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 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.

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.

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.

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.

Enhanced thermic effect of food, postprandial NEFA suppression and raised adiponectin in obese women who eat slowly.

OBJECTIVE: Meal duration may influence cardiometabolic health. The aim of this study was to explore postprandial effects of meal duration on human metabolism and appetite. DESIGN: Postprandial comparisons following a standard meal eaten slowly over 40 min ('D40') and the same meal eaten quickly over 10 min ('D10') on a different day. Each participant therefore acted as their own control, thereby limiting confounding factors. PATIENTS: Obese premenopausal Caucasian women (n = 10) with confirmed normoglycaemia were recruited from an obesity clinic at UHCW, Coventry UK. Subjects underwent whole-body calorimetry (8-h) on two separate days. MEASUREMENTS: Following standard lunch (D40 vs D10), 4-h postprandial analysis included thermic effect of food (TEF) and bloods taken at predefined times (including baseline fasting). Analytes included lipid profile, adiponectin, insulin, glucose, ghrelin, leptin, endotoxin, gut and pancreatic hormones. Appetite was measured using visual-analogue scales and ad libitum food intake at subsequent meal. Paired sample t-tests [including area under the curve (AUC)] were used to compare D40 and D10 trials. RESULTS: Postprandial TEF (over 240-min) was significantly greater for D40 than D10 [mean (SEM): 80·9 kcal (3·8) vs 29·9 kcal (3·4); 10·6% vs 3·9%, respectively, P = 0·006; AUC 71·7 kcal.h vs 22·4 kcal.h, respectively, P = 0·02]. Postprandial plasma NEFA was significantly lower, and adiponectin levels were significantly higher for D40 than D10 [AUC (SEM): NEFA 627 µmol.h/l (56) vs 769 µmol.h/l (60), respectively, P = 0·02; adiponectin 33·4 µg.h/ml (3·9) vs 27·3 µg.h/ml (3·8), respectively, P = 0·04]. Other postprandial analytes and appetite measures were equivalent. CONCLUSIONS: In obese women, eating slowly associates with enhanced TEF, elevated serum adiponectin and suppressed NEFA.

The identification of irisin in human cerebrospinal fluid: influence of adiposity, metabolic markers, and gestational diabetes.

Peripheral action of irisin improves glucose homeostasis and increases energy expenditure, with no data on a central role of irisin in metabolism. These studies sought to examine 1) presence of irisin in human cerebrospinal fluid (CSF) and banked human hypothalamic tissue, 2) serum irisin in maternal subjects across varying adiposities with or without gestational diabetes (GDM), and 3) their respective neonate offspring. CSF, serum, and neonatal cord serum were collected from 91 pregnant women with and without GDM attending for an elective cesarean section [body mass index (BMI): 37.7 ± 7.6 kg/m(2); age: 32 ± 8.3 yr]. Irisin was assessed by ELISA and correlated with biochemical and anthropometric data. Irisin expression was examined in human hypothalamus by immunohistochemical staining. Serum irisin in pregnant women was significantly lower in nonobese compared with obese and GDM subjects, after adjusting for BMI, lipids, and glucose. Irisin was present in neonatal cord serum (237 ± 8 ng/ml) and maternal CSF (32 ± 1.5 ng/ml). CSF irisin correlated positively with serum irisin levels from nonobese and obese pregnant women (P < 0.01), with CSF irisin significantly raised in GDM subjects (P < 0.05). Irisin was present in human hypothalamic sections in the paraventricular neurons, colocalized with neuropeptide Y. Irisin was detectable in CSF and in paraventricular neurons. Maternal serum irisin was lower in nonobese pregnant women after adjusting for BMI and a number of metabolic parameters. These studies indicate that irisin may have a central role in metabolism in addition to the known peripheral role. Further studies investigating the central action of irisin in human metabolic disease are required.

Vitamin B12 deficiency is associated with adverse lipid profile in Europeans and Indians with type 2 diabetes.

