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We investigated the potential associations of embryo quality with serum and/or follicular fluid (FF) concentrations of the molecules of the activin-follistatin-inhibin (AFI) axis and antimüllerian hormone and aimed to identify molecules that could predict a positive assisted reproductive technology (ART) outcome.In this cross-sectional study, we measured AFI hormone and antimüllerian hormone levels in the serum and FF of follicles (n = 101) obtained from healthy oocyte donors who underwent an assisted reproductive technology course (n = 32). After egg retrieval, embryos were characterized as good or bad quality according to the European Society of Human Reproduction and Embryology criteria. Women were divided into 3 groups (50%; 50%-66.7%; and66.7%) according to the percentage of good quality embryos obtained.There was no difference between good and bad quality embryos in any of the molecules measured in FF. Moreover, there was no difference in the parameters measured in the serum among women according to the percentage of good quality embryos (ie, suitable for transfer or freezing) except for inhibin B, which tended to increase along with a good quality embryo rate (55.6 ± 7.9 vs 95.3 ± 14.3 vs 113.9 ± 36.9; P = .045).Among the molecules of the AFI axis, only serum but not FF inhibin B levels were marginally associated with good quality embryo rates.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is rising. NAFLD/nonalcoholic steatohepatitis (NASH) is associated not only with hepatic morbidity and mortality but also with an increased cardiovascular risk. NAFLD and cardiovascular disease (CVD) share several risk factors, such as obesity, metabolic syndrome, hypertension, dyslipidemia, type 2 diabetes, and chronic kidney disease. This review summarizes the evidence linking cardiometabolic risk factors and NAFLD in the context of risk for CVD. The cause of NAFLD/NASH is complex, involving a range of factors from genetics to lifestyle and energy balance. Genetically driven high liver fat content does not appear to be causally associated with increased CVD risk. In contrast, metabolic dysfunction not only predisposes to liver pathology but also leads to a significantly higher CVD risk. Given that NAFLD pathophysiology is influenced by multiple factors, each patient is unique as to their risk of developing CVD and liver pathology. At the same time, the rising burden of NAFLD/NASH is closely linked with the global increase in metabolic disorders, including obesity and type 2 diabetes. Therefore, both personalized therapeutic approaches that recognize individual pathophysiology, as well as public health policies that address the root causes of cardiometabolic risk factors for NAFLD may be needed to effectively address the NAFLD/NASH epidemic.

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PDF file - 74K, The cell culture and introduction of AdipRs siRNA were performed as described in detail in the "Methods" section. The cells were treated with adiponectin (20 �g/ml) for 24 hr (A) and for 30 min (B). The proliferation assay and Western Blotting were performed as described in detail in the "Methods" section. All data were analyzed using one-way ANOVA followed by post-hoc test for multiple comparisons. Values are means (n=3) � SD. Means with different letters are significantly different, p

Perspective on This Article from Abdominal Obesity, Independent from Caloric Intake, Accounts for the Development of Intestinal Tumors in Apc1638N/+ Female Mice

PDF file - 134K, Immunohistochemical analysis was performed as described in detail in the "Materials and Methods" section. A&F: normal human proliferative endometrial tissue, B&G: human decidual, C&H: human hyperplastic endometrium, D&I: normal human secretory endometrial tissue, E&J: human endometrial adenocarcinoma. (400x magnification for all)

