bluuebunny/crossref_metadata_2025 huggingface dataset:
Carotid Intima Media Thickness in Young Peruvians With Onset of Type 2 Diabetes Mellitus, an Early Marker of Vascular Compromise
Authors: Manrique Helard Andres , Nuñez Pedro
Published: May 2021

Objective: To evaluate the relationship between the thickness of the carotid intima media (GIMT) with clinical and laboratory parameters in young people to identify asymptomatic endothelial dysfunction and prevent future vascular complications. Methods: This is a cross-sectional study of 81 adolescents from 10 to 18 years of age distributed in three groups: (i) 27 with onset of type 2 diabetes (DM2), (ii) 22 were non-diabetic obese; and (iii) 32 with normal weight, non-diabetic BMI from a National Reference Hospital in Lima, Peru. Laboratory evaluation consisted of fasting glucose levels, HbA1C, lipid profile, us-CRP, and Doppler ultrasound for measurement of the common carotid artery (right and left, both?). Results: In total 81 participants, 27 of them with a previous diagnosis of type 2 diabetes mellitus, of which 22 obese patients without the onset of type 2 diabetes mellitus and 32 normal weight without onset of type 2 diabetes mellitus, the median for age was 20, 19.5 and 20 years respectively, with a predominance of the female sex in the three groups; the median time of illness in years for the study group was 6 years (IQR 3–8) with DM2; Regarding treatment, metformin was the main drug used (20 patients) followed by sulfonylureas (glimepiride and glyburide, 9 patients), insulin (7 patients) and DPP4 inhibitors (vildagliptin and sitagliptin, 06 patients); Differences were found between the groups of patients with DM2, obese patients without DM2, and normal weight subjects without DM2, this difference being stronger in terms of body mass index (26.29, 31.35, 23.73 kg / m2, respectively); abdominal girth (91, 97.25, 78 cm, respectively); fasting blood glucose (126, 87.5, 94 mg / dl, respectively); glycosylated hemoglobin (7.77, 4.85, 4.97%, respectively), all of these with a p: 0.001; diastolic blood pressure (74, 68, 64 mmHg, respectively); and triglycerides (112, 112.5 and 65.5 mg / dl, respectively); The median IMT ± iqr was 0.430 ± 0.08 mm in adolescents with DM2; 0.420 ± 0.03 mm, in non-diabetic obese adolescents; and 0.405 mm ± 0.02 mm, in non-diabetic adolescents with normal weight. In general, lean, non-diabetic adolescents had a lower IMT than adolescents with DM2 (p = 0.003) and obese adolescents (p = 0.006). Conclusions: Adolescents with DM2 had a higher median IMT compared to lean, non-diabetic adolescents that reflect the onset of early vascular damage due to DM 2.
Epigenetic Programming Reverses Cardiometabolic Dysfunctions and Modulates Hypothalamic Genes Involved in Oxidative Stress and Inflammation in Angiotensin II-Treated Male Mice
Authors: Elgazzaz Mona , Mauvais-Jarvis Franck , Lazartigues Eric
Published: May 2021

Cardiometabolic disease is a global health issue that affects millions of people worldwide. Environmental perinatal exposure affects the health outcomes of the offspring and determines their disease susceptibility later in life. Angiotensin-II (Ang-II) is a peptide known to cause vasoconstriction, elevated blood glucose levels and inflammation. Previously, we reported that perinatal exposure to a hypercaloric diet (HD) results in elevated blood pressure (BP), weight gain, fasting hyperglycemia and glucose intolerance only in male mice. In addition, subcutaneous infusion of a sub-pressor dose of Ang-II was associated with a normalization in fasting blood glucose levels and a reversal of glucose intolerance only in programmed male mice. We hypothesize that epigenetic programming blocks the deleterious effects of Ang-II by altering its inflammatory signaling pathway. C57BL6/J dams were fed HD or regular diet (RD) for 1 month before mating with RD-fed males. After weaning, offspring of HD dams (programmed) and of RD dams (controls) were maintained on RD until 3 months of age. Mice then underwent 24 h BP recording (telemetry) and were implanted with Ang-II osmotic pumps (200 ng/kg/min/2 weeks). BP (24 h) was recorded weekly for 2 weeks. Mice were then sacrificed and hypothalami were harvested for mRNA sequencing (Illumina NextSeq). Programmed mice had lower 24 h systolic BP levels compared to control males (area under the curve: 41844 ±263.2 vs. 44522 ±275.6; p<0.0001). For RNAseq analysis, data showed 62 differentially expressed genes (DEG) in programmed males compared to controls. Using iPathway analysis, we found that some of the DEG are correlated to cholinergic synapse pathway (p=0.005) and neuroactive ligand-receptor interaction pathway (p=0.003). Nicotinic acetylcholine alpha-7 receptor (Chrna7) gene, known for its anti-inflammatory and hypoglycemic effects was upregulated in programmed males (p=0.024). On the other hand, genes involved in metabolic pathways and oxidative stress were differentially expressed as well. Phospholipase A2 group 3 (Pla2g3) gene, known to be overexpressed in oxidative stress was downregulated in programmed males (p=0.04). Moreover, Thiosulfate sulfurtransferase (Tst) gene, an antioxidant enzyme and used as a marker for enhanced insulin sensitivity was upregulated (p=0.023) in programmed males. Interestingly, female mice did not show any changes in BP or gene expression between the two groups. In conclusion, perinatal exposure to HD alters the cardiovascular response to Ang-II possibly through the modulation of gene expression of Chrna7 gene and genes involved in oxidative stress. Future experiments will be investigating the signaling pathways used in epigenetic programming to affect inflammation and oxidative stress in male mice.
External Validation of Prediction Models for Unilateral Primary Aldosteronism
Authors: Sam Davis , Kline Gregory A , So Benny , Pasieka Janice L , Harvey Adrian , Hundemer Gregory L , Chin Alex , Przybojewski Stefan J , Leung Alexander A
Published: May 2021

