An Increasing Triglyceride-Glucose Index Is Associated with a Pro-Inflammatory and Pro-Oxidant Phenotype.

Background/Objectives: Insulin resistance is crucial in the pathogenesis of Metabolic Syndrome (MetS), type 2 diabetes mellitus (T2DM) and premature atherosclerotic cardiovascular disease (ASCVD). The triglyceride-glucose index (TyG index), a validated measure of insulin resistance, also predicts MetS, T2DM, the severity of albuminuria and ASCVD. There are scant data providing mechanistic insights into these sequalae. Accordingly, we investigated the relationship between the TyG index and biomarkers of inflammation, oxidative stress, free fatty acid (FFA) levels and adipokine dysregulation in a cohort comprising both controls and patients with nascent MetS. Methods: Participants (n = 102) included 59 patients with MetS and 43 controls. People with diabetes, ASCVD, smoking and macro-inflammation were excluded. Fasting blood was obtained for both plasma and monocyte isolation. Results: Receiver Operating Characteristic (ROC) curve analysis revealed that the TyG index was an excellent predictor of MetS with an area under the curve of 0.87, and it correlated with both hepatic and adipose tissue insulin resistance. Both serum RBP-4 levels and non-HDL cholesterol increased significantly over tertiles of the TyG index. Based on the TyG index tertiles and/or correlations, oxidized LDL, nitrotyrosine, C-reactive protein, endotoxin, chemerin, interleukin-6 levels and monocyte toll-like receptor (TLR)-4 and TLR-2 and their cellular signaling were significantly associated with the TyG index. Conclusions: Increased non-HDL-C and, most importantly, a pro-inflammatory and pro-oxidant state could be advanced as potential mechanisms explaining the increased risk for T2DM and ASCVD with an increasing TyG index.

Increased Adipocyte Hypertrophy in Patients with Nascent Metabolic Syndrome.

Background and Aims: Metabolic Syndrome (MetS), a global problem, predisposes to an increased risk for type 2 diabetes and premature cardiovascular disease. While MetS is associated with central obesity, there is scanty data on adipocyte hypertrophy, increased fat cell size (FCS), in MetS. The aim of this study was to investigate FCS status in adipose tissue (AT) biopsy of patients with nascent MetS without the confounding of diabetes, cardiovascular disease, smoking, or lipid therapy. Methods and Results: Fasting blood and subcutaneous gluteal AT biopsies were obtained in MetS (n = 20) and controls (n = 19). Cardio-metabolic features, FFA levels, hsCRP, and HOMA-IR were significantly increased in patients with MetS. Waist-circumference (WC) adjusted-FCS was significantly increased in patients with MetS and increased with increasing severity of MetS. Furthermore, there were significant correlations between FCS with glucose, HDL-C, and the ratio of TG: HDL-C. There were significant correlations between FCS and FFA, as well as endotoxin and monocyte TLR4 abundance. Additionally, FCS correlated with readouts of NLRP3 Inflammasome activity. Most importantly, FCS correlated with markers of fibrosis and angiogenesis. Conclusions: In conclusion, in patients with nascent MetS, we demonstrate WC-adjusted increase in FCS from gluteal adipose tissue which correlated with cellular inflammation, fibrosis, and angiogenesis. While these preliminary observations were in gluteal fat, future studies are warranted to confirm these findings in visceral and other fat depots.

Correlates of Insulin Resistance in Nascent Metabolic Syndrome.