To determine whether visceral fat (VF), independent of other confounders, is causally linked to intestinal tumorigenesis, we surgically removed visceral fat in Apc1638/N+ mice. At 15 weeks of age, male and female Apc1638/N+ mice were randomized to one of three groups: ad libitum, visceral fat removal (VF-) and ad libitum fed, or caloric restriction, and were studied for effects on tumorigenesis and survival. As compared with ad libitum, VF− and caloric restriction reduced macroadenomas to a similar extent (P < 0.05), but only caloric restriction significantly improved survival (P < 0.05). Given that a significant group × gender interaction was observed, we next examined males and females separately. In females, macroadenomas were markedly attenuated by VF− (1.33 ± 0.23 mean ± SE; P < 0.05), but not by caloric restriction (2.35 ± 0.25; P = 0.71), as compared with ad libitum (2.50 ± 0.34). In males, however, caloric restriction (1.71 ± 0.26; P < 0.01), but not VF− (2.94 ± 0.42; P = 0.29), reduced macroadenomas, as compared with ad libitum males (3.47 ± 0.30). In females, both VF− (P = 0.05) and caloric restriction (P < 0.01) improved survival, but not in male mice (P = 0.15). The benefits observed with caloric restriction were consistent with favorable metabolic adaptations, but protection conferred in VF− females was despite lower adiponectin levels (P < 0.05), and failure to reduce body mass, total adiposity, glucose, insulin, leptin, and chemokine (C–X–C motif) ligand 1 (CXCL-1) levels. In conclusion, these data provide the first causal evidence linking visceral fat to intestinal cancer risk, and suggest that factors, other than known metabolic mediators, may impact tumor development. Furthermore, these data emphasize that strategies designed to deplete visceral fat stores in humans should be considered in the prevention of intestinal cancer. Cancer Prev Res; 6(3); 177–87. ©2012 AACR.

PDF file - 67K, The cells were cultured as described in detail in the "Materials and Methods" section. Expression of adiponectin receptors in KLE and RL95-2 cell lines was detected by Western Blotting. Human subcutaneous adipose tissue (SCF) was used as a positive control. B: blank. 9.AdipoR1 and AdipoR2 mediate the anti-proliferative effect of adiponectin in endometrial cancer cells.

Sarcopenia and sarcopenic obesity may be associated with nonalcoholic fatty liver disease (NAFLD). This study examined the association between low skeletal muscle mass, with or without central obesity, with NAFLD, as well as their interaction on predicting 10-year incidence of cardiovascular disease (CVD).This was a post-hoc analysis of the ATTICA study. At baseline, 3042 participants from the Attica region of Greece were recruited; 2020 completed the 10-year follow-up visit for CVD. NAFLD was assessed through hepatic steatosis index (HSI). Skeletal muscle mass index (SMI) was calculated to assess skeletal muscle mass. SMI was studied in tertiles, stratified by sex; the first tertile corresponds to the lowest SMI, the second to middle, and the third to highest SMI. Abnormal waist circumference was defined as ≥102 cm for men and ≥88 cm for women. The combined 10-year endpoint was the development of a fatal or nonfatal CVD event. Logistic regression analysis was used to assess the association between NAFLD prevalence and SMI as well as Cox regression analysis to assess the interaction of both variables on the incidence of CVD over 10 years.Higher rates of NAFLD were observed in the first (45%) compared to the second [33%; odds ratio (OR): 0.50, 95% confidence interval (95%CI): 0.41-0.61] and the third (22%; OR: 0.24, 95%CI: 0.19-0.29) SMI tertile. This association remained robust after multiple adjustments; significance was marginally lost, when waist circumference was added to the model. When SMI and waist circumference were evaluated jointly, participants with moderate/high SMI and normal waist circumference had the lowest and those with low SMI and abnormal waist circumference the highest NAFLD rate (24.3 and 60.5%, respectively; P 0.001). Ten-year CVD incidence was gradually lower from the first (22.8%) to second (16.1%) and third SMI tertile (8.2%) (P 0.001). The hazard ratio (HR) for the third vs. the first SMI tertile for predicting CVD in fully adjusted model was 0.69 (95%CI: 0.46, 1.00). The unadjusted HR for NAFLD predicting CVD was 3.00 (95%CI: 2.28-3.95). Finally, there was a significant interaction among NAFLD, SMI and waist circumference (P = 0.04) in determining the 10-year CVD incidence; the association between NAFLD and 10-year CVD remained significant for the participants with low SMI and normal or abnormal waist circumference, but not those with moderate/high SMI and normal or abnormal waist circumference.Increasing SMI and lower abdominal obesity are independently associated with lower rates of NAFLD, and the two interact as key determinants of NAFLD. Low SMI and central obesity are independent predictors of CVD and were shown to interact with NAFLD in determining 10-year CVD risk.