Primary aldosteronism (PA) is the most common cause of remediable hypertension. Treatment is informed by establishing whether disease is unilateral (localized to one adrenal gland) or bilateral. Adrenalectomy is the guideline-recommended treatment of choice for unilateral PA. However, the currently recommended subtyping test, adrenal vein sampling (AVS), is often limited in accessibility. Thus, prediction models have been developed to diagnose unilateral PA and therefore bypass AVS. However, their generalizability remains unknown. In this retrospective study, we aimed to externally validate the performance of prediction models for unilateral PA in a large population of PA patients at a Canadian referral center who underwent AVS during 2006–2018. The presence of unilateral disease was indicated by a lateralization index of >3 on AVS. We identified 6 clinical prediction models from the literature. The discrimination and calibration of each model were systematically evaluated. For the original models, the derivation cohorts were based out of Japan, France, Italy, and England, with mean age between 46–54 years and 43–56% being male. The derivation cohorts were generally small, with 4 of the 6 studies reporting less than 50 people with unilateral PA. Common variables reported to be predictive of unilateral PA included male sex, hypokalemia, elevated aldosterone-renin ratio, and the presence of a unilateral adrenal nodule on imaging. The validation cohort included 342 PA patients who underwent successful AVS (average age, 52.1 years; 58.8% male). Among them, 186 (54.4%) demonstrated unilateral disease, and the remaining 156 (45.6%) were considered to have bilateral disease. The baseline characteristics of the validation cohort were broadly similar to those of the derivation cohorts, except for potential differences in ethnicity. When applying the models to the validation cohort, subjects were excluded if any candidate variables were missing. All 6 models demonstrated poor discrimination in the validation set (C-statistics; range, 0.59–0.72), representing a marked decrease compared to the derivation sets where they were reported (range, 0.80–0.87). Assessment of calibration by comparing observed and predicted probabilities of the unilateral subtype revealed significant miscalibration. Calibration-in-the-large for every model was >0 (range, 0.36–2.23), signifying systematic underprediction of unilateral PA. Calibration slopes were all <1 (range, 0.35–0.85), indicating poor performance at the extremes of risk. These results suggest that the original models were optimistic due to overfitting in the derivation cohorts and therefore lack generalizability. This is primarily because these models were developed in small data sets. In conclusion, clinical assessment with prediction models for unilateral PA cannot be readily used to bypass AVS in the general PA population.
Insulin Resistance Is Associated With Impaired HDL Function and Atherogenic Modification of LDL in Polycystic Ovarian Syndrome
Authors: Ho Jan Hoong , Adam Safwaan , Liu Yifen , Dhage Shaishav , Tsimikas Sotirios , Soran Handrean , Gibney James
Published: May 2021

Background and Aims: Polycystic ovarian syndrome (PCOS) is associated with increased risk of cardiovascular disease (CVD). The aim of this study was to assess the association between PCOS and markers of HDL functionality and atherogenic LDL modification. Methods: This is a cross-sectional study of 104 women with PCOS [median (IQR); age 29 (24–36) years, and BMI 32.9 (25.7–38.5) kg/m2] and 103 BMI-matched healthy participants (age 34 (27–37) years, and BMI 31.1 (27.6–35.5) kg/m2). PCOS was defined using the NIH criteria. Measurement of lipid profile and glycaemic blood parameters were undertaken. Patients with PCOS were divided into tertiles of insulin resistance assessed using the homeostatic model assessment (HOMA-IR). Cholesterol efflux capacity (CEC), and paraoxonase-1 (PON1) activity were measured as markers of HDL functionality. Oxidized LDL (OxLDL), lipoprotein-associated phospholipase A2 (LpPLA2), oxidized phoshopholipids on apolipoprotein B-100 (OxPL-apoB) and apolipoprotein(a) (OxPL-apo(a)), and glycated apoB were used as markers of atherogenic modification of LDL. Results: Patients with PCOS in the upper tertile of insulin resistance had impaired HDL functionality compared to the lower tertile and controls, with lower CEC [13.7 (12.4–14.6) vs 14.9 (13.6–17.0), P=0.003; and 14.5 (13.0–16.0) %, P=0.063 respectively] and PON1 activity [77.2 (48.2–129.2) vs 112.9 (54.0–175.4), P=0.043; and 131.6 (89.5–195.1) nmol/ml/min, P<0.001 respectively]. Markers of atherogenic modification of LDL were also increased in the upper tertile compared to the lower tertile and controls, with higher levels of OxLDL [91.6 (58.8–120.9) vs 67.2 (20.1–86.3), P=0.016; and 74.8 (47.6–89.5) ng/ml, P=0.013 respectively], LpPLA2 [1.66 (1.48–1.84) vs 1.48 (1.39–1.60), P=0.004; and 1.53 (1.37–1.70) µg/ml, P=0.015 respectively], small-dense LDL cholesterol (sdLDL) [24.8 (16.8–35.0) vs 15.3 (11.3–20.1), P<0.001; and 20.9 (14.6–29.0) mg/dl, P<0.001 respectively], and glycated apoB [4.02 (3.63–4.33) vs 3.51 (3.27–3.70), P<0.001; and 3.48 (3.20–3.96), P<0.001 respectively]. Both BMI and insulin resistance were associated with adverse lipoprotein modification, correlating positively with OxLDL, LpPLA2, sdLDL, and glycated apoB (Spearman’s ρ=0.244–0.325 and Spearman’s ρ=0.254–0.377 respectively, all P<0.050); and negatively with CEC (Spearman’s ρ=-0.244 and

