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Lactic acidosis associated with metformin treatment is a rare but important adverse event, and unravelling the problem is critical. First, this potential event still influences treatment strategies in type 2 diabetes mellitus, particularly in the many patients at risk of kidney failure, in those presenting contraindications to metformin and in the elderly. Second, the relationship between metformin and lactic acidosis is complex, since use of the drug may be causal, co-responsible or coincidental. The present review is divided into three parts, dealing with the incidence, management and prevention of lactic acidosis occurring during metformin treatment. In terms of incidence, the objective of this article is to counter the conventional view of the link between metformin and lactic acidosis, according to which metformin-associated lactic acidosis is rare but is still associated with a high rate of mortality. In fact, the direct metformin-related mortality is close to zero and metformin may even be protective in cases of very severe lactic acidosis unrelated to the drug. Metformin has also inherited a negative class effect, since the early biguanide, phenformin, was associated with more frequent and sometimes fatal lactic acidosis. In the second part of this review, the objective is to identify the most efficient patient management methods based on our knowledge of how metformin acts on glucose/lactate metabolism and how lactic acidosis may occur (at the organ and cellular levels) during metformin treatment. The liver appears to be a key organ for both the antidiabetic effect of metformin and the development of lactic acidosis; the latter is attributed to mitochondrial impairment and subsequent adenosine triphosphate depletion, acceleration of the glycolytic flux, increased glucose uptake and the generation of lactate, which effluxes into the circulation rather than being oxidized further. Haemodialysis should systematically be performed in severe forms of lactic acidosis, since it provides both symptomatic and aetiological treatment (by eliminating lactate and metformin). In the third part of the review (prevention), the objective is to examine the list of contraindications to metformin (primarily related to renal and cardiovascular function). Diabetes is above all a vascular disease and metformin is a vascular drug with antidiabetic properties. Given the importance of the liver in lactate clearance, we suggest focusing on the severity of and prognosis for liver disease; renal dysfunction is only a prerequisite for metformin accumulation, which may only be dangerous per se when associated with liver failure. Lastly, in view of metformin's impressive overall effectiveness profile, it would be paradoxical to deny the majority of patients with long-established diabetes access to metformin because of the high prevalence of contraindications. The implications of these contraindications are discussed. [ABSTRACT FROM AUTHOR]

Purpose: Metabolic changes during the perinatal period are known to promote obesity and type-2 diabetes in adulthood via perturbation of the microbiota. The risk factors for metabolic disorders include a high-fat diet (HFD) and exposure to pesticide residues. The objective of the present study was to evaluate the effects of perigestational exposure to a HFD and chlorpyrifos (CPF) on glycemia, lipid profiles, and microbial populations in Wistar dams and their female offspring. We also tested a preventive strategy based on treatment with the prebiotic inulin., Methods: From 4 months before gestation to the end of the lactation period, six groups of dams were exposed to either a standard diet, a HFD alone, CPF alone, a combination of a HFD and CPF, and/or inulin supplementation. All female offspring were fed a standard diet from weaning to adulthood. We measured the impacts of these exposures on glycemia, the lipid profile, and the microbiota (composition, metabolite production, and translocation into tissues)., Results: HFD exposure and CPF + HFD co-exposure induced dysmetabolism and an imbalance in the gut flora in both the dams and the female offspring. Inulin mitigated the impact of exposure to a HFD alone but not that of CPF + HFD co-exposure., Conclusion: Our results provide a better understanding of the complex interactions between environmental pollutants and diet in early life, including in the context of metabolic diseases., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: The objectives of this study were (1) to compare TSH levels between inpatients with critical versus non-critical coronavirus disease 19 (COVID-19), and (2) to describe the status of TSH levels three months after hospitalization., Methods: We collected data on adult patients hospitalized with COVID-19 at Amiens University Hospital. We compared TSH levels between inpatients with critical (intensive care unit admission and/or death) versus non-critical COVID-19. Thereafter, survivors were invited to return for a three-month post-discharge visit where thyroid function tests were performed, regardless of the availability of TSH measurement during hospitalization., Results: Among 448 inpatients with COVID-19, TSH assay data during hospitalization were available for 139 patients without prior thyroid disease. Patients with critical and non-critical forms of COVID-19 did not differ significantly with regard to the median (interquartile range) TSH level (0.96 (0.68-1.71) vs. 1.27 mIU/L (0.75-1.79), p = 0.40). Abnormal TSH level was encountered in 17 patients (12.2%); most of them had subclinical thyroid disease. TSH assay data at the three-month post-discharge visit were available for 151 patients without prior thyroid disease. Only seven of them (4.6%) had abnormal TSH levels. Median TSH level at the post-discharge visit was significantly higher than median TSH level during hospitalization., Conclusions: Our findings suggest that COVID-19 is associated with a transient suppression of TSH in a minority of patients regardless of the clinical form. The higher TSH levels three months after COVID-19 might suggest recovery from non-thyroidal illness syndrome.

