Explanatory variables of objectively measured 24-h movement behaviors in people with prediabetes and type 2 diabetes: A systematic review.

AIM: Physical activity (PA), sedentary behavior (SB) and sleep (i.e. 24-h movement behaviors) are associated with health indicators in people with prediabetes and type 2 diabetes (T2D). To optimize 24-h movement behaviors, it is crucial to identify explanatory variables related to these behaviors. This review aimed to summarize the explanatory variables of 24-h movement behaviors in people with prediabetes or T2D. METHODS: A systematic search of four databases (PubMed, Web of Science, Scopus & Embase) was performed. Only objective measurements of 24-h movement behaviors were included in the search strategy. The explanatory variables were classified according to the levels of the socio-ecological model (i.e. intrapersonal, interpersonal and environmental). The risk of bias was assessed using the Joanna Briggs Institute appraisal checklist. RESULTS: None of the 78 included studies investigated 24-h movement behaviors. The majority of the studies investigated PA in isolation. Most studied explanatory variables were situated at the intrapersonal level. Being male was associated with more moderate to vigorous PA but less light PA in people with T2D, and more total PA in people with prediabetes. An older age was associated with a decrease in all levels of PA in people with T2D. HbA1c was positively associated with sleep and SB in both groups. No associations were found at the interpersonal or environmental level. CONCLUSION: The results of this review underscore the lack of a socio-ecological approach toward explanatory variables of 24-h movement behaviors and the lack of focus on an integrated 24-h movement behavior approach in both populations.

Basal metabolic rate using indirect calorimetry among individuals living with overweight or obesity: The accuracy of predictive equations for basal metabolic rate.

BACKGROUND & AIMS: Weight reduction programs in people with overweight or obesity can be informed by indirect calorimetry (IC) which is the gold standard to measure basal metabolic rate (BMR). Since IC is labor intensive and expensive, predictive equations are often used as an alternative. In this study the accuracy rate was assessed and bias statistics of predictive equations were compared to IC among subjects with overweight or obesity. Secondly, differences in clinical features between individuals with over-, accurate or underestimation of their BMR were evaluated. METHODS: This cross sectional study included 731 subjects from the outpatient obesity clinic of the Antwerp University Hospital, Belgium. Fourteen equations were evaluated. Overestimation and underestimation was defined as >10 % and <10 % of measured BMR. RESULTS: In the total population, mean age was 43 ± 13 years, mean BMI 35.6 ± 5.8 kg/m2 and 79.5 % were female. The highest accuracy rates were reached by the Henry (73 %), Ravussin (73 %) and Mifflin St. Jeor (73 %) equations. In the total population, the Mifflin St. Jeor and Henry equation were unbiased. The Akern, Livingston and Ravussin equations were biased to underestimation. All other equations were biased to overestimation. Subjects with an underestimation of BMR had significantly higher waist-hip ratio (1.02 ± 0.13 vs 0.91 ± 0.11; P < 0.001), higher visceral adipose tissue (239 ± 96 vs 162 ± 93; P < 0.001), lower fat free mass (kg) (67.6 (45.4-95.9) vs 54.0 (39.6-95.5); P < 0.001) and a higher prevalence of the Metabolic Syndrome (24 (77.4) vs 112 (37.5); P < 0.001). Individuals with an overestimation of BMR had significantly higher subcutaneous adipose tissue (545 ± 149 vs 612 ± 149; P < 0.05), lower fasting plasma insulin (81 (10-2019) vs 67 (27-253); P < 0.001) and lower 2-h plasma glucose (132 (30-430) vs 116 (43-193); P < 0.001) during OGTT. CONCLUSIONS: In this study, the Henry and Mifflin St. Jeor equations have the highest accuracy and lowest bias to estimate the basal metabolic rate in a Caucasian, predominantly female, population living with overweight or obesity. Visceral and subcutaneous adipose tissue and presence of metabolic syndrome were significantly different in individuals with over- or underestimation of BMR.

Insulin resistance and CGM-derived parameters in people with type 1 diabetes: are they associated?