Spearman’s ρ=0.254 respectively, both P<0.050). OxPL-apoB, OxPL-apo(a), and lipoprotein(a) did not differ between PCOS and controls. Conclusions: Insulin resistance is a key determinant of decreased HDL functionality and increased oxidative modification and glycation of LDL in PCOS, which is likely to contribute to the increased CVD risk.
Laterality Diagnosis of Adrenal Vein Sampling for Primary Aldosteronism Using Aldosterone Alone
Authors: Wada Norio , Baba Shuhei , Sugawara Hajime , Miyoshi Arina , Obara Shinji , Usubuchi Hiroaki , Terae Satoshi
Published: May 2021

Background: In adrenal vein sampling (AVS) for primary aldosteronism (PA), cortisol concentration is used to determine successful AVS, and laterality diagnosis is performed using a combination of aldosterone and cortisol concentrations. In this study, we examined the comparison with the conventional method when AVS was determined by aldosterone alone. Subjects and methods: We studied the data from 277 patients with PA who underwent AVS in Sapporo City General Hospital from July 2007 to April 2020. The patients with autonomous cortisol production were excluded. Using the blood samples from adrenal veins and inferior vena cava (IVC) after ACTH stimulation, the predicting ability of the left and right ratio of aldosterone concentration (aldosterone ratio, AR) for lateralization Index (LI) was examined by Receiver operating characteristic (ROC) analysis. The predicting abilities of the ratio of aldosterone concentration between adrenal vein and IVC (aldosterone index, AI) and aldosterone concentration for selectivity index (SI) and contralateral ratio (CR) were also examined by ROC analysis. Results: Six samples (0.01%) with SI <5 after ACTH stimulation those were determined unsuccessful AVS. The results of the area under the curve (AUC) in ROC analysis of aldosterone concentration and AI for prediction of SI>5 was 0.998, 0.990, respectively, p=0.39. The optimal cut-off values of aldosterone concentration and AI for prediction successful AVS were 1700 pg/ml (sensitivity 99.5%, specificity 100%), 7.44 (sensitivity 94.0%, specificity 100%), respectively. Seventy-two patients (27.3%) had LI >4 who were diagnosed as unilateral aldosterone excess. AR had 0.94 of AUC for prediction of LR >4. The optimal cut-off value of AR was 3.53 (sensitivity 86.1%, specificity 94.8%). Eighty-two patients (31.1%) had unilateral CR<1. The AUC of aldosterone concentration and AI for prediction of CR<1 was 0.96, 0.98, respectively, p=0.07. The optimal cut-off values of aldosterone concentration and AI were 13600 pg/ml, 42, respectively. The sensitivity and the specificity at the optimal cut-off points of aldosterone concentration and AI were 91.5%, 91.5% and 91.5%, 94.8%, respectively. Conclusions: The determination of successful AVS and unilateral result in AVS can be predicted using aldosterone alone. It was suggested that AR is useful for tentative interpretation in the cases where the results of aldosterone were previously reported and lateralizing diagnosis of the cases with autonomous cortisol production.
Meal-Related Changes in Apolipoprotein Particles After Treatment With an Antisense Oligonucleotide to Apolipoprotein CIII
Authors: Brite Brianna , Lightbourne Marissa , Startzell Megan S , Shamburek Robert , Brown Rebecca J
Published: May 2021

Background: Lipodystrophy (LD) is defined by partial or complete absence of adipose tissue causing metabolic complications such as high triglycerides (TG). Apolipoprotein CIII (ApoCIII) contributes to high TG by inhibiting lipoprotein lipase (LPL). Measurement of lipoprotein particles using NMR can offer insights into lipid metabolism. Hypothesis: We hypothesized that during a mixed meal test (MMT), clearance of TG-rich lipoprotein particles (TRLP) measured by NMR would increase in LD patients given an antisense oligonucleotide (ASO) to lower ApoCIII. Experimental Design: Five adults with partial LD underwent an MMT (with 18g fat) at week 0 and after 16 weeks (wk) of the ApoCIII ASO. Blood samples were obtained at 0, 30, 60, 120, 180, 240, 300, and 360 minutes (min) and assessed using NMR with the LP4 deconvolution algorithm, which separates TRLPs into 5 size categories: very large (VL), large (L), medium (M), small (S), and very small (VS), all expressed as nmol/L. Major Results: At wk 0, patients had high fasting TG (median 523 mg/dL, IQR 335–1060 mg/dL, normal <150), which decreased after 16wk of ASO[BR([1] (196 mg/dL) Mean TRLP over the 360 min of the MMT was lower after ASO (181.6±14.1 at wk 0, 80.4±2.2 at wk 16). At wk 0, mean L_TRLP during the MMT was 26.8 ± 6.9 and decreased to 9.3±1.3 at wk 16. At wk 0, L_TRLP rose during the MMT to a peak at 180min; at wk 16 there was no rise in L_TRLP during the MMT. Mean S_TRLP during the MMT increased from wk 0 (5.4±3.9) to wk 16 (13.4±10.4). At wk 0, S_TRLP increased minimally during the MMT from 5.2±11.7 at 0 min to 10.9±15.2 at 360 min. At wk 16 there was a more notable rise in S_TRLP in the last 3 hrs of the MMT, from 12.2±15.1 at 0 min to 37.6±28.6 at 360 min. Interpretation of Results and Conclusions: As expected, an ApoCIII ASO lowered fasting and postprandial TG and TRLP. There was minimal rise or fall in any subclass of TRLP during the MMT, either before or after ASO, likely due to the small fat load, which was chosen due to concern for triggering pancreatitis in this at-risk group. The greater post-prandial fluctuation of L_TRLP prior to ASO may represent appearance and disappearance of chylomicron remnants; at wk 16 this was not seen, perhaps due to more rapid clearance of chylomicron remnants by LPL. The larger increase in S_TRLP at the end of the MMT at wk 16 may reflect more rapid lipolysis of L_TRLP by LPL during ASO treatment, thus generating S_TRLP. Next steps include measuring apoB48 and apoB100 during the MMT to distinguish VLDL from chylomicrons, accruing a larger sample size, and collecting MMT data in healthy controls.
Muscle Function is Associated With Presence, New-onset, or Worsening of Hepatic Steatosis Assessed by Biochemical Parameters, Independent of Muscle Mass
Authors: Hong Namki , Lee Seunghyun , Kim Kyoungjin , Shim Jee-Seon , Kim Hyeon Chang , Rhee Yumie
Published: May 2021

