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Mario A Jimenez-Mora,1 Luz D Nieves-Barreto,1 Angélica Montaño-Rodríguez,1 Eddy C Betancourt-Villamizar,2 Carlos O Mendivil1,3 1Universidad de los Andes, School of Medicine, Bogotá, Colombia; 2Team Foods, Bogotá, Colombia; 3Fundación Santa Fe De Bogotá, Section of Endocrinology, Bogotá, ColombiaCorrespondence: Carlos O Mendivil Email cmendivi@uniandes.edu.coObjective: Latin American countries are experiencing a nutritional and demographic transition that predisposes to the spread of the obesity epidemic, especially among the socially and economically disadvantaged. We aimed to describe the prevalence of obesity, overweight and abdominal obesity and their association with household socioeconomic status (SES) and personal educational level in the five major cities of Colombia (Bogotá, Medellín, Cali, Barranquilla and Bucaramanga).Materials and Methods: We collected demographic and anthropometric measurements from a population-based, stratified, multi-stage probability sample of individuals aged 2– 75 years. Study surveys and anthropometric measurements were administered by highly trained staff. All reported prevalences are expanded to the target population, taking into account the sampling design.Results: The study sample included 1922 participants. In children and adolescents, the prevalence of overweight and obesity were respectively 23% and 8.8%. Overweight was most prevalent in the 2– 4 (30.9%), followed by the 5– 11 (23.8%) and the 12– 17 age group (17.8%). The combined prevalence of childhood overweight and obesity increased with SES (16.8% in the lowest vs 42.8% in the highest stratum). In adults (18– 75 years), the prevalence of excess body weight was 57.5% (36.2% overweight, 21.3% obesity), the prevalence of abdominal obesity was 34.4%, all prevalences increased with age. Obesity was far more prevalent among adult women (29.4%) than men (12.6%) (p˂0.001). Adult obesity and abdominal obesity decreased significantly and monotonically with SES and were most prevalent in individuals with the lowest educational level (35.3% and 50.7%, respectively). Almost 40% of overweight adults had abdominal obesity.Conclusion: Obesity and abdominal obesity are highly prevalent in the urban population of Colombia, and much more frequent among adults of lower SES and educational level. Excess body weight affected more often children of higher SES. Public health measures are urgently needed to tackle the spread of the obesity epidemic in Colombia and other Latin American countries, with a focus on low-income and low-educational level segments of society.Keywords: obesity, overweight, abdominal obesity, socioeconomic status, inequality, Latin America, epidemiology

Carlos O Mendivil,1,2 Freddy JK Toloza,1 Maria L Ricardo-Silgado,1 Martha C Morales-Álvarez,1 Jose O Mantilla-Rivas,1 Jairo A Pinzón-Cortés,1 Hernán N Lemus1 1School of Medicine, Universidad de los Andes, 2Section of Endocrinology, Fundación Santa Fe de Bogotá, Bogotá, Colombia Background: Autoimmunity against insulin-producing beta cells from pancreatic islets is a common phenomenon in type 1 diabetes and latent autoimmune diabetes in adults. Some reports have also related beta-cell autoimmunity to insulin resistance (IR) in type 2 diabetes. However, the extent to which autoimmunity against components of beta cells is present and relates to IR and insulin secretion in nondiabetic adults is uncertain.Aim: To explore the association between antibodies against glutamic acid decarboxylase (GADA), a major antigen from beta cells, and indices of whole-body IR and beta-cell capacity/insulin secretion in adults who do not have diabetes.Methods: We studied 81 adults of both sexes aged 30–70, without known diabetes or any autoimmune disease. Participants underwent an oral glucose tolerance test (OGTT) with determination of plasma glucose and insulin at 0, 30, 60, 90, and 120 minutes. From these results we calculated indices of insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] and incremental area under the insulin curve [iAUCins]) and insulin secretion (corrected insulin response at 30 minutes and HOMA beta-cell%). GADAs were measured in fasting plasma using immunoenzymatic methods.Results: We found an overall prevalence of GADA positivity of 21.3%, without differences by sex and no correlation with age. GADA titers did not change monotonically across quartiles of any of the IR or insulin secretion indices studies. GADA did not correlate linearly with fasting IR expressed as HOMA-IR (Spearman’s r=−0.18, p=0.10) or postabsorptive IR expressed as iAUCins (r=−0.15, p=0.18), but did show a trend toward a negative correlation with insulin secretory capacity expressed by the HOMA-beta cell% index (r=−0.20, p=0.07). Hemoglobin A1c, body mass index, and waist circumference were not associated with GADA titers.Conclusion: GADA positivity is frequent and likely related to impaired beta-cell function among adults without known diabetes. Keywords: insulin resistance, autoimmunity, glutamate decarboxylase, latent autoimmune diabetes in adults, beta cell

Abstract Background/Aim: There are few data regarding insulin levels in the lungs during diabetes therapy with inhaled insulin. We examined the disposition of inhaled human insulin (Exubera((R)) [EXU] human insulin [recombinant DNA origin], Pfizer, New York, NY) in the lungs by measuring trough insulin levels in bronchoalveolar lavage (BAL) fluid after 12 weeks of EXU treatment. Methods: After a 4-week run-in period of subcutaneous insulin therapy, 24 subjects with type 1 diabetes mellitus (T1DM) and 26 with type 2 diabetes mellitus (T2DM) continued their basal insulin regimen and received premeal subcutaneous (SC) insulin for 13 weeks, followed by 12 weeks of premeal EXU. BAL was performed approximately 12 h after the last insulin dose at (1) baseline, (2) following SC insulin, and (3) following EXU. Results: Twenty patients with T1DM and 24 patients with T2DM completed all three bronchoscopies. BAL trough insulin levels were undetectable at baseline or following SC insulin. After EXU therapy, they increased to a median of 4.5 nM (1.6-9.0 nM) and 2.3 nM (0.5-9.4 nM) in T1DM and T2DM, respectively. BAL trough insulin levels did not correlate with treatment efficacy, adverse effects, plasma insulin levels, or changes in pulmonary function. A larger proportion of previous EXU doses was present in the BAL in patients with T1DM. We found no correlation between average daily insulin doses and BAL trough insulin levels. Conclusions: BAL trough insulin increased following EXU therapy, but this increase did not correlate with other clinical or laboratory parameters, suggesting no significant biological action. Further studies are warranted to better understand inhaled insulin deposition and clearance and possible effects of increased insulin levels on the lungs. [ABSTRACT FROM AUTHOR]

Background: Low-density lipoprotein (LDL) that contains apolipoprotein (apo) C-III makes up only 10% to 20% of plasma LDL but has a markedly altered metabolism and proatherogenic effects on vascular cells.Methods and Results: We examined the association between plasma LDL with apoC-III and coronary heart disease in 320 women and 419 men initially free of cardiovascular disease who developed a fatal or nonfatal myocardial infarction during 10 to 14 years of follow-up and matched controls who remained free of coronary heart disease. Concentrations of LDL with apoC-III (measured as apoB in this fraction) were associated with risk of coronary heart disease in multivariable analysis that included the ratio of total cholesterol to high-density lipoprotein cholesterol, LDL cholesterol, apoB, triglycerides, or high-density lipoprotein cholesterol and other risk factors. In all models, the relative risks for the top versus bottom quintile of LDL with apoC-III were greater than those for LDL without apoC-III. When included in the same multivariable-adjusted model, the risk associated with LDL with apoC-III (relative risk for top versus bottom quintile, 2.38; 95% confidence interval, 1.54-3.68; P for trend <0.001) was significantly greater than that associated with LDL without apoC-III (relative risk for top versus bottom quintile, 1.25; 95% confidence interval, 0.76-2.05; P for trend=0.97; P for interaction <0.001). This divergence in association with coronary heart disease persisted even after adjustment for plasma triglycerides.Conclusions: The risk of coronary heart disease contributed by LDL appeared to result to a large extent from LDL that contains apoC-III. [ABSTRACT FROM AUTHOR]