Background: Metabolic Syndrome (MetS), a major global problem, is a cluster of cardio-metabolic risk factors that predisposes to both type 2 diabetes mellitus (T2DM) and premature atherosclerotic cardiovascular disease (ASCVD). Insulin resistance is a major underpinning of MetS. Objectives: We investigated the relationship between insulin resistance and biomarkers of inflammation, oxidative stress, free fatty acids (FFA) levels and adipokine dysregulation in a cohort of nascent MetS. Design: This was a cross-sectional study comparing patients with MetS with matched controls. Patients and Methods: Participants included 47 patients with MetS and 41 controls. Persons with diabetes, ASCVD, smoking and macro-inflammation were excluded. Fasting blood was obtained for both plasma and monocyte isolation. Homeostasis model assessment insulin resistance index (HOMA-IR) was calculated from fasting glucose and insulin levels. Results: The patients were insulin resistant as determined by a valid measure, HOMA-IR. HOMA-IR increased with increasing severity of MetS and correlated with cardio-metabolic features, hsCRP, FFA levels, and adipose tissue insulin resistance. Insulin resistance also correlated with biomarkers of oxidative stress and both circulating and cellular biomarkers of inflammation. Receiver operating Characteristic (ROC) curve analysis revealed that HOMA-IR was an excellent predictor of MetS with an area under the curve of 0.80. Conclusion: In our patients with nascent MetS we show that they have significant insulin resistance. Based on our findings, elevated FFA levels, oxidative stress and inflammation could contribute to the insulin resistance.

Comparison of the triglyceride-waist circumference and the C-reactive protein-waist circumference indices in nascent metabolic syndrome.

The Hypertriglyceridemia waist (HTGW) appears to be a valid measure of visceral adiposity, metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD). Since the cut points differ for different race groups recent studies have instead used the simplified product of triglycerides and waist circumference (TG.WC). In our patients with nascent MetS (without the confounding of T2DM, ASCVD, smoking and macro-inflammation) we found that only 41% had an increased HTGW. Since MetS is a pro-inflammatory disorder we compared the product of CRP to WC (CRP.WC) to TG.WC in our patients with nascent MetS as biomarkers. Patients with MetS (n=58) and matched controls (n=44) were recruited. Fasting blood samples were obtained for routine laboratories including the lipid profile, insulin, and adipokines. Both the TG.WC and CRP.WC indices were significantly increased in MetS and both increased with increasing severity of MetS. Whilst both correlated with cardio-metabolic features and insulin resistance, only the CRP.WC correlated significantly with adiponectin, an adipokine largely deriving from visceral adipose tissue. The TG.WC correlated with LDL-cholesterol which was not increased in this group. Receiver Operating Characteristic (ROC) curve analysis showed that both ratios showed good discrimination for MetS with no significant differences between ratios. Thus both the TG.WC and CRP.WC indices are significantly increased in patients with nascent MetS and appear to be valid biomarkers of MetS.

Hypophosphatemia in acute liver failure of a broad range of etiologies is associated with phosphaturia without kidney damage or phosphatonin elevation.

Hypophosphatemia is a common and dangerous complication of acute liver failure (ALF) of various etiologies. While various mechanisms for ALF-associated hypophosphatemia have been proposed including high phosphate uptake into regenerating hepatocytes, acetaminophen (APAP)-associated hypophosphatemia was linked to renal phosphate wasting, and APAP-induced renal tubular injury was proposed as underlying mechanism. We studied 30 normophosphatemic and 46 hypophosphatemic (serum phosphate < 2.5 mg/dL) patients from the Acute Liver Failure Study Group registry with APAP- or non-APAP-induced ALF. Since kidney injury affects phosphate excretion, patients with elevated serum creatinine (>1.2 mg/dL) were excluded. Maximal amount of renal tubular phosphate reabsorption per filtered volume (TmP/GFR) was calculated from simultaneous serum and urine phosphate and creatinine levels to assess renal phosphate handling. Instead of enhanced renal phosphate reabsorption as would be expected during hypophosphatemia of non-renal causes, serum phosphate was positively correlated with TmP/GFR in both APAP- and non-APAP-induced ALF patients (R2 = 0.66 and 0.46, respectively; both P < 0.0001), indicating renal phosphate wasting. Surprisingly, there was no evidence of kidney damage based on urinary markers including neutrophil gelatinase-associated lipocalin and cystatin C even in the APAP group. Additionally, there was no evidence that the known serum phosphatonins parathyroid hormone, fibroblast growth factor 23, and α-Klotho contribute to the observed hypophosphatemia. We conclude that the observed hypophosphatemia with renal phosphate wasting in both APAP- and non-APAP-mediated ALF is likely the result of renal tubular phosphate leak from yet-to-be identified factor(s) with no evidence for proximal tubular damage or contribution of known phosphatonins.

