Impact of Drain Placement on Postoperative Complications after Thyroidectomy for Substernal Goiter.

Introduction Despite the evidence against drain placement after thyroidectomy, there is a lack of consensus on drain use in patients with substernal goiter. Objective To assess the factors that increase the likelihood of drain placement and its impact on postoperative hematoma and other 30-day complications among adult patients undergoing thyroidectomy for substernal goiter. Methods A retrospective cohort study that used data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). Adult patients (aged ≥ 18 years) who underwent elective thyroidectomy for substernal goiter from 2016 to 2020 were included. Cases with closed suction neck drains placed upon completion of surgery were included in the drain group, and the remaining cases formed the nondrain group. Results A total of 1,229 patients were included (46.5% with drain placement). The factors that increased the likelihood of drain placement included body mass index (BMI) ≥ 30 kg/m 2 , score between 3 and 5 on the American Society of Anesthesiologists (ASA) physical status classification, sternal split/transthoracic surgical approach, operative time ≥ 90 minutes, and surgery conducted by otolaryngologists. Patients with clean-contaminated or contaminated wound classifications were less likely to be submitted to drain placement. In addition, drain use had no impact on postoperative hematoma formation but was found to independently increase the risk of prolonged length of hospital stay. Conclusion Thyroidectomy without drain placement might be safe for substernal goiter. However, this decision should be individualized for each patient. Level Of Evidence: 3.

Acute iv CRH administration significantly increases serum active ghrelin in postmenopausal PCOS women compared to postmenopausal controls.

PURPOSE: In women with Polycystic Ovarian Syndrome (PCOS), an increased risk of disordered eating has been described. There is growing interest regarding a possible interconnection between psychological states and increased appetite in women with PCOS. Acute stress is characterized by increased Corticotropin Releasing Hormone (CRH) secretion. The aim was to estimate the ghrelin concentrations during CRH test. METHODS: Twenty postmenopausal women with PCOS and twenty age- and BMI- matched postmenopausal control women were recruited at Aretaieion University Hospital. In the morning (9 am) all subjects had anthropometric measurements (weight, height, waist circumference) and a fasting sample for hormonal measurements. An intravenous (iv) CRH stimulation test conducted over 1 min. Serum active ghrelin levels were measured at 0, 15, 30, 60, 90, 120 min after iv CRH administration. RESULTS: The postmenopausal PCOS group had a higher waist circumference compared to postmenopausal controls. Active ghrelin concentrations increased significantly from 0 to 15 min, to 30 min, to 60 min, to 90 min and then decreased to 120 min. However, within the postmenopausal control group there were no significant changes in serum active ghrelin levels. Serum active ghrelin concentrations were significantly greater in the postmenopausal control group at 0, 15 and 120 min compared to the postmenopausal PCOS group. At 90 min active ghrelin concentrations were significantly greater in the postmenopausal PCOS group. Delta Area Under the Curve of active ghrelin (ΔAUCghr) was significantly greater in the postmenopausal PCOS group compared to controls. CONCLUSIONS: In postmenopausal PCOS, but not in postmenopausal controls, iv CRH administration induces increased serum active ghrelin secretion, suggesting a possible anti-stress adaptive mechanism. An increase in serum active ghrelin may induce hunger as a side-effect of this presumed adaptive mechanism.

The impact of metabolic endotoxaemia on the browning process in human adipocytes.

BACKGROUND: Dysfunctional adipose tissue (AT) is known to contribute to the pathophysiology of metabolic disease, including type 2 diabetes mellitus (T2DM). This dysfunction may occur, in part, as a consequence of gut-derived endotoxaemia inducing changes in adipocyte mitochondrial function and reducing the proportion of BRITE (brown-in-white) adipocytes. Therefore, the present study investigated whether endotoxin (lipopolysaccharide; LPS) directly contributes to impaired human adipocyte mitochondrial function and browning in human adipocytes, and the relevant impact of obesity status pre and post bariatric surgery. METHODS: Human differentiated abdominal subcutaneous (AbdSc) adipocytes from participants with obesity and normal-weight participants were treated with endotoxin to assess in vitro changes in mitochondrial function and BRITE phenotype. Ex vivo human AbdSc AT from different groups of participants (normal-weight, obesity, pre- and 6 months post-bariatric surgery) were assessed for similar analyses including circulating endotoxin levels. RESULTS: Ex vivo AT analysis (lean & obese, weight loss post-bariatric surgery) identified that systemic endotoxin negatively correlated with BAT gene expression (p < 0.05). In vitro endotoxin treatment of AbdSc adipocytes (lean & obese) reduced mitochondrial dynamics (74.6% reduction; p < 0.0001), biogenesis (81.2% reduction; p < 0.0001) and the BRITE phenotype (93.8% reduction; p < 0.0001). Lean AbdSc adipocytes were more responsive to adrenergic signalling than obese AbdSc adipocytes; although endotoxin mitigated this response (92.6% reduction; p < 0.0001). CONCLUSIONS: Taken together, these data suggest that systemic gut-derived endotoxaemia contributes to both individual adipocyte dysfunction and reduced browning capacity of the adipocyte cell population, exacerbating metabolic consequences. As bariatric surgery reduces endotoxin levels and is associated with improving adipocyte functionality, this may provide further evidence regarding the metabolic benefits of such surgical interventions.