Since the outbreak of Covid-19, several observational studies on diabetes and Covid-19 have reported a favourable association between metformin and Covid-19-related outcomes in patients with type 2 diabetes mellitus (T2DM). This is not surprising since metformin affects many of the pathophysiological mechanisms implicated in SARS-CoV-2 immune response, systemic spread and sequelae. A comparison of the multifactorial pathophysiological mechanisms of Covid-19 progression with metformin's well-known pleiotropic properties suggests that the treatment of patients with this drug might be particularly beneficial. Indeed, metformin could alleviate the cytokine storm, diminish virus entry into cells, protect against microvascular damage as well as prevent secondary fibrosis. Although our in-depth analysis covers many potential metformin mechanisms of action, we want to highlight more particularly its unique microcirculatory protective effects since worsening of Covid-19 disease clearly appears as largely due to severe defects in the structure and functioning of microvessels. Overall, these observations confirm that metformin is a unique, pleiotropic drug that targets many of Covid-19's pathophysiology processes in a diabetes-independent manner., Competing Interests: Declaration of Competing Interest NW declares no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported. AAS reports personal fees from AstraZeneca, Lilly, and Novo Nordisk. BC reports BC reports grants and personal fees from Amgen, personal fees from AstraZeneca, personal fees from Akcea, personal fees from Genfit, personal fees from Gilead, personal fees from Eli Lilly, personal fees from Novo Nordisk, personal fees from MSD, grants and personal fees from Sanofi, and grants and personal fees from Regeneron. JDL reports personal fees from AstraZeneca, Brothier, Lilly, MSD, Novo Nordisk, Pfizer, and Sanofi., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Aims: There are few published data on sleep-disordered breathing (SDB) in type 1 diabetes (T1DM). Here, we used a combination of polysomnography and glucose variability assessment to screen for SDB., Methods: In a prospective, single-centre study, adults with T1DM underwent polysomnography and continuous glucose monitoring during a single night. We measured high glucose variability and the occurrence of a low or very low glucose level. Mild and moderate-to-severe SDB were defined as an apnoea-hypopnoea index above 5/h and 15/h, respectively., Results: We studied 46 patients (25 men; median age: 42 [35-54]; diabetes duration: 18 years [13-29]; body mass index (BMI): 24.8 kg/m 2 [23.0-28.9]). SDB was present in 17 patients (37.0%) overall (mild SDB: n = 9; moderate-to-severe SDB; n = 8). When compared with the absence of SDB or mild SDB, moderate-to-severe SDB was associated with a higher BMI (29.8 kg/m 2 [27.8-31.1]) and a longer diabetes duration (26 years [18-31]) but not with above-target glucose variability or more sleep disorder symptoms. Conversely, sleep disorder symptoms were not more frequent in patients with above-target glucose variability., Conclusion: SDB was highly prevalent and associated with obesity. According to the methods used here, sleep disorders were not associated with above-target glucose variability or low glucose values., (Copyright © 2022. Published by Elsevier B.V.)

Pesticides have long been used in agriculture and household treatments. Pesticide residues can be found in biological samples for both the agriculture workers through direct exposure but also to the general population by indirect exposure. There is also evidence of pesticide contamination in utero and trans-generational impacts. Whilst acute exposure to pesticides has long been associated with endocrine perturbations, chronic exposure with low doses also increases the prevalence of metabolic disorders such as obesity or type 2 diabetes. Dysmetabolism is a low-grade inflammation disorder and as such the microbiota plays a role in its etiology. It is therefore important to fully understand the role of microbiota on the genesis of subsequent health effects. The digestive tract and mostly microbiota are the first organs of contact after oral exposure. The objective of this review is thus to better understand mechanisms that link pesticide exposure, dysmetabolism and microbiota. One of the key outcomes on the microbiota is the reduced Bacteroidetes and increased Firmicutes phyla, reflecting both pesticide exposure and risk factors of dysmetabolism. Other bacterial genders and metabolic activities are also involved. As for most pathologies impacting microbiota (including inflammatory disorders), the role of prebiotics can be suggested as a prevention strategy and some preliminary evidence reinforces this axis., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Metformin exerts anti-inflammatory and immunosuppressive effects. We addressed the impact of prior metformin use on prognosis in patients with type 2 diabetes hospitalised for COVID-19., Methods: CORONADO is a nationwide observational study that included patients with diabetes hospitalised for COVID-19 between March 10 and April 10, 2020 in 68 French centres. The primary outcome combined tracheal intubation and/or death within 7 days of admission. A Kaplan-Meier survival curve was reported for death up to day 28. The association between metformin use and outcomes was then estimated in a logistic regression analysis after applying a propensity score inverse probability of treatment weighting approach., Results: Among the 2449 patients included, 1496 were metformin users and 953 were not. Compared with non-users, metformin users were younger with a lower prevalence of diabetic complications, but had more severe features of COVID-19 on admission. The primary endpoint occurred in 28.0% of metformin users (vs 29.0% in non-users, P =  0.6134) on day 7 and in 32.6% (vs 38.7%, P = 0.0023) on day 28. The mortality rate was lower in metformin users on day 7 (8.2 vs 16.1%, P <  0.0001) and on day 28 (16.0 vs 28.6%, P < 0.0001). After propensity score weighting was applied, the odds ratios for primary outcome and death (OR [95%CI], metformin users vs non-users) were 0.838 [0.649-1.082] and 0.688 [0.470-1.007] on day 7, then 0.783 [0.615-0.996] and 0.710 [0.537-0.938] on day 28, respectively., Conclusion: Metformin use appeared to be associated with a lower risk of death in patients with diabetes hospitalised for COVID-19., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