BACKGROUND: Insulin resistance (IR) is increasingly more prevalent in people with type 1 diabetes (T1D). We investigated whether IR is associated with continuous glucose monitor (CGM)-derived parameters (glucometrics) such as time in range (TIR), time above range (TAR), time below range (TBR) and glycaemic variability (CV). METHODS: This is a retrospective analysis of two databases: IR was quantified according to the estimated glucose disposal rate (eGDR) (NCT04664036) and by performing a hyperinsulinaemic-euglycaemic clamp (HEC) (NCT04623320). All glucometrics were calculated over 28 days. RESULTS: A total of 287 subjects were included. Mean age was 46 ± 17 years, 55% were male, TIR was 57 ± 14% and eGDR was 7.6 (5.6 - 9.3) mg/kg min. The tertile of people with the lowest eGDR (highest level of IR) had a higher TAR compared to the tertile with the highest eGDR (39 ± 15% versus 33 ± 14, p = 0.043). Using logistic regression, a higher eGDR was associated with a higher chance to fall in a higher TIR- (OR 1.251, p < 0.001), a lower TAR- (OR 1.281, p < 0.001) and a higher TBR-tertile (OR 0.893, p = 0.039), adjusted for age, sex, diabetes duration, smoking status and alcohol intake. In the 48 people undergoing a HEC, no significant association between glucometrics and the HEC-determined glucose disposal rate (M-value) was observed. CONCLUSION: In people with T1D, an association between IR, measured by eGDR, and worse CGM profiles was observed.

Pathophysiological interactions between sarcopenia and type 2 diabetes: A two-way street influencing diagnosis and therapeutic options.

This review will try to elucidate the interconnected pathophysiology of sarcopenia and type 2 diabetes (T2D) and will try to identify a common pathway to explain their development. To this end, the PubMed and Scopus databases were searched for articles published about the underlying pathophysiology, diagnosis and treatment of both sarcopenia and T2D. The medical subject heading (MeSH) terms 'sarcopenia' AND 'diabetes mellitus' AND ('physiopathology' OR 'diagnosis' OR 'therapeutics' OR 'aetiology' OR 'causality') were used. After screening, 32 papers were included. It was evident that sarcopenia and T2D share multiple pathophysiological mechanisms. Common changes in muscle architecture consist of a shift in myocyte composition, increased myosteatosis and a decreased capacity for muscle regeneration. Further, both diseases are linked to an imbalance in myokine and sex hormone production. Chronic low-grade inflammation and increased levels of oxidative stress are also known pathophysiological contributors. In the future, research efforts should be directed towards discovering common checkpoints in the development of T2D and sarcopenia as possible shared therapeutic targets for both diseases. Current treatment for T2D with biguanides, incretins and insulin may already convey a protective effect on the development of sarcopenia. Furthermore, attention should be given to early diagnosis of sarcopenia within the population of people with T2D, given the sizeable physical and medical burden it encompasses. A combination of simple diagnostic techniques could be used at regular diabetes check-ups to identify sarcopenia at an early stage and start lifestyle modifications and treatment as soon as possible.

The impact of diabetes on mortality rates after lower extremity amputation.

OBJECTIVE: To assess the impact of diabetes, amputation level, sex and age on mortality rates after lower extremity amputation (LEA) in Belgium, and to assess temporal trends in one-year survival rates from 2009 to 2018. METHODS: Nationwide data on individuals who underwent minor and major LEA from 2009 to 2018 were collected. Kaplan-Meier survival curves were constructed. A Cox regression model with time-varying coefficients was used to estimate the likelihood of mortality after LEA in individuals with or without diabetes. Matched amputation-free individuals with or without diabetes were used for comparison. Time trends were analysed. RESULTS: Amputations 41,304 were performed: 13,247 major and 28,057 minor. Five-year mortality rates in individuals with diabetes were 52% and 69% after minor and major LEA, respectively (individuals without diabetes: 45% and 63%, respectively). In the first six postoperative months, no differences in mortality rates were found between individuals with or without diabetes. Later, hazard ratios (HRs) for mortality in individuals with diabetes (compared with no diabetes) after minor LEA ranged from 1.38 to 1.52, and after major LEA from 1.35 to 1.46 (all p ≤ 0.005). Among individuals without LEA, HRs for mortality in diabetes (versus no diabetes) were systematically higher compared to the HRs for mortality in diabetes (versus no diabetes) after minor and major LEA. One-year survival rates did not change for individuals with diabetes. CONCLUSIONS: In the first six postoperative months, mortality rates after LEA were not different between individuals with or without diabetes; later, diabetes was significantly associated with increased mortality. However, as HRs for mortality were higher in amputation-free individuals, diabetes impacts mortality less in the minor and major amputation groups relative to the comparison group of individuals without LEA.