The mid-term and long-term effects of tourniquet use in total knee arthroplasty: systematic review.

PURPOSE: A tourniquet is routinely used during total knee arthroplasty (TKA) to reduce intra-operative hemorrhage, though surgery without a tourniquet is becoming popular. To address concerns about the effect of blood at cement interfaces on long-term implant stability, we conducted a systematic review among patients undergoing total knee arthroplasty to determine if TKA with a tourniquet, compared to TKA without a tourniquet or with reduced tourniquet duration, is associated with better mid-term and long-term implant stability. METHODS: A literature search was conducted without language restriction in PubMed, Cochrane database and Web of Science from conception to 17th March, 2021. Prospective cohorts, randomized and observational, that compared tourniquet use with a control group, followed patients for 3 months or more and reported outcomes concerning implant stability, limb function, pain and inflammation. Article selection, quality assessment according to the Revised Cochrane risk assessment scale and Newcastle Ottawa Scale, and data extraction were conducted in duplicate. PROSPERO: CRD42020179020. RESULTS: The search yielded 4868 articles, from which 16 randomized controlled trials (RCT) and four prospective cohort studies, evaluating outcomes of 1884 knees, were included. Eleven RCTs were evaluated to be low overall risk of bias, five RCTs had some concerns and four cohort studies were good quality. Few studies showed benefits of tourniquet use in mid-term implant stability (1/6), pain (1/11) and limb inflammation (1/5), and long-term implant stability (1/1). One study reported a significantly improved range of motion (1/14) while another reported significantly reduced quadriceps strength (1/6) in the tourniquet group. The remaining studies reported non-significant effect of tourniquet use. CONCLUSION: Although few studies indicated benefits of tourniquet use in mid-term pain, limb inflammation, implant loosening and function, and long-term implant loosening, the majority of studies report no significant advantage of tourniquet use in total knee arthroplasty.

Is minimally invasive orthopedic surgery safer than open? A systematic review of systematic reviews.

BACKGROUND: To assess the safety of minimally invasive surgery (MIS) for orthopedic spinal, upper limb and lower limb procedures, this systematic review of systematic reviews compared their complications with open procedures. MATERIALS AND METHODS: A literature search was conducted electronically (PubMed, Cochrane library and Web of Science; May 8, 2021) without language restriction in the past five years. Reviews that consulted at least two databases, compared MIS with open orthopedic surgery, and reported the following: intraoperative, post-operative or total complications, function, ambulation, pain, hospital stay, reoperation rate and operation time were included. Article selection, quality assessment using AMSTAR-2, and data extraction were conducted in duplicate on predesigned forms. In each review, a subset analysis focusing on prospective cohort and randomized studies was additionally performed. PROSPERO: CRD42020178171. RESULTS: The search yielded 531 articles from which 76 reviews consisting of 1104 primary studies were included. All reviews were assessed as being low quality. Compared to open surgery, MIS had fewer total, postoperative and intraoperative complications in 2/10, 2/11 and 2/5 reviews of spinal procedures respectively, 1/3, 1/4 and 1/2 reviews of upper limb procedures respectively, and 4/6, 2/7 and 0/2 reviews of lower limb procedures respectively. CONCLUSIONS: MIS had greater overall safety compared to open surgery in spinal procedures. In upper limb and lower limb procedures, MIS was not outright superior to open procedures in terms of safety hence a general preference of MIS is not justified on the premise of a better safety profile compared to open procedures.

The Gestational Effects of Maternal Appetite Axis Molecules on Fetal Growth, Metabolism and Long-Term Metabolic Health: A Systematic Review.