Background: The genetic substrate of severe hypertriglyceridemia (sHTG) in Latin America is insufficiently understood., Objective: To identify genetic variants in genes related to triglyceride (TG) metabolism among adults with sHTG from Colombia., Methods: In individuals with plasma TG≥880 mg/dL at least once in their lifetime, we amplified and sequenced all exons and intron/exon boundaries of the genes LPL, APOC2, APOA5, GPIHBP1 and LMF1. For each variant we ascertained its location, zygosity, allelic frequency and pathogenicity classification according to American College of Medical Genetics (ACMG) criteria., Results: The study included 166 participants (62 % male, mean age 50), peak TG levels ranged between 894 and 11,000 mg/dL. We identified 92 variants: 19 in LPL, 7 in APOC2, 11 in GPIHBP1, 38 in LMF1, and 17 in APOA5. Eighteen of these variants had not been reported. We identified a new pathogenic variant in LMF1 (c.41C>A; p.Ser14*), a new likely pathogenic variant in LMF1 (c.1527 C > T; p.Pro509=, also expressed as c.1447C>T; p.Gln483*), and a known pathogenic variant in LMF1 (c.779G>A; p.Trp260*). Four participants were heterozygous for variant c.953A>G; p.Asn318Ser in LPL, a known risk factor for hypertriglyceridemia. Participants with variants of unknown significance (VUS) in LMF1 had significantly higher peak TG than those with VUS in other genes. Peak TG were 4317 mg/dL in participants with a history of pancreatitis, and 1769 mg/dL in those without it (p = 0.001)., Conclusion: Our study identified variants associated with sHTG among Latinos, and showed that genetic variation in LMF1 may be frequently associated with sHTG in this population., Competing Interests: Declaration of competing interest This study was funded by PTC Therapeutics through an investigator-initiated grant, but the sponsor had no incidence in the design or execution of the study, or on the decision to publish., (Copyright © 2024. Published by Elsevier Inc.)

Obesity is both a major risk factor for diabetes and a serious comorbidity of the condition. The twin epidemics of obesity and diabetes have spread globally over the past few decades. Treatment of obesity in patients with diabetes provides a host of clinical benefits that encompass virtually all body systems. Despite this, multiple lines of evidence suggest that the efficacy of most therapies for weight loss is significantly reduced among patients with diabetes. With this background, we summarize the evidence of a differential effect of lifestyle, pharmacological, and surgical treatments for obesity in patients with existing diabetes, and explore the potential mechanisms involved in this phenomenon. This information is then used to formulate strategies to improve weight loss outcomes for patients with diabetes., (© 2024. The Author(s).)

In this randomised, placebo-controlled trial, adults with impaired sleep (Pittsburgh Sleep Quality Index ≥ 5) were randomly assigned using a minimization algorithm to receive a formulation containing L-theanine plus lemon balm, valerian, and saffron extracts, or placebo, during 6 weeks. Objective sleep quality parameters were measured using an actigraphy device. We enrolled and randomised 64 individuals, 31 from the active group and 27 from the placebo group completed the 6 week follow-up. Mean sleep efficiency remained unmodified in the active group, and increased by 3% in the placebo group, the between-group difference in the change was not statistically significant (p = 0.49). Total sleep time also improved more with placebo (13.0 vs. 1.33 min, p = 0.66). Time wake after sleep onset (WASO) decreased more in the active group (4.6% vs. 2.4%), but the difference was not significant (p = 0.33). Mean PSQI decreased by 3.11 points (32.3%) in the active group, and by 3.86 points (39.5%) in the placebo group (p = 0.41). SF-36 increased more with placebo (+ 18.3 in active, + 32.1 in placebo, p = 0.68). Salivary cortisol remained unchanged in both groups. No serious adverse events were reported. Among adults with impaired sleep, a nutraceutical combination did not improve objective or subjective sleep parameters more than a placebo infusion., (© 2024. The Author(s).)

There is great interest on medium chain fatty acids (MCFA) for cardiovascular health. We explored the effects of MCFA on the expression of lipid metabolism and inflammatory genes in macrophages, and the extent to which they were mediated by the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR β/δ). J774A.1 murine macrophages were exposed to octanoate or decanoate as MCFA, a long-chain fatty acid control (palmitate), or the PPAR β/δ agonist GW501516, with or without lipopolysaccharide (LPS) stimulation, and with or without an siRNA-induced knockdown of PPAR β/δ. MCFA increased the expression of Plin2, encoding a lipid-droplet associated protein with anti-inflammatory effects in macrophages, in a partially PPAR β/δ-dependent manner. Both MCFA stimulated expression of the cholesterol efflux pump ABCA1, more pronouncedly under LPS stimulation and in the absence of PPAR β/δ. Octanoate stimulated the expression of Pltp, encoding a phospholipid transfer protein that aids ABCA1 in cellular lipid efflux. Only palmitate increased expression of the proinflammatory genes Il6, Tnf, Nos2 and Mmp9. Non-stimulated macrophages exposed to MCFA showed less internalization of fluorescently labeled lipoproteins. MCFA influenced the transcriptional responses of macrophages favoring cholesterol efflux and a less inflammatory response compared to palmitate. These effects were partially mediated by PPAR β/δ., (© 2023. The Author(s).)

Introduction: We compared the association of glomerular filtration rate (GFR) estimated with the Cockcroft-Gault, Modification of Diet in Renal Disease study (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), or the new CKD-EPI without race (CKD-EPI-NR) equations, with 4-year all-cause mortality in patients with diabetes., Research Design and Methods: We analyzed a nationwide, centralized database of all adults diagnosed with diabetes assisted by the Colombian Health System between July 1, 2015, and June 30, 2019. Plasma creatinine was used to calculate baseline estimated glomerular filtration rate (eGFR) and classify each patient in a chronic kidney disease (CKD) stage, by each of the four equations. We used multivariate logistic regression to compare the association between CKD stage and mortality, and receiver operating characteristic (ROC) analyses to assess the overall association of eGFR by each equation and mortality., Results: The study included 758,219 patients (58% female, 7.2% black race, mean age 62.3, Glycated hemoglobin A1c [HbA1c] 7.4%). There were 35,296 deaths over the study follow-up. Considering eGFR by each equation as a continuous variable, the odds of death decreased by 1.1%-1.5% for each additional mL/min. Compared with CKD stage 1 of each equation, being placed in CKD stages 3a, 3b, or 4 by MDRD or CKD-EPI-NR was associated with greater odds of death than being categorized in the same stages by CKD-EPI. Among patients of black race, the adjusted OR of mortality for CKD stage 4 relative to stage 1 was 4.63 (95% CI 3.39 to 6.35) for MDRD, 3.66 (2.85 to 4.69) for CKD-EPI-NR, 3.01 (2.38 to 3.81) for CKD-EPI, and 2.82 (2.29 to 3.49) for Cockcroft-Gault. The area under the ROC curve to discriminate by survival status was greatest for MDRD, followed by CKD-EPI-NR, CKD-EPI, and Cockcroft-Gault, in that order (p<0.001 for all differences)., Conclusions: Compared with other eGFR equations, MDRD showed the strongest association with all-cause mortality in a sample of Latin-American patients with diabetes. This difference was most pronounced among patients of black race., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Calories from sugar-sweetened beverages (SSBs) contribute to the development of noncommunicable diseases. There is limited knowledge of the intake of SSBs and their correlates in developing countries. Thus, this study aimed to estimate the consumption of multiple SSBs and their sociodemographic correlates in an urban adult population from Colombia, South America., Methods: This was a probabilistic, population-level study of adults aged 18 to 75 from five cities representing different regions of Colombia. Dietary intake was assessed employing a 157-item semiquantitative food frequency questionnaire that inquired about intake over the last year. The consumption of regular soda, low-calorie soda, homemade and industrialized fruit juices, energy drinks, sport drinks, malt drinks and traditional sugar cane infusion (" agua de panela ") was analyzed for the total sample and subgroups defined by sociodemographic and clinical factors of interest., Results: The study included 1491 individuals (female: 54.2%, mean age: 45.3, overweight: 38.0%, obese: 23.3%). Sugary beverages contributed, on average, 287 Cal/d among women and 334 Cal/d among men, representing 8.9% of total daily calories (TDC). Women in the lowest SEL consumed 10.6% of their TDC from sugary drinks, as opposed to 6.6% for those in a high SEL. For men, this difference was not present ( p-value for interaction = 0.039). Interestingly, a higher educational level correlated with a lower consumption of calories from sugary drinks only among men. Fruit juices were by far the main source of sugary drinks, and their consumption did not change sizably by sex and socioeconomic or educational level. Among women, there was a negative association between socioeconomic level (SEL) and consumption of regular soda, a 50% difference between extreme levels. The intake of low-calorie soda was much higher among men than women, and it more than tripled in the highest vs. lowest SEL among men. The consumption of energy drinks was heavily concentrated in men of low SEL., Conclusion: Colombian urban adults obtain a considerable proportion of their calories from sugary drinks, especially vulnerable groups such as women with lower education. Given the recent acceleration of the obesity epidemic in Latin America, strategies to limit the intake of such liquid calories may provide important public health benefits.