Impact of diabetes on medical costs in the pre- and postoperative year of lower extremity amputations in Belgium.

AIMS: To compare the medical costs of individuals undergoing lower extremity amputation (LEA) in Belgium with those of amputation-free individuals. METHODS: Belgian citizens undergoing LEAs in 2014 were identified. The median costs per capita in euros for the 12 months preceding and following minor and major LEAs were compared with those of matched amputation-free individuals. RESULTS: A total of 3324 Belgian citizens underwent LEAs (2295 minor, 1029 major), 2130 of them had diabetes. The comparison group included 31,716 individuals. Amputation was associated with high medical costs (individuals with diabetes: major LEA €49,735, minor LEA €24,243, no LEA €2,877 in the year preceding amputation; €45,740, €21,445 and €2,284, respectively, in the post-amputation year). Significantly higher costs were observed in the individuals with (versus without) diabetes in all groups. This difference diminished with higher amputation levels. Individuals undergoing multiple LEAs generated higher costs (individuals with diabetes: €39,313-€89,563 when LEAs preceded index amputation; €46,629-€92,877 when LEAs followed index amputation). Individuals dying in the year after a major LEA generated remarkably lower costs. CONCLUSIONS: LEA-related medical costs were high. Diabetes significantly impacted costs, but differences in costs diminished with higher amputation levels. Individuals with multiple amputations generated the highest costs.

Prevalence, risk factors and diagnostic accuracy of non-invasive tests for NAFLD in people with type 1 diabetes.

Background & Aims: The epidemiology of non-alcoholic fatty liver disease (NAFLD) in people with type 1 diabetes (T1D) is not yet elucidated. This study aimed to assess the diagnostic accuracy of non-invasive tests for NAFLD, to investigate the prevalence and severity of NAFLD, and to search for factors contributing to NAFLD in people with T1D. Methods: In this prospective cohort study, we consecutively screened 530 adults with T1D from a tertiary care hospital, using ultrasound (US), vibration-controlled transient elastography equipped with liver stiffness measurement (LSM) and controlled attenuation parameter, and the fatty liver index. Magnetic resonance spectroscopy (MRS) was performed in a representative subgroup of 132 individuals to validate the diagnostic accuracy of the non-invasive tests. Results: Based on MRS as reference standard, US identified individuals with NAFLD with an AUROC of 0.98 (95% CI 0.95-1.00, sensitivity: 1.00, specificity: 0.96). The controlled attenuation parameter was also accurate with an AUROC of 0.85 (95% CI 0.77-0.93). Youden cut-off was ≥270 dB/m (sensitivity: 0.90, specificity: 0.74). The fatty liver index yielded a similar AUROC of 0.83 (95% CI 0.74-0.91), but the conventional cut-off used to rule in (≥60) had low sensitivity and specificity (0.62, 0.78). The prevalence of NAFLD in the overall cohort was 16.2% based on US. Metabolic syndrome was associated with NAFLD (OR: 2.35 [1.08-5.12], p = 0.031). The overall prevalence of LSM ≥8.0 kPa indicating significant fibrosis was 3.8%, but reached 13.2% in people with NAFLD. Conclusions: NAFLD prevalence in individuals with T1D is 16.2%, with approximately one in 10 featuring elevated LSM. US-based screening could be considered in people with T1D and metabolic syndrome. Impact and Implications: We aimed to report on the prevalence, disease severity, and risk factors of NAFLD in type 1 diabetes (T1D), while also tackling which non-invasive test for NAFLD is the most accurate. We found that ultrasound is the best test to diagnose NAFLD. NAFLD prevalence is 16.2%, and is associated with metabolic syndrome and BMI. Elevated liver stiffness indicating fibrosis is overall not prevalent in people with T1D (3.8%), but it reaches 13.2% in those with T1D and NAFLD.

Roux-en-Y gastric bypass induces hepatic transcriptomic signatures and plasma metabolite changes indicative of improved cholesterol homeostasis.

BACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB), the most effective surgical procedure for weight loss, decreases obesity and ameliorates comorbidities, such as non-alcoholic fatty liver (NAFLD) and cardiovascular (CVD) diseases. Cholesterol is a major CVD risk factor and modulator of NAFLD development, and the liver tightly controls its metabolism. How RYGB surgery modulates systemic and hepatic cholesterol metabolism is still unclear. METHODS: We studied the hepatic transcriptome of 26 patients with obesity but not diabetes before and 1 year after undergoing RYGB. In parallel, we measured quantitative changes in plasma cholesterol metabolites and bile acids (BAs). RESULTS: RYGB surgery improved systemic cholesterol metabolism and increased plasma total and primary BA levels. Transcriptomic analysis revealed specific alterations in the liver after RYGB, with the downregulation of a module of genes implicated in inflammation and the upregulation of three modules, one associated with BA metabolism. A dedicated analysis of hepatic genes related to cholesterol homeostasis pointed towards increased biliary cholesterol elimination after RYGB, associated with enhancement of the alternate, but not the classical, BA synthesis pathway. In parallel, alterations in the expression of genes involved in cholesterol uptake and intracellular trafficking indicate improved hepatic free cholesterol handling. Finally, RYGB decreased plasma markers of cholesterol synthesis, which correlated with an improvement in liver disease status after surgery. CONCLUSIONS: Our results identify specific regulatory effects of RYGB on inflammation and cholesterol metabolism. RYGB alters the hepatic transcriptome signature, likely improving liver cholesterol homeostasis. These gene regulatory effects are reflected by systemic post-surgery changes of cholesterol-related metabolites, corroborating the beneficial effects of RYGB on both hepatic and systemic cholesterol homeostasis. IMPACT AND IMPLICATIONS: Roux-en-Y gastric bypass (RYGB) is a widely used bariatric surgery procedure with proven efficacy in body weight management, combatting cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). RYGB exerts many beneficial metabolic effects, by lowering plasma cholesterol and improving atherogenic dyslipidemia. Using a cohort of patients undergoing RYGB, studied before and 1 year after surgery, we analyzed how RYGB modulates hepatic and systemic cholesterol and bile acid metabolism. The results of our study provide important insights on the regulation of cholesterol homeostasis after RYGB and open avenues that could guide future monitoring and treatment strategies targeting CVD and NAFLD in obesity.

A cross-sectional analysis of the association between testosterone and biopsy-proven non-alcoholic fatty liver disease in men with obesity.

PURPOSE: To study the association between testosterone and non-alcoholic fatty liver disease (NAFLD) since prior studies have reported inconsistent results. METHODS: A retrospective analysis was performed including obese men who underwent a liver biopsy and a metabolic and hepatological work-up. Free testosterone (CFT) was calculated by the Vermeulen equation. The association between total testosterone (total T) and CFT on the one hand and NAFLD and fibrosis on the other hand was investigated and corrected for biasing factors such as metabolic parameters. RESULTS: In total, 134 men (mean age 45 ± 12 years, median BMI 39.6 (25.0-64.9) kg/m²) were included. The level of total T and CFT did not significantly differ between NAFL and NASH and the stages of steatosis and ballooning. CFT was significantly lower in a higher stage of fibrosis (p = 0.013), not seen for total T and not persisting after controlling for the influence of BMI, HDL cholesterol and HOMA-IR. A higher stage of lobular inflammation was associated with a lower level of total T (p = 0.033), not seen for CFT and not persisting after controlling for the influence of visceral adipose tissue surface and HOMA-IR. CONCLUSIONS: This is the second largest study investigating the association between testosterone and biopsy-proven NAFLD. No significant association between testosterone levels and NAFLD, and the different histological subgroups or fibrosis was seen. The lower level of CFT in a higher stage of fibrosis and the association between total T and lobular inflammation was driven by poor metabolic parameters.

The Belgian Diabetes in Pregnancy Follow-Up Study (BEDIP-FUS): A Multi-Centric Prospective Cohort Study on the Long-Term Metabolic Risk across Different Degrees of Gestational Glucose Intolerance: Methodology and Design.