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.

Chronic kidney disease (CKD) worsens ischemic stroke severity in both patients and animals. In mice, these poorer functional outcomes are associated with decreased brain activity of AMP-activated protein kinase (AMPK), a molecule that recently emerged as a potential therapeutic target for ischemic stroke. The antidiabetic drug metformin, a well-known activator of AMPK, has improved stroke outcomes in diabetic patients with normal renal function. We investigated whether chronic metformin pre-conditioning can rescue AMPK activity and prevent stroke damage in non-diabetic mice with CKD. Eight-week-old female C57BL/6J mice were assigned to CKD or SHAM groups. CKD was induced through right kidney cortical electrocautery, followed by left total nephrectomy. Mice were then allocated to receive metformin (200 mg/kg/day) or vehicle for 5 weeks until stroke induction by transient middle cerebral artery occlusion (tMCAO). The infarct volumes were lower in CKD mice exposed to metformin than in vehicle-treated CKD mice 24 h after tMCAO. Metformin pre-conditioning of CKD mice improved their neurological score, grip strength, and prehensile abilities. It also enhanced AMPK activation, reduced apoptosis, increased neuron survival and decreased microglia/macrophage M 1 signature gene expression as well as CKD-induced activation of the canonical NF-κB pathway in the ischemic lesions of CKD mice.

Background: Coronavirus disease 2019 (COVID-19) is a rapidly progressing pandemic, with four million confirmed cases and 280 000 deaths at the time of writing. Some studies have suggested that diabetes is associated with a greater risk of developing severe forms of COVID-19. The primary objective of the present study was to compare the clinical features and outcomes in hospitalized COVID-19 patients with vs without diabetes., Methods: All consecutive adult patients admitted to Amiens University Hospital (Amiens, France) with confirmed COVID-19 up until April 21st, 2020, were included. The composite primary endpoint comprised admission to the intensive care unit (ICU) and death. Both components were also analysed separately in a logistic regression analysis and a Cox proportional hazards model., Results: A total of 433 patients (median age: 72; 238 (55%) men; diabetes: 115 (26.6%)) were included. Most of the deaths occurred in non-ICU units and among older adults. Multivariate analyses showed that diabetes was associated neither with the primary endpoint (odds ratio (OR): 1.12; 95% confidence interval (CI): 0.66-1.90) nor with mortality (hazard ratio: 0.73; 95%CI: 0.40-1.34) but was associated with ICU admission (OR: 2.06; 95%CI 1.09-3.92, P = .027) and a longer length of hospital stay. Age was negatively associated with ICU admission and positively associated with death., Conclusions: Diabetes was prevalent in a quarter of the patients hospitalized with COVID-19; it was associated with a greater risk of ICU admission but not with a significant elevation in mortality. Further investigation of the relationship between COVID-19 severity and diabetes is warranted., (© 2020 John Wiley & Sons Ltd.)

