Perigestational exposure of a combination of a high-fat diet and pesticide impacts the metabolic and microbiotic status of dams and pups; a preventive strategy based on prebiotics.

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.

The association between body mass index class and coronavirus disease 2019 outcomes.

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.

Characteristics and outcomes of COVID-19 in hospitalized patients with and without diabetes.

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.

Chronic oral exposure to pesticides and their consequences on metabolic regulation: role of the microbiota.

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.

A Study of Associations Between Plasma Metformin Concentration, Lactic Acidosis, and Mortality in an Emergency Hospitalization Context.

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.

Metformin prevents the development of severe chronic kidney disease and its associated mineral and bone disorder.

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.

Association between metformin use and below-the-knee arterial calcification score in type 2 diabetic patients.

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, HbA1c 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.

Metformin-associated lactic acidosis (MALA): Moving towards a new paradigm.

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.

[Management of eating disorders in schizophrenia]. / Prise en charge des troubles du comportement alimentaire dans la schizophrénie.

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.

Metformin and other antidiabetic agents in renal failure patients.

This review mainly focuses on metformin, and considers oral antidiabetic therapy in kidney transplant patients and the potential benefits and risks of antidiabetic agents other than metformin in patients with chronic kidney disease (CKD). In view of the debate concerning lactic acidosis associated with metformin, this review tries to solve a paradox: metformin should be prescribed more widely because of its beneficial effects, but also less widely because of the increasing prevalence of contraindications to metformin, such as reduced renal function. Lactic acidosis appears either as part of a number of clinical syndromes (i.e., unrelated to metformin), induced by metformin (involving an analysis of the drug's pharmacokinetics and mechanisms of action), or associated with metformin (a more complex situation, as lactic acidosis in a metformin-treated patient is not necessarily accompanied by metformin accumulation, nor does metformin accumulation necessarily lead to lactic acidosis). A critical analysis of guidelines and literature data on metformin therapy in patients with CKD is presented. Following the present focus on metformin, new paradoxical issues can be drawn up, in particular: (i) metformin is rarely the sole cause of lactic acidosis; (ii) lactic acidosis in patients receiving metformin therapy is erroneously still considered a single medical entity, as several different scenarios can be defined, with contrasting prognoses. The prognosis for severe lactic acidosis seems even better in metformin-treated patients than in non-metformin users.

Mortality rate in so-called "metformin-associated lactic acidosis": a review of the data since the 1960s.

AIMS: The aim of this study is to study the mortality rate in so-called "metformin-associated lactic acidosis" (MALA) from the 1960s to date and to establish whether the rate has changed over time. RESEARCH DESIGN AND METHODS: We systematically searched two data sources for information on mortality in cases recorded as MALA: (i) series in the scientific literature containing over 20 case reports and (ii) a large pharmacovigilance database (containing 869 reports logged between 1995 and 2010). RESULTS: We identified 12 series published between the 1960s and 2013 (mean ± SD [range] number of case reports per series: 51.4 ± 24.7) [23-110]) and 722 case reports with a specified outcome in the pharmacovigilance database. None of the sources specified all three criteria for determining MALA (i.e., the pH level, blood lactate concentration, and blood metformin concentration). The mortality rate in the literature series ranged from 3% to 61%. The value was 47% in the earliest series (1960-1993) and below 25% in the last series. The mean pH per literature series varied widely (from 6.89 to 7.20). The mortality rates in the pharmacovigilance database fell from around 50% to 25% over the study period, while the pH remained in a narrow range (6.94-7.07). CONCLUSIONS: The overall mortality rate for MALA was around 50% during the period 1960-2000 but has since fallen to around 25%.

Metformin therapy and kidney disease: a review of guidelines and proposals for metformin withdrawal around the world.

OBJECTIVE: We compared and contrasted guidelines on metformin treatment in patients with chronic kidney disease (CKD) around the world, with the aim of helping physicians to refine their analysis of the available evidence before deciding whether to continue or withdraw this drug. METHODS: We performed a systematic research for metformin contraindications in: (i) official documents from the world's 20 most populated countries and the 20 most scientifically productive countries in the field of diabetology and (ii) publications referenced in electronic databases from 1990 onwards. RESULTS: We identified three international guidelines, 31 national guidelines, and 20 proposals in the scientific literature. The criteria for metformin withdrawal were (i) mainly qualitative in the most populated countries; (ii) mainly quantitative in the most scientifically productive countries (with, in all cases, a suggested threshold for withdrawing metformin); and (iii) quantitative in all, but one of the literature proposals, with a threshold for withdrawal in most cases (n = 17) and/or adjustment of the metformin dose as a function of renal status (n = 8). There was a good degree of consensus on serum creatinine thresholds; whereas guidelines based on estimated glomerular filtration rate thresholds varied from 60 mL/minute/1.73 m(2) up to stage 5 CKD. Only one of the proposals has been tested in a prospective study. CONCLUSIONS: In general, proposals for continuing or stopping metformin therapy in CKD involve a threshold (whether based on serum creatinine or estimated glomerular filtration rate) rather than the dose adjustment as a function of renal status (in stable patients) performed for other drugs excreted by the kidney.

Protection by metformin against severe Covid-19: An in-depth mechanistic analysis.

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.

Screening for sleep-disordered breathing in people with type 1 diabetes by combining polysomnography with glucose variability assessment.

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/m2 [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/m2 [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.

Thyrotropin Levels in Patients with Coronavirus Disease 2019: Assessment during Hospitalization and in the Medium Term after Discharge.

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.

Metformin prevents stroke damage in non-diabetic female mice with chronic kidney disease.

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 M1 signature gene expression as well as CKD-induced activation of the canonical NF-κB pathway in the ischemic lesions of CKD mice.