Objective: The magnitude of the mortality benefit conferred by good integral metabolic control in diabetes in not sufficiently known, especially among Latin American patients. We prospectively studied the association between sustained control of blood glucose (HbA1c<7%), systolic blood pressure (SBP) (<130 mmHg) and LDL (LDLc, <100mg/dL) and non-HDL (non-HDLc, <130 mg/dL) cholesterol, and death from any cause among all adult patients with diagnosed diabetes in Colombia., Methods: We retrospectively analyzed data from a nationwide, centralized, mandatory registry of all patients with diagnosed diabetes assisted by the Colombian health system between July 1, 2015, and June 30, 2019. We estimated the associations of sustained achievement of each goal, and of the joint triple goal (HbA1c + SBP + LDLc) with all-cause death. Associations were assessed after adjustment for sex, age, race, insurance type and BMI in multivariable logistic models., Results: We studied 1 352 846 people with diabetes. Sustained SBP (OR 0.42 [0.41-0.43]), HbA1c (OR 0.25 [0.24-0.26]) and LDLc (OR 0.28 [0.27-0.29]) control had strong negative associations with death. Moreover, among the 5.4% of participants who achieved joint, sustained metabolic control, the OR for death was 0.19 (0.18-0.21). Importantly, the impact of sustained, joint metabolic control was significantly smaller for patients of black race compared to other races (OR 0.31 [0.23-0.43] versus 0.18 [0.17-0.20], p-value for interaction <0.001), mostly at the expense of a smaller impact of LDLc control. The results were similar across body-mass index categories., Conclusions: Sustained and simultaneous metabolic control was associated with remarkably lower odds of death., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mendivil, Amaya-Montoya, Hernández-Vargas, Ramírez-García, Herrera-Parra, Guatibonza-García, Romero-Díaz, Pérez-Londoño and Acuña-Merchán.)

Context: The relative importance of the control of different metabolic risk factors for the prevention of chronic kidney disease among patients with diabetes in real life conditions is insufficiently understood., Objective: We evaluated the effect of the achievement of glycated hemoglobin A 1c (HbA 1c ), systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDLc) or non-high-density lipoprotein cholesterol (non-HDLc) goals (ABC goals) on the development of incident chronic kidney disease (iCKD) among patients with diabetes., Methods: In a nationwide registry of all individuals diagnosed with diabetes assisted by the health system in Colombia, we analyzed the association between baseline or sustained goal achievement and development of iCKD over a 4-year follow-up. iCKD was defined as a new occurrence of an estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 , hemodialysis, peritoneal dialysis, or kidney transplant., Results: The study included 998 790 adults with diabetes (56% female, mean age 59). There were 125 626 cases of iCKD. After adjustment for multiple confounders, a baseline SBP less than 130 mm Hg (odds ratio [OR] 0.79 [0.78-0.80]) and a baseline HbA 1c less than 7.0% (OR 0.86 [0.85-0.87]) were negatively associated with iCKD. Sustained achievement showed stronger negative associations with iCKD than just baseline achievement. Considering each goal separately, sustained non-HDLc less than 130 mg/dL had the strongest negative association with iCKD (OR 0.67 [0.65-0.69]). Patients who maintained the triple ABC goal over the entire follow-up had 32% (29-34) lower odds of developing CKD, 38% (34-42) if they additionally kept a normal body mass index (BMI). Sustained ABC control including a normal BMI was more strongly associated with a lower incidence of CKD in patients of Black race (OR 0.72 vs 0.89; P for interaction = .002)., Conclusion: At the country level, sustained achievement of ABC goals and most especially non-HDLc were associated with substantial reductions in iCKD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Diabetic retinopathy is a devastating and frequent complication of poorly controlled diabetes, whose pathogenesis is still only partially understood. Advances in basic research over the last two decades have led to the discovery of angiopoietins, proteins that strongly influence the growth and integrity of blood vessels in many vascular beds, with particular importance in the retina. Angiopoietin 1 (Ang1), produced mostly by pericytes and platelets, and angiopoietin 2 (Ang2), produced mainly by endothelial cells, bind to the same receptor (Tie2), but exert opposing effects on target cells. Ang1 maintains the stability of the mature vasculature, while Ang2 promotes vessel wall destabilization and disruption of the connections between endothelial cells and pericytes. Human retinal endothelial cells exposed to Ang2 show reduced membrane expression of the adhesion molecule VE-cadherin, and patients with proliferative diabetic retinopathy or diabetic macular edema have markedly increased vitreal concentrations of Ang2. Faricimab, a bi-specific antibody simultaneously directed against Ang2 and VEGF, has shown promising results in clinical trials among patients with diabetic retinopathy, and other agents targeting the angiopoietin system are currently in development., (© 2022. The Author(s).)

Background: It is important to identify patients at increased risk of worsening of left ventricular ejection fraction (LVEF) after a myocardial infarction (MI). We aimed to identify the association of various potential biomarkers with LVEF impairment after an MI in South American patients., Methods: We studied adult patients admitted to a University Hospital and diagnosed with an acute MI. Plasma concentrations of high-sensitivity C-reactive protein (hsCRP), proprotein convertase subtilisin/kexin type 9 (PCSK9), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and heart-type fatty-acid-binding protein (FABP3) were determined in samples drawn shortly after the event. Participants had a follow-up visit at least 45 days after the event. The primary endpoint was defined as any decline in LVEF at follow-up relative to baseline., Results: The study included 106 patients (77.4% men, 22.6% women), mean age was 64.1, mean baseline LVEF was 56.6, 19% had a prior MI. We obtained a follow-up evaluation in 100 (94.4%) of participants, mean follow-up time was 163 days. There was a significant correlation between baseline PCSK9 and hsCRP (r = 0.39, p < 0.001). Baseline hsCRP concentrations were higher in patients who developed the endpoint than in those who did not (32.1 versus 21.2 mg/L, p = 0.066). After multivariate adjustment, baseline PCSK9, male sex and age were significantly associated with impairment in LVEF. The absolute change in LVEF was inversely correlated with baseline hsCRP (standardized coefficient = - 0.246, p = 0.004)., Conclusion: High plasma levels of PCSK9 and hsCRP were associated with early decreases in LVEF after an MI in Latin American patients., (© 2022. The Author(s).)

Rare pathogenic variants in the LMF1 gene, which encodes lipase maturation factor 1, are a minor cause of familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia. In this report we present three adult patients, all of them born and raised in Quito, Ecuador, with severe hypertriglyceridemia secondary to biallelic LMF1 variants. In two of the three cases (patients 1 and 3), the presentation was acute pancreatitis secondary to plasma triglycerides well above 10 mmol/L. The other case (patient 2) was a sibling of one of the initial patients, who was asymptomatic but markedly hypertriglyceridemic. Next-generation sequencing revealed a homozygous splice-site variant in exon 6 of LMF1 in patients 1 and 2 (c.897G>A, p.Gln299=), and a homozygous missense variant in exon 2 of LMF1 in patient 3 (c.233T>C, p.Leu78Pro). The finding of two disease-causing variants in three patients from the same location raises the question of whether LMF1 may be a more prevalent cause of severe hypertriglyceridemia among Latin-American patients., (Copyright © 2022. Published by Elsevier Inc.)