Increased maternal food intake is considered a normal pregnancy adjustment. However, the overavailability of nutrients may lead to dysregulated fetal development and increased adiposity, with long-lasting effects on offspring in later life. Several gut-hormone molecules regulate maternal appetite, with both their orexigenic and anorectic effects being in a state of sensitive equilibrium. The aim of this manuscript is to systematically review literature on the effects of maternal gut-hormone molecules on fetal growth and metabolism, birth weight and the later metabolic health of offspring. Maternal serum ghrelin, leptin, IGF-1 and GLP-1 appear to influence fetal growth; however, a lack of consistent and strong correlations of maternal appetite axis hormones with birth weight and the concomitant correlation with fetal and birth waist circumference may suggest that these molecules primarily mediate fetal energy deposition mechanisms, preparing the fetus for survival after birth. Dysregulated intrauterine environments seem to have detrimental, sex-dependent effects on fetal energy stores, affecting not only fetal growth, fat mass deposition and birth weight, but also future metabolic and endocrine wellbeing of offspring.

Association between vitamin D supplementation or serum vitamin D level and susceptibility to SARS-CoV-2 infection or COVID-19 including clinical course, morbidity and mortality outcomes? A systematic review.

OBJECTIVE: To systemically review and critically appraise published studies of the association between vitamin D supplementation or serum vitamin D level and susceptibility to SARS-CoV-2 infection or COVID-19, including clinical course, morbidity and mortality outcomes. DESIGN: Systematic review. DATA SOURCES: MEDLINE (OVID), Embase (OVID), Cochrane Central Register of Controlled Trials, MedRxiv and BioRxiv preprint databases. COVID-19 databases of the WHO, Cochrane, CEBM Oxford and Bern University up to 10 June 2020. STUDY SELECTION: Studies that assessed vitamin D supplementation and/or low serum vitamin D in patients acutely ill with, or at risk of, severe betacoronavirus infection (SARS-CoV, MERS-CoV, SARS-CoV-2). DATA EXTRACTION: Two authors independently extracted data using a predefined data extraction form and assessed risk of bias using the Downs and Black Quality Assessment Checklist. RESULTS: Searches elicited 449 papers, 59 studies were eligible full-text assessment and 4 met the eligibility criteria of this review. The four studies were narratively synthesised and included (1) a cross-sectional study (n=107) suggesting an inverse association between serum vitamin D and SARS-CoV-2; (2) a retrospective cohort study (348 598 participants, 449 cases) in which univariable analysis showed that vitamin D protects against COVID-19; (3) an ecological country level study demonstrating a negative correlation between vitamin D and COVID-19 case numbers and mortality; and (4) a case-control survey (n=1486) showing cases with confirmed/probable COVID-19 reported lower vitamin D supplementation. All studies were at high/unclear risk of bias. CONCLUSION: There is no robust evidence of a negative association between vitamin D and COVID-19. No relevant randomised controlled trials were identified and there is no robust peer-reviewed published evidence of association between vitamin D levels and severity of symptoms or mortality due to COVID-19. Guideline producers should acknowledge that benefits of vitamin D supplementation in COVID-19 are as yet unproven despite increasing interest.

Relationship Between Maternal Bone Biomarkers and Fetal Adiposity Through Normal Pregnancy.

PURPOSE: To examine the association of maternal bone markers [sclerostin, soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteocalcin, 25-hydroxyvitamin D3] with fetal intra-abdominal and subcutaneous adipose tissue deposition and birthweight during normal pregnancy. METHODS: One hundred pregnant women (aged 30.4 ±â€…5.6 years, mean ±â€…SD) with prepregnancy body mass index = 24.1 ±â€…4.6 kg/m2 were seen prospectively during each trimester. At each visit they were submitted to anthropometric measurements, a fasting blood sampling, a 75-g oral glucose tolerance test, and a fetal ultrasonogram. At birth, neonates had birth weight measurement. RESULTS: In the second trimester, maternal sclerostin concentrations correlated positively with fetal abdominal circumference and birth weight; maternal sRANKL concentrations correlated positively with fetal abdominal subcutaneous fat thickness, sagittal abdominal diameter, and abdominal circumference. Fetuses born to mothers with greater (>254 ng/mL), compared to fetuses born to mothers with lower (≤254ng/mL), sRANKL concentrations had greater abdominal circumference, sagittal diameter, and abdominal subcutaneous fat thickness. Maternal serum sclerostin concentrations were the best positive predictors of birth weight. In the third trimester maternal sclerostin concentrations correlated positively with fetal sagittal abdominal diameter; maternal sRANKL concentrations positively correlated with fetal abdominal circumference and fetal abdominal sagittal diameter. CONCLUSIONS: Maternal bone markers sclerostin and sRANKL may relate to fetal intra-abdominal adipose tissue deposition through as yet unknown direct or indirect mechanisms, thus contributing to birthweight.