This study aimed at assessing the long-term effects of intranasal insulin (INI) on cognition and gait in older people with and without type 2 diabetes mellitus (T2DM).Phase 2 randomized, double-blinded trial consisted of 24 week treatment with 40 IU of INI (NovolinDM-INI had faster NW (~ 7 cm/s; p = 0.025) and DTW on-treatment (p = 0.007; p = 0.812 adjusted for baseline difference) than DM-Placebo. Control-INI had better executive functioning on-treatment (p = 0.008) and post-treatment (p = 0.007) and verbal memory post-treatment (p = 0.004) than Control-Placebo. DM-INI increased cerebral blood flow in medio-prefrontal cortex (p 0.001) on MRI. Better vasoreactivity was associated with faster DTW (p 0.008). In DM-INI, plasma insulin (p = 0.006) and HOMA-IR (p 0.013) decreased post-treatment. Overall INI effect demonstrated faster walking (p = 0.002) and better executive function (p = 0.002) and verbal memory (p = 0.02) (combined DM-INI and Control-INI cohort, hemoglobin A1c-adjusted). INI was not associated with serious adverse events, hypoglycemic episodes, or weight gain.There is evidence for positive INI effects on cognition and gait. INI-treated T2DM participants walked faster, showed increased cerebral blood flow and decreased plasma insulin, while controls improved executive functioning and verbal memory. The MemAID trial provides proof-of-concept for preliminary safety and efficacy and supports future evaluation of INI role to treat T2DM and age-related functional decline.

We prospectively evaluated the association between quality of plant-based diets and 10-year first fatal/non-fatal cardiovascular disease (CVD) incidence.ATTICA study was conducted in the greater metropolitan Athens area, Greece, during 2001-2002 studying men and women (aged 18 years old) free of CVD at baseline. Follow-up CVD assessment (2011-2012) was achieved in n = 2,020 participants (n = 317 cases). Dietary assessment was based on a validated semi-quantitative paper-based food frequency questionnaire. Overall, healthful, and unhealthful plant-based dietary indices (PDI, hPDI and uPDI) were calculated through a standard published procedure. The association between plant-based indices and CVD outcome has been evaluated via Cox regression analysis.The CVD event rate was 15.7% (n = 317) with a median follow-up time of 8.41 years. The highest (3Quality of plant-based diets is important and needs to be considered, as not all plant-source foods have beneficial cardiovascular effects.

Purpose The role of adipokines in causing inflammation and insulin resistance in normal weight and obese patients is generally well studied. However, there are often conflicting results regarding their levels in type 1 diabetes mellitus (T1DM) patients and their relationship to micro- and macrovascular disease. We therefore investigated which serum adipokine levels are independently associated with markers of early atherosclerosis and microvascular complications in patients with T1DM. Methods A cross-sectional study was performed in the Diabetes Outpatient Clinic of Hippokrateion General Hospital, Thessaloniki, Greece. Sixty T1DM patients (30 females, mean age 38.8 ± 10.6 years, mean diabetes duration 17.4 ± 9.9 years) were included. Plasma adiponectin, leptin, and resistin, carotid artery intima media thickness (cIMT), and arterial stiffness (pulse wave velocity, PWV/SpygmoCor CP System and Mobil-O-Graph 24 h PWA) were assessed. Results Leptin and resistin levels were significantly higher in overweight and obese patients (p = 0.002 and p = 0.039, respectively). Adiponectin was the only adipokine negatively correlated with BMI (rs = - 0.41, p = 0.001). We report a bivariate association between serum adiponectin levels and retinopathy (p = 0.007). Resistin was the only adipokine that showed significant correlation with systolic (rs = 0.42, p = 0.001) and diastolic (rs = 0.29, p = 0.024) hypertension and PWV (p = 0.035). Conclusions Serum adipokine levels demonstrate similar bivariate associations with anthropometric variables in patients with T1DM to those in normal weight subjects. Although microvascular complications are associated with serum adipokine levels by bivariate analysis, only resistin, an inflammatory marker, is independently associated with arterial stiffness in patients with T1DM.