Aims: To assess the achievement of essential treatment goals among patients with diabetes in Colombia., Methods: We analyzed data from a nationwide registry of all individuals with diagnosed diabetes, hypertension or CKD assisted by the health system. We explored the prevalence of treatment goals (HbA1c < 7% [<53 mmol/mol], systolic blood pressure (SBP) < 130 mmHg and LDLc < 100 mg/dL), and their variations by race and type of health insurance, between July 1, 2015, and June 30, 2019., Results: We studied 1 352 846 patients with diagnosed diabetes. The prevalence of HbA1c < 7% (<53 mmol/mol) remained steady at 52%, systolic blood pressure (SBP) < 130 mmHg was also stable at 80-82%. Meanwhile, the prevalence of both LDLc < 100 mg/dL and non-HDLc < 130 mg/dL increased by 6 percentage points. Achievement of the triple HbA1c + SBP + LDLc goal was only 21.4% in 2015, increasing to 24.4% by 2019. Goal achievement was consistently lower among patients of black race, especially for HbA1c (5% lower than other races), but also for the SBP, LDLc and joint goals. Patients under third-party insurance reached better HbA1c, SBP, and LDLc control., Conclusions: Achievement of treatment goals of patients with diabetes in Colombia remains substantially low, despite improvements in LDLc control., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To explore the influence of socioeconomic position on habitual dietary intake in Colombian cities., Design: We conducted a cross-sectional, population-based study in five Colombian cities. Dietary intake was assessed with a 157-item semi-quantitative food frequency questionnaire previously developed for the Colombian population. Nutrient analysis was performed using national and international food composition tables. Socioeconomic position was assessed with two indicators: a government-defined, asset-based, household-level index called socioeconomic stratum (SES) and, among adults, highest educational level attained., Setting: The five main urban centers of Colombia: Bogotá, Medellin, Barranquilla, Cali and Bucaramanga., Participants: Probabilistic, multistage sample of 1865 participants (n=1491 for analyses on education)., Results: For both sexes, increasing SES was associated with a lower consumption of energy (p-trend <0.001 in both sexes), carbohydrates (p-trend ˂0.001 in both sexes), sodium (p-trend=0.005 in males, <0.001 in females), saturated fatty acids (p-trend <0.001 in both sexes) and among females, cholesterol (p-trend=0.002). More educated men consumed significantly less energy and carbohydrates (p-trend=0.036 and ˂0.001, respectively). Among men, intake of trans fats increased monotonically with educational level, being 21% higher among college graduates relative to those with only elementary education (p-trend=0.023). Among women, higher educational level was associated with higher MUFA intake (p-trend=0.027)., Conclusions: SES and educational level are strong correlates of the usual diet of urban Colombians. Economically deprived and less educated segments of society display dietary habits that make them vulnerable to chronic diseases and should be the primary target of public health nutrition policies.

Data on dietary calcium and vitamin D intake from Latin America are scarce. We explored the main correlates and dietary sources of calcium and vitamin D in a probabilistic, population-based sample from Colombia. We studied 1554 participants aged 18-75 from five different geographical regions. Dietary intake was assessed by employing a 157-item semi-quantitative food frequency questionnaire and national and international food composition tables. Daily vitamin D intake decreased with increasing age, from 230 IU/day in the 18-39 age group to 184 IU/day in the 60-75 age group (P -trend < 0.001). Vitamin D intake was positively associated with socioeconomic status (SES) (196 IU/day in lowest vs 234 in highest SES, P-trend < 0.001), and with educational level (176 IU/day in lowest vs 226 in highest education level, P-trend < 0.001). Daily calcium intake also decreased with age, from 1376 mg/day in the 18-39 age group to 1120 mg/day in the 60-75 age group (P -trend < 0.001). Calcium intake was lowest among participants with only elementary education, but the absolute difference in calcium intake between extreme education categories was smaller than for vitamin D (1107 vs 1274 mg/day, P-trend = 0.023). Daily calcium intake did not correlate with SES (P -trend = 0.74). Eggs were the main source of overall vitamin D, albeit their contribution decreased with increasing age. Dairy products contributed at least 48% of dietary calcium in all subgroups, mostly from cheese-containing traditional foods. SES and education were the key correlates of vitamin D and calcium intake. These findings may contribute to shape public health interventions in Latin American countries.

Background: Primary biliary cholangitis (PBC) is a serious disease that causes significant morbidity. PBC is confirmed with liver biopsy but autoantibodies are frequently used as proxies for diagnosis. The performance of autoantibodies for the diagnosis of PBC seems to vary widely across populations., Aim: To assess the diagnostic performance of several autoantibodies for the diagnosis of PBC in Latin American individuals., Methods: We studied 85 female adult Colombians, 43 cases with biopsy-confirmed PBC and 42 controls in whom a liver biopsy ruled out PBC. Plasma anti-mitochondrial antibodies (AMAs), anti-smooth muscle antibodies (ASMAs) and anti-nuclear antibodies (ANAs), as well as total immunoglobulin (Ig) M and IgG were determined using immunofluorescence or enzyme-linked immunosorbent assay in all study participants within 1 year of the biopsy. For all variables, values analyzed were those closest to the date of the biopsy. Patients with viral or alcoholic hepatitis were excluded., Results: Mean age at diagnosis was 58.7 years for cases and 56.9 years for controls, and the body mass index was lower among cases. Most cases received ursodeoxycholic acid, while most controls received vitamin E. Sjögren syndrome and Hashimoto's thyroiditis were the most frequent autoimmune comorbidities of PBC. The prevalence of AMA positivity among PBC cases was unexpectedly low. The sensitivity and specificity values were respectively 44.2% and 76.2% for AMA, 74.4% and 38.1% for ANA, 14.0% and 73.8% for ASMA, 26.7% and 80.0% for IgG, and 57.1% and 85.7% for IgM. The combination of positive AMA plus positive IgM had 91% positive predictive value for PBC. Among AMA-negative cases, the most prevalent antibodies were ANA (87.5%). In all, 62% of AMA-positive and 84.6% of IgM-positive individuals had fibrosis in their biopsy., Conclusion: AMA positivity was very low among female Latin American patients with PBC. The performance of all antibodies was quite limited. These results highlight the urgent need for better PBC biomarkers., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objectives: Diabetes is increasing rapidly in low-income and middle-income countries. We aimed to estimate the prevalence of diabetes, describe its correlates and its associated dietary intake in urban adults from Colombia., Setting: The Colombian Study of Nutritional Profiles was a population-based, cross-sectional, multi-stage probabilistic sampling survey designed to represent the five main Colombian cities., Participants: Between June and November 2018, we studied 736 non-pregnant participants aged 18 or older. Diabetes was defined as a random plasma glucose ≥200 mg/dL, self-reported prior diagnosis of diabetes or use of any oral or injectable antidiabetic medication(s). Participants also fulfilled a detailed 157-item food-frequency questionnaire., Primary and Secondary Outcome Measures: Prevalence of diabetes, dietary intake of key nutrients, achievement of dietary goals among individuals with diabetes., Results: The overall estimated prevalence of diabetes was 10.1%, with no difference by sex (9.6% in women, 10.8% in men, p=0.43). The association between diabetes and education level depended on sex, diabetes was more prevalent among more educated men and less educated women. Abdominal obesity was associated with a 65% increase in diabetes prevalence among men, and a 163% increase in women. Individuals with diabetes reported lower mean consumption of all nutrients, but after adjustment by sex, age, socioeconomic level (SEL) and body mass index, only their lower sodium consumption remained significant (p=0.013). The proportion of non-achievement of dietary intake goals among participants with diabetes was 94.4% for saturated fats, 86.7% for sodium, 84.4% for fibre and 80% for trans fats. In multivariate logistic regression models, age was the strongest independent correlate of diabetes., Conclusions: Diabetes by self-report, random plasma glucose or medication use was highly prevalent among Colombian adults. There were large differences by abdominal obesity status, region of residence, SEL and educational level. The proportion of individuals with diabetes meeting dietary recommendations was alarmingly low., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Dietary habits are a major determinant of the risk of chronic disease, particularly metabolic and endocrine disorders. Fish as a food group are a unique source of nutrients with metabolic and hormonal importance including omega-3 fatty acids, iodine, selenium, vitamin D, taurine and carnitine. Fish are also a source of high quality protein and have in general low caloric density. The impact of these nutrients on cardiovascular risk has been extensively reviewed, but the impact of fish on the broader field of endocrine and metabolic health is sometimes not sufficiently appreciated. This article aimed to summarize the impact the effect of regular fish consumption on conditions like the metabolic syndrome, obesity, diabetes, hypothyroidism, polycystic ovary syndrome and the menopausal transition, which are in and of themselves significant causes of morbidity and mortality worldwide. The review revealed that scientific evidence from food science, translational research, epidemiologic studies and interventional trials shows that regular fish consumption has a positive impact on thyroid homeostasis, facilitates maintenance of a healthy body weight, reduces the magnitude of age-associated increases in blood pressure, improves glucose homeostasis helping prevent diabetes and the metabolic syndrome, and has a positive impact on muscle mass preservation among the elderly. These effects are mediated by multiple mechanisms, only some of which have been identified. For most of these effects it holds true that the potential benefits are more substantial when baseline fish consumption is low., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Dietary habits have a major impact on the development and function of the immune system. This impact is mediated both by the intrinsic nutritional and biochemical qualities of the diet, and by its influence on the intestinal microbiota. Fish as a food is rich in compounds with immunoregulatory properties, among them omega-3 fatty acids, melatonin, tryptophan, taurine and polyamines. In addition, regular fish consumption favors the proliferation of beneficial members of the intestinal microbiota, like short-chain fatty acid-producing bacteria. By substituting arachidonic acid in the eicosanoid biosynthesis pathway, long-chain omega-3 fatty acids from fish change the type of prostaglandins, leukotrienes and thromboxanes being produced, resulting in anti-inflammatory properties. Further, they also are substrates for the production of specialized pro-resolving mediators (SPMs) (resolvins, protectins, and maresins), lipid compounds that constitute the physiological feedback signal to stop inflammation and give way to tissue reparation. Evidence from human observational and interventional studies shows that regular fish consumption is associated with reduced incidence of chronic inflammatory conditions like rheumatoid arthritis, and that continuous infusion of fish oil to tube-fed, critically ill patients may improve important outcomes in the ICU. There is also evidence from animal models showing that larger systemic concentrations of omega-3 fatty acids may counter the pathophysiological cascade that leads to psoriasis. The knowledge gained over the last few decades merits future exploration of the potential role of fish and its components in other conditions characterized by deregulated activation of immune cells and a cytokine storm like viral sepsis or COVID-19., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mendivil.)