Tunicamycin-Induced Endoplasmic Reticulum Stress Mediates Mitochondrial Dysfunction in Human Adipocytes.

CONTEXT: Dysfunctional endoplasmic reticulum (ER) and mitochondria are known to contribute to the pathology of metabolic disease. This damage may occur, in part, as a consequence of ER-mitochondria cross-talk in conditions of nutrient excess such as obesity. To date, insight into this dynamic relationship has not been characterized in adipose tissue. Therefore, this study investigated whether ER stress contributes to the development of mitochondrial inefficiency in human adipocytes from lean and obese participants. METHODS: Human differentiated adipocytes from Chub-S7 cell line and primary abdominal subcutaneous adipocytes from lean and obese participants were treated with tunicamycin to induce ER stress. Key parameters of mitochondrial function were assessed, including mitochondrial respiration, membrane potential (MMP), and dynamics. RESULTS: ER stress led to increased respiratory capacity in a model adipocyte system (Chub-S7 adipocytes) in a concentration and time dependent manner (24 h: 23%↑; 48 h: 68%↑, P < 0.001; 72 h: 136%↑, P < 0.001). This corresponded with mitochondrial inefficiency and diminished MMP, highlighting the formation of dysfunctional mitochondria. Morphological analysis revealed reorganization of mitochondrial network, specifically mitochondrial fragmentation. Furthermore, p-DRP1, a key protein in fission, significantly increased (P < 0.001). Additionally, adipocytes from obese subjects displayed lower basal respiration (49%↓, P < 0.01) and were unresponsive to tunicamycin in contrast to their lean counterparts, demonstrating inefficient mitochondrial oxidative capacity. CONCLUSION: These human data suggest that adipocyte mitochondrial inefficiency is driven by ER stress and exacerbated in obesity. Nutrient excess-induced ER stress leads to mitochondrial dysfunction that may therefore shift lipid deposition ectopically and thus have further implications on the development of related metabolic disorders.

Effects of A 12-Month Intensive Lifestyle Monitoring Program in Predominantly Overweight/Obese Arab Adults with Prediabetes.

This 12-month, randomized, controlled lifestyle intervention study was aimed at assessing the effectiveness of a lifestyle intervention in terms of (1) the reduction of at least 5% of body weight compared to baseline and (2) the percentage of participants in which fasting blood glucose (FBG) normalizes (<5.6 mmol/L) post-intervention, in predominantly overweight/obese Saudi adults with impaired fasting glucose. A total of 300 Saudi adults with prediabetes at baseline (FBG 5.6-6.9 mmol/L) were enrolled to receive either general advice (GA) or a rigorous, self-monitored, lifestyle modification program (intervention group, IG) for 12 months, focused on food choices, physical activity, and weight loss. Anthropometric and biochemical estimations were analyzed at baseline, 6, and 12 months. At baseline, 136/150 in the GA group (90.7%) and 127/150 in the IG group (84.7%) were either overweight or obese. A total of 14% (n = 21) of the subjects in the IG arm discontinued, compared to 8% (n = 12) in the GA arm. Data from completers (92% (n = 138) and 86% (n= 129) participants in GA and IG arms, respectively) were considered for the final analysis. Post-intervention, 37.2% (n = 48) of participants in the IG group had ≥5% weight reduction, as compared to 12.3% (n = 17) in the GA group (p < 0.01). Similarly, the percentage of participants who normalized their FBG post-intervention was 46.5% (n = 60) in the IG group compared to 21.7% (n = 30) in the GA group (p < 0.01). A 12-month Diabetes Prevention Program (DPP)-styled intensive lifestyle program translated effectively in decreasing weight and improving fasting glucose compared to the GA group in predominantly overweight/obese Saudi adults with prediabetes, suggesting that in the case of guided intervention programs, people are willing to participate and possibly change a sedentary lifestyle.

Maternal chronic stress correlates with serum levels of cortisol, glucose and C-peptide in the fetus, and maternal non chronic stress with fetal growth.