The Belgian Diabetes in Pregnancy follow-up study (BEDIP-FUS) aims to investigate the impact of body mass index (BMI), adiposity and different degrees of glucose intolerance on the metabolic profile and future risk for type 2 diabetes (T2D) in women and offspring five years after delivery in the BEDIP study. The BEDIP study was a prospective cohort study to evaluate different screening strategies for gestational diabetes (GDM) based on the 2013 WHO criteria. The aim of the BEDIP-FUS is to recruit 375 women-offspring pairs, stratified according to three different subgroups based on the antenatal result of the glucose challenge test (GCT) and oral glucose tolerance test (OGTT) during the BEDIP pregnancy. The follow-up visit consists of a 75 g OGTT, anthropometric measurements and questionnaires for the mothers, and a fasting blood sample with anthropometric measurements for the child. Primary outcome for the mother is glucose intolerance defined by the American Diabetes Association criteria and for the offspring the BMI z-score. Recruitment began in January 2021. The BEDIP-FUS study will help to better individualize follow-up in women with different degrees of hyperglycemia in pregnancy and their offspring.

Sex differences in diabetic foot ulcer severity and outcome in Belgium.

BACKGROUND: Sex differences are increasingly recognized to play an important role in the epidemiology, treatment and outcomes of many diseases. This study aims to describe differences between sexes in patient characteristics, ulcer severity and outcome after 6 months in individuals with a diabetic foot ulcer (DFU). METHODS: A total of 1,771 patients with moderate to severe DFU participated in a national prospective, multicenter cohort study. Data were collected on demographics, medical history, current DFU and outcome. For data analysis, a Generalized Estimating Equation model and an adjusted Cox proportional hazards regression were used. RESULTS: The vast majority of patients included were male (72%). Ulcers in men were deeper, more frequently displaying probe to bone, and more frequently deeply infected. Twice as many men presented with systemic infection as women. Men demonstrated a higher prevalence of previous lower limb revascularization, while women presented more frequently with renal insufficiency. Smoking was more common in men than in women. No differences in presentation delay were observed. In the Cox regression analysis, women had a 26% higher chance of healing without major amputation as a first event (hazard ratio 1.258 (95% confidence interval 1.048-1.509)). CONCLUSIONS: Men presented with more severe DFU than women, although no increase in presentation delay was observed. Moreover, female sex was significantly associated with a higher probability of ulcer healing as a first event. Among many possible contributing factors, a worse vascular state associated with a higher rate of (previous) smoking in men stands out.

Effect of switching from intermittently scanned to real-time continuous glucose monitoring in adults with type 1 diabetes: 24-month results from the randomised ALERTT1 trial.

BACKGROUND: Comparing Continuous With Flash Glucose Monitoring In Adults With Type 1 Diabetes (ALERTT1) examined whether switching from first-generation intermittently scanned continuous glucose monitoring (isCGM) without alerts to real-time continuous glucose monitoring (rtCGM) with alert functionality offers additional benefits to adults with type 1 diabetes. The extension of the randomised ALERTT1 trial assessed the effect of switching from isCGM to rtCGM up to 24 months. METHODS: In this 6-month, double-arm, parallel-group, non-masked, randomised, controlled trial, done across six hospitals in Belgium, 254 adults aged 18 years or older with type 1 diabetes previously using isCGM were randomly assigned (1:1) to rtCGM with alerts (intervention; n=127) or isCGM without alerts (control; n=127). Upon completion of the 6-month trial, the control group switched to rtCGM (is-rtCGM group), and the intervention group continued rtCGM (rt-rtCGM group). The extension focused on within-group changes in time in range (TIR; 3·9-10·0 mmol/L; primary outcome), HbA1c, time in clinically significant hypoglycaemia (<3·0 mmol/L), and Hypoglycaemia Fear Survey worry (HFS-worry) score (all prespecified key secondary outcomes). Mean within-group change versus the start of rtCGM is reported, with a positive value referring to a lower value at start of rtCGM. This trial is registered at ClinicalTrials.gov (NCT03772600). FINDINGS: 119 participants were assigned to the is-rtCGM group of whom 112 (94%) completed the 24-month trial, and 123 participants were assigned to the rt-rtCGM group of whom 117 (95%) completed the 24-month trial. TIR increased from 51·8% (95% CI 49·1-54·5) at start of rtCGM (month 6) to 63·5% (60·7-66·3) at month 12 in the is-rtCGM group, and remained stable up to month 24 (change 11·7 percentage points [pp] [9·4-14·0; p<0·0001). In the rt-rtCGM group, TIR increased from 52·5% (95% CI 49·8-55·1) at start of rtCGM (month 0) to 63·0% (60·3-65·8) at month 12, also remaining stable up to month 24 (change 10·5 pp [8·2-12·8]; p<0·0001). HbA1c decreased from 7·4% (57 mmol/mol; month 6) to 6·9% (52 mmol/mol) at month 24 (change -0·54 pp [95% CI -0·64 to -0·44]; -5 mmol/mol [95% CI -6 to -4]; p<0·0001) in the is-rtCGM group, and from 7·4% (57 mmol/mol; month 0) to 7·0% (53 mmol/mol) at month 24 (change -0·43 pp [95% CI -0·53 to -0·33]; -4 mmol/mol [95% CI -5 to -3]; p<0·0001) in the rt-rtCGM group. The change in HFS-worry score was -2·67 (month 24 vs month 6; p=0·0008) in the is-rtCGM group and -5·17 points (month 24 vs month 0; p<0·0001) in the rt-rtCGM group. Time in clinically significant hypoglycaemia was unchanged in both groups after month 12. Severe hypoglycaemia decreased from 31·0 to 3·3 per 100 patient-years after switching to rtCGM. INTERPRETATION: Glycaemic control and hypoglycaemia worry improved significantly up to 24 months after switching from isCGM without alerts to rtCGM with alerts, supporting the use of rtCGM in the care of adults with type 1 diabetes. FUNDING: Dexcom.