Non-alcoholic fatty liver disease (NAFLD) becomes a major health problem leading to metabolic complications and end-stage liver disease, lacking effective therapeutic interventions. Skeletal muscle deficit, or sarcopenia, is related to accelerated accumulation of ectopic fat at liver. Skeletal muscle can be a novel intervention target of NAFLD. However, previous studies focused on the association between muscle mass and NAFLD, whereas the association of muscle function with NAFLD, a more clinically relevant assessment regarding skeletal muscle, remains unclear. Among participants enrolled between 2013 to 2014 in cardiovascular and Metabolic Diseases Etiology Research Center (CMERC) study (n=807), a cohort of community-dwelling Korean adults to study cardiovascular risk factors, a total of 500 individuals were recruited for 5-year follow-up. Hepatic steatosis was defined by hepatic steatosis index 36 or higher (HSI=8X(AST/ALT)+BMI+2 [if diabetes]+2 [if female]). New-onset of hepatic steatosis was defined as newly developed hepatic steatosis at current follow-up compared to baseline and worsening of HSI was defined as the highest quartile of HSI changes (2 or higher HSI increase). Muscle function was assessed by peak countermovement jump power relative weight (W/kg), 5 times chair rise test (CRT; in seconds), and grip strength (GS; in kg). Appendicular lean mass (ALM) was measured using bioimpedance analysis (InBody770, Biospace, Seoul, Korea). A total of 439 subjects (women 74%; mean age 57 ± 8 year) were analyzed after excluding those with excessive alcohol intake (n=51) and any missing values (n=10). Hepatic steatosis was present in 40% of subjects, which was increased from baseline period (33%, p<0.001). Low peak jump power (adjusted odds ratio [aOR] 1.14 per 1 W/kg decrease), GS (aOR 1.08 per 1kg decrease), and CRT performance (aOR 1.09 per 1 second increase; p<0.05 for all) were all associated with elevated odds of hepatic steatosis, after adjustment for age, gender, height, ALM, and metabolic syndrome components. Compared to those without hepatic steatosis at baseline and follow-up, those with persistent hepatic steatosis had significantly lower jump power in both men and women (33 vs. 40 W/kg in men, p=0.027; 26 vs. 29 W/kg in women, p<0.001). Jump power remained as robust predictor for new-onset hepatic steatosis or worsening of HSI (aOR 1.05 per 1W/kg decrease, p=0.044), whereas GS, CRT, and ALM were not. Muscle function measured by jump power was associated with presence or worsening of hepatic steatosis assessed by biochemical parameters, independent of muscle mass. Acknowledgement: We thank CMERC participants and all research staffs for this work. Funding: This study was supported by research grants from Hanmi Pharmaceutical Co.,Ltd. (4-2018-0845).
Serum Soluble (Pro)renin Receptor Level as a Prognostic Factor in Patients Undergoing Maintenance Hemodialysis
Authors: Morimoto Satoshi , Amari Yoshifumi , Suda Chikahito , Ichihara Atsuhiro
Published: May 2021

Background: The (pro)renin receptor [(P)RR)] is a multifunctional protein with roles in angiotensin II-dependent and -independent intracellular cell signaling and as an adaptor protein between the Wnt receptor complex and vacuolar proton-translocating adenosine triphosphatase. The (P)RR is cleaved to generate soluble (P)RR [s(P)RR], reflecting the status of the tissue renin-angiotensin system and/or activity of the (P)RR. Patients undergoing hemodialysis (HD) have poor prognosis because of the increased prevalence of cardiovascular and malignant diseases. This study was conducted to investigate whether the s(P)RR level is associated with new onset of cardiovascular events or malignant diseases and prognosis in patients undergoing HD. Methods: A total of 258 patients undergoing maintenance HD who were enrolled in our cohort study investigating the relationships between serum s(P)RR levels and background factors were prospectively followed up for 60 months. We investigated the relationships between s(P)RR levels and new onset of cardiovascular events or malignant diseases and mortality during the follow-up period. Results: The cumulative incidence of new onset of cardiovascular events (P = 0.009) and cardiovascular deaths (P < 0.001), but not of malignant diseases, was significantly greater in patients with higher serum s(P)RR level (≥ 29.8 ng/ml) than in those with lower s(P)RR level (< 29.8 ng/ml). A high serum s(P)RR level was independently correlated with cardiovascular mortality (P = 0.046). Conclusions: These data showed that the serum s(P)RR level is associated with cardiovascular events and mortality, suggesting that the serum s(P)RR level could be used as a biomarker for selecting patients requiring intensive care.
Statin Intolerance: Prevalence and Management in a Specialized Lipid Clinic
Authors: Turdo Yannick , Collet Tinh-Hai
Published: May 2021