Impact of age and renal function on urine chemistry in patients with calcium oxalate kidney stones.

Nephrolithiasis is associated with an increased risk of chronic kidney disease, and its incidence varies with age. However, little is known on the combined impact of aging and declining renal function on urinary risk factors for calcium oxalate stone formation. A retrospective analysis was performed on 24-h urine collections from 993 calcium oxalate stone-forming patients. We first tested for interactions between age and creatinine clearance on various urinary determinants of calcium oxalate nephrolithiasis, and then examined their separate and combined effects in univariable and multivariable analyses adjusting for demographic and biochemical covariates. We identified significant interactions between age and creatinine clearance in predicting 24-h urine pH, calcium, and citrate. In view of the small number of stone formers with low creatinine clearance, we limited further regression analyses to patients with creatinine clearance ≥ 60 mL/min. In multivariable analyses, urine citrate, oxalate, and total volume were positively correlated with age, whereas urine pH, citrate, calcium, oxalate, total volume, and RSR of calcium oxalate all significantly decreased with lower creatinine clearance. A decrease in creatinine clearance from 120 to 60 mL/min was associated with clinically significant decreases in the daily excretion rate of citrate (by 188 mg/day), calcium (by 33 mg/day), and oxalate (by 4 mg/day), and in RSR calcium oxalate (by 1.84). Age and creatinine clearance are significant and independent predictors of several urinary determinants of calcium oxalate nephrolithiasis. The impacts of aging and declining renal function should be considered during the management of calcium oxalate stone-forming patients.

The platelet to high density lipoprotein -cholesterol ratio is a valid biomarker of nascent metabolic syndrome.

AIMS: The metabolic syndrome (MetS) is a major global problem, and inflammation and insulin resistance appear to be key underpinnings in this cardio-metabolic cluster. MetS predisposes to an increased risk of diabetes and atherosclerotic cardiovascular disease (ASCVD). It has a procoagulant diathesis which included increased platelet activity and impaired fibrinolysis. High density lipoprotein (HDL) appears to be anti-thrombotic. Accordingly, we examined the ratios between platelets to HDL-cholesterol(C) and adiponectin (Adipo) in patients with nascent MetS without the confounding of diabetes, ASCVD and smoking to determine their validity as biomarkers of MetS. METHODS: Patients with nascent MetS (n = 58) and matched controls (n = 44) were recruited. Fasting blood samples were obtained for complete blood counts, basic metabolic panel, lipids, insulin, and Adipo. Ratios of platelets to HDL-C and Adipo were calculated. RESULTS: Following adjustment for adiposity, only the platelet: HDL ratio was significantly increased in MetS and increased with severity of MetS. Receiver operating characteristic curve analysis showed that the platelet: HDL-C area under the curve (AUC) significantly added to both platelets and platelet lymphocyte ratio AUCs. Also the platelet: HDL-C ratio correlated with all cardio-metabolic features of MetS, high sensitivity C-reactive protein, insulin resistance chemerin, and leptin. CONCLUSIONS: The ratio of platelets: HDL-C is significantly increased in patients with nascent MetS and appear to be a valid biomarker of MetS. It could also emerge as a biomarker for athero-thrombotic risk. However, these preliminary findings need confirmation in large prospective studies.

Increased inflammasome activity in subcutaneous adipose tissue of patients with metabolic syndrome.