Apolipoprotein F is reduced in humans with steatosis and controls plasma triglyceride-rich lipoprotein metabolism.

BACKGROUND: NAFLD affects nearly 25% of the global population. Cardiovascular disease (CVD) is the most common cause of death among patients with NAFLD, in line with highly prevalent dyslipidemia in this population. Increased plasma triglyceride (TG)-rich lipoprotein (TRL) concentrations, an important risk factor for CVD, are closely linked with hepatic TG content. Therefore, it is of great interest to identify regulatory mechanisms of hepatic TRL production and remnant uptake in the setting of hepatic steatosis. APPROACH AND RESULTS: To identify liver-regulated pathways linking intrahepatic and plasma TG metabolism, we performed transcriptomic analysis of liver biopsies from two independent cohorts of obese patients. Hepatic encoding apolipoprotein F ( APOF ) expression showed the fourth-strongest negatively correlation with hepatic steatosis and the strongest negative correlation with plasma TG levels. The effects of adenoviral-mediated human ApoF (hApoF) overexpression on plasma and hepatic TG were assessed in C57BL6/J mice. Surprisingly, hApoF overexpression increased both hepatic very low density lipoprotein (VLDL)-TG secretion and hepatic lipoprotein remnant clearance, associated a ~25% reduction in plasma TG levels. Conversely, reducing endogenous ApoF expression reduced VLDL secretion in vivo , and reduced hepatocyte VLDL uptake by ~15% in vitro . Transcriptomic analysis of APOF -overexpressing mouse livers revealed a gene signature related to enhanced ApoB-lipoprotein clearance, including increased expression of Ldlr and Lrp1 , among others. CONCLUSION: These data reveal a previously undescribed role for ApoF in the control of plasma and hepatic lipoprotein metabolism by favoring VLDL-TG secretion and hepatic lipoprotein remnant particle clearance.

Microbiome-derived ethanol in nonalcoholic fatty liver disease.

To test the hypothesis that the gut microbiota of individuals with nonalcoholic fatty liver disease (NAFLD) produce enough ethanol to be a driving force in the development and progression of this complex disease, we performed one prospective clinical study and one intervention study. Ethanol was measured while fasting and 120 min after a mixed meal test (MMT) in 146 individuals. In a subset of 37 individuals and in an external validation cohort, ethanol was measured in portal vein blood. In an intervention study, ten individuals with NAFLD and ten overweight but otherwise healthy controls were infused with a selective alcohol dehydrogenase (ADH) inhibitor before an MMT. When compared to fasted peripheral blood, median portal vein ethanol concentrations were 187 (interquartile range (IQR), 17-516) times higher and increased with disease progression from 2.1 mM in individuals without steatosis to 8.0 mM in NAFL 21.0 mM in nonalcoholic steatohepatitis. Inhibition of ADH induced a 15-fold (IQR,1.6- to 20-fold) increase in peripheral blood ethanol concentrations in individuals with NAFLD, although this effect was abolished after antibiotic treatment. Specifically, Lactobacillaceae correlated with postprandial peripheral ethanol concentrations (Spearman's rho, 0.42; P < 10-5) in the prospective study. Our data show that the first-pass effect obscures the levels of endogenous ethanol production, suggesting that microbial ethanol could be considered in the pathogenesis of this highly prevalent liver disease.