Statins are recommended and used as first-line treatment to prevent cardiovascular disease, but high rates of adverse events and subsequent discontinuation can prevent effective treatment in some patients. We aimed to describe the intensity, nature and frequency of adverse effects caused by statins and other lipid-lowering drugs, and to assess their association with clinical predictors and treatment strategies. This is a retrospective study of 121 consecutive unselected patients followed at a specialized lipid referral clinic in Lausanne University Hospital, Switzerland, in 2018. Adverse effects were reported by 58% of patients, causing musculoskeletal (72%), neurologic (40%), gastrointestinal (25%) and other (25%) symptoms. Gastrointestinal symptoms affected 35% of women, but only 12% of men (p=0.06). Statins caused more adverse effects than other drugs, with atorvastatin (63%) and simvastatin (64%) achieving the lowest rates, pravastatin (87%) and fluvastatin (100%) the highest. Fenofibrate was associated with significantly less frequent adverse effects than statins (p=0.006). Either adapting, or terminating the treatment, led to 86% and 88% lower intensity of symptoms, respectively. While the predominance of musculoskeletal symptoms caused by lipid-lowering drugs is known, symptoms affecting other organ systems should not be ignored. Statins were the lipid-lowering drug class with the highest rates of adverse effects. To maintain compliance and cardiovascular prevention, treatment strategies such as a change of dosage, frequency of administration, daily timing, or switching active substance can contribute to better tolerance of statin treatment. Further investigation is needed to establish specific treatment strategies for individual patient profiles.
Total Testosterone Confounds the Association Between Total Bilirubin and Dyslipidemia
Authors: Visaria Aayush , Raju Priyanka , James Joel , Islam Sumaiya , Khangura Karen K , Amanullah Amir , Polamarasetti Pooja
Published: May 2021

Background: The mechanism for the association between total bilirubin (TBili) and dyslipidemia remains unclear. Total testosterone (TT) has been implicated in reducing bilirubin conjugation and decreasing atherogenic lipids. We hypothesized that 1) TBili was inversely associated with dyslipidemia, and 2) TT confounded this association.

Methods: Our study population consisted of 5,878 (2,730 male and 3,148 non-pregnant female) adults aged ≥20 years from the 2011–2016 National Health and Nutrition Examination Survey (NHANES). We excluded those taking self-reported cholesterol medications. Participants with transaminitis (AST or ALT >45 IU/L; AST/ALT >5), excessive alcohol consumption (>20 drinks/week for males; >10 for females), iron overload (transferrin >50%), or positive hepatitis B/C serology were also excluded. We categorized TBili into sex-specific quartiles (Male: <0.5, 0.5–0.6, 0.6–0.8, ≥0.8 mg/dl; Female: <0.4, 0.4–0.5, 0.5–0.6, ≥0.6). Dyslipidemia was defined as elevated TG (≥150 mg/dl) or low HDL (<40 mg/dl for male; <50 for female). We used survey design-adapted multivariable logistic regression, adjusting for TT, demographics, cardiometabolic factors, and liver function. We also stratified by sex-specific median TT levels (386 ng/dl in males; 18.5 ng/dl in females) to determine effect modification. Further, we determined whether the association between TBili and dyslipidemia persisted in males with TT deficiency (<280 ng/dl).

Results: Among the 5,878 adults, 1,013 (38%) males & 958 (30%) females had elevated TG, and 803 (29%) males & 1,146 (33%) females had low HDL. Males in the highest quartile (Q4) of TBili had age-adjusted, mean (SD) 50.1 (3.5) mg/dl lower TG and 4.0 (0.9) mg/dl higher HDL than males in the lowest quartile (Q1; p<0.0001). Females in Q4 had 36.4 (4.9) mg/dl lower TG and 5.1 (1.4) mg/dl higher HDL than Q1 (p<0.0001). Males and females in Q4 had 60% and 59% lower odds, respectively, of elevated TG compared to Q1 (adjusted OR [95% CI]; Male: 0.40 [0.28, 0.57], Female: 0.41 [0.32, 0.52]). Males and females in Q4 had 44% and 39% lower odds, respectively, of low HDL compared to Q1 (Male: 0.56 [0.38, 0.81], Female: 0.61 [0.42, 0.90]). Adjusting for TT increased the parameter estimate for Q4, relative to the univariate estimate, by 21% in both sexes. There was no significant difference in TT-stratified odds of elevated TG or low HDL. Among the 544 (19%) males with TT deficiency, Q4 had 56% lower odds of elevated TG and 46% lower, but insignificant, odds of low HDL (aOR [95% CI]; TG: 0.44 [0.21, 0.89], HDL: 0.54 [0.26, 1.12]).

Conclusion: TBili was inversely associated with elevated TG and low HDL. TT confounded, but did not modify, this association. Future studies examining TBili’s antiatherogenic role should adjust for TT.
ULK1 Regulates Hepatic Lipid Metabolism via Autophagy Independent Mechanisms
Authors: Koo Young Do , Castillo Romilia Tatiana , Hinton Antentor Othrell , Abel Evan Dale
Published: May 2021