AIMS: The metabolic syndrome (MetS) is an inflammatory disorder associated with an increased risk for diabetes and atherosclerotic cardiovascular disease (ASCVD). Studies in patients and animal models of obesity and diabetes have shown increased NOD-like receptor family pyrin domain containing 3 (NLPR3) inflammasome activity. However, there is scanty data on the activity of the NLRP3 inflammasome in patients with nascent MetS. The aim of this study was to determine the status of the inflammasome in subcutaneous adipose tissue (SAT) of patients with nascent MetS without concomitant diabetes, ASCVD and smoking. MATERIALS AND METHODS: Patients with nascent MetS and controls were recruited from Sacramento County. Fasting blood samples were collected for biomediators of inflammation and SAT was obtained by biopsy for immunohistochemical (IHC) staining for caspase 1, IL-1ß and IL-18. RESULTS: Caspase1, a marker of inflammasome activity and its downstream mediators IL-1ß and IL-18 were significantly increased in SAT of patients with MetS compared to controls. Significant positive correlations of caspase 1 were obtained with certain cardio-metabolic features, biomediators of inflammation and markers of angiogenesis and fibrosis in SAT. Both mast cell and eosinophil abundance but not macrophage density correlated with caspase1. CONCLUSIONS: We make the novel observation that the SAT of patients with nascent MetS displays increased NLRP3 inflammasome activity manifest by increased caspase 1 in SAT and this may contribute to increased insulin resistance, inflammation and SAT fibrosis in these patients.

Chemerin Ratios to HDL-cholesterol and Adiponectin as Biomarkers of Metabolic Syndrome.

AIMS: Metabolic Syndrome (MetS) a global problem, which comprises a cardio-metabolic cluster of risk factors, increases the risk for type-2 diabetes (T2DM) and atherosclerotic cardiovascular diseases (ASCVD). To date, the best laboratory-based biomarker for MetS appears to be high-sensitivity C-reactive protein (hsCRP). Chemerin, a novel adipokine is increased in MetS and appears to contribute to both insulin resistance and inflammation. In this pilot study, we tested if the chemerin:HDL-C or chemerin:adiponectin ratios are better biomarkers for predicting MetS than hsCRP. PATIENTS AND METHODS: We enrolled patients and controls with nascent MetS, uncomplicated by diabetes, ASCVD, macro-inflammation, and smoking using rigorous criteria. Fasting blood samples were obtained in order to calculate insulin resistance in the liver (HOMA-IR) and adipose tissue (ADIPO-IR) and for measurement of chemerin and adiponectin levels. Statistical analyses including receiver operating characteristic (ROC) curves were used to evaluate data. RESULTS: We observed the chemerin:HDL-C ratio is significantly increased in MetS and increases with severity of MetS (p < .001). The chemerin: adiponectin ratio was not significantly increased following adjustment for age and waist circumference. The chemerin:HDL-C ratio correlated with BMI, WC, triglycerides, plasma glucose, HDL-C, and both HOMA-IR and ADIPO-IR. ROC curve analysis showed that the chemerin:HDL-C ratio area under the curve (AUC) was greater than the AUC for hsCRP. CONCLUSION: In this preliminary report, we demonstrate that the ratio of chemerin to HDL-C is a valid biomarker of MetS and appears to be a better predictor than hsCRP. These findings need to be confirmed in larger studies.

Neutrophil and monocyte ratios to high-density lipoprotein-cholesterol and adiponectin as biomarkers of nascent metabolic syndrome.

