-resistant mice fed high fat diet. We performed glucose and insulin tolerance tests, assayed circulating chemokines in plasma and measured glucose uptake in insulin sensitive tissues. We evidenced an increase in insulin sensitivity during an oral glucose tolerance test in ALF-5755 treated mice vs controls and decreased the pro-inflammatory cytokine C-X-C Motif Chemokine Ligand 5 (CXCL5). We also demonstrated an increase in glucose uptake in skeletal muscle. Finally, correlation studies using human and mouse muscle biopsies showed negative correlation between intramuscular Reg3α mRNA expression (or its murine isoform Reg3γ) and insulin resistance. Thus, we have established the proof of concept that Reg3α could be a novel molecule of interest in the treatment of T2D by increasing insulin sensitivity via a skeletal muscle effect., Competing Interests: The authors declare the following conflict of interests: Lyse Santoro is CEO of The Healthy Aging Company (THAC). Laure Jamot and Fanny Roth are employees of THAC. Gilles Amouyal, Paul Amouyal, Christian Bréchot and Christophe Magnan are co-founders of THAC., (© 2022 Published by Elsevier Ltd.)

Background: COVID-19 diabetic adults are at increased risk of severe forms irrespective of obesity. In patients with type-II diabetes, fat distribution is characterized by visceral and ectopic adipose tissues expansion, resulting in systemic inflammation, which may play a role in driving the COVID-19 cytokine storm. Our aim was to determine if cardiac adipose tissue, combined to interleukin-6 levels, could predict adverse short-term outcomes, death and ICU requirement, in COVID-19 diabetic patients during the 21 days after admission., Methods: Eighty one consecutive patients with type-II diabetes admitted for COVID-19 were included. Interleukin-6 measurement and chest computed tomography with total cardiac adipose tissue index (CATi) measurement were performed at admission. The primary outcome was death during the 21 days following admission while intensive care requirement with or without early death (ICU-R) defined the secondary endpoint. Associations of CATi and IL-6 and threshold values to predict the primary and secondary endpoints were determined., Results: Of the enrolled patients (median age 66 years [IQR: 59-74]), 73% male, median body mass index (BMI) 27 kg/m 2 [IQR: 24-31]) 20 patients had died from COVID-19, 20 required intensive care and 41 were in conventional care at day 21 after admission. Increased CATi and IL-6 levels were both significantly related to increased early mortality (respectively OR = 6.15, p = 0.002; OR = 18.2, p < 0.0001) and ICU-R (respectively OR = 3.27, p = 0.01; OR = 4.86, p = 0.002). These associations remained significant independently of age, sex, BMI as well as troponin-T level and pulmonary lesion extension in CT. We combined CATi and IL-6 levels as a multiplicative interaction score (CATi*IL-6). The cut-point for this score was ≥ 6386 with a sensitivity of 0.90 and a specificity of 0.87 (AUC = 0.88) and an OR of 59.6 for early mortality (p < 0.0001)., Conclusions: Cardiac adipose tissue index and IL-6 determination at admission could help physicians to better identify diabetic patients with a potentially severe and lethal short term course irrespective of obesity. Diabetic patients with high CATi at admission, a fortiori associated with high IL-6 levels could be a relevant target population to promptly initiate anti-inflammatory therapies., (© 2021. The Author(s).)

Background: Bariatric surgery is an effective treatment for type 2 diabetes. Early post-surgical enhancement of insulin secretion is key for diabetes remission. The full complement of mechanisms responsible for improved pancreatic beta cell functionality after bariatric surgery is still unclear. Our aim was to identify pathways, evident in the islet transcriptome, that characterize the adaptive response to bariatric surgery independently of body weight changes., Methods: We performed entero-gastro-anastomosis (EGA) with pyloric ligature in leptin-deficient ob/ob mice as a surrogate of Roux-en-Y gastric bypass (RYGB) in humans. Multiple approaches such as determination of glucose tolerance, GLP-1 and insulin secretion, whole body insulin sensitivity, ex vivo glucose-stimulated insulin secretion (GSIS) and functional multicellular Ca 2+ -imaging, profiling of mRNA and of miRNA expression were utilized to identify significant biological processes involved in pancreatic islet recovery., Findings: EGA resolved diabetes, increased pancreatic insulin content and GSIS despite a persistent increase in fat mass, systemic and intra-islet inflammation, and lipotoxicity. Surgery differentially regulated 193 genes in the islet, most of which were involved in the regulation of glucose metabolism, insulin secretion, calcium signaling or beta cell viability, and these were normalized alongside changes in glucose metabolism, intracellular Ca 2+ dynamics and the threshold for GSIS. Furthermore, 27 islet miRNAs were differentially regulated, four of them hubs in a miRNA-gene interaction network and four others part of a blood signature of diabetes resolution in ob/ob mice and in humans., Interpretation: Taken together, our data highlight novel miRNA-gene interactions in the pancreatic islet during the resolution of diabetes after bariatric surgery that form part of a blood signature of diabetes reversal., Funding: European Union's Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking (RHAPSODY), INSERM, Société Francophone du Diabète, Institut Benjamin Delessert, Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1), Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/0005485) project grants, National Science Foundation (310030-188447), Fondation de l'Avenir., Competing Interests: Declaration of Competing Interest G.R. has received research grant funding from Sun Pharmaceuticals Inc and Les Laboratoires Servier, and is a consultant for Sun Pharmaceuticals. Other authors have nothing to disclose., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans 1,2 . Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities 1,2 , and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease 2 . Reported changes in stool consistency 3 and inflammation status 4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics.