Non-alcoholic steatohepatitis (NASH), a major complication of obesity, diabetes, and metabolic syndrome has emerged as a leading cause of chronic liver disease and a risk factor for hepatocellular carcinoma. Autophagy is a critical pathway for the degradation of intracellular components by lysosomes. Established functions for autophagy in hepatic lipid metabolism and insulin sensitivity suggest a mechanistic link between altered autophagy and NASH. However, the interactions between insulin sensitivity, NASH, and autophagy are incompletely understood. The Unc-51 Like Autophagy Activating Kinase 1 (ULK1) is the only serine/threonine kinase in the core autophagy pathway and thus represents an excellent drug target. In this study, we observed that ULK1 may directly regulate insulin signaling and lipid metabolism via mechanisms that might involve modulation of AKT dephosphorylation. Surprisingly, silencing ULK1 did not significantly alter autophagy in hepatocytes despite impairing insulin-stimulated activation of AKT. To further elucidate the autophagy-independent role of ULK1 in hepatic lipid metabolism and insulin action, ULK1 liver-specific knock-out mice were generated. L-ULK1 KO mice exhibited impaired glucose tolerance and insulin resistance on a normal chow diet or 60% high-fat diet (HFD). In young mice (4 weeks after birth), the expression of genes that regulate de novo lipogenesis, such as FAS, SCD1, and SREBP1-c were induced in livers of L-ULK1KO mice even prior to the development of insulin resistance and obesity. Hepatomegaly and lipid accumulation developed in L-ULK1KO on normal chow and was exacerbated relative to wild type mice on a HFD. Serum concentrations of insulin, triglyceride, cholesterol, AST and ALT were significantly increased. In contrast, L-ULK2 KO mice were phenotypically normal. To identify putative novel ULK1 targets, we conducted a phospho-proteomics screen in a ULK1 deficient hepatocyte cell line. We identified a relatively small number of novel proteins whose phosphorylation levels were reduced by ULK1 deficiency. The identification of these targets supports autophagy-independent mechanisms of action of ULK1. Recently, we confirmed that NCOA3, one of the targets regulates hepatic lipid metabolism by interacting directly with ULK1. These data suggest that ULK-1 may regulate cellular targets that regulate hepatic lipid metabolism and insulin sensitivity.
A Case of Primary Hyperaldosteronism Presenting as Hemorrhagic Stroke
Authors: Anjum Azeen , Tumyan Gayane , Tayon Kevin
Published: May 2021

Background: Primary aldosteronism (PA) is the most common form of secondary hypertension. Patients with PA are more likely to suffer from end-organ damage compared to matched controls with essential hypertension. We present a case of PA identified in a patient who presented with hypertensive emergency and hemorrhagic stroke.

Clinical Case: A 52-year-old man with hypertension and chronic kidney disease presented with sudden onset left-sided weakness. He had a ten year history of hypertension and was taking carvedilol, losartan, and hydralazine prior to presentation. On arrival, his blood pressure was 263/142 mmHg. He had 3/5 grade weakness in the left upper and lower extremities. Laboratory analysis showed a potassium level of 2.8 mmol/L (n = 3.5–5 mmol/L) and a bicarbonate level of 33 mmol/L (n = 21–29 mmol/L). Screening labs for PA were drawn after potassium repletion. CT Head without contrast revealed an acute 2.5-centimeter intracerebral hemorrhage of the right basal ganglia. He was admitted to the intensive care unit and was started on a nicardipine drip with an improvement of blood pressure. His weakness improved and he was discharged home on carvedilol, hydralazine, nifedipine, and losartan.

Screening for PA revealed a plasma aldosterone concentration (PAC) of 22.8 ng/dL (n < 16 ng/dL) and a plasma renin activity (PRA) of 0.1 ng/ml/hr (n = 0.2–1.6 ng/ml/hr). The PAC/PRA ratio was therefore extremely elevated at 228. The presence of spontaneous hypokalemia, very low renin, and PAC >20 ng/dL confirmed the diagnosis of primary aldosteronism. He underwent an adrenal MRI which revealed two left adrenal nodules, the largest measuring 10 mm, and a 7.3 mm right adrenal nodule, consistent with bilateral adrenal adenomas. The patient did not desire surgery, therefore adrenal vein sampling was deferred. His hypertension improved with the addition of a mineralocorticoid receptor antagonist. Eight weeks after his stroke the patient was readmitted due to chest pain. He was found to have severe multi-vessel coronary artery disease and underwent a four vessel coronary artery bypass.

Conclusion: Patients with PA have higher rates of adverse cardiovascular events compared to age-, sex-, and blood pressure-matched controls with essential hypertension. Studies demonstrate that aldosterone excess has blood pressure independent proinflammatory and profibrotic effects on the vessel wall which leads to endothelial dysfunction and thus accelerated atherosclerosis. Appropriate treatment can eliminate the excess cardiovascular risk associated with PA. This case highlights the importance of including PA in the differential diagnosis of secondary hypertension, particularly among patients presenting with spontaneous hypokalemia, severe uncontrolled hypertension and early onset cardiovascular or cerebrovascular disease.
Impact of Provider-Directed Plant-Strong Nutrition & Counseling on Cardiometabolic Health: A Case Series at the Michael E. DeBakey VA Medical Center
Authors: Ahmad Sara Miriam , Joad Sabaa Salim , Pham Codey , Vasudevan Madhuri Mukhopadhyay
Published: May 2021

Background:

Cardiometabolic syndrome, Type 2 diabetes mellitus (DM), and non-alcoholic fatty liver disease (NAFLD) share common pathogenic mechanisms including inflammation, insulin resistance, lipid accumulation, and increased oxidation. Diet is an important modifiable determinant in cardio-metabolic diseases (CMD) progression. The clinician/specialist provides pharmacotherapeutic guidance, but often defers nutrition guidance to supportive services. We present the impact of specialist-directed nutrition counseling for 3 patients with various manifestations of CMD.

Clinical Case Series:

A 63-year-old man with Type 1DM, status post coronary artery bypass grafting (CABG), reported high animal fat/protein intake, very low carbohydrate (CHO) intake and soda consumption. The specialist educated the patient on anti-inflammatory benefits of plant-strong nutrition, recommended liberalizing healthy CHO, grains, fruits and vegetable intake, limiting animal products to 1 serving daily and eliminating processed foods and beverages. The patient followed the diet, lost 50 pounds in 7 months with improvement in blood pressure and lipids. Insulin requirements reduced by 50% while maintaining HbA1C 7%.

A 71-year-old man with T2DM, NAFLD, obesity, coronary artery disease status post CABG, HbA1C 9.6% reported increased fatigue, depressive symptoms, and maladaptive coping strategies including excessive alcohol consumption. The endocrinologist recommended plant-strong nutrition for weight loss and glycemic benefits, reduced animal fat/protein consumption and complete elimination of alcohol intake. The patient adopted plant-based nutrition and stopped alcohol consumption. After 18 months, he lost 100 pounds, achieved HbA1C 7.6%, without additional medication.