Background/objectives: A growing body of data suggests that obesity influences coronavirus disease 2019 (COVID-19). Our study's primary objective was to assess the association between body mass index (BMI) categories and critical forms of COVID-19., Subjects/methods: Data on consecutive adult patients hospitalized with laboratory-confirmed COVID-19 at Amiens University Hospital (Amiens, France) were extracted retrospectively. The association between BMI categories and the composite primary endpoint (admission to the intensive care unit or death) was probed in a logistic regression analysis., Results: In total, 433 patients were included, and BMI data were available for 329: 20 were underweight (6.1%), 95 have a normal weight (28.9%), 90 were overweight (27.4%), and 124 were obese (37.7%). The BMI category was associated with the primary endpoint in the fully adjusted model; the odds ratio (OR) [95% confidence interval (CI)] for overweight and obesity were respectively 1.58 [0.77-3.24] and 2.58 [1.28-5.31]. The ORs [95% CI] for ICU admission were similar for overweight (3.16 [1.29-8.06]) and obesity (3.05 [1.25-7.82]) in the fully adjusted model. The unadjusted ORs for death were similar in all BMI categories while obesity only was associated with higher risk after adjustment., Conclusions: Our results suggest that overweight (and not only obesity) is associated with ICU admission, but overweight is not associated with death.

Objectives: To determine the plasma metformin concentration threshold associated with lactic acidosis and analyze the outcome in metformin-treated patients with lactic acidosis hospitalized in an emergency context., Design: A retrospective, observational, single-center study., Setting: Emergency department and ICUs at Amiens University Hospital (Amiens, France)., Patients: All consecutive patients with data on arterial lactate and pH up to 12 hours before or after a plasma metformin assay within 24 hours of admission, over a 9.7-year period., Intervention: None., Measurements and Main Results: The study population consisted of 194 metformin-treated diabetic patients (median age: 68.6; males: 113 [58.2%]); 163 (84%) had acute kidney injury, which was associated variously with dehydration (45.4%), sepsis (41.1%), cardiogenic shock (20.9%), and diabetic ketoacidosis (16%). Eighty-seven patients (44.8%) had lactic acidosis defined as an arterial blood pH less than 7.35 and a lactate concentration greater than or equal to 4 mM, and 38 of them (43.7%) died in the ICU. A receiver operating characteristic curve analysis showed that a metformin concentration threshold of 9.9 mg/L was significantly associated with the occurrence of lactic acidosis (specificity: 92.9%; sensitivity: 67.1%; area under the receiver operating characteristic curve: 0.83; p < 0.0001). Among lactic acidosis-positive patients, however, in-ICU death was less frequent when the metformin concentration was greater than or equal to 9.9 mg/L (33.9% vs 61.3% for < 9.9 mg/L; p = 0.0252). After adjustment for the Simplified Acute Physiology Score II, in-ICU death was positively associated with prothrombin activity less than 70% and negatively associated with the initiation of renal replacement therapy at admission., Conclusions: In metformin-treated patients admitted in an emergency context, a plasma metformin concentration greater than or equal to 9.9 mg/L was strongly associated with the presence of lactic acidosis. This threshold may assist with the delicate decision of whether or not to initiate renal replacement therapy. Indeed, the outcome of lactic acidosis might depend on the prompt initiation of renal replacement therapy-especially when liver failure reduces lactate elimination.

Metabolic syndrome (MetS) is a clustering of several cardiovascular risk factors that include: obesity, dyslipidemia, hypertension and high blood glucose, and often requires multidrug pharmacological interventions. The management of MetS therefore requires high healthcare cost, and can result in poor drug treatment compliance. Hence drug therapies that have pleiotropic beneficial effects may be of value. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are the newest anti-diabetic drugs that mimic incretin effects in the body. They appear to be safe and well tolerable. Herein, the pharmacology of GLP-1RAs, their side effects, drug interactions and their effects in MetS is assessed. We conducted a Google Scholar, PubMed, Scopus, and Web of Science search since 2010 to identify publications related to the use of GLP-1RAs in treating component features of the MetS. Keywords used for the search were: GLP-1 receptor agonist, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, MetS, obesity, triglyceride, cholesterol, lipid, hypercholesterolemia hyperlipidemia, atherosclerosis, hypertension, blood pressure, hyperglycemia, hypoglycemia and blood glucose. According to the gathered data, GLP-1RAs appear safe and well tolerated. Pre-clinical and clinical studies have evaluated the lipid-lowering, anti-atherosclerotic, anti-hypertensive and anti-diabetic effects of this class of drugs. Some these effects are related to a reduction in food-seeking behavior, an increase in atrial natriuretic peptide level and hence vascular relaxation and natriuresis, and an increase of pancreas β-cell mass and protection against glucotoxicity. Collectively, this review indicates that there may be some value in GLP-1RAs repositioning to manage MetS risk factors beyond their anti-diabetic effects.