The effect of peptide tyrosine-tyrosine (PYY) on feeding is well established but currently its role in glucose homeostasis is poorly defined. Here we show in mice, that intraperitoneal (ip) injection of PYY3-36 or Y2R agonist improves nutrient-stimulated glucose tolerance and enhances insulin secretion; an effect blocked by peripheral, but not central, Y2R antagonist administration. Studies on isolated mouse islets revealed no direct effect of PYY3-36 on insulin secretion. Bariatric surgery in mice, enterogastric anastomosis (EGA), improved glucose tolerance in wild-type mice and increased circulating PYY and active GLP-1. In contrast, in Pyy-null mice, post-operative glucose tolerance and active GLP-1 levels were similar in EGA and sham-operated groups. PYY3-36 ip increased hepato-portal active GLP-1 plasma levels, an effect blocked by ip Y2R antagonist. Collectively, these data suggest that PYY3-36 therefore acting via peripheral Y2R increases hepato-portal active GLP-1 plasma levels and improves nutrient-stimulated glucose tolerance.

Type 2 diabetes is one of the fastest growing public health problems worldwide, resulting from both genetic factors and inadequate adaptation to environmental changes. It is characterized by abnormal glucose and lipid metabolism due in part to resistance to the actions of insulin in skeletal muscle, liver and fat. AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, acts as an integrator of regulatory signals monitoring systemic and cellular energy status. The growing realization that AMPK regulates the coordination of anabolic and catabolic metabolic processes represents an attractive concept for type 2 diabetes therapy. Recent findings showing that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profile and blood pressure in insulin-resistant rodents suggest that this kinase could be a novel therapeutic target in the treatment of type 2 diabetes. Consistent with these results, physical exercise and major classes of antidiabetic drugs have recently been reported to activate AMPK. In the present review, we update these topics and discuss the concept of targeting the AMPK pathway for the treatment of type 2 diabetes.

AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, has been proposed to function as a fuel gauge to monitor cellular energy status in response to nutritional environmental variations. AMPK system is a regulator of energy balance that, once activated by low energy status, switches on ATP-producing catabolic pathways (such as fatty acid oxidation and glycolysis), and switches off ATP-consuming anabolic pathways (such as lipogenesis), both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. Numerous observations obtained with pharmacological activators and agents that deplete intracellular ATP have been supportive of AMPK playing a role in the control of energy metabolism but none of these studies have provided conclusive evidence. Relatively recent developments in our understanding of precisely how AMPK complexes might operate to control energy metabolism is due in part to the development of transgenic and knockout mouse models. Although there are inevitable caveats with genetic models, some important findings have emerged. In the present review, we discuss recent findings obtained from animal models with inhibition or activation of AMPK signaling pathway.

Intestinal flora can be modified by diet in both humans and rodents. Excess caloric intake in obese humans and rodents promotes proliferation of the bacterial phylum Firmicutes. Bacteria of the Firmicutes phylum permit more efficient intestinal extraction of nutrients. Oral transplantation of Firmicutes flora into axenic mice is sufficient to make them obese. The translocation towards the general circulation of the lipopolysaccharides released by lysis of Gram-negative intestinal bacilli promotes systemic inflammation. This inflammation plays a role in the genesis of insulin resistance and hepatic steatosis in rodents. Pharmacological or dietary manipulation of intestinal flora may be a new strategy for treatment of overweight and its complications.