BACKGROUND: Metformin, a standard therapy in type 2 diabetes, reduces vitamin B12 levels. Studies linking low vitamin B12 levels and cardiovascular disease are equivocal and suggest improving B12 levels may help in primary prevention. The role of vitamin B12 deficiency on cardiovascular risk factors, especially in type 2 diabetes has not been explored. The aim of this study is to investigate whether vitamin B12 deficiency in type 2 diabetes patients is associated with cardiovascular risk factors in two different ethnic groups in UK and India. METHODS: Type 2 diabetes patients from two secondary care diabetic centres (Europeans - UK and Indians - India) were studied. Serum vitamin B12, folate and biochemical parameters were measured. RESULTS: The prevalence rates of vitamin B12 deficiency (<191 ng/L) were 27% and 12% in Europeans and Indians, respectively and higher in metformin treated type 2 diabetes patients. In linear regression analysis, after adjusting for all likely confounding factors, vitamin B12 independently associated with triglycerides in both the populations and cholesterol/HDL ratio in Indians. Logistic regression showed type 2 diabetes patients with vitamin B12 deficiency were at significantly higher odds of having coexisting coronary artery disease (CAD) in Europeans with similar but non-significant trend in Indians, after adjusting for all likely confounding factors. CONCLUSIONS: The prevalence of vitamin B12 deficiency is common in type 2 diabetes patients and is associated with adverse lipid parameters. Type 2 diabetes management guidelines should include the recommendation for regular testing for B12 levels, especially for those on metformin.

Managing hyperglycemia in patients with Cushing's disease treated with pasireotide: medical expert recommendations.

To recommend an approach to monitoring and treating hyperglycemia in pasireotide-treated patients with Cushing's disease, a severe clinical condition caused by a pituitary adenoma hypersecreting adrenocorticotropic hormone. Advisory Board meeting of ten European experts in pituitary disease and diabetes mellitus in Munich, Germany, on February 23, 2012, to obtain expert recommendations. Cushing's disease presents a number of management challenges. Pasireotide, a novel agent for the treatment of Cushing's disease with proven biochemical and clinical efficacy, improves outcomes and expands treatment options. Clinical trials have shown that the pasireotide adverse event profile is similar to that of other somatostatin analogs, except for a higher frequency of hyperglycemia. Mechanistic studies in healthy volunteers suggest that pasireotide-associated hyperglycemia is due to reduced secretion of glucagon-like peptide (GLP)-1, glucose-dependent insulinotropic polypeptide, and insulin; however, it is associated with intact postprandial glucagon secretion. Individual patients' results demonstrate effective hyperglycemia management by following standard guidelines for the treatment of diabetes mellitus with individual adaptation to the specific underlying pathophysiology, i.e., preferential use of GLP-1 based-medications. Patients on pasireotide treatment should be monitored for changes in glucose metabolism and hyperglycemia. Diabetes mellitus should be managed by initiation of medical therapy with metformin and staged treatment intensification with a dipeptidyl peptidase-4 inhibitor, with a switch to a GLP-1 receptor agonist and initiation of insulin, as required, to achieve and maintain glycemic control. Further research into hyperglycemia following pasireotide treatment will help refine the optimal strategy in Cushing's disease.

A 6-month "self-monitoring" lifestyle modification with increased sunlight exposure modestly improves vitamin D status, lipid profile and glycemic status in overweight and obese Saudi adults with varying glycemic levels.

BACKGROUND: The over-all age-adjusted prevalence of diabetes mellitus type 2 (DMT2) in Saudi Arabia is unprecedented at 31%. Aggressive measures should be done to curb down increasing incidence. In this prospective 6-month study we aim to determine whether a self-monitoring, life-style modification program that includes increased sunlight exposure confer improvement in vitamin D status and health benefits among adult Saudi overweight and obese patients with varying glycemic status. METHODS: A total of 150 overweight and obese Saudi adults with varying glycemic status aged 30-60 years were included in this study. They were divided into 3 groups (Non-DMT2, Pre-diabetes and DMT2). Baseline anthropometrics and blood glucose were taken at baseline and after 6 months. Fasting blood sugar, lipid profile, calcium, albumin and phosphate were measured routinely. Serum 25(OH) vitamin D was measured using standard assays. Within the time period they were instructed to reduce total intake of fat, increased fiber intake and increase sun exposure. RESULTS: In all groups there was a significant improvement in vitamin D levels as well as serum triglycerides, LDL- and total cholesterol. However, a significant increase in serum glucose levels was noted in the non-DMT2 group, and a significant decrease in HDL-cholesterol in both non-DMT2 and pre-diabetes group. In the pre-diabetes group, 53.2% were able to normalize their fasting blood levels after 6 months, with 8.5% reaching the DMT2 stage and 38.3% remaining pre-diabetic. In all groups there was a significant increase in the prevalence of hypertension. CONCLUSION: Improving vitamin D status with modest lifestyle modifications over a short-period translates to improvement in lipid profile except HDL-cholesterol among overweight and obese Saudi adults, but not BMI and blood pressure. Findings of the present study merit further investigation as to whether full vitamin D status correction can delay or prevent onset of DMT2.