Background: Metformin is the first prescribed drug for hyperglycemia in type 2 diabetes mellitus. Mainly by activating AMPK pathway, this drug exerts various functions that among them protective effects are of the interest., Purpose: Herein, we aimed to gather data about the protective impacts of metformin against various natural or chemical toxicities., Results: An extensive search among PubMed, Scopus, and Google Scholar was conducted by keywords related to protection, toxicity, natural and chemical toxins and, metformin. Our literature review showed metformin alongside its anti-hyperglycemic effect has a wide range of anti-toxic effects against anti-tumour and routine drugs, natural and chemical toxins, herbicides and, heavy metals., Conclusion: It is evident that metformin is a potent drug against the toxicity of a broad spectrum of natural, chemical toxic agents which is proved by a vast number of studies. Metformin mainly through AMPK axis can protect different organs against toxicities. Moreover, metformin preserves DNA integrity and can be an option for adjuvant therapy to ameliorate side effect of other therapeutics.

Background: Severe obesity is associated with a high prevalence of moderate-to-severe obstructive sleep apnea syndrome (OSA). Bariatric surgery has been shown to effectively reduce excess weight and comorbidities., Methods: We evaluated the remission rate of moderate-to-severe OSA (apnea-hypopnea index (AHI) ≥ 15) following sleeve gastrectomy. We performed a single-center retrospective chart review of all patients who underwent preoperative polysomnography (PSG) or polygraphy before primary sleeve gastrectomy. Patients with moderate-to-severe OSA treated by continuous positive airway pressure (CPAP) also underwent postoperative PSG. Bivariate analysis was performed to evaluate the criteria associated with remission of moderate-to-severe OSA., Results: From 2013 to 2018, 39 of 162 patients (24.1%) scheduled for sleeve gastrectomy (SG) presented moderate-to-severe OSA requiring CPAP. Postoperative PSG was performed in 36 patients a mean of 9.9 ± 6.1 months after SG. Mean BMI decreased from 47.4 ± 8.4 to 36.3 ± 7.1 kg/m 2 (p < 0.001), and all patients reported clinical improvement of OSA symptoms. A remission of moderate-to-severe OSA was observed in 72.2% of patients with a mean decrease of AHI from 45.8 events/h to 11.3 events/h (p < 0.001). Postoperative neck circumference was the only factor associated with OSA remission., Conclusion: SG is associated with a rapid improvement of moderate-to-severe OSA partially as a result of a reduction of neck circumference. However, the absence of correlation with excess weight loss suggests that other weight-independent factors may also be involved.

Objective: To evaluate perceptions of people with type 2 diabetes (T2D) and treating physicians living in France toward insulin therapy., Methods: Adults with T2D receiving oral glucose-lowering treatment alone (INS - ) or basal insulin for ≥2 months (INS + ) completed an online cross-sectional survey comprising 39 questions, including some regarding perceptions and fears of insulin therapy. Physicians were interviewed by telephone using eleven similar questions. The survey was designed by French clinicians experienced in treating diabetes and conducted under the auspices of an independent market-research agency., Results: The questionnaire was completed by 590 adults with T2D (two-thirds INS + ) and 130 physicians (65 diabetologists/endocrinologists, 65 general practitioners). INS + adults reported fewer negative feelings and more positive feelings than INS - adults. Two-thirds of INS + adults reported that transitioning to insulin therapy was less difficult than expected. Overall, 44% of INS + adults and 26% of physicians reported a fear of diabetic complications as being important, and 80% of physicians and 21% of INS + adults considered injections to be a major patient fear., Conclusion: Most people with T2D reported that transitioning to insulin therapy was less difficult than they had feared. People with T2D and physicians exhibited differing perceptions regarding the transition. Reasons for the apprehension surrounding the transition to insulin therapy in people with T2D need to be better identified. Support from insulin-treated peers may enable this transition to occur with fewer anxieties in insulin-naïve people with T2D., Competing Interests: Disclosure EC has received honoraria and medical training from Eli Lilly and Company, Novo Nordisk, and Sanofi Aventis. J-DL has received honoraria and medical training from Eli Lilly, Merck, MSD, Novo Nordisk, and Sanofi. CM, IB, MLB, and FB are full-time employees of and minor shareholders in Eli Lilly. The authors report no other conflicts of interest in this work.

Whilst people with schizophrenia have high levels of obesity and metabolic disease, our understanding of their eating behaviors is still limited. Our aim was to evaluate the relationships between eating behavior and clinical data in schizophrenia. A cross-sectional study including 66 schizophrenia outpatients compared to 81 healthy controls was undertaken. Eating behavior was assessed using the shortened 21-item version of the Three-Factor Eating Questionnaire (TFEQ-R21). The patients had a mean of 44 ± 11 years; a mean BMI of 30.3 ± 8 kg/m 2 (vs. 24 ± 3.3 kg/m 2 for controls) and a mean duration of illness of 7.2 ± 6 years. All mean TFEQ scores were significantly higher in patients (indicating poorer eating behaviors) compared to controls after adjustment for age and sex, BMI and smoking status. Among patients, mean TFEQ scores were not significantly different between men and women samples. The "cognitive restraint" factor was significantly higher in schizophrenia patients with a BMI < 25 than in the group of overweight patients with a BMI > 25. Our findings suggest that disordered eating behaviors affect schizophrenia patients regardless of gender or duration of disease compared to controls. More research is needed to help clarify the relationships between eating behaviors and weight-related outcomes in schizophrenia., (Copyright © 2018. Published by Elsevier B.V.)