Recent insights into the pathophysiologic underlying mechanisms of obesity have led to the discovery of several promising drug targets and novel therapeutic strategies to address the global obesity epidemic and its comorbidities. Current pharmacologic options for obesity management are largely limited in number and of modest efficacy/safety profile. Therefore, the need for safe and more efficacious new agents is urgent. Drugs that are currently under investigation modulate targets across a broad range of systems and tissues, including the central nervous system, gastrointestinal hormones, adipose tissue, kidney, liver, and skeletal muscle. Beyond pharmacotherapeutics, other potential antiobesity strategies are being explored, including novel drug delivery systems, vaccines, modulation of the gut microbiome, and gene therapy. The present review summarizes the pathophysiology of energy homeostasis and highlights pathways being explored in the effort to develop novel antiobesity medications and interventions but does not cover devices and bariatric methods. Emerging pharmacologic agents and alternative approaches targeting these pathways and relevant research in both animals and humans are presented in detail. Special emphasis is given to treatment options at the end of the development pipeline and closer to the clinic (ie, compounds that have a higher chance to be added to our therapeutic armamentarium in the near future). Ultimately, advancements in our understanding of the pathophysiology and interindividual variation of obesity may lead to multimodal and personalized approaches to obesity treatment that will result in safe, effective, and sustainable weight loss until the root causes of the problem are identified and addressed.

Due to insufficient insulin secretion, patients with type 1 diabetes mellitus (T1DM) are prone to blood glucose fluctuations ranging from hypoglycemia to hyperglycemia. While dangerous hypoglycemia may lead to coma immediately, chronic hyperglycemia increases patients’ risks for cardiorenal and vascular diseases in the long run. In principle, an artificial pancreas – a closed-loop insulin delivery system requiring patients manually input insulin dosage according to the upcoming meals – could supply exogenous insulin to control the glucose levels and hence reduce the risks from hyperglycemia. However, insulin overdosing in some type 1 diabetic patients, who are physically active, can lead to unexpected hypoglycemia beyond the control of common artificial pancreas. Therefore, it is important to take into account the glucose decrease due to physical exercise when designing the next-generation artificial pancreas. In this work, we develop a deep reinforcement learning algorithm using a T1DM dataset, containing data from wearable devices, to automate insulin dosing for patients with T1DM. In particular, we build patient-specific computational models using systems biology informed neural networks (SBINN), to mimic the glucose-insulin dynamics for a few patients from the dataset, by simultaneously considering patient-specific carbohydrate intake and physical exercise intensity.

Bone metabolism has been proposed to be affected by the activins-follistatins-inhibins (AFI) hormonal system. We aimed to evaluate AFI in patients with osteoporosis and osteopenia compared with postmenopausal and premenopausal controls.In this case-control study, circulating levels of the AFI system were evaluated, individually and jointly, between postmenopausal women with osteoporosis (BMD T-score ≤-2.5; n = 25) or osteopenia (BMD T-score-2.5 and ≤-1; n = 25) and postmenopausal women with normal BMD (T-score-1.0; n = 25) or premenopausal women with normal BMD (Z-score-1.0; n = 25), with and without adjustment for potential confounders.In the sum of participants, AFI molecules and their ratios followed an opposite pattern of correlations for age and BMI vs. BMD. In unadjusted models, FSLT-3 concentrations were higher, whereas activin B, inhibin A and inhibin B and the ratios of activin B/follistatin and activin B/FSTL3 were lower in the three postmenopausal groups compared with the premenopausal group. Activin A/follistatin and activin AB/follistatin ratios were lower in the osteoporosis group than the other three groups. After adjustment for BMI and age, inhibin B (p = 0.005), and the ratios of activin A/follistatin (p = 0.009), activin B/follistatin (p = 0.040) and activin AB/follistatin (p = 0.003) were lower in the osteoporotic group compared with the other groups. In fully adjusted logistic regression analysis log(inhibin B) (p = 0.041), log(activinA/follistatin) (p = 0.014), log(activinB/follistatin) (p = 0.025) and log(activinAB/follistatin) (p = 0.021), but not FSTL-3, remained independently associated with the presence of osteoporosis.Lower inhibin B and higher ratios of activins A, B, and AB to follistatin are associated with lumbar spine BMD and the presence of osteoporosis independently from age or BMI.