Diabetes is a highly prevalent disease with complications that impact most bodily systems. However, the impact of diabetes on bone health is frequently ignored or underestimated. Both type 1 (T1D) and type 2 diabetes (T2D) are associated with a higher risk of fractures, albeit through different mechanisms. T1D is characterized by near total insulinopenia, which affects the anabolic tone of bone and results in reduced bone mineral density (BMD). Meanwhile, patients with T2D have normal or high BMD, but carry an increased risk of fractures due to alterations of bone microarchitecture and a local humoral environment that stimulates osteoclast activity. Chronic hyperglycemia induces non-enzymatic glycation of collagen in both types of diabetes. Epidemiological evidence confirms a largely increased fracture risk in T1D and T2D, but also that it can be substantially reduced by opportune monitoring of fracture risk and appropriate treatment of both diabetes itself and osteopenia or osteoporosis if they are present. In this review, we summarize the mechanistic, epidemiological, and clinical evidence that links diabetes and bone fragility, and describe the impact of available diabetes treatments on bone health.

Objective: To estimate the effect of oral contraceptives (OC) containing different progestins on parameters of lipid and carbohydrate metabolism through a systematic review and meta-analysis., Patients and Methods: Premenopausal women aged 18 or older, who received oral contraceptives containing chlormadinone, cyproterone, drospirenone, levonorgestrel, desogestrel, dienogest, gestodene or norgestimate, for at least 3 months. Outcome variables were changes in plasma lipids, BMI, insulin resistance and plasma glucose. We searched MEDLINE and EMBASE for randomized trials and estimated the pooled within-group change in each outcome variable using a random-effects model. We performed subgroup analyses by study duration (<12 months vs ≥12 months) and polycystic ovary syndrome (PCOS) status., Results: Eighty-two clinical trials fulfilled the inclusion criteria. All progestins (except dienogest) increased plasma TG, ranging from 12.1 mg/dL for levonorgestrel (P < 0.001) to 35.1 mg/dL for chlormadinone (P < 0.001). Most progestins also increased HDLc, with the largest effect observed for chlormadinone (+9.6 mg/dL, P < 0.001) and drospirenone (+7.4 mg/dL, P < 0.001). Meanwhile, levonorgestrel decreased HDLc by 4.4 mg/dL (P < 0.001). Levonorgestrel (+6.8 mg/dL, P < 0.001) and norgestimate (+11.5 mg/dL, P = 0.003) increased LDLc, while dienogest decreased it (-7.7 mg/dL, P = 0.04). Cyproterone slightly reduced plasma glucose. None of the progestins affected BMI or HOMA-IR. Similar results were observed in subgroups defined by PCOS or study duration., Conclusion: Most progestins increase both TG and HDLc, their effect on LDLc varies widely. OC have minor or no effects on BMI, HOMA-IR and glycemia. The antiandrogen progestins dienogest and cyproterone displayed the most favorable metabolic profile, while levonorgestrel displayed the least favorable.

Rationale: The optimal modality, intensity, duration, frequency, and dose-response of exercise as a therapy for Parkinson's Disease (PD) are insufficiently understood. Objective: To assess the impact of a high-intensity tandem bicycle program on clinical severity, biomarkers, and functional MRI (fMRI) in PD. Methods: A single-center, parallel-group clinical trial was conducted. Thirteen PD patients aged 65 or younger were divided in two groups: a control group and an intervention group that incorporated a cycling program at 80% of each individual's maximum heart rate (HR) (≥80 rpm), three times a week, for 16 weeks. Both groups continued their conventional medications for PD. At baseline and at the end of follow-up, we determined in all participants the Unified Parkinson's Disease Rating Scale, anthropometry, VO 2 max, PD biomarkers, and fMRI. Results: VO 2 max improved in the intervention group (IG) (+5.7 ml/kg/min), while it slightly deteriorated in the control group (CG) (-1.6 ml/kg/min) ( p = 0.041). Mean Unified Parkinson's Disease Rating Scale (UPDRS) went down by 5.7 points in the IG and showed a small 0.9-point increase in the CG ( p = 0.11). fMRI showed activation of the right fusiform gyrus during the motor task and functional connectivity between the cingulum and areas of the frontal cortex, and between the cerebellar vermis and the thalamus and posterior temporal gyrus. Plasma brain-derived neurotrophic factor (BDNF) levels increased more than 10-fold in the IG and decreased in the CG ( p = 0.028). Larger increases in plasma BDNF correlated with greater decreases in UPDRS ( r = -0.58, p = 0.04). Conclusions: Our findings suggest that high-intensity tandem bicycle improves motor function and biochemical and functional neuroimaging variables in PD patients. Trial registration number: ISRCTN 13047118, Registered on February 8, 2018., (Copyright © 2020 Segura, Eraso, Bonilla, Mendivil, Santiago, Useche, Bernal-Pacheco, Monsalve, Sanchez, Hernández, Peláez-Jaramillo and Cárdenas-Mojica.)

Aim: To study the criterion validity of three indirect maximal oxygen uptake ([Formula: see text]O 2 max) assessment equations at altitude. Methods: We studied 64 young adults (53% men) at Bogota, Colombia (2600 m altitude). Direct [Formula: see text]O 2 max was measured by indirect calorimetry using a maximal incremental treadmill protocol. Indirect [Formula: see text]O 2 max was estimated by two exercise field tests (the 20-m shuttle-run test [20-MST] and the 2-km walking test (UKK)) and one nonexercise method (the perceived functional ability-physical activity rating questionnaire [PFA-PAR]). Altitude-adjusted PFA-PAR was estimated as a 13% linear reduction in PFA-PAR. We calculated Lin concordance coefficients (LCC) and standard error of the estimates (SEEs), and we performed Bland-Altman analyses for each indirect method. Results: Mean [Formula: see text]O 2 max was 41.2 ± 5.8 mL/kg/min in men and 32.2 ± 3.6 mL/kg/min in women. We found the highest agreement with direct [Formula: see text]O 2 max for the 20-MST (LCC = 0.79, SEE = 3.91 mL/kg/min), followed in order by the altitude-adjusted PFA-PAR (LCC = 0.71, SEE = 4.12 mL/kg/min), the UKK (LCC = 0.67, SEE = 5.48 mL/kg/min), and the unadjusted PFA-PAR (LCC = 0.57, SEE = 4.75 mL/kg/min). The unadjusted PFA-PAR tended to overestimate [Formula: see text]O 2 max, but Bland-Altman analysis showed that this bias disappeared after altitude adjustment. Conclusion: Several maximal, submaximal, and nonexercise methods provide estimates of [Formula: see text]O 2 max with acceptable validity for use in epidemiological studies of populations living at moderate altitude.