Chronic kidney disease (CKD) causes dysregulation of mineral metabolism, vascular calcification and renal osteodystrophy, an entity called 'CKD-Mineral and Bone Disorder' (CKD-MBD). Here we determine whether metformin, an anti-diabetic drug, exerts favorable effects on progressive, severe CKD and concomitant mineral metabolism disturbances. Rats with CKD-MBD, induced by a 0.25% adenine diet for eight weeks, were treated with 200 mg/kg/day metformin or vehicle from one week after CKD induction onward. Severe, stable CKD along with marked hyperphosphatemia and hypocalcemia developed in these rats which led to arterial calcification and high bone turnover disease. Metformin protected from development toward severe CKD. Metformin-treated rats did not develop hyperphosphatemia or hypocalcemia and this prevented the development of vascular calcification and inhibited the progression toward high bone turnover disease. Kidneys of the metformin group showed significantly less cellular infiltration, fibrosis and inflammation. To study a possible direct effect of metformin on the development of vascular calcification, independent of its effect on renal function, metformin (200 mg/kg/day) or vehicle was dosed for ten weeks to rats with warfarin-induced vascular calcification. The drug did not reduce aorta or small vessel calcification in this animal model. Thus, metformin protected against the development of severe CKD and preserved calcium phosphorus homeostasis. As a result of its beneficial impact on renal function, associated comorbidities such as vascular calcification and high bone turnover disease were also prevented., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objective: This study was conducted to define a safe, effective dose regimen for metformin in moderate and severe chronic kidney disease (CKD; stages 3A/3B and 4, respectively), after the lifting of restrictions on metformin use in patients with diabetes with moderate-to-severe CKD in the absence of prospective safety and efficacy studies., Research Design and Methods: Three complementary studies were performed: 1 ) a dose-finding study in CKD stages 1-5, in which blood metformin concentrations were evaluated during a 1-week period after each dose increase; 2 ) a 4-month metformin treatment study for validating the optimal metformin dose as a function of the CKD stage (3A, 3B, and 4), with blood metformin, lactate, and HbA 1c concentrations monitored monthly; and 3 ) an assessment of pharmacokinetic parameters after the administration of a single dose of metformin in steady-state CKD stages 3A, 3B, and 4., Results: First, in the dose-finding study, the appropriate daily dosing schedules were 1,500 mg (0.5 g in the morning [qam] +1 g in the evening [qpm]) in CKD stage 3A, 1,000 mg (0.5 g qam + 0.5 g qpm) in CKD stage 3B, and 500 mg (qam) in CKD stage 4. Second, after 4 months on these regimens, patients displayed stable metformin concentrations that never exceeded the generally accepted safe upper limit of 5.0 mg/L. Hyperlactatemia (>5 mmol/L) was absent (except in a patient with myocardial infarction), and HbA 1c levels did not change. Third, there were no significant differences in pharmacokinetic parameters among the CKD stage groups., Conclusions: Provided that the dose is adjusted for renal function, metformin treatment appears to be safe and still pharmacologically efficacious in moderate-to-severe CKD., (© 2018 by the American Diabetes Association.)

Background/aims: It has become clear that metformin exerts pleiotropic actions beyond its glucose-lowering agent effect. In this review, we summarise the state of the art concerning the potential renoprotective effects of metformin in vitro, animal models and clinical nephrology., Methods: A literature search was performed in PUBMED, ScienceDirect, between January 1957 and March 2017 using the following keywords: "metformin," "nephroprotection," "renoprotection," "survival," "renal failure," "chronic kidney diseases," "fibrosis," "polycystic kidney disease" and "microalbuminuria.", Results: A recent review of 17 observational studies concluded that metformin use appeared associated with reduced all-cause mortality in patients with CKD. Metformin has been shown to exert positive effects on the kidney in vitro and animal models representing different types of renal diseases, from acute kidney injury to chronic kidney disease. A retrospective cohort study from the Scientific Registry of Transplant Recipients indicated that metformin was associated with lower adjusted hazards for living donor and deceased donor allograft survival at 3 years posttransplant, and with lower mortality., Conclusion: Based on experimental evidence and some relevant clinical observations, metformin seems to be a promising drug in the treatment of progressive renal damage. RCT studies are the next essential step., (© 2017 S. Karger AG, Basel.)