A 63-year-old man with Crohn’s disease, NAFLD, obesity, referred for NAFLD, reported consuming six servings of soda, unchecked fried foods with limited vegetable intake. Exam was notable for abdominal adiposity. The endocrinologist recommended to eliminate soda and fried foods. The patient initially declined, but after 4 months of continued reinforcement, he adopted a plant-forward diet. After 2 years, the patient lost 160 pounds and transaminitis resolved. All specialist-directed nutrition counseling was in accordance with American Heart Association and American Diabetes Association recommendations for macronutrient and micronutrient nutrition consumption.

Conclusion:

These cases signify how provider-directed nutrition counseling can have an impact on CMD. The first step to integrate nutrition counseling into practice is to become well-versed in basic concepts of nutrition science and develop a broader understanding of nutrient composition. We therefore encourage the integration of nutrition science into medical curricula that could translate into improved cardiometabolic health outcomes.
Both Elafibranor and Liraglutide Improve NAFLD / NASH but Affect Differentially the Hepatic Lipidome and Metabolome in a Diet-Induced Obese and Biopsy-Confirmed Mouse Model of NASH
Authors: Perakakis Nikolaos , Stefanakis Konstantinos , Feigh Michael , Veidal Sanne S , Mantzoros Christos S
Published: May 2021

Treatment of Nonalcoholic fatty liver disease (NAFLD) constitutes an unmet clinical need owing to the relatively limited efficacy of both novel and readily available metabolic medications, thus warranting pathobiological investigations on the mechanisms of single or combination regimens. In this context, our study aimed to assess and compare whether and how liraglutide, a glucagon-like peptide-1 receptor agonist, and elafibranor, a dual peroxisome proliferator-activated receptor alpha-delta agonist, may affect hepatic histology and metabolipidomic fingerprints in a model of advanced NAFLD. Male C57BL/6JRj mice with biopsy-confirmed hepatosteatosis and fibrosis induced by AMLN diet (40% fat with 20% trans-fat, 2% cholesterol and 22% fructose) were randomized to receive for 12 weeks: a) Liraglutide (0.4 mg/kg/d s.c.), b) Elafibranor (30 mg/kg/d p.o.), c) vehicle. Metabolic indices, liver function markers, liver pathology, and metabolomics/lipidomics were assessed at study completion. Both drugs markedly reduced body weight and fat percentage (p-value <0.001), and improved glucose tolerance and insulin sensitivity, as indicated by oral glucose and intraperitoneal insulin tolerance tests. Hepatic lipid content was downregulated under both treatments (p-value <0.001), especially under elafibranor, which also elevated liver weight in contrast with liraglutide (p-value vs liraglutide <0.001). NAFLD activity score (pre-to-post) and its histological components were substantially improved (mean difference ± standard error of mean: -1.4 ± 0.3 for liraglutide; -2.0 ± 0.2 for elafibranor), with elafibranor demonstrating a more robust anti-steatotic effect vs liralgutide (p-value <0.01) as well as anti-fibrotic effects (-0.5 ± 0.1). Liraglutide also limited the immunohistochemical expression of pro-inflammatory markers of Kupffer and hepatic stellate cell function (Galectin-3, Collagen type I alpha 1, and alpha-smooth muscle actin). In the omics analysis, elafibranor profoundly ameliorated the hepatic lipidome by diminishing the concentrations of glyceride species, increasing phospholipids and carnitine metabolites, and modifying key regulators of fatty acid oxidation, inflammation, and oxidative stress, including metabolites of methionine, glutathione, and pantothenate. Liraglutide significantly affected bile acid and carbohydrate metabolism by restoring the concentrations of metabolically beneficial primary and secondary bile acids, glycogen metabolism by-products, and pentoses, thus probably driving glycogen utilization-turnover and nucleic acid synthesis. Thus, liraglutide and elafibranor diverge in their mechanistic treatment of advanced NAFLD pathology, indicated by their robust but differential regulation of the hepatic metabolipidome. These findings support their combinatory therapeutic evaluation in future studies.
Analysis of Novel Histone Methylase MLL Function for Glucose Metabolism in Mouse Pancreas
Authors: Yoshino Satoshi , Ishida Emi , Horiguchi Kazuhiko , Matsumoto Shunichi , Nakajima Yasuyo , Yamada Eijiro , Okada Shuichi , Yamada Masanobu
Published: May 2021

Background) Myeloid / Lymphoid or Mixed-lineage leukemia gene (MLL) is translocated to chromosome 11 long arm q23 region (11q23) and the MLL fusion gene expressed as a result of translocation reconstruction plays an important role in MLL-related leukemia development. It has also been reported that MLL and MLL protein play an important role in tumor development as a Menin-binding protein in Multiple Endocrine Neoplasia Type I (MEN1). More recently, normal MLL protein has been shown to have histone H3 lysine 4-methylation (H3K4-HMT) activity and to be an epigenetic transcriptional regulator. In addition, the function of MLL protein as a histone methylase has been reported in the gene region involved in metabolism regions. Here, we analyzed the involvement of MLL in glucose metabolism in the pancreas using MLL knockout mice. Methods:) Glucose metabolism in MLL knockout mice and the function of MLL in cultured cells were analyzed. Result) Since the homozygotes of MLL knockout mice are embryonic lethal, we analyzed them using Heterozygous mice. MLL heterozygous mice showed significantly weight loss compared to the wild type mice. MLL heterozygous mice showed no difference in food intake compared to wild type mice. IPGTT showed impaired glucose tolerance in MLL heterozygous mice. However, ITT showed no insulin resistance and decreased insulin secretion during glucose loading. In GSIS tests, Islets isolated from heterozygous mice pancreas have been observed to decrease insulin secretion in the response to glucose stimulation. In comprehensive gene analysis using Microarray analysis of mRNA extracted from mice islet, the gene expression changes related insulin secretion and apoptosis have been revealed in MLL heterozygous mice. Histological search showed no decrease in β-cell number, and immunohistological search showed no difference in insulin, glucagon, and TUNEL staining between heterozygous and wild type mice. And also, MLL knockdown was performed in a cultured cell line. Insulin secretion was decreased to glucose stimulation in MLL knockdown cell line same as in MLL knockout mice. In addition, RNA microarrays were performed to these cell lines, several same genes that have confirmed in MLL mouse islets were observed in MLL knockdown cell. In conclusion, MLL knockout mice showed decreased insulin secretion. It was suggested that MLL may be involved in insulin secretion in islets.
BLNK/BTK: Novel Components in the NF-kappa B Pathways of Endothelial Cells in Diabetic Condition
Authors: Singh Madhu V , Wong Thomas , Dokun Ayotunde O
Published: May 2021