Background: The functionality of high-density lipoproteins (HDL) is a better cardiovascular risk predictor than HDL concentrations. One of the key elements of HDL functionality is its apolipoprotein composition. Lecithin-cholesterol acyl transferase (LCAT) and cholesterol-ester transfer protein (CETP) are enzymes involved in HDL-mediated reverse cholesterol transport. This study assessed the concentration and activity of LCAT and CETP in HDL subspecies defined by their content of apolipoproteins E (apoE) and C-III (apoC-III) in humans., Methods: Eighteen adults (ten women and eight men, mean age 55.6, BMI 26.9 Kg/m 2 , HbA1c 5.4%) were studied. HDL from each participant were isolated and divided into four subspecies containing respectively: No apoE and no apoC-III (E-C-), apoE but not apoC-III (E + C-), apoC-III but no apoE (E-C+) and both apoE and apoC-III (E + C+). The concentration and enzymatic activity of LCAT and CETP were measured within each HDL subspecies using immunoenzymatic and fluorometric methods. Additionally, the size distribution of HDL in each apolipoprotein-defined fraction was determined using non-denaturing electrophoresis and anti-apoA-I western blotting., Results: HDL without apoE or apoC-III was the predominant HDL subtype. The size distribution of HDL was very similar in all the four apolipoprotein-defined subtypes. LCAT was most abundant in E-C- HDL (3.58 mg/mL, 59.6% of plasma LCAT mass), while HDL with apoE or apoC-III had much less LCAT (19.8, 12.2 and 8.37% of plasma LCAT respectively for E + C-, E-C+ and E + C+). LCAT mass was lower in E + C- HDL relative to E-C- HDL, but LCAT activity was similar in both fractions, signaling a greater activity-to-mass ratio associated with the presence of apoE. Both CETP mass and CETP activity showed only slight variations across HDL subspecies. There was an inverse correlation between plasma LCAT activity and concentrations of both E-C+ pre-beta HDL (r = - 0.55, P = 0.017) and E-C- alpha 1 HDL (r = - 0.49, P = 0.041). Conversely, there was a direct correlation between plasma CETP activity and concentrations of E-C+ alpha 1 HDL (r = 0.52, P = 0.025)., Conclusions: The presence of apoE in small HDL is correlated with increased LCAT activity and esterification of plasma cholesterol. These results favor an interpretation that LCAT and apoE interact to enhance anti-atherogenic pathways of HDL.

Life expectancy has increased substantially over the last few decades, leading to a worldwide increase in the prevalence and burden of aging-associated diseases. Recent evidence has proven that cellular senescence contributes substantially to the development of these disorders. Cellular senescence is a state of cell cycle arrest with suppressed apoptosis and concomitant secretion of multiple bioactive factors (the senescence-associated secretory phenotype-SASP) that plays a physiological role in embryonic development and healing processes. However, DNA damage and oxidative stress that occur during aging cause the accumulation of senescent cells, which through their SASP bring about deleterious effects on multiple organ and systemic functions. Ablation of senescent cells through genetic or pharmacological means leads to improved life span and health span in animal models, and preliminary evidence suggests it may also have a positive impact on human health. Thus, strategies to reduce or eliminate the burden of senescent cells or their products have the potential to impact multiple clinical outcomes with a single intervention. In this review, we touch upon the basics of cell senescence and summarize the current state of development of therapies against cell senescence for human use.

Introduction: To evaluate the effect of a lipid-based formulation containing unusual polyunsaturated fatty acids, trace elements, polyphenols and plant sterols on insulin resistance and its associated disturbances among adults at risk of diabetes., Methods: This was an 8-week, three-arm, open-label randomized clinical trial. We studied individuals aged ≥ 18 years old with diabetes risk given by a body mass index ≥ 25 kg/m 2 or a FinnRisc score ≥ 13/20. Participants were randomly assigned to receive: 7 ml sunflower oil (control group), 3.5 ml of the study formulation + 3.5 ml of sunflower oil (low-dose group) or 7 ml of study formulation (high-dose group)., Results: We randomized 25 individuals. After one withdrawal in the high-dose group, the study sample comprised nine patients in the control, nine in the low-dose and six in the high-dose groups. The insulin sensitivity increased significantly and in a dose-dependent fashion, up to 10% in the high-dose group. At week 8 the low-dose group exhibited lower glycemic excursions during the oral glucose tolerance test (OGTT), especially 1 h after the glucose challenge (32 mg/dl or 23% lower vs. control group). The incremental area under the glucose curve in the OGTT was 17.1% lower in the low-dose group vs. the control group. Waist circumference increased in the control group, remained constant in the low-dose group and decreased in the high-dose group. C-reactive protein decreased in both formulation groups, up to 50% in the high-dose group. Participants in the formulation groups exhibited increased secretion of GLP-1 and plasma irisin at week 8 vs. the control group., Conclusion: The formulation induced favorable changes in insulin sensitivity, glucose tolerance, abdominal obesity and inflammation. These effects and their durability will need to be assessed in larger studies., Trial Registration: NCT03512665., Funding: Team Foods Colombia.

Familial chylomicronemia is a disease in which a genetic mutation affects the ability of the organism to metabolize triglycerides bound to lipoproteins, causing extremely high plasma triglycerides and associated consequences. The most frequent complication is acute pancreatitis, which may lead to multiorganic failure or pancreatic insufficiency. Familial chylomicronemia also exerts a profound negative impact on quality of life, social relationships and professional development. The gene most frequently affected is lipoprotein lipase-1 gene (LPL), the enzyme in charge of hydrolyzing circulating triglycerides for tissue uptake. Mutations in other genes regulating maturation, transport or polymerization (eg. APOC2, APOAV, LMF-1, GPIHBP-1) of lipoprotein lipase-1, may also be involved. However, in about 30% of patients the causal variant is not identified. Familial chylomicronemia should be suspected in patients with severe hypertriglyceridemia with poor response to conventional treatment, or accompanied by eruptive xanthomas, lipemia retinalis or abdominal pain. The availability of risk scores and genetic tests should facilitate its opportune detection and management. Nutritional therapy is based on a very-low-fat diet with adequate supply of lipid-soluble vitamins and essential fatty acids, plus avoidance of alcohol consumption. Current pharmacological treatment may include fibrates and omega-3 fatty acids but prioritizes biotechnological agents targeting the molecular disturbances of the disease. These include an antisense oligonucleotide against apoC-III (volanesorsen), a monoclonal antibody against angiopoietin-like protein-3 (evinacumab), and other agents currently in development.

Background: HDL that contains apolipoprotein E (apoE) is a subspecies especially active in steps in reverse cholesterol transport, a process that brings cholesterol from peripheral cells to the liver. Here, we studied the effect of dietary unsaturated fat compared with carbohydrate on the metabolism of HDL containing apoE., Methods: We enrolled 9 adults who were overweight or obese and had below-average HDL-cholesterol in a crossover study of a high-fat diet, primarily unsaturated, and a low-fat, high-carbohydrate diet. A metabolic tracer study was performed after each diet period., Results: Dietary fat increased the secretion, metabolism, and clearance of HDL subspecies containing apoE. Dietary fat increased the rate of clearance of large cholesterol-rich HDL containing apoE and increased their conversion to small HDL containing apoE, indicating selective cholesterol ester delivery to the liver. The high-unsaturated-fat diet did not affect the metabolism of HDL lacking apoE., Conclusion: HDL containing apoE is a diet-responsive metabolic pathway that renders HDL more biologically active in reverse cholesterol transport. This may be a mechanism by which unsaturated fat protects against coronary heart disease. Protein-based HDL subspecies such as HDL containing apoE may be used to identify additional atheroprotective treatment targets not evident in the total HDL-cholesterol measurement., Trial Registration: ClinicalTrials.gov NCT01399632., Funding: NIH and the National Center for Advancing Translational Science.

Post-liver transplantation diabetes mellitus (PLTDM) develops in up to 30% of liver transplant recipients and is associated with increased risk of mortality and multiple morbid outcomes. PLTDM is a multicausal disorder, but the main risk factor is the use of immunosuppressive agents of the calcineurin inhibitor (CNI) family (tacrolimus and cyclosporine). Additional factors, such as pre-transplant overweight, nonalcoholic steatohepatitis and hepatitis C virus infection, may further increase risk of developing PLTDM. A diagnosis of PLTDM should be established only after doses of CNI and steroids are stable and the post-operative stress has been overcome. The predominant defect induced by CNI is insulin secretory dysfunction. Plasma glucose control must start immediately after the transplant procedure in order to improve long-term results for both patient and transplant. Among the better known antidiabetics, metformin and DPP-4 inhibitors have a particularly benign profile in the PLTDM context and are the preferred oral agents for long-term management. Insulin therapy is also an effective approach that addresses the prevailing pathophysiological defect of the disorder. There is still insufficient evidence about the impact of newer families of antidiabetics (GLP-1 agonists, SGLT-2 inhibitors) on PLTDM. In this review, we summarize current knowledge on the epidemiology, pathogenesis, course of disease and medical management of PLTDM.