Although metformin has been used for over 60 years, the balance between the drug's beneficial and adverse effects is still subject to debate. Following an analysis of how cases of so-called "metformin-associated lactic acidosis" (MALA) are reported in the literature, the present article reviews the pitfalls to be avoided when assessing the purported association between metformin and lactic acidosis. By starting from pathophysiological considerations, we propose a new paradigm for lactic acidosis in metformin-treated patients. Metformin therapy does not necessarily induce metformin accumulation, just as metformin accumulation does not necessarily induce hyperlactatemia, and hyperlactatemia does not necessarily induce lactic acidosis. In contrast to the conventional view, MALA probably accounts for a smaller proportion of cases than either metformin-unrelated lactic acidosis or metformin-induced lactic acidosis. Lastly, this review highlights the need for substantial improvements in the reporting of cases of lactic acidosis in metformin-treated patients. Accordingly, we propose a check-list as a guide to clinical practice., (© 2017 John Wiley & Sons Ltd.)

Background: Good surgical practice guidelines in France state that patients eligible for bariatric surgery must always be discussed at a multidisciplinary team (MDT) meeting., Objective: Describe MDT meetings and assess their possible impact on the postoperative course., Setting: University Hospital, France, public practice., Methods: From April 2009 to March 2013, we included all patients reviewed in a MDT meeting before bariatric surgery. The primary endpoint was the case validation rate. The secondary endpoints were the number of MDT meetings, the number of submissions discussed or refused, outcomes in patients who underwent surgery in another center after refusal, or deferral in our MDT meeting., Results: Forty-nine MDT meetings were held representing 1099 case files (816 patients) that were discussed. Of the case files, 84.5% concerned first-line surgery, 14% concerned second-line surgery, and 1.4% concerned third-line surgery. Overall, 776 (70.6%) of these submissions were approved, accounting for 95% of the patients. Further investigation before a decision was required in 13.3%. Surgery was definitively refused in 1% (n = 11). For the 776 patients having undergone surgery, the complication rate was 10.1%, the major complication rate was 6%, and the reoperation rate was 3.2%. For the 11 patients for whom bariatric surgery was refused, 7 patients underwent surgery in another center (without MDT meetings). There were 4 postoperative complications (57.1%; 3 major and 1 minor)., Conclusion: The MDT meeting's decision is important for standardizing the management of obese patients before bariatric surgery. MDT meetings might help to reduce complication by optimizing patient selection and preoperative care., (Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Vascular calcification (VC) is common in type 2 diabetes, and is associated with cardiovascular complications. Recent preclinical data suggest that metformin inhibits VC both in vitro and in animal models. However, metformin's effects in patients with diabetic VC have not previously been characterized. The present study investigated the association between metformin use and lower-limb arterial calcification in patients with type 2 diabetes and high cardiovascular risk., Methods: The DIACART cross-sectional cohort study included 198 patients with type 2 diabetes but without severe chronic kidney disease. Below-the-knee calcification scores were assessed by computed tomography and supplemented by colour duplex ultrasonography. Data on anti-diabetic drugs were carefully collected from the patients' medical records and during patient interviews. Biochemical and clinical data were studied as potential confounding factors., Results: Metformin-treated patients had a significantly lower calcification score than metformin-free patients (mean ± standard deviation: 2033 ± 4514 and 4684 ± 9291, respectively; p = 0.01). A univariate analysis showed that metformin was associated with a significantly lower prevalence of severe below-the-knee arterial calcification (p = 0.02). VC was not significantly associated with the use of other antidiabetic drugs, including sulfonylureas, insulin, gliptin, and glucagon like peptide-1 analogues. A multivariate logistic regression analysis indicated that the association between metformin use and calcification score (odds ratio [95% confidence interval] = 0.33 [0.11-0.98]; p = 0.045) was independent of age, gender, tobacco use, renal function, previous cardiovascular disease, diabetes duration, neuropathy, retinopathy, HbA 1c levels, and inflammation., Conclusions: In patients with type 2 diabetes, metformin use was independently associated with a lower below-the-knee arterial calcification score. This association may contribute to metformin's well-known vascular protective effect. Further prospective investigations of metformin's potential ability to inhibit VC in patients with and without type 2 diabetes are now needed to confirm these results.