INTRODUCTION: During pregnancy, maternal stressors cause changes in both maternal and fetal HPA axes. We therefore investigated the impact of maternal non chronic and chronic stress on fetal glucose metabolism and growth, and serum levels of cortisol in the fetus. MATERIALS AND METHODS: Normal weight pregnant women (n = 192; mean ± SD 27.9 ± 4.2 years old, and; 26.9 ± 2.4 kg/m²) were assessed during the 2nd and 3rd trimester with anthropometry, fetal ultrasound, blood samples for serum CRH, cortisol and IL6, and STAI trait and state stress questionnaires. We measured serum cortisol, insulin and c-peptide, and plasma glucose from cord blood. Neonates underwent anthropometry at the 3rd post-delivery day. RESULTS: In both 2nd and 3rd trimesters, women with STAI trait scores ≥40 had significantly greater levels of fasting serum CRH and cortisol than those with STAI trait scores<40. 2nd trimester: STAI trait scores correlated positively with cord blood glucose and c-peptide. Maternal serum CRH correlated negatively with U/S fetal biparietal head diameter, while serum cortisol correlated positively with abdominal circumference. Maternal serum IL6, CRH and cortisol all correlated positively with birth waist circumference. 3rd trimester: Women with STAI state scores ≥40 had fetuses with larger U/S abdominal and smaller head circumferences compared to those of women with STAI scores <40. Women with STAI trait scores ≥40 had greater levels of cord blood cortisol, glucose, and c-peptide compared to women with STAI scores <40. STAI state scores ≥40 correlated positively with maternal CRH and U/S fetal abdominal circumference, and negatively with fetal head circumference and biparietal diameter. STAI trait scores correlated positively with cord blood c-peptide, glucose, insulin and cortisol. Maternal serum levels of CRH correlated positively with U/S fetal abdominal circumference and cord blood cortisol, and negatively with fetal head circumference and biparietal head diameter. Maternal serum levels of both CRH and cortisol correlated positively with cord blood c-peptide, glucose, and insulin. STAI trait was the best positive predictor of cord blood cortisol, glucose and c-peptide, whilst STAI state was the best positive and negative predictor, respectively of fetal abdominal circumference and fetal head circumference or biparietal diameter. CONCLUSIONS: Increased maternal chronic stress (reflected by the STAI trait score) associates with increased fetal cortisol, glucose, c-peptide secretion and thus, insulin resistance. Maternal non chronic stress (STAI state) in the 3rd trimester associates with changes in fetal growth pattern, including increased and decreased measurements of fetal abdominal and head growth respectively.

Top-down guidance of attention to food cues is enhanced in individuals with overweight/obesity and predicts change in weight at one-year follow up.

BACKGROUND: Changing eating behaviour may be challenging for individuals with obesity and this may be related to attentional bias towards food. Previous paradigms used to assess attentional bias to food stimuli have not distinguished between bottom-up processes related to assessment of rewarding stimuli versus top-down processes related to effects of mind-set on attention. We investigated whether attentional bias for food cues varies between individuals with overweight/obesity and healthy weight individuals, due to differential top-down control of attention. We also determined whether top-down biases predict food consumption in the lab and weight change in our sample over one-year. METHODS: Forty-three participants with overweight/obesity and 49 healthy weight participants between the ages of 18 and 58 participated. Participants completed two attention tasks in a counterbalanced order: (i) a priming task assessing bottom-up control of attention and (ii) a working memory task assessing top-down control of attention. Eating behaviour was assessed by a taste test. At one-year follow-up participants returned to the laboratory to assess changes in their body mass index (BMI). RESULTS: The healthy weight and overweight/obese groups did not differ in demographics and baseline measures (appetite, food liking, taste test food intake). Participants with overweight/obesity showed greater top-down attentional bias towards food cues than did healthy weight participants but had no difference in bottom-up attentional bias. Top down attentional bias towards food cues predicted weight change over one-year but did not predict food intake in the taste test. CONCLUSIONS: The present findings illustrate that the relationship between attentional bias for food, food intake, and body weight is complex. Top-down effects of mind-set on attention, rather than bottom-up control of attention to food may contribute to patterns of eating that result in development and/or maintenance of overweight/obesity. Interventions targeted at top down biases could be effective in facilitating prevention of weight gain.

Effects of Different Dietary and Lifestyle Modification Therapies on Metabolic Syndrome in Prediabetic Arab Patients: A 12-Month Longitudinal Study.

This three-arm, randomized, controlled study aimed to determine the differences in the effects of general advice (GA) on lifestyle change, intensive lifestyle modification programme (ILMP) and GA + metformin (GA + Met) in reducing the prevalence of full metabolic syndrome (MetS) in subjects with prediabetes; 294 Saudis with prediabetes (fasting glucose 5.6-6.9 mmol/L) were initially randomized, 263 completed 6 months and 237 completed 12 months. They were allocated into three groups: GA group which received a standard lifestyle change education; ILMP which followed a rigorous lifestyle modification support on diet and physical activity; and a GA + Met group. Anthropometric and biochemical estimations were measured. Full MetS (primary endpoint) and its components (secondary endpoint) were screened at baseline, 6 and 12 months. Full MetS in the ILMP group decreased by 26% (p < 0.001); in GA + Met group by 22.4% (p = 0.01) and in GA group by 8.2% (p = 0.28). The number of MetS components decreased significantly in the ILMP and GA + Met groups (mean change 0.81, p < 0.001 and 0.35, p = 0.05, respectively). Between-group comparison revealed a clinically significant decrease in MetS components in favor of the ILMP group (-0.58 (-0.88-0.28), p < 0.001). This study highlights the clinical potency of ILMP versus other diabetes prevention options in reducing MetS in Saudi adults with elevated fasting glucose.