Background/objectives Evidence regarding the influence of coffee on appetite and weight control is equivocal and the influence of covariates, such as genetic variation in caffeine metabolism, remains unknown. Herein, we addressed the novel hypothesis that genetic variation in CYP1A2, a gene responsible for more than 95% of caffeine metabolism, differentially impacts the association of coffee consumption with appetite and BMI among individuals with different genetic predispositions to obesity. Subjects/methods A cross-over randomized intervention study involving 18 volunteers assessed the effects of coffee consumption on dietary intake, appetite, and levels of the appetite-controlling hormones asprosin and leptin. Data on habitual coffee intake, BMI, and perceived appetite were obtained from an observational cohort of 284 volunteers using validated questionnaires. Participants were stratified according to a validated genetic risk score (GRS) for obesity and to the -163C > A (rs762551) polymorphism of CYP1A2 as rapid (AA), intermediate (AC), or slow (CC) caffeine metabolizers. Results Coffee consumption led to lower energy and dietary fat intake and circulating asprosin levels (P for interaction of rs762551 genotype*coffee consumption=0.056, 0.039, and 0.043, respectively) as compared to slow/intermediate metabolizers. High coffee consumption was more prevalent in rapid compared to slow metabolizers (P = 0.008 after adjustment for age, sex, and BMI) and was associated with lower appetite perception and lower BMI only in rapid metabolizers (P for interaction of rs762551 genotype*coffee consumption = 0.002 and 0.048, respectively). This differential association of rs762551 genotype and coffee consumption with BMI was more evident in individuals at higher genetic risk of obesity (mean adjusted difference in BMI = -5.82 kg/m2 for rapid versus slow/intermediate metabolizers who consumed more than 14 cups of coffee per week). Conclusions CYP1A2 rs762551 polymorphism modifies the association of habitual coffee consumption with BMI, in part by influencing appetite, energy intake and circulating levels of the orexigenic hormone asprosin. This association is more evident in subjects with high genetic predisposition to obesity. ClinicalTrials.gov: registered Clinical Trial NCT04514588.

Accurate prediction of blood glucose variations in type 2 diabetes (T2D) will facilitate better glycemic control and decrease the occurrence of hypoglycemic episodes as well as the morbidity and mortality associated with T2D, hence increasing the quality of life of patients. Owing to the complexity of the blood glucose dynamics, it is difficult to design accurate predictive models in every circumstance, i.e., hypo/normo/hyperglycemic events. We developed deep-learning methods to predict patient-specific blood glucose during various time horizons in the immediate future using patient-specific every 30-min long glucose measurements by the continuous glucose monitoring (CGM) to predict future glucose levels in 5 min to 1 h. In general, the major challenges to address are (1) the dataset of each patient is often too small to train a patient-specific deep-learning model, and (2) the dataset is usually highly imbalanced given that hypo- and hyperglycemic episodes are usually much less common than normoglycemia. We tackle these two challenges using transfer learning and data augmentation, respectively. We systematically examined three neural network architectures, different loss functions, four transfer-learning strategies, and four data augmentation techniques, including mixup and generative models. Taken together, utilizing these methodologies we achieved over 95% prediction accuracy and 90% sensitivity for a time period within the clinically useful 1 h prediction horizon that would allow a patient to react and correct either hypoglycemia and/or hyperglycemia. We have also demonstrated that the same network architecture and transfer-learning methods perform well for the type 1 diabetes OhioT1DM public dataset.