Unlike the adjustable gastric banding procedure (AGB), Roux-en-Y gastric bypass surgery (RYGBP) in humans has an intriguing effect: a rapid and substantial control of type 2 diabetes mellitus (T2DM). We performed gastric lap-band (GLB) and entero-gastro anastomosis (EGA) procedures in C57Bl6 mice that were fed a high-fat diet. The EGA procedure specifically reduced food intake and increased insulin sensitivity as measured by endogenous glucose production. Intestinal gluconeogenesis increased after the EGA procedure, but not after gastric banding. All EGA effects were abolished in GLUT-2 knockout mice and in mice with portal vein denervation. We thus provide mechanistic evidence that the beneficial effects of the EGA procedure on food intake and glucose homeostasis involve intestinal gluconeogenesis and its detection via a GLUT-2 and hepatoportal sensor pathway.

The AMP-activated kinase (AMPK) is a serine threonine kinase that functions as a fuel sensor to regulate energy balance at both cellular and whole-body levels. Here we studied how hepatic AMPKalpha2 isoform affects hepatic glucose production and peripheral glucose uptake in vivo. We generated mice deleted for the AMPKalpha2 gene specifically in the liver (liveralpha2KO). Liveralpha2KO mice were glucose intolerant and hyperglycemic in the fasted state. Hyperglycemia was associated with a 50% higher endogenous glucose production than in controls as assessed in vivo. We then investigated whether this increased glucose production was sensitive to insulin. Insulin, when infused at a rate inducing physiological hyperinsulinemia, totally inhibited endogenous glucose production in liveralpha2KO mice, showing that they had normal insulin sensitivity. This was confirmed in vivo by normal insulin-induced phosphorylation of Akt and transcriptional regulation of the phosphoenolpyruvate carboxykinase, glucose-6 phosphatase, and pyruvate kinase in liver during the fasted/fed transition. Leptin and adiponectin regulate hepatic glucose production, so we then infused these adipokines into liveralpha2KO mice. Neither of these adipokines regulated hepatic glucose production in mice lacking hepatic AMPKalpha2, whereas both did so in control mice. In conclusion, we show that the hepatic AMPKalpha2 isoform is essential for suppressing hepatic glucose production and maintaining fasting blood glucose levels in the physiological range. We also demonstrate that regulation of hepatic glucose production by leptin and adiponectin, but not insulin, requires hepatic AMPKalpha2 activity.

The 5' AMP-activated protein kinase (AMPK) is a sensor of cellular energy homeostasis well conserved in all eukaryotic cells. AMPK is activated by rising AMP and falling ATP, either by inhibiting ATP production or by accelerating ATP consumption, by a complex mechanism that results in an ultrasensitive response. AMPK is a heterotrimeric enzyme complex consisting of a catalytic subunit alpha and two regulatory subunits beta and gamma. AMP activates the system by binding to the gamma subunit that triggers phosphorylation of the catalytic alpha subunit by the upstream kinases LKB1 and CaMKKbeta. Once activated, it switches on catabolic pathways (such as fatty acid oxidation and glycolysis) and switches off ATP-consuming pathways (such as lipogenesis) both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. Dominant mutations in the regulatory gamma subunit isoforms cause hypertrophy of cardiac and skeletal muscle providing a link in human diseases caused by defects in energy metabolism. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of adipokines such as leptin and adiponectin. Moreover, the AMPK system is one of the probable target for the anti-diabetic drug metformin and rosiglitazone. The relationship between AMPK activation and beneficial metabolic effects provides the rationale for the development of new therapeutic strategies. Thus, pharmacological AMPK activation may, through signaling, metabolic and gene expression effects, reduce the risk of Type 2 diabetes, metabolic syndrome and cardiac diseases.

AMP-activated protein kinase (AMPK) is viewed as a fuel sensor for glucose and lipid metabolism. To better understand the physiological role of AMPK, we generated a knockout mouse model in which the AMPKalpha2 catalytic subunit gene was inactivated. AMPKalpha2(-/-) mice presented high glucose levels in the fed period and during an oral glucose challenge associated with low insulin plasma levels. However, in isolated AMPKalpha2(-/-) pancreatic islets, glucose- and L-arginine-stimulated insulin secretion were not affected. AMPKalpha2(-/-) mice have reduced insulin-stimulated whole-body glucose utilization and muscle glycogen synthesis rates assessed in vivo by the hyperinsulinemic euglycemic clamp technique. Surprisingly, both parameters were not altered in mice expressing a dominant-negative mutant of AMPK in skeletal muscle. Furthermore, glucose transport was normal in incubated isolated AMPKalpha2(-/-) muscles. These data indicate that AMPKalpha2 in tissues other than skeletal muscles regulates insulin action. Concordantly, we found an increased daily urinary catecholamine excretion in AMPKalpha2(-/-) mice, suggesting altered function of the autonomic nervous system that could explain both the impaired insulin secretion and insulin sensitivity observed in vivo. Therefore, extramuscular AMPKalpha2 catalytic subunit is important for whole-body insulin action in vivo, probably through modulation of sympathetic nervous activity.