Peripheral artery disease (PAD) is atherosclerotic occlusion of vessel outside the heart that most commonly affects the lower extremities. The effects of PAD-related ischemia are exacerbated under diabetic hyperglycemic conditions. Under ischemic conditions, an adaptive induction of the NFkB pathways is in vascular endothelial cells is required for recovery. We have recently shown that prolonged exposure of cells to high glucose before ischemia resulted in impairment of the canonical NFkB pathway through decrease in IkBa degradation. However, the signaling pathways involved in hyperglycemia and ischemia mediated effects on the NFkB pathways are not well understood. Since the NFkB signaling pathways propagate through a cascade of phosphorylation events, we used arrays of antibodies to approximately 100 proteins known to participate in the NFkB pathway to identify the changes in their phosphorylation states in human umbilical vein endothelial cells (HUVEC). Cells grown for three days either in culture medium with normal glucose (LG) or high glucose (HG) were subjected to ischemia for 24 hours (LGI and HGI, respectively). Cell lysates were then incubated with the array of antibodies printed on glass slides (Full Moon Biosystems, Sunnyvale, CA) and fluorescent signals were digitally recorded and normalized. The change in protein phosphorylation was calculated by dividing the intensity of the phosphorylated spot by the signal intensity of the corresponding non-phosphorylated spot for each protein. Differential expression between LG and LGI samples, and HG and HGI were calculated by dividing the phosphorylation ratio of the LGI and HGI with that of the LG and HG controls, respectively. A threshold of 1.5-fold increase or decrease was used to determine changes. Compared to the LG, LGI samples had 26 protein sites with increased phosphorylation whereas 36 sites had decreased phosphorylation. Similarly, compared to HG, HGI samples increased phosphorylation of 25 protein sites and decreased phosphorylation of 40 sites. A Venn-diagram analysis of LGI and HGI sites revealed 8 sites with an increase and 12 sites with a decrease in phosphorylation were specific to HGI. Pathway analyses using bioinformatics tools on 65 modulated phosphorylation sites in HGI (represented by 35 genes) suggested involvement of B cell linker/adapter protein (BLNK)/Bruton’s tyrosine kinase (BTK) that are critical for B cell antigen receptor (BCR)-coupled signaling. BTK expression in EC was confirmed by immunoblotting. Inhibition of BTK by a specific inhibitor terreic acid restored IkBa degradation in EC grown in high glucose suggesting a critical role of BLNK/BTK in diabetic ischemia. Thus, we have identified BLNK/BTK as potentially new components of the NFkB pathway in endothelial cells that contributes to the poor recovery during hyperglycemic ischemia.
Definition of Norma / Prediabetes Cut-off Point for Fasting Glycaemia on the Basis of Glucose Tolerance Test and HbA1c Interrelationships
Authors: Ismayilova Sevil , Sultanova Sadaqat , Huseynova Aygun , Mirzazade Valeh
Published: May 2021

Unification of the approach to the diagnosis of prediabetes (PD) is hardly in doubt. The borderline between PD and diabetes is recognized by all, as well as the upper and lower bounds of PD according to the results of glycemia 120 minutes after 75 g glucose loading (GL120). There are still ambiguities regarding glycohemoglobin (HbA1c) and fasting glycemia (FG). For determination of the Norma/PD cut-off point for FG, we analyzed 85 nondiabetic glucose tolerance test results (75.0 glucose; Samples of fasting blood, and 30, 60, 90, 120 minutes after glucose loading) by using correlation and regression analysis. Glycemic values were measured in mg/dl, HbA1c values were measured in %. The fact of identifying the relationship between FG and Gl120 (r=+0.52 [95%CI +0.346, +0.659]; p<0.001), as well as between FG and HbA1c (r=+0.59 [95%CI +0.432, +0.713]; p<0.001) were the basis of this study. As a result of using regression analysis, multiple regression equations were obtained. GL0 =-4.2439 + 0.1927 * GL120 + 15.462 * HbA1c If GL120 is equal to 139 mg/dl (in accordance with all recommendations), and HbA1c is equal to 5.9% (in accordance with the recommendations of NICE, Canadian Diabetes Association, Australian Diabetes Association, et al.), the maximal normal value for FG should be equal to 114 mg/dl. If GL120 is 139 mg/dl and HbA1c is 5.6% (as recommended by the American Diabetes Association), the maximum normal value of FG should be 109 mg/dl. The optimal upper limit of normal carbohydrate metabolism is levels of GL120 equal to 139 mg/dl, HbA1c - equal to 5.6%, and FG - equal to 109 mg/dl. Values above these and below diabetic levels (200 mg/dl, 6.5%, and 126 mg/dl, respectively) can be considered as prediabetes.