Telmisartan reverses antiretroviral-induced adipocyte toxicity and insulin resistance in vitro.

BACKGROUND: Antiretroviral therapy in HIV-positive patients leads to insulin resistance which is central to the pathogenesis of various metabolic abnormalities and cardiovascular disease seen in this patient group. We have investigated the dose-response relationship of telmisartan, an antihypertensive, on adipocytes in vitro in order to determine whether it may have metabolic beneficial effects. METHODS: Using in vitro chronic toxicity models (3T3-F442A murine and primary human adipocytes), we evaluated the effects of different concentrations of telmisartan on adipocyte differentiation and adipogenic gene expression using lipid accumulation assays and real-time polymerase chain reaction, respectively. Adipokine secretion and expression of insulin signalling mediators were evaluated using enzyme-linked immunosorbent assays. RESULTS: Telmisartan partially reversed the deleterious effects of antiretrovirals on adipocyte lipid accumulation, expression of adipogenic regulators (peroxisome proliferator receptor-gamma and lipin 1), adipokine secretion and expression of the insulin signalling mediator pAktSer473. The metabolic effects of telmisartan followed a non-monotonic response with the maximal effect observed at 5 µM in the primary human adipocyte model. CONCLUSION: Telmisartan has beneficial metabolic effects in adipocytes in vitro, but its potential to reduce antiretroviral-induced cardiometabolic disease in HIV-infected individuals needs to be evaluated in a well-designed adequately powered clinical trial.

Differential expression of Lp-PLA2 in obesity and type 2 diabetes and the influence of lipids.

AIMS/HYPOTHESIS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulatory macrophage-derived factor that increases with obesity and leads to a higher risk of cardiovascular disease (CVD). Despite this, its role in adipose tissue and the adipocyte is unknown. Therefore, the aims of this study were to clarify the expression of Lp-PLA2 in relation to different adipose tissue depots and type 2 diabetes, and ascertain whether markers of obesity and type 2 diabetes correlate with circulating Lp-PLA2. A final aim was to evaluate the effect of cholesterol on cellular Lp-PLA2 in an in vitro adipocyte model. METHODS: Analysis of anthropometric and biochemical variables from a cohort of lean (age 44.4 ± 6.2 years; BMI 22.15 ± 1.8 kg/m2, n = 23), overweight (age 45.4 ± 12.3 years; BMI 26.99 ± 1.5 kg/m2, n = 24), obese (age 49.0 ± 9.1 years; BMI 33.74 ± 3.3 kg/m2, n = 32) and type 2 diabetic women (age 53.0 ± 6.13 years; BMI 35.08 ± 8.6 kg/m2, n = 35), as part of an ethically approved study. Gene and protein expression of PLA2 and its isoforms were assessed in adipose tissue samples, with serum analysis undertaken to assess circulating Lp-PLA2 and its association with cardiometabolic risk markers. A human adipocyte cell model, Chub-S7, was used to address the intracellular change in Lp-PLA2 in adipocytes. RESULTS: Lp-PLA2 and calcium-independent PLA2 (iPLA2) isoforms were altered by adiposity, as shown by microarray analysis (p < 0.05). Type 2 diabetes status was also observed to significantly alter gene and protein levels of Lp-PLA2 in abdominal subcutaneous (AbdSc) (p < 0.01), but not omental, adipose tissue. Furthermore, multivariate stepwise regression analysis of circulating Lp-PLA2 and metabolic markers revealed that the greatest predictor of Lp-PLA2 in non-diabetic individuals was LDL-cholesterol (p = 0.004). Additionally, in people with type 2 diabetes, oxidised LDL (oxLDL), triacylglycerols and HDL-cholesterol appeared important predictors, accounting for 59.7% of the variance (p < 0.001). Subsequent in vitro studies determined human adipocytes to be a source of Lp-PLA2, as confirmed by mRNA expression, protein levels and immunochemistry. Further in vitro experiments revealed that treatment with LDL-cholesterol or oxLDL resulted in significant upregulation of Lp-PLA2, while inhibition of Lp-PLA2 reduced oxLDL production by 19.8% (p < 0.05). CONCLUSIONS/INTERPRETATION: Our study suggests adipose tissue and adipocytes are active sources of Lp-PLA2, with differential regulation by fat depot and metabolic state. Moreover, levels of circulating Lp-PLA2 appear to be influenced by unfavourable lipid profiles in type 2 diabetes, which may occur in part through regulation of LDL-cholesterol and oxLDL metabolism in adipocytes.