The Impact of Baseline User Characteristics on the Benefits of Real-Time Versus Intermittently Scanned Continuous Glucose Monitoring in Adults With Type 1 Diabetes: Moderator Analyses of the ALERTT1 Trial.

BACKGROUND: ALERTT1 showed that switching from intermittently scanned continuous glucose monitoring (isCGM) without alerts to real-time CGM (rtCGM) with alert functionality improved time in range (TIR; 70-180 mg/dL), glycated hemoglobin (HbA1c), time <54 mg/dL, and Hypoglycemia Fear Survey version II worry subscale (HFS-worry) score after six months in adults with type 1 diabetes (T1D). Moderator analyses aimed to identify certain subgroups that would benefit more from switching to rtCGM than others. METHODS: Post hoc analyses of ALERTT1 evaluated the impact of 14 baseline characteristics on the difference (delta) in mean TIR, HbA1c, time <54 mg/dL, and HFS-worry score at six months between rtCGM and isCGM. Therefore, the delta was allowed to depend on each of these variables by including interactions in the moderator analysis model. Analyses were performed separately for each variable; variables with P < .10 in the univariable analysis were combined into a single model. RESULTS: Univariable analyses showed no dependency of delta TIR, HbA1c, or time <54 mg/dL on variables other than CGM type. Only delta HFS-worry score depended on baseline HbA1c (P = .0059), indicating less worries with rtCGM in people with baseline HbA1c <6.5% or ≥8%. Given P < .10 for dependency of delta TIR on insulin therapy type (favoring multiple daily injections), baseline HbA1c, and baseline TIR, these variables were combined into a multivariable analysis; interactions were not statistically significant. CONCLUSIONS: Except for HFS-worry score, no interactions between 14 baseline characteristics and the six-month intervention effect of rtCGM on TIR, HbA1c, or time <54 mg/dL were observed, supporting the conclusion of ALERTT1 that switching from isCGM without alerts to rtCGM with alert functionality is beneficial for a wide range of people with T1D.

Temporal trends in major, minor and recurrent lower extremity amputations in people with and without diabetes in Belgium from 2009 to 2018.

AIMS: This study assessed temporal trends in the incidence of lower extremity amputations (LEA) in Belgium from 2009 to 2018, and subsequent secondary amputation rates. METHODS: Nationwide data on LEA were collected. Sex- and age-adjusted annual incidence rates were calculated. Time trends were analysed in negative binomial models. The incidence of secondary interventions, defined as either any ipsilateral reamputation or any contralateral amputation, was studied with death as competing risk. RESULTS: 41 304 amputations were performed (13 247 major, 28 057 minor). In individuals with diabetes, the amputation rate (first amputation per patient per year) decreased from 143.6/100.000 person-years to 109.7 (IRR 0.97 per year, 95 %CI 0.96-0.98, p < 0.001). The incidence of major LEAs decreased from 56.2 to 30.7 (IRR 0.93, 95 %CI 0.91-0.94, p < 0.001); the incidence of minor amputations showed a non-significant declining trend in women (54.3 to 45.0/100 000 person years, IRR 0.97 per year, 95 %CI 0.96-0.99), while this remained stable in men with diabetes (149.2 to 135.3/100 000 person years, IRR 1.00 per year, 95 %CI 0.98-1.01). In individuals without diabetes, the incidence of major amputation didn't change significantly, whereas minor amputation incidence increased (8.0 to 10.6, IRR 1.04, 95 %CI 1.03-1.05, p < 0.001). In individuals with diabetes, one-year secondary intervention rates were high (31.3% after minor, 18.4% after major LEA); the incidence of secondary amputations didn't change. CONCLUSIONS: A significant decline in the incidence rate of major LEA was observed in people with diabetes. This decline was not accompanied by a significant rise in minor LEA. The incidence of secondary interventions remained stable.

Rapid-acting insulin analogues: Theory and best clinical practice in type 1 and type 2 diabetes.