Effective recruitment and retention strategies are essential in clinical trials.The MemAID trial consisted of 12 visits during 24 weeks of intranasal insulin or placebo treatment and 24 weeks of post-treatment follow-up in older people with and without diabetes. Enhanced retention strategies were implemented mid study to address high drop-out rate. Baseline variables used in Cox regression models to identify dropout risk factors were: demographics and social characteristics, functional measures, metabolic and cardiovascular parameters, and medications.244 participants were randomized; 13 (5.3%) were discontinued due to adverse events. From the remaining 231 randomized participants, 65 (28.1%) dropped out, and 166 (71.9%) did not. The Non-retention group included 95 participants not exposed to retention strategies, of which 43 (45.2%) dropped out. The Retention group included 136 participants exposed to enhanced retention strategies, of which 22 (16.2%) dropped out. Dropout risk factors included being unmarried, a longer diabetes duration, using oral antidiabetics as compared to not using, worse executive function and chronic pain. After adjusting for exposure to retention strategies, worse baseline executive function composite score (p = 0.001) and chronic pain diagnosis (p = 0.032) were independently associated with a greater risk of dropping out. The probability of dropping out decreased with longer exposure to retention strategies and the dropout rate per month decreased from 4.1% to 1.8% (p = 0.04) on retention strategies.Baseline characteristics allow prediction of dropping out from a clinical trial in older participants. Retention strategies has been effective at minimizing the impact of dropout-related risk factors.Clinical trials.gov NCT2415556 3/23/2015 (www.gov).

Glucagon-like peptide-1 receptor agonists (GLP-1RA) and bariatric surgery have proven to be effective treatments for obesity and cardiometabolic conditions. We aimed to explore the early metabolomic changes in response to GLP-1RA (liraglutide) therapy vs. placebo and in comparison to bariatric surgery.Three clinical studies were conducted: a bariatric surgery cohort study of participants with morbid obesity who underwent either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) studied over four and twelve weeks, and two randomized placebo-controlled, crossover double blind studies of liraglutide vs. placebo administration in participants with type 2 diabetes (T2D) and participants with obesity studied for three and five weeks, respectively. Nuclear magnetic resonance spectroscopy-derived metabolomic data were assessed in all eligible participants who completed all the scheduled in-clinic visits. The primary outcome of the study was to explore the changes of the metabolome among participants with obesity with and without T2D receiving the GLP-1RA liraglutide vs. placebo and participants with obesity undergoing bariatric surgery during the three to five-week study period. In addition, we assessed the bariatric surgery effects longitudinally over the twelve weeks of the study and the differences between the bariatric surgery subgroups on the metabolome. The trials are registered with ClinicalTrials.gov, numbers NCT03851874, NCT01562678 and NCT02944500.Bariatric surgery had a more pronounced effect on weight and body mass index reduction (-14.19 ± 5.27 kg and - 5.19 ± 5.27, respectively, p 0.001 for both) and resulted in more pronounced metabolomic and lipidomic changes compared to liraglutide therapy at four weeks postoperatively. Significant changes were observed in lipoprotein parameters, inflammatory markers, ketone bodies, citrate, and branched-chain amino acids after the first three to five weeks of intervention. After adjusting for the amount of weight loss, a significant difference among the study groups remained only for acetoacetate, β-hydroxybutyrate, and citrate (p 0.05 after FDR correction). Glucose levels were significantly reduced in all intervention groups but mainly in the T2D group receiving GLP-1RA treatment. After adjusting for weight loss, only glucose levels remained significant (p = 0.001 after FDR correction), mainly due to the glucose change in the T2D group receiving GLP-1RA. Similar results with those observed at four weeks were observed in the surgical group when delta changes at twelve weeks were assessed. Comparing the two types of bariatric surgery, an intervention effect was more pronounced in the RYGB subgroup regarding total triglycerides, triglyceride-rich lipoprotein size, and trimethylamine-N-oxide (p for intervention: 0.031, 0.028, 0.036, respectively). However, after applying FDR correction, these changes deemed to be only suggestive; only time effects remained significant with no significant changes persisting in relation to the types of bariatric surgery.The results of this study suggest that the early metabolomic, lipid and lipoprotein changes observed between liraglutide treatment and bariatric surgery are similar and result largely from the changes in patients' body weight. Specific changes observed in the short-term post-surgical period between bariatric vs. nonsurgical treated participants, i.e., acetoacetate, β-hydroxybutyrate, and citrate changes, may reflect changes in patient diets and calorie intake indicating potential calorie and diet-driven metabolomics/lipidomic effects in the short-term postoperatively. Significant differences observed between SG and RYGB need to be confirmed and extended by future studies.