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.

Vitamin D supplementation in patients with diabetes mellitus type 2 on different therapeutic regimens: a one-year prospective study.

BACKGROUND: Little or no research has determined the effect of vitamin D3 supplementation in conjunction with pharmacological and non-pharmacological approaches in the diabetes mellitus type 2 (DMT2) patients. The objective of this study was to determine the effect of vitamin D3 supplementation in a cohort of Saudi DMT2 population on diet, insulin and/or different oral hypoglycemic agents and compare them with a non-DMT2 control cohort. METHODS: A total of 499 randomly selected Saudi subjects divided into 8 groups [Non-DMT2 Control = 151; Rosiglitazone alone = 49; Diet = 15; Insulin alone = 55; Insulin + Orals = 12; Metformin alone = 121; Oral agents combination = 37; Sulphonylurea alone = 59] were included in this 12-month interventional study. All DMT2 patients were given 2000 IU vitamin D3 daily, while the control group received none but were advised to increase sun exposure. Anthropometrics, glucose, lipid profile and 25-hydroxyvitamin D (25-OHVitD) were measured at baseline, 6 and 12 months. RESULTS: Circulating 25-OHVitD concentrations improved in all patient groups. The metformin group showed the highest change in circulating vitamin D levels both at 6 months (62.6%) and 12 months (50.6%) as compared to baseline (p < 0.001). No significant changes were observed in the BMI and glucose in any of the DMT2 groups. In contrast, the insulin + oral agents group showed more significant improvements in the metabolic profile, which included triglycerides and total cholesterol, as well as systolic blood pressure and HDL-cholesterol in males. Also, significant decreases in triglycerides were observed in the rosiglitazone and insulin + oral hypoglycemic agent groups both at 6 and 12 months of supplementation (both p-values <0.001). CONCLUSION: While in all DMT2 groups circulating levels of 25-OHVitD increased after supplementation, in DMT2 patients on insulin in combination with other drugs benefitted the most in improving cardiovascular risk. Metformin improves 25-hydroxyvitamin D levels but did not seem to confer other added cardiometabolic benefits.

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.

Increased vitamin D supplementation recommended during summer season in the gulf region: a counterintuitive seasonal effect in vitamin D levels in adult, overweight and obese Middle Eastern residents.

PURPOSE: Seasonal variations in circulating vitamin D levels provide vital information as to the most appropriate time to either start or increase vitamin D supplementation to maintain optimal vitamin D levels. In this follow-up study, we determined seasonal differences in serum 25(OH)-vitamin D (25(OH)D) levels, as well as parallel changes in metabolic parameters, in a cohort of adult, overweight and obese Saudis. METHODS: A total of 121 adult, overweight, obese, and consenting Saudis aged 18-70 years were randomly recruited from four Primary Health Care Centers in Riyadh, Saudi Arabia. They were divided according to the season when baseline measurements were made [74 summer (April-October); 47 winter (November-March)]. Anthropometrics were obtained, and fasting blood samples were taken at baseline and every 3 months for 1 year. Fasting blood glucose, corrected calcium levels, and lipid profiles were measured routinely. Serum 25(OH)-vitamin D was quantified using a specific enzyme-linked immunosorbent assay (ELISA). RESULTS: Age- and BMI-matched mean 25(OH)-vitamin D levels from the winter group were significantly higher than those of the summer group (P < 0·001). In both groups, HDL-C levels improved significantly as 25(OH)-vitamin D levels increased with subsequent follow-ups, even after adjusting for age, gender and BMI (P < 0·001). CONCLUSION: Seasonal differences in serum 25(OH)-vitamin D levels in Saudi Arabia are counterintuitive, with circulating levels being higher during the winter than the summer season. Increased vitamin D supplementation is thus recommended to maintain optimal serum 25(OH)-vitamin D levels during the summer season.