Background Metabolic syndrome (MetS) continues to be a significant problem globally, affecting nearly 35% of adults in the USA. Whilst there is no ideal biomarker that captures this disorder, high sensitivity C-reactive protein (hsCRP) appears to be most widely accepted. We examined the ratios between neutrophils (PMNs) and monocytes to high-density lipoprotein (HDL)-cholesterol and adiponectin, two anti-inflammatory proteins, in patients with nascent MetS without the confounding of diabetes, atherosclerotic cardiovascular diseases (ASCVD), smoking or lipid therapy to determine if they were also valid biomarkers of MetS. Materials and methods Patients with nascent MetS (n = 58) and matched controls (n = 44) were recruited from Sacramento County. Fasting blood samples were obtained for complete blood counts, basic metabolic panel, lipid profile, insulin and adiponectin. Ratios of PMNs and monocytes to HDL-C and adiponectin were calculated and compared statistically. Results The PMN:HDL-C, monocyte:HDL-C, PMN:adiponectin and monocyte:adiponectin ratios were significantly increased in patients with MetS and increased with increasing severity of MetS. Receiver operating characteristic (ROC) curve analysis showed that both the PMN:HDL-C and monocyte:HDL-C areas under the curve (AUCs) significantly added to the CRP AUC. Also both the ratios correlated with cardio-metabolic features of MetS, hsCRP and insulin resistance. Conclusions Our data indicates that ratios of neutrophils and monocytes to HDL-C are significantly increased in patients with nascent MetS and both ratios appear to be better predictors of MetS than hsCRP alone. These important preliminary findings need to be confirmed in large prospective databases.

The relationship between tyramine levels and inflammation in metabolic syndrome.

Background Metabolic syndrome (MetS) is an important contributor to both type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD). Although MetS affects one third of American adults, its pathogenesis remains to be elucidated. Tyramine, a derivative of tyrosine, has been shown to act as a catecholamine releasing agent in the human body. The aim of this study is to investigate the role of tyramine as an early biomarker for nascent MetS without the confounding of T2DM, ASCVD or smoking. Patients and methods This was an exploratory study of 28 patients with nascent MetS and 20 matched controls carried out in 2018. Metabolites were evaluated from patient's frozen early morning urine samples and were correlated with biomarkers of inflammation and adipokines. They were assayed by the National Institutes of Health (NIH) Western Metabolomics Center using liquid chromatography/mass spectrometry (LC/MS) and standardized to urinary creatinine. All patients had normal hepatic and renal function. Results Tyramine concentrations were significantly reduced in patients with MetS compared to controls, p = 0.0009. In addition, tyramine was significantly inversely correlated with multiple biomarkers of inflammation and cardiometabolic risk factors such as RBP4, monocyte TLR-4 abundance and P38MAPKinase activity, body mass index (BMI) and blood pressure (BP) (both systolic and diastolic). Conclusion In conclusion, low levels of tyramine could contribute to the proinflammatorty state of MetS.

Increased eosinophils in adipose tissue of metabolic syndrome.

AIMS: Metabolic Syndrome (MetS) is a common global disorder that predisposes to both Type 2 diabetes mellitus (T2DM) and cardiovascular disease (ASCVD). Adipose tissue (AT) contributes significantly to increased inflammation and insulin resistance (IR) in MetS which appear to be the crucial underpinnings of MetS. Compared to macrophages and lymphocytes in human subcutaneous AT (SAT), there is sparse data on the role of other immune cells, especially eosinophils (EOS). In this study, we investigated the abundance of EOS in the SAT of 19 patients with MetS without diabetes, ASCVD, smoking or any inflammatory condition, and matched controls. METHODS: SAT EOS were quantified by immunohistochemistry. RESULTS: Both circulating and SAT EOS were significantly increased 2-fold in MetS and correlated with each other. Circulating EOS correlated significantly with triglycerides (TG), high-sensitivity CRP, leptin, and IL-6. SAT EOS correlated significantly with plasma glucose, TG, FFA, adipose-IR, leptin, IL-6, endotoxin, chemerin and inversely with adiponectin. They also correlated with SAT markers of fibrosis: collagen and Sirius red staining of SAT. CONCLUSION: We make the novel and seminal observation that eosinophils are increased in SAT of MetS patients, and are associated with the pro-inflammatory state. Hence, in humans, they appear to contribute to the dysregulation of SAT biology in MetS.

A Team Disclosure of Error Educational Activity: Objective Outcomes.