Low Vitamin B12 in Pregnancy Is Associated With Adipose-Derived Circulating miRs Targeting PPARγ and Insulin Resistance.

Context: Low vitamin B12 during pregnancy is associated with higher maternal obesity, insulin resistance (IR), and gestational diabetes mellitus. B12 is a key cofactor in one-carbon metabolism. Objective: We hypothesize that B12 plays a role in epigenetic regulation by altering circulating microRNAs (miRs) during adipocyte differentiation and results in an adverse metabolic phenotype. Design, Settings, and Main Outcome Measure: Human preadipocyte cell line (Chub-S7) was differentiated in various B12 concentrations: control (500 nM), low B12 (0.15 nM), and no B12 (0 nM). Maternal blood samples (n = 91) and subcutaneous adipose tissue (SAT) (n = 42) were collected at delivery. Serum B12, folate, lipids, plasma one-carbon metabolites, miR profiling, miR expression, and gene expression were measured. Results: Our in vitro model demonstrated that adipocytes in B12-deficient conditions accumulated more lipids, had higher triglyceride levels, and increased gene expression of adipogenesis and lipogenesis. MiR array screening revealed differential expression of 133 miRs involving several metabolic pathways (adjusted P < 0.05). Altered miR expressions were observed in 12 miRs related to adipocyte differentiation and function in adipocytes. Validation of these data in pregnant women with low B12 confirmed increased expression of adipogenic and lipogenic genes and altered miRs in SAT and altered levels of 11 of the 12 miRs in circulation. After adjustment for other possible confounders, multiple regression analysis revealed an independent association of B12 with body mass index (ß: -0.264; 95% confidence interval, -0.469 to -0.058; P = 0.013) and was mediated by four circulating miRs targeting peroxisome proliferator-activated receptor γ and IR. Conclusions: Low B12 levels in pregnancy alter adipose-derived circulating miRs, which may mediate an adipogenic and IR phenotype, leading to obesity.

Impact of gut hormone FGF-19 on type-2 diabetes and mitochondrial recovery in a prospective study of obese diabetic women undergoing bariatric surgery.

BACKGROUND: The ileal-derived hormone, fibroblast growth factor 19 (FGF-19), may promote weight loss and facilitate type-2 diabetes mellitus remission in bariatric surgical patients. We investigated the effect of different bariatric procedures on circulating FGF-19 levels and the resulting impact on mitochondrial health in white adipose tissue (AT). METHODS: Obese and type-2 diabetic women (n = 39, BMI > 35 kg/m2) undergoing either biliopancreatic diversion (BPD), laparoscopic greater curvature plication (LGCP), or laparoscopic adjustable gastric banding (LAGB) participated in this ethics approved study. Anthropometry, biochemical, clinical data, serum, and AT biopsies were collected before and 6 months after surgery. Mitochondrial gene expression in adipose biopsies and serum FGF-19 levels were then assessed. RESULTS: All surgeries led to metabolic improvements with BPD producing the greatest benefits on weight loss (↓30%), HbA1c (↓28%), and cholesterol (↓25%) reduction, whilst LGCP resulted in similar HbA1c improvements (adjusted for BMI). Circulating FGF-19 increased in both BPD and LGCP (χ2(2) = 8.088; P = 0.018), whilst, in LAGB, FGF-19 serum levels decreased (P = 0.028). Interestingly, circulating FGF-19 was inversely correlated with mitochondrial number in AT across all surgeries (n = 39). In contrast to LGCP and LAGB, mitochondrial number in BPD patients corresponded directly with changes in 12 of 14 mitochondrial genes assayed (P < 0.01). CONCLUSIONS: Elevated serum FGF-19 levels post-surgery were associated with improved mitochondrial health in AT and overall diabetic remission. Changes in circulating FGF-19 levels were surgery-specific, with BPD producing the best metabolic outcomes among the study procedures (BPD > LGCP > LAGB), and highlighting mitochondria in AT as a potential target of FGF-19 during diabetes remission.

Addition of or switch to insulin therapy in people treated with glucagon-like peptide-1 receptor agonists: A real-world study in 66 583 patients.