Since the discovery of insulin 100 years ago, insulin preparations have improved significantly. Starting from purified animal insulins, evolving to human insulins produced by genetically modified organisms, and ultimately to insulin analogues, all in an attempt to mimic physiological insulin action profiles seen in individuals without diabetes. Achieving strict glucose control without hypoglycaemia and preventing chronic complications of diabetes while preserving quality of life remains a challenging goal, but the advent of newer ultra-rapid-acting insulin analogues may enable intensive insulin therapy without being too disruptive to daily life. Ultra-rapid-acting insulin analogues can be administered shortly before meals and give better coverage of mealtime-induced glucose excursions than conventional insulin preparations. They also increase convenience with timing of bolus dosing. In this review, we focus on the progress that has been made in rapid-acting insulins. We summarize pharmacokinetic and pharmacodynamic data, clinical trial data supporting the use of these new formulations as part of a basal-bolus regimen and continuous subcutaneous insulin infusion, and provide a clinical perspective to help guide healthcare professionals when and for whom to use ultra-fast-acting insulins.

Obesity influences the microbiotic biotransformation of chlorogenic acid.

Obesity is a major public health problem. Gut microbiome dysbiosis has been associated with obesity, however, little is known on the effect of the dysbiosis on the microbiotic bio-transformation of xenobiotics. Fecal samples of lean (n = 9) and obese (n = 4) female volunteers were collected and characterized by 16 S rDNA gene sequencing. The microbiotic biotransformation of chlorogenic acid was studied using the collected fecal samples of lean and obese subjects in the colon stage of the gastro-intestinal dialysis model with colon stage (GIDM-Colon). The concentration of anaerobic bacteria was lower for all obese samples in comparison to the samples of the lean volunteers. Differences in gut microbiome composition and bacterial concentration were observed between the two populations. The obese gut microbiome presented a lower metabolic activity in comparison to the lean population. Chlorogenic acid was completely biotransformed after 24 h colonic dialysis in the lean population while it was still present in the obese population. Furthermore, 23 and 13 biotransformation products were identified in the lean and obese population, respectively; 11 unique biotransformation products from the caffeic, feruoylquinic and quinic acid pathways were identified in the lean population. The results confirm that changes in gut microbiota related to obesity are associated with differences in microbiotic biotransformation of xenobiotics and thus possibly influencing the activity, bioavailability and toxicity of orally administered xenobiotics and drugs.

Efficacy and safety of high-dose glucagon-like peptide-1, glucagon-like peptide-1/glucose-dependent insulinotropic peptide, and glucagon-like peptide-1/glucagon receptor agonists in type 2 diabetes.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become agents of choice for people with type 2 diabetes (T2D) with established cardiovascular disease or in high-risk individuals. With currently available GLP-1 RAs, 51%-79% of subjects achieve an HbA1c target of less than 7.0% and 4%-27% lose 10% of body weight, illustrating the need for more potent agents. Three databases (PubMed, Cochrane, Web of Science) were searched using the MESH terms 'glucagon-like peptide-1 receptor agonist', 'glucagon receptor agonist', 'glucose-dependent insulinotropic peptide', 'dual or co-agonist', and 'tirzepatide'. Quality of papers was scored using PRISMA guidelines. Risk of bias was evaluated using the Cochrane assessment tool. An HbA1c target of less than 7.0% was attained by up to 80% with high-dose GLP-1 RAs and up to 97% with tirzepatide, with even up to 62% of people with T2D reaching an HbA1c of less than 5.7%. A body weight loss of 10% or greater was obtained by up to 50% and up to 69% with high-dose GLP-1 RAs or tirzepatide, respectively. The glucose- and weight-lowering effects of the GLP-1/glucagon RA cotadutide equal those of liraglutide 1.8 mg. Gastrointestinal side effects of high-dose GLP-1 RAs and co-agonists occurred in 30%-70% of patients, mostly arising within the first 2 weeks of the first dose, being mild or moderate in severity, and transient. The development of high-dose GLP-1 RAs and the dual GLP-1/glucose-dependent insulinotropic peptide RA tirzepatide resulted in increasing numbers of people reaching HbA1c and body weight targets, with up to 62% attaining normoglycaemia with 15-mg tirzepatide. Whether this will also translate to better cardiovascular outcomes and affect treatment guidelines remains to be studied.