Medical errors can involve multiple team members. Few curricula are being developed to provide instruction on disclosing medical errors that include simulation training with interprofessional team disclosure. To explore more objective evidence for the value of an educational activity on team disclosure of errors, faculty developed and assessed the effectiveness of a multimodal educational activity for learning team-based disclosure of a medical error. This study employed a methodological triangulation research design. Participants (N = 458) included students enrolled in academic programs at three separate institutions. The activity allowed students to practice team communication while: (1) discussing a medical error within the team; (2) planning for the disclosure of the error; and (3) conducting the disclosure. Faculty assessed individual student's change in knowledge and, using a rubric, rated the performance of the student teams during a simulation with a standardized family member (SFM). Students had a high level of preexisting knowledge and demonstrated the greatest knowledge gains in questions regarding the approach to disclosure (P < .001) and timing of an apology (P < .001). Both SFMs and individual students rated the team error disclosure behavior highly (rho = 0.54; P < .001). Most participants (more than 80%) felt the activity was worth their time and that they were more comfortable with disclosing a medical error as a result of having completed the activity. This activity for interprofessional simulation of team-based disclosure of a medical error was effective for teaching students about and how to perform this type of important disclosure.

Increased mast cell abundance in adipose tissue of metabolic syndrome: relevance to the proinflammatory state and increased adipose tissue fibrosis.

Metabolic Syndrome (MetS) affects 35% of American adults > 40 yr and portends an increased risk for both atherosclerotic cardiovascular disease (ASCVD) and diabetes. The role of mast cells in the proinflammatory state of MetS is not well elucidated. We propose that mast cells in subcutaneous adipose tissue (SAT) of MetS patients without diabetes or clinical ASCVD contribute to insulin resistance and inflammation. Matched controls ( n = 15) and MetS ( n = 19) subjects were recruited from Sacramento, CA, and selected based on Adult Treatment Panel III criteria. SAT biopsy was performed on all subjects and processed for immunohistochemistry. The SAT sections were stained using Astra Blue stain and tryptase stain for mast cells. Fasting blood was obtained for chemistries and biomarkers. Abundance of mast cells (Astra Blue stain) in SAT of MetS subjects compared with controls was increased 2.5-fold ( P < 0.0001). Mast cells correlated positively and significantly with waist circumference, glucose, triglycerides, homeostatic model of assessment-insulin resistance (HOMA-IR), AT insulin resistance, leptin, interleukin (IL)-1ß, IL-6, chemerin, p38 MAPK activity, and nuclear factor κB activity in circulating monocytes. Mast cells also correlated significantly with markers of fibrosis and angiogenesis. Tryptase staining of mast cells in AT revealed a significant increase ( P = 0.008) with similar correlations. We make the novel observation that there are increased mast cells in SAT of MetS, and these mast cells correlate with insulin resistance (hepatic and adipose tissue), inflammation, and AT fibrosis. Hence, these immune cells appear to occupy a pivotal role in the pathogenesis of MetS.

Improved Survival in Surgically Resected Distal Cholangiocarcinoma Treated with Adjuvant Therapy: a Propensity Score Matched Analysis.

BACKGROUND: Data on the efficacy of adjuvant therapy (AT) in distal cholangiocarcinoma (dCCA) is limited. This study aimed to determine the role of AT in resected dCCA and identify subgroups that benefit from AT. METHODS: We conducted a retrospective review of surgically resected dCCA in the NCDB from 2004 to 2013. Patients who received AT or observation (OB) were matched by propensity score. Log-rank test was used to compare OS. RESULTS: Of 1782 patients with resected dCCA, 840 (47%) were in the OB group and 942 (53%) in the AT group. AT was younger (64.0 vs. 68.7 years, p < 0.001), had less comorbidities (Charlson Deyo score 0) (74.6 vs. 68.0%, p < 0.001), and more likely to have private insurance (p < 0.001). AT was more likely to present with T3/T4 stage (72 vs. 57%, p < 0.001), N1/N2 disease (58 vs. 37%, p < 0.001), and positive surgical margins (26 vs. 16%, p < 0.001). After 1:1 propensity score matching, 500 OB and 500 AT patients were compared. AT was associated with better OS (HR 0.79; 95% CI 0.67-0.93). Median OS was 31 and 25 months for the AT and OB (p = 0.006). The 1-, 3-, and 5-year survival rates were 87, 46, and 31% for AT; 79, 39, and 24% for OB. Subgroup analysis revealed an associated survival advantage for AT in T3/T4 tumors (HR = 0.72; 95% CI 0.59-0.89), node positive disease (HR 0.70; 95% CI 0.56-0.87), and positive margins (HR 0.58; 95% CI 0.42-0.81). CONCLUSION: AT is associated with improved OS in resected dCCA, especially in T3/T4 tumors, node positive disease, and positive margins.