Scientific evidence has accumulated on the beneficial effects of nut consumption on cardiovascular risk and cholesterol reduction, but few studies have examined the effects of nuts on advanced measures of lipoprotein atherogenicity determined by nuclear magnetic resonance (NMR) spectroscopy. We analyzed associations between the amount and type of of nuts consumed and advanced measures of lipoprotein atherogenity and insulin resistance in older individuals at high cardiovascular risk.The present observational study was carried out within the framework of the Prevención con Dieta Mediterránea (PREDIMED) trial. Cross-sectional and longitudinal analyses after 1-year of follow-up were conducted in 196 men and women recruited in the PREDIMED-Reus (Spain) center. Dietary intake was assessed using a validated semi-quantitative food questionnaire. Baseline and 1-year fasting plasma lipoprotein and metabolite profiling were performed in plasma using NMR spectra VanteraCompared to paticipants in the bottom tertile, those in the top tertile of total nut consumption showed higher levels of large HDL particles and HDL-cholesterol, lower levels of branched-chain amino acids (BCAA) and GlycA, and reduced lipoprotein insulin resistance and diabetes risk index. Participants in the top tertile of walnut consumption disclosed lower levels of very large VLDL, total LDL particles, LDL-cholesterol, and GlycA. Participants in the top tertile of non-walnut nut consumption displayed higher levels of total HDL particles, HDL-cholesterol and apoliporotein A1, lower BCAA and GlycA, and reduced lipoprotein insulin resistance. Participants in the top tertile of 1-year changes in walnut consumption showed increases in medium-sized HDL particles in comparison to the bottom tertile.In older individuals at high cardiovascular risk, increasing nut consumption was associated with a shift of the NMR lipoprotein subfraction profile to a less atherogenic pattern, as well as lower circulating concentrations of BCAA and decreased insulin resistance. These results provide novel mechanistic insight into the cardiovascular benefit of nut consumption. Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003.

Nearly 100 years ago, diabetes, a disease expected to reach global prevalence of at least 10% within the decade, was a fatal diagnosis. This year of 2022 marks a century since insulin, a lifesaving treatment for those living with diabetes, was purified, tested in humans, and brought to the bedside through widespread commercial production, thus saving countless lives. Insulin's arrival to the world stage was acknowledged with the 1923 Nobel Prize in Physiology or Medicine for "the discovery of insulin", the first among several Prizes awarded to honor scientific work on insulin. This initial awarding has been the subject of significant controversy since, as numerous other scientists paved the way towards the ultimate success, and priority for the true "discovery of insulin" has been argued for many other scientists. The intention and regulations around the Nobel Prize nomination and award process presented herein offer insight into the 1923 Nobel prize designation for the Toronto group, which distinguished itself in the accomplishment by their success in purifying insulin from pancreatic extract and in bringing insulin to worldwide production and the homes of those who needed it. However, a continuous, collaborative process involving contributors spanning centuries and continents was required for the development, rather than discovery, of insulin therapy and its benefits to humanity. This should be the story's enduring legacy. The prior 100 years have witnessed a series of significant innovations in insulin development and therapeutics, but both a cure for diabetes and equitable insulin access remain out of reach and require inspired attention and continuous diligent efforts.