Background: Subspecies of HDL contain apolipoprotein E (apoE) and/or apoCIII. Both proteins have properties that could affect HDL metabolism. The relation between HDL metabolism and risk of coronary heart disease (CHD) is not well understood., Methods: Eighteen participants were given a bolus infusion of [D3]L-leucine to label endogenous proteins on HDL. HDL was separated into subspecies containing apoE and/or apoCIII and then into 4 sizes. Metabolic rates for apoA-I in HDL subspecies and sizes were determined by interactive modeling. The concentrations of apoE in HDL that contain or lack apoCIII were measured in a prospective study in Denmark including 1,949 incident CHD cases during 9 years., Results: HDL containing apoE but not apoCIII is disproportionately secreted into the circulation, actively expands while circulating, and is quickly cleared. These are key metabolic steps in reverse cholesterol transport, which may protect against atherosclerosis. ApoCIII on HDL strongly attenuates these metabolic actions of HDL apoE. In the epidemiological study, the relation between HDL apoE concentration and CHD significantly differed depending on whether apoCIII was present. HDL apoE was associated significantly with lower risk of CHD only in the HDL subspecies lacking apoCIII., Conclusions: ApoE and apoCIII on HDL interact to affect metabolism and CHD. ApoE promotes metabolic steps in reverse cholesterol transport and is associated with lower risk of CHD. ApoCIII, when coexisting with apoE on HDL, abolishes these benefits. Therefore, differences in metabolism of HDL subspecies pertaining to reverse cholesterol transport are reflected in differences in association with CHD., Trial Registration: Clinicaltrials.gov NCT01399632., Funding: This work was supported by NIH grant R01HL095964 to FMS and by a grant to the Harvard Clinical and Translational Science Center (8UL1TR0001750) from the National Center for Advancing Translational Science.

Background: Myokines are a group of protein mediators produced by skeletal muscle under stress or physical exertion. Even though their discovery and effects in cell culture and animal models of disease have elicited great enthusiasm, very little is known about their role in human metabolism. We assessed whether plasma concentrations of three known myokines [myonectin, myostatin, and fibroblast-derived growth factor 21 (FGF-21)] would be associated with direct and indirect indicators of insulin resistance (IR) in individuals who did not have a diagnosis of diabetes., Methods: We studied 81 adults of both sexes comprising a wide range of body adiposity and insulin sensitivity. All participants underwent a thorough clinical assessment and a 5-point oral glucose tolerance test with calculation of multiple IR and insulin sensitivity indices. Twenty-one of them additionally underwent a hyperinsulinemic-euglycemic clamp with determination of steady-state whole-body insulin-stimulated glucose disposal ("M"). We compared plasma myokine concentrations across quartiles of IR indices and clinical IR surrogates, and explored the correlation of each myokine with the M -value., Results: Plasma myonectin levels increased monotonically across quartiles of the incremental area under the insulin curve (higher values indicate more IR) ( p -trend = 0.021) and decreased monotonically across quartiles of the insulin sensitivity index (ISI - higher values indicate less IR) ( p -trend = 0.012). After multivariate adjustment for other relevant determinants of IR (body mass index, age, and sex), the negative association of myonectin with ISI persisted (standardized beta = -0.235, p  = 0.023). Myostatin was not associated with any clinical IR indicator or direct IR index measure. In multivariate analyses, FGF-21 showed a trend toward a positive correlation with glucose disposal that did not reach statistical significance (standardized beta = 0.476, p  = 0.091)., Conclusion: The secretion of myonectin may constitute an attempt at a compensatory mechanism against IR in humans.

Disorders of lipid and lipoprotein metabolism play a central role in the pathogenesis of atherosclerotic cardiovascular diseases (CVDs). Despite the widespread use of efficacious lipid-modifying therapies, the residual risk of CVD remains unacceptably high. The purpose of this manuscript is to review the application of new technologies in the treatment of lipid disorders. New therapies work mostly at the gene expression level and are, therefore, different from traditional small-molecule drugs that work mainly by inhibiting already synthesized proteins. We will briefly lay out the function of the gene products targeted by the new agents. Then, we will organize our review of new biotechnological treatments by the molecular approach, namely: monoclonal antibodies, antisense oligonucleotides, small-interfering RNAs, and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated 9 (Cas9)-based genome editing. The paper concludes with the description of the current clinical studies and the perspectives for the use of these agents. (REV INVEST CLIN. 2018;70:244-54)., (Copyright: © 2018 SecretarÍa de Salud.)

To understand the status of prediabetes diagnosis and treatment in Latin America and to evaluate the use of metformin for diabetes prevention in this context . A panel of 15 diabetes experts from seven countries in Latin America met on 14 - 15 August 2014 in Lima, Peru, to review the available literature, discuss the role of prediabetes in type 2 diabetes mellitus and cardiovascular disease, analyze collected information, and make conclusions for prediabetes diagnosis and treatment in Latin America . Prediabetes diagnosis, screening, and treatment, including lifestyle changes, pharmacological treatment, and cost-effectiveness were discussed. Five resulting statements were issued for Latin America: prediabetes is a clinical and public health problem; health care systems do not currently diagnose/treat prediabetes; use of prediabetes risk detection tools are needed region-wide; treatment includes lifestyle changes, multidisciplinary education, and metformin; and registries of patient records and further studies should be supported . The expert panel concluded that in Latin America, preventive treatment through lifestyle changes and metformin are cost-effective interventions. It is important to improve prediabetes identification and management at the primary care level ., Competing Interests: Conflict of interests: Manuela Restrepo is associated with Merck Colombia, an affiliate of Merck KGaA (Darmstadt, Germany).

Background: Plasma concentrations of some lysophospholipids correlate with metabolic alterations in humans, but their potential as biomarkers of insulin resistance (IR) is insufficiently known. We aimed to explore the association between plasma linoleoylglycerophosphocholine (LGPC) and objective measures of IR in adults with different metabolic profiles., Methods: We studied 62 men and women, ages 30 to 69 years, (29% normal weight, 59% overweight, 12% obese). Participants underwent a 5-point oral glucose tolerance test (5p-OGTT) from which we calculated multiple indices of IR and insulin secretion. Fifteen participants additionally underwent a hyperinsulinemic-euglycemic clamp for estimation of insulin-stimulated glucose disposal. Plasma LGPC was determined using high performance liquid chromatography/time-of-flight mass spectrometry. Plasma LGPC was compared across quartiles defined by the IR indices., Results: Mean LGPC was 15.4±7.6 ng/mL in women and 14.1±7.3 ng/mL in men. LGPC did not correlate with body mass in-dex, percent body fat, waist circumference, blood pressure, glycosylated hemoglobin, log-triglycerides, or high density lipoprotein cholesterol. Plasma LGPC concentrations was not systematically associated with any of the studied 5p-OGTT-derived IR indices. However, LGPC exhibited a significant negative correlation with glucose disposal in the clamp (Spearman r=-0.56, P=0.029). Despite not being diabetic, participants with higher plasma LGPC exhibited significantly higher post-challenge plasma glucose excursions in the 5p-OGTT (P trend=0.021 for the increase in glucose area under the curve across quartiles of plasma LGPC)., Conclusion: In our sample of Latino adults without known diabetes, LGPC showed potential as a biomarker of IR and impaired glucose metabolism., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2017 Korean Diabetes Association)

Type 2 diabetes mellitus (T2DM) is characterized by oxidative stress that could lead to chronic micro- and macrovascular complications. We hypothesized that some of the target organ damage is mediated by oxidative alterations in epigenetic mechanisms involving DNA methylation (5mC) and DNA hydroxymethylation (5hmC). We analyzed global DNA methylation and hydroxymethylation in peripheral blood cells in well-controlled and poorly controlled patients with T2DM and compared them with healthy controls. We also analyzed microarrays of DNA methylation and gene expression of other important tissues in the context of diabetes from the GEO database repository and then compared these results with our experimental gene expression data. DNA methylation and, more importantly, DNA hydroxymethylation levels were increased in poorly controlled patients compared to well-controlled and healthy individuals. Both 5mC and 5hmC measurements were correlated with the percentage of glycated hemoglobin, indicating a direct impact of hyperglycemia on changes over the epigenome. The analysis of methylation microarrays was concordant, and 5mC levels were increased in the peripheral blood of T2DM patients. However, the DNA methylation levels were the opposite of those in other tissues, such as the pancreas, adipose tissue and skeletal muscle. We hypothesize that a process of DNA oxidation associated with hyperglycemia may explain the DNA demethylation in which the activity of ten-eleven translocation (TET) proteins is not sufficient to complete the process. High levels of glucose lead to cellular oxidation, which triggers the process of DNA demethylation aided by TET enzymes, resulting in epigenetic dysregulation of the damaged tissues., (© 2017 The authors.)