Roux-en-Y gastric bypass compared with equivalent diet restriction: Mechanistic insights into diabetes remission.

AIMS: To investigate the physiological mechanisms leading to rapid improvement in diabetes after Roux-en-Y gastric bypass (RYGB) and specifically the contribution of the concurrent peri-operative dietary restrictions, which may also alter glucose metabolism. MATERIALS AND METHODS: In order to assess the differential contributions of diet and surgery to the mechanisms leading to the rapid improvement in diabetes after RYGB we enrolled 10 patients with type 2 diabetes scheduled to undergo RYGB. All patients underwent a 10-day inpatient supervised dietary intervention equivalent to the peri-operative diet (diet-only period), followed by, after a re-equilibration (washout) period, an identical period of pair-matched diet in conjunction with RYGB (diet and RYGB period). We conducted extensive metabolic assessments during a 6-hour mixed-meal challenge test, with stable isotope glucose tracer infusion performed before and after each intervention. RESULTS: Similar improvements in glucose levels, ß-cell function, insulin sensitivity and post-meal hepatic insulin resistance were observed with both interventions. Both interventions led to significant reductions in fasting and postprandial acyl ghrelin. The diet-only intervention induced greater improvements in basal hepatic glucose output and post-meal gastric inhibitory polypeptide (GIP) secretion. The diet and RYGB intervention induced significantly greater increases in post-meal glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and glucagon levels. CONCLUSIONS: Strict peri-operative dietary restriction is a main contributor to the rapid improvement in glucose metabolism after RYGB. The RYGB-induced changes in the incretin hormones GLP-1 and PYY probably play a major role in long-term compliance with such major dietary restrictions through central and peripheral mechanisms.

The prevalence and etiology of extreme hypertriglyceridemia in children: Data from a tertiary children's hospital.

BACKGROUND: Extreme hypertriglyceridemia (eHTG; serum triglycerides ≥ 2000 mg/dL) poses a significant risk for acute pancreatitis. There is paucity of data regarding the prevalence and etiology of eHTG in children. OBJECTIVE: To determine the prevalence, clinical features and etiologies of patients with eHTG at a tertiary children's hospital in the United States and in the United States National Health and Nutrition Examination Survey (NHANES). METHODS: A retrospective analysis was conducted of the electronic medical records of the Children's Medical Center, Dallas, from 2000-2015, and the NHANES data from 2005-2014 for eHTG. RESULTS: Of 30,623 children, 36 (∼ 1 in 1000) had eHTG and one-third of them developed acute pancreatitis. They tended to be female (61%), Hispanic (39%), and nonobese (median body mass index z-score 1.60 and 1.25 in males and females, respectively). Most patients had secondary causes such as uncontrolled diabetes mellitus (30%), L-asparaginase and high-dose corticosteroid therapy for acute lymphoblastic leukemia (28%), and sirolimus/tacrolimus therapy after solid organ transplantation (14%). Five patients (14%) had type 1 hyperlipoproteinemia (T1HLP; familial chylomicronemia syndrome). The NHANES data revealed that none of the 2362 children had eHTG, and the prevalence in adults was 0.02%. CONCLUSIONS: Extreme HTG is rare in children and majority of the children had secondary causes. Patients with diabetes mellitus or receiving drugs, such as, L-asparaginase, corticosteroids, and sirolimus, should be closely monitored for eHTG. Prevalence of T1HLP is approximately 1 in 6000 at a tertiary care center with an estimated population prevalence of 1 in 3,00,000. Early neonatal screening and intervention for T1HLP can prevent life-threatening morbidities such as acute pancreatitis.