Context Autism spectrum disorders (ASDs) are a group of conditions characterized by impaired social function and repetitive behaviors. Their etiology is largely unknown. Objective This work aims to examine the associations of maternal second-trimester and cord blood leptin and adiponectin levels with ASDs in offspring. Methods We used data from 1164 mother-child pairs enrolled in Project Viva, a prospective prebirth cohort. We used logistic regression analysis to examine the associations of leptin and adiponectin levels in maternal second-trimester blood and cord blood obtained at birth with ASDs. Additionally, we examined the association of maternal prepregnancy body mass index (BMI) as an exposure. Main outcome measures included doctor-diagnosed ASDs reported by mothers using questionnaires in midchildhood and early adolescence. Results The cumulative incidence of ASDs was 3.4%. Maternal prepregnancy BMI (per 5 points) was positively associated with ASDs in a logistic regression model adjusted for maternal race/ethnicity, education, smoking status and child sex (adjusted odds ratio [OR] 1.38; 95% CI, 1.06-1.79). Higher second-trimester adiponectin was associated with lower odds of ASD in offspring (unadjusted OR 0.49; 95% CI, 0.30-0.78; and OR 0.54; 95% CI, 0.32-0.91 after adjusting for maternal race/ethnicity, education, child sex, OR 0.55; 95% CI, 0.33-0.93 after adjusting for BMI, gestational weight gain, gestational diabetes, and smoking status). Maternal leptin and cord blood leptin and adiponectin levels were not associated with ASDs. Conclusion Prepregnancy BMI and adiponectin during pregnancy may be useful as a tool to monitor the risk of autism. Increasing adiponectin levels prenatally may play a role in the prevention of ASDs.

Summary Background and aims We assessed the association of Mediterranean diet with NAFLD and their interaction in predicting ten-year diabetes onset and first fatal/non-fatal cardiovascular disease (CVD) incidence. Methods The ATTICA prospective observational study in Athens, Greece included 1,514 men and 1,528 women (>18 years old) free-of-CVD at baseline. Liver steatosis and fibrosis indices were calculated. Mediterranean diet adherence was assessed through MedDietScore. At the ten-year follow-up visit, CVD evaluation was performed in an a priori specified subgroup of n = 2,020 participants and diabetes onset in n = 1,485 free-of-diabetes participants. Results MedDietScore was inversely associated with steatosis and fibrosis; e.g. in the case of the TyG index the Odds Ratio (OR) of the 3rd vs. 1st MedDietScore tertile was = 0·53, [95% Confidence Interval (95% CI) (0·29, 0·95)] and the associations persisted in multi-adjusted models. NAFLD predicted incident diabetes prospectively over a ten year period [HR = 1·87, 95% CI (0·75, 4·61)] and the association remained significant only in subjects with low MedDietScore (below median) whereas diabetes onset among subjects with higher MedDietScore was not influenced by NAFLD. Similarly, NAFLD predicted CVD [Hazard Ratio (HR) = 3·01, 95%CI(2·28, 3·95)]; the effect remained significant only in subjects with MedDietScore below median [HR = 1·38, 95% CI (1·00, 1·93)] whereas it was essentially null [HR = 1·00,95% CI (0·38, 2·63)] among subjects with higher score. Mediation analysis revealed that adiponectin and adiponectin-to-leptin ratio were the strongest mediators. Conclusions We report an inverse association between Mediterranean diet and NAFLD. Mediterranean diet protected against diabetes and CVD prospectively among subjects with NAFLD.