Aims: To evaluate and compare the association of four potential insulin resistance (IR) biomarkers (pigment-epithelium-derived factor [PEDF], retinol-binding-protein-4 [RBP-4], chitinase-3-like protein 1 [YKL-40] and brain-derived neurotrophic factor [BDNF]) with objective measures of IR., Methods: We studied 81 subjects with different metabolic profiles. All participants underwent a 5-point OGTT with calculation of multiple IR indexes. A subgroup of 21 participants additionally underwent a hyperinsulinemic-euglycemic clamp. IR was defined as belonging to the highest quartile of incremental area under the insulin curve (iAUCins), or to the lowest quartile of the insulin sensitivity index (ISI)., Results: PEDF was associated with adiposity variables. PEDF and RBP4 increased linearly across quartiles of iAUCins (for PEDF p-trend=0.029; for RBP-4 p-trend=0.053). YKL-40 and BDNF were not associated with any adiposity or IR variable. PEDF and RBP-4 levels identified individuals with IR by the iAUCins definition: A PEDF cutoff of 11.9ng/mL had 60% sensitivity and 68% specificity, while a RBP-4 cutoff of 71.6ng/mL had 70% sensitivity and 57% specificity. In multiple regression analyses simultaneously including clinical variables and the studied biomarkers, only BMI, PEDF and RBP-4 remained significant predictors of IR., Conclusions: Plasma PEDF and RBP4 identified IR in subjects with no prior diagnosis of diabetes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Diabetic polyneuropathy (DPN) encompasses multiple syndromes with a common pathogenesis. Glycemic control shows a limited correlation with DPN, arguing in favor of major involvement of other factors, one of which is alterations of lipid and lipoprotein metabolism. Consistent associations have been found between plasma triglycerides/remnant lipoproteins and the risk of DPN. Studies in cultured nerve tissue or in murine models of diabetes have unveiled mechanisms linking lipid metabolism to DPN. Deficient insulin action increases fatty acids flux to nerve cells, inducing mitochondrial dysfunction, anomalous protein kinase C signaling, and perturbations in the physicochemical properties of the plasma membrane. Oxidized low-density lipoproteins bind to cellular receptors and promote generation of reactive oxygen species, worsening mitochondrial function and altering the electrical properties of neurons. Supplementation with specific fatty acids has led to prevention or reversal of different modalities of DPN in animal models. Post hoc and secondary analyses of clinical trials have found benefits of cholesterol reducing (statins and ezetimibe), triglyceride-reducing (fibrates), or lipid antioxidant (thioctic acid) therapies over the progression and severity of DPN. However, these findings are mostly hypothesis-generating. Randomized trials are warranted in which the impact of intensive plasma lipids normalization on DPN outcomes is specifically evaluated., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Endogenous labeling with stable isotopes is used to study the metabolism of proteins in vivo. However, traditional detection methods such as GC/MS cannot measure tracer enrichment in multiple proteins simultaneously, and multiple reaction monitoring MS cannot measure precisely the low tracer enrichment in slowly turning-over proteins as in HDL. We exploited the versatility of the high-resolution/accurate mass (HR/AM) quadrupole Orbitrap for proteomic analysis of five HDL sizes. We identified 58 proteins in HDL that were shared among three humans and that were organized into five subproteomes according to HDL size. For seven of these proteins, apoA-I, apoA-II, apoA-IV, apoC-III, apoD, apoE, and apoM, we performed parallel reaction monitoring (PRM) to measure trideuterated leucine tracer enrichment between 0.03 to 1.0% in vivo, as required to study their metabolism. The results were suitable for multicompartmental modeling in all except apoD. These apolipoproteins in each HDL size mainly originated directly from the source compartment, presumably the liver and intestine. Flux of apolipoproteins from smaller to larger HDL or the reverse contributed only slightly to apolipoprotein metabolism. These novel findings on HDL apolipoprotein metabolism demonstrate the analytical breadth and scope of the HR/AM-PRM technology to perform metabolic research., (Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.)

Background: Cardiovascular autonomic neuropathy (CAN) is a prevalent and neglected chronic complication of diabetes, with a large impact on morbidity and mortality. Part of the reason why it is not detected and treated opportunely is because of the complexity of the tests required for its diagnosis. We evaluated the Neuropad®, a test based on sudomotor function, as a screening tool for CAN in adult patients with type 2 diabetes in Bogotá, Colombia., Methods: This was a cross-sectional evaluation of Neuropad® for the detection of CAN. Patients were 20-75years of age and did not suffer from any other type of neuropathy. CAN was diagnosed using the Ewing battery of tests for R-R variability during deep breathing, Valsalva and lying-to-standing maneuvers. Additionally, distal symmetric polyneuropathy (DSP) was diagnosed using a sign-based scale (Michigan Neuropathy Disability Score - NDS) and a symptom-based score (Total Symptom Score - TSS). The primary outcome was the sensitivity and specificity of the Neuropad® for the diagnosis of CAN, and secondary outcomes were the sensitivity and specificity of Neuropad® for DSP., Results: We studied 154 patients (74 men and 80 women). Prevalence of CAN was extremely high (68.0% of study participants), but also DSP was prevalent, particularly according to the signs-based definition (45%). The sensitivity of the Neuropad® for any degree of CAN was 70.1%, being slightly higher for the deep breathing and Valsalva tests than for lying-to-standing. The specificity of the Neuropad® for any type of CAN was only 37.0%, as expected for a screening exam. The negative predictive value was higher for the deep breathing and Valsalva tests (69.4 and 81.6%, respectively). Neuropad showed also a good sensitivity and negative predictive value for DSP. The sensitivity and specificity of Neuropad were better among men, and among patients with diabetes duration above the group median., Conclusions: The Neuropad is a simple and inexpensive device that demonstrated an adequate performance as a screening tool for cardiovascular autonomic neuropathy in Latin American patients with DM2., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: A prevailing concept is that high-density lipoprotein (HDL) is secreted into the systemic circulation as a small mainly discoidal particle, which expands progressively and becomes spherical by uptake and esterification of cellular cholesterol and then contracts by cholesterol ester delivery to the liver, a process known as reverse cholesterol transport, thought to be impaired in people with low HDL cholesterol (HDLc). This metabolic framework has not been established in humans., Approach and Results: We studied the metabolism of apolipoprotein A-I in 4 standard HDL sizes by endogenous isotopic labeling in 6 overweight adults with low HDLc and in 6 adults with normal body weight with high plasma HDLc. Contrary to expectation, HDL was secreted into the circulation in its entire size distribution from very small to very large similarly in both groups. Very small (prebeta) HDL comprised only 8% of total apolipoprotein A-I secretion. Each HDL subfraction circulated mostly within its secreted size range for 1 to 4 days and then was cleared. Enlargement of very small and medium to large and very large HDL and generation of very small from medium HDL were minor metabolic pathways. Prebeta HDL was cleared slower, whereas medium, large, and very large HDL were cleared faster in the low HDLc group., Conclusions: A new model is proposed from these results in which HDL is metabolized in plasma mainly within several discrete, stable sizes across the common range of HDLc concentrations., (© 2015 American Heart Association, Inc.)

Despite major advances in pharmacologic therapy over the last few decades, dyslipidemia remains a prevalent, insufficiently recognized, and undercontrolled risk factor for cardiovascular disease. Statins are the mainstay of hypercholesterolemia treatment, but because of adherence and tolerability issues that limit dose titration, there is a need for additional therapies with good efficacy and better tolerability. Adenosine triphosphate (ATP) citrate lyase, a cytoplasmic enzyme responsible for the generation of acetyl coenzyme A for the de novo synthesis of fatty acids and cholesterol, is a very interesting molecular target for the reduction of plasma lipids. Furthermore, ATP citrate lyase inhibition may be accompanied by activation of 5'-adenosine monophosphate-activated protein kinase, a key signaling molecule that acts a central hub in cellular metabolic regulation. ETC-1002 is a small molecule inhibitor of ATP citrate lyase that also activates 5'-adenosine monophosphate-activated protein kinase, effectively reducing low-density lipoprotein cholesterol and inducing some other positive metabolic changes. Recent evidence from phase I and II clinical trials in humans has shown a positive efficacy and safety profile of ETC-1002, with low-density lipoprotein cholesterol reductions similar to those attainable by usual doses of many statins and with no major apparent side effects. These results potentially introduce a new family of medications that may expand our therapeutic arsenal against hypercholesterolemia., (Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.)