Metabolic response 4 years after gastric bypass in a complete cohort with type 2 diabetes mellitus.

AIMS: To evaluate the long-term remission rates of type 2 diabetes mellitus and associated comorbidities after gastric bypass surgery in a complete cohort, in a real-life clinic setting. METHODS: A retrospective study of all consecutive patients with type 2 diabetes mellitus who underwent gastric bypass at a Veterans Affairs Medical Center from 2003 to 2010. The main outcome was remission of type 2 diabetes mellitus defined as HbA1c <6.5% (49 mmol/mol) without diabetic medication usage. Secondary outcomes were remission of hypertension and hyperlipidemia, weight loss, and long-term complications four years post-gastric bypass. RESULTS: Eighty-four patients with type 2 diabetes mellitus underwent gastric bypass. Four-year follow-up data were available for 92% (77/84) of patients. The patients (73% male; mean age 54 years) had a mean body mass index of 49 kg/m2 ±â€¯8.3. Hypertension and hyperlipidemia prevalence were 92% and 85%, respectively. The mean total body weight decrease over four years was 35 kg ±â€¯21. Remission of type 2 diabetes mellitus occurred in 15% at 6 months and 49% four years after surgery. Diabetes remission was more likely (OR 3.2; 95% confidence interval 1.2-9.7) in patients not using insulin at baseline. Remission rates were 12% (9/74) for hypertension and 16% (11/68) for hyperlipidemia. Long-term surgical complications included reoperation (11%), incisional hernia (10%) and anastomotic ulcer (10%). Forty-four percent of patients had one or more nutritional complications. CONCLUSIONS: The metabolic effects of gastric bypass are significant and durable for at least four years, even in a predominantly male cohort and real-life clinical setting.

The Differential Effects of Human Immunodeficiency Virus and Hepatitis C Virus on Bone Microarchitecture and Fracture Risk.

Background: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected individuals have a significantly greater osteoporotic fracture risk than HIV-monoinfected persons, despite the fact that HIV/HCV coinfection has not been associated with lower bone mineral density (BMD) than HIV or HCV alone. To evaluate if changes in bone microarchitecture, measured by trabecular bone score (TBS), could explain these differences, we performed a prospective, cross-sectional cohort study of virologically suppressed HIV-infected subjects, untreated HCV-infected subjects, HIV/HCV-coinfected subjects, and uninfected controls. Methods: We enrolled 532 male subjects: 57 HIV/HCV coinfected, 174 HIV infected, 123 HCV infected, and 178 controls. We conducted analysis of covariance comparing BMD and TBS between groups, controlling for age, race, body mass index, and smoking. We used linear regression to evaluate predictors of BMD and TBS and evaluated the effects of severity of HCV infection and tenofovir disoproxil fumarate use. Results: Despite both infections being associated with decreased BMD, only HCV, but not HIV, was associated with lower TBS score. Also, HIV/HCV-coinfected subjects had lower TBS scores than HIV-monoinfected, HCV-monoinfected, and uninfected subjects. Neither the use of TDF or HCV viremia nor the severity of HCV liver disease was associated with lower TBS. Conclusions: HCV infection is associated with microarchitectural changes at the lumbar spine as assessed by the low TBS score, suggesting that microstructural abnormalities underlie some of the higher fracture risk in HCV infection. TBS might improve fracture risk prediction in HCV infection.

A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation.

Background: Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods: We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results: Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions: Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.