BACKGROUND: Real world outcomes of addition or switch to insulin therapy in type 2 diabetes (T2DM) patients on glucagon-like paptide-1 receptor agonist (GLP-1RA) with inadequately controlled hyperglycaemia, are not known. MATERIALS AND METHODS: Patients with T2DM (n = 66 583) with a minimum of 6 months of GLP-1RA treatment and without previous insulin treatment were selected. Those who added insulin (n = 39 599) or switched to insulin after GLP-1RA cessation (n = 4706) were identified. Adjusted changes in glycated haemoglobin (HbA1c), weight, systolic blood pressure (SBP), and LDL cholesterol were estimated over 24 months follow-up. RESULTS: Among those who continued with GLP-1RA treatment without adding or switching to insulin, the highest adjusted mean HbA1c change was achieved within 6 months, with no further glycaemic benefits observed during 24 months of follow-up. Addition of insulin within 6 months of GLP-1RA initiation was associated with 18% higher odds of achieving HbA1c <7% at 24 months, compared with adding insulin later. At 24 months, those who added insulin reduced HbA1c significantly by 0.55%, while no glycaemic benefit was observed in those who switched to insulin. Irrespective of intensification with insulin, weight, SBP and LDL cholesterol were significantly reduced by 3 kg, 3 mm Hg, and 0.2 mmol/L, respectively, over 24 months. CONCLUSIONS: Significant delay in intensification of treatment by addition of insulin is observed in patients with T2DM inadequately controlled with GLP-1RA. Earlier addition of insulin is associated with better glycaemic control, while switching to insulin is not clinically beneficial during 2 years of treatment. Non-responding patients on GLP-1RA would benefit from adding insulin therapy, rather than switching to insulin.

Insulin Sensitivity and Secretion in Obese Type 2 Diabetic Women after Various Bariatric Operations.

OBJECTIVE: To compare the effects of biliopancreatic diversion (BPD) and laparoscopic gastric banding (LAGB) on insulin sensitivity and secretion with the effects of laparoscopic gastric plication (P). METHODS: A total of 52 obese women (age 30-66 years) suffering from type 2 diabetes mellitus (T2DM) were prospectively recruited into three study groups: 16 BPD; 16 LAGB, and 20 P. Euglycemic clamps and mixed meal tolerance tests were performed before, at 1 month and at 6 months after bariatric surgery. Beta cell function derived from the meal test parameters was evaluated using mathematical modeling. RESULTS: Glucose disposal per kilogram of fat free mass (a marker of peripheral insulin sensitivity) increased significantly in all groups, especially after 1 month. Basal insulin secretion decreased significantly after all three types of operations, with the most marked decrease after BPD compared with P and LAGB. Total insulin secretion decreased significantly only following the BPD. Beta cell glucose sensitivity did not change significantly post-surgery in any of the study groups. CONCLUSION: We documented similar improvement in insulin sensitivity in obese T2DM women after all three study operations during the 6-month postoperative follow-up. Notably, only BPD led to decreased demand on beta cells (decreased integrated insulin secretion), but without increasing the beta cell glucose sensitivity.

Circulating betatrophin in healthy control and type 2 diabetic subjects and its association with metabolic parameters.

AIMS: Betatrophin, a newly identified liver and adipose tissue-derived hormone, has been suggested as an inducer of ß-cell proliferation in mice. However, the physiological role of betatrophin remains poorly understood in humans. Hence, the aim of this study was to investigate circulating betatrophin concentrations in normal and type 2 diabetes mellitus (T2DM) Saudi subjects and its association with various metabolic parameters. METHODS: In this cross-sectional study, 200 Saudi adults (81 healthy non-T2DM controls, age: 41.43±8.35 [mean±SD]; BMI: 31.58±5.49 and 119 T2DM subjects, age: 48.78±11.76years; BMI: 30.25±4.83kg/m(2)) were studied. Anthropometric and fasting serum biochemical data were collected. Circulating betatrophin was measured using an enzyme-linked immunosorbent assay (ELISA) based kit. RESULTS: We observed significantly higher levels of betatrophin in T2DM subjects compared to healthy controls (882.19±329.06 vs 657.14±261.04pg/ml, p<0.001). Furthermore, in T2DM subjects, betatrophin level was positively associated with blood pressure and serum fasting glucose (p<0.05). CONCLUSIONS: Our results suggest that circulating betatrophin is significantly elevated in subjects with T2DM compared to healthy controls. Increase in the level of betatrophin in T2DM subjects might be a compensatory mechanism for enhanced insulin demand in T2DM condition.