Vitamin D supplementation as an adjuvant therapy for patients with T2DM: an 18-month prospective interventional study.

BACKGROUND: Vitamin D deficiency has been associated with impaired human insulin action, suggesting a role in the pathogenesis of diabetes mellitus type 2 (T2DM). In this prospective interventional study we investigated the effects of vitamin D3 supplementation on the metabolic profiles of Saudi T2DM subjects pre- and post-vitamin D supplementation over an 18-month period. METHODS: T2DM Saudi subjects (men, N = 34: Age: 56.6 ± 8.7 yr, BMI, 29.1 ± 3.3 kg/m2; women, N = 58: Age: 51.2 ± 10.6 yr, BMI 34.3 ± 4.9 kg/m2;) were recruited and given 2000 IU vitamin D3 daily for 18 months. Anthropometrics and fasting blood were collected (0, 6, 12, 18 months) to monitor serum 25-hydroxyvitamin D using specific ELISA, and to determine metabolic profiles by standard methods. RESULTS: In all subjects there was a significant increase in mean 25-hydroxyvitamin D levels from baseline (32.2 ± 1.5 nmol/L) to 18 months (54.7 ± 1.5 nmol/L; p < 0.001), as well as serum calcium (baseline = 2.3 ± 0.23 mmol/L vs. 18 months = 2.6 ± 0.1 mmol/L; p = 0.003). A significant decrease in LDL- (baseline = 4.4 ± 0.8 mmol/L vs. 18 months = 3.6 ± 0.8 mmol/L, p < 0.001] and total cholesterol (baseline = 5.4 ± 0.2 mmol/L vs. 18 months = 4.9 ± 0.3 mmol/L, p < 0.001) were noted, as well as a significant improvement in HOMA-ß function (p = 0.002). Majority of the improvements elicited were more prominent in women than men. CONCLUSION: In the Saudi T2DM population receiving oral Vitamin D3 supplementation (2000 IU/day), circulating 25-hydroxyvitamin D levels remained below normal 18 months after the onset of treatment. Yet, this "suboptimal" supplementation significantly improved lipid profile with a favorable change in HDL/LDL ratio, and HOMA-ß function, which were more pronounced in T2DM females.

Tea and coffee consumption in relation to vitamin D and calcium levels in Saudi adolescents.

BACKGROUND: Coffee and tea consumption was hypothesized to interact with variants of vitamin D-receptor polymorphisms, but limited evidence exists. Here we determine for the first time whether increased coffee and tea consumption affects circulating levels of 25-hydroxyvitamin D in a cohort of Saudi adolescents. METHODS: A total of 330 randomly selected Saudi adolescents were included. Anthropometrics were recorded and fasting blood samples were analyzed for routine analysis of fasting glucose, lipid levels, calcium, albumin and phosphorous. Frequency of coffee and tea intake was noted. 25-hydroxyvitamin D levels were measured using enzyme-linked immunosorbent assays. RESULTS: Improved lipid profiles were observed in both boys and girls, as demonstrated by increased levels of HDL-cholesterol, even after controlling for age and BMI, among those consuming 9-12 cups of coffee/week. Vitamin D levels were significantly highest among those consuming 9-12 cups of tea/week in all subjects (p-value 0.009) independent of age, gender, BMI, physical activity and sun exposure. CONCLUSION: This study suggests a link between tea consumption and vitamin D levels in a cohort of Saudi adolescents, independent of age, BMI, gender, physical activity and sun exposure. These findings should be confirmed prospectively.

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.

Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance.

PPARgamma is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARgamma in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARgamma coactivators and inhibit coexpressed wild-type receptor. Expression of PPARgamma target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARgamma action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.