Aim: Although diabetes-related erectile dysfunction (ED) has many etiological factors, little is known about the putative pathophysiological role of advanced glycation end products (AGEs). Skin autofluorescence is a noninvasive marker of AGEs. Recent studies have evidenced a relationship between skin autofluorescence and several complications of diabetes. We hypothesized that AGEs (assessed by skin autofluorescence) are associated with ED in diabetes patients., Methods: Between March 2014 and April 2015, 42 patients with type 1 diabetes (T1D) and 44 patients with type 2 diabetes (T2D) were consecutively enrolled in a descriptive, cross-sectional study and compared to 54 healthy controls. ED was evaluated via the 5-item version of the International Index of Erectile Function (IIEF-5). Skin autofluorescence was measured on the volar aspect of the arm with an AGE-Reader., Results: Patients with diabetes had a mean±standard deviation age of 50±15 and a mean duration of diabetes of 16±12years. Skin autofluorescence was strongly and significantly correlated with the IIEF-5 score in the T1D subgroup (r=-0.52; P=0.004), the T2D subgroup (r=-0.32; P<0.03) and in the whole group of diabetic patients (r=-0.49; P<0.0001). In multivariate analyses that controlled for potentially confounding clinical and biochemical factors, only skin autofluorescence was still significantly correlated with the IIEF-5 score (P<0.0001). A receiver operating characteristic analysis revealed that a skin autofluorescence value ≥3.2AU determined severe ED with a sensitivity of 60% and a specificity of 87% in diabetic patients., Conclusion: Skin autofluorescence is significantly associated with ED in diabetes, independently of classical confounding factors., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Little known in this contexte, the association between eating disorders (EDs) and schizophrenia is however common. EDs are involved in impaired quality of life and the development of many metabolic disorders in these vulnerable patients. Antipsychotic medications may lead to EDs and should be more extensively explored. We should sensitize patients, their families and caregivers, to improve screening and management of EDs in schizophrenia., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: Metformin has been available since 1957. Over 50 years later, one can legitimately question whether a clear definition of its "therapeutic concentrations" is available., Objective: The objective of this systematic review was to establish whether or not there is a literature consensus on the "therapeutic concentrations" of metformin., Methods: We systematically searched the scientific literature with the keywords "metformin", "therapeutic concentration", "therapeutic level", and "therapeutic range". When the suggested values were defined by citing a literature reference, the types of studies in cited references and the concordance of data between the citations and theirs sources were studied., Results: We identified 120 documents that reported or cited 65 different "therapeutic" plasma metformin concentrations or ranges. The values ranged from 0.129 to 90 mg/L, and the lowest and highest boundaries were 0 and 1800 mg/L. Only four original research studies determined a "therapeutic concentration". Fifty-four publications cited previous studies as defining the therapeutic concentrations, whereas 62 publications mentioned "therapeutic concentrations" but did not even cite a supporting reference. The supporting references were mostly reviews, pharmacokinetic studies and in vitro studies. In the 54 publications that cited references, concordance between the wording of the citation and the true nature of the source data was observed in only 23 cases (42.6%)., Limitations: Given the nature of a systematic literature search, the only possible limitation would be incomplete identification and retrieval of publications on therapeutic concentrations. An extensive study of the literature has, however, been performed by examining nearly 1000 potentially relevant publications., Guidance for Clinical Practice: The only valid way of defining the therapeutic concentration window for metformin would be to relate dose efficacy (in terms of blood glucose control) to the corresponding plasma concentration in long-term treated patients., Conclusions: Although metformin has been available for over 50 years and it is the key medication in first-line treatment of type 2 diabetes mellitus, major methodological and/or conceptual errors have confounded the literature on its therapeutic concentrations.

Introduction: In a study of the oral administration of a single dose of metformin to healthy participants, the estimated half-life (t½ ) for the elimination of the drug from erythrocytes was found to be 23.4 h (compared with 2.7 h for metformin in plasma). However, these pharmacokinetic indices have not been well defined in metformin accumulation., Methods: We systematically reviewed all the data on plasma and erythrocyte metformin assays available in our centre. We then selected patients with a plasma metformin concentration ≥ 5 mg/l and in whom the metformin concentration had been remeasured once or more at least 5 days after admission., Results: Twelve patients met the aforementioned criteria. All but one of these patients displayed generally severe lactic acidosis on admission (mean ± sd pH and lactate: 6.88 ± 0.35 and 14.8 ± 6.56 mmol/l, respectively) and 11 were treated with dialysis. The mean ± sd time interval between the first and last blood sample collections for metformin measurement was 8.3 ± 3.2 days (range 5-14 days). Five days after the first sample had been collected, metformin was still detectable in plasma and in erythrocytes in all patients. Metformin remained detectable for up to 13 days (both in plasma and in erythrocytes). The estimated mean terminal t½ for metformin in plasma and erythrocytes was 51.9 and 43.4 h, respectively., Conclusions: The prolonged elimination of accumulated metformin (even after dialysis therapy) challenges the traditional view that the drug clears rapidly because of a short half-life in plasma., (© 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.)