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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 ( 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.

Objective 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 (Bogota, Medellin, 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.

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/m2, 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.

ObjectivesDiabetes 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.SettingThe Colombian Study of Nutritional Profiles was a population-based, cross-sectional, multi-stage probabilistic sampling survey designed to represent the five main Colombian cities.ParticipantsBetween 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 measuresPrevalence of diabetes, dietary intake of key nutrients, achievement of dietary goals among individuals with diabetes.ResultsThe 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.ConclusionsDiabetes 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.

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.

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.

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, VO2max, PD biomarkers, and fMRI. Results: VO2max 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.

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

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/m2 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.

The liver is a key organ in lipid and lipoprotein metabolism, hence hepatic diseases often manifest as lipid disturbances. Cholestatic liver diseases are frequently associated with an important increase in total cholesterol at the expense of lipoprotein X (LpX), an abnormal lipoprotein isolated and characterized in the 1960s to 1970s in patients with obstructive jaundice. Lipoprotein X is rich in phospholipids, albumin, and free cholesterol, has a density similar to low-density lipoprotein (LDL), and a size similar to very low-density lipoprotein (VLDL), which has hampered its detection through routine laboratory tests. Unlike LDL, LpX has no apoB-100, so it is not removed from circulation via the LDL receptor, and it is not clear whether or not it can be atherogenic. Although LpX was initially described in patients with cholestasis, it has also been found in patients with genetic deficiency of lecithin-cholesterol acyltransferase (LCAT), in patients who receive lipid-rich parenteral nutrition and most recently in patients with graft versus host disease of the liver. In the presence of LpX, plasma total cholesterol can rise up to 1000 mg/dL, which may lead to the development of skin xanthomas and hyperviscosity syndrome. Treatment of LpX-dependent hypercholesterolemia with conventional hypolipidemic drugs is frequently ineffective, and definitive treatment relies on correction of the underlying cause of cholestasis. Here, we present the case of a patient with LpX-dependent hypercholesterolemia in the context of primary biliary cholangitis.

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.

Resumen Introduccion Los viajes urbanos pueden ser una actividad estresante con impacto la capacidad cognitiva, un componente central de la salud de las personas. El proposito de esta investigacion es explorar si el desempeno cognitivo se ve afectado de forma diferencial por el estres producido por el viaje en bicicleta o en transporte publico, en adultos que viajan a estudiar. Metodos Para este estudio, se diseno un experimento en el que se midieron, de forma sistematica el estres y el desempeno cognitivo, en siete participantes, en triplicado, en dias separados, antes y despues de cada viaje, para transporte publico y para bicicleta (6 viajes en total). Todos los participantes completaron una prueba de Stroop y una muestra de saliva antes y despues de cada viaje. Las diferencias de antes y despues de cada viaje en el cortisol salival, en el tiempo de respuesta del Stroop y del porcentaje de exito del Stroop, fueron comparadas entre los modos de transporte por medio de un analisis de varianza de dos vias (ANOVA), usando el modo de transporte y el participante como factores fijos. Resultados El cambio medio en el tiempo ajustado del Stroop fue similar entre los dos modos de transporte (1,392 ms ± 8,379 ms para bicicletas, 889 ms ± 6,675 ms para transporte publico, p = 0.85). Lo mismo ocurrio para el cambio medio en el porcentaje de exito del Stroop (1.39% ±5.16% para bicicletas, −0.59±5.79% para transporte publico, p = 0.83). Para el porcentaje de exito en el Stroop, el valor-p para el termino participante*modo fue p = 0.051. El cambio medio en el cortisol salival fue −0.39±1.69 ng/mL para la bicicleta y −1.02± 1.97 ng/mL para transporte publico (p = 0.11). El termino asociado a la variabilidad inter-individual en el cambio del cortisol fue significativo (p˂0.001). Conclusiones Los viajes urbanos en bicicleta o en transporte publico inducen un efecto comparable tanto en estres biologico como en desempeno cognitivo. Se conoce que la bicicleta otorga beneficios personales y para la sociedad. Nuestros resultados, adicionalmente muestran que a pesar del esfuerzo fisico, la bicicleta no induce un mayor estres biologico que el transporte publico.

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 {"type":"clinical-trial","attrs":{"text":"NCT01399632","term_id":"NCT01399632"}}NCT01399632. FUNDING. NIH and the National Center for Advancing Translational Science.

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.

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 (OGTT) 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 (iAUCins, higher values indicate more insulin resistance) (p-trend=0.021) and decreased monotonically across quartiles of the insulin sensitivity index (ISI – higher values indicate less insulin resistance) (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.

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 {"type":"clinical-trial","attrs":{"text":"NCT01399632","term_id":"NCT01399632"}}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.

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.

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 11.9 ng/mL had 60% sensitivity and 68% specificity, while a RBP-4 cutoff of 71.6 ng/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.

Hereditary fructose intolerance, caused by mutations in the ALDOB gene, is an unusual cause of hypoglycemia. ALDOB encodes the enzyme aldolase B, responsible for the hydrolysis of fructose 1-phosphate in the liver. Here, we report the case of a 33-year-old female patient who consulted due to repetitive episodes of weakness, dizziness and headache after food ingestion. An ambulatory 72-h continuous glucose monitoring revealed multiple short hypoglycemic episodes over the day. After biochemical exclusion of other endocrine causes of hypoglycemia, hereditary fructose intolerance seemed a plausible diagnosis. Repeated measurements of urinary fructose revealed pathologic fructosuria, but genetic testing for the three most common mutations in ALDOB resulted negative. We decided to perform complete Sanger sequencing of the ALDOB gene and encountered a variant consisting of a T>A substitution in position 1963 of the ALDOB transcript (c.1693T>A). This position is located within the 3′ untranslated region of exon 9, 515 nucleotides downstream the stop codon. After complete withdrawal of dietary fructose and sucrose, the patient presented no new hypoglycemic episodes.

Comprender el estado del diagnóstico y el tratamiento de la prediabetes en América Latina y evaluar el uso de la metformina para la prevención de la diabetes en este contexto.Un panel de 15 expertos en diabetes de siete países de América Latina se reunió del 14 al 15 de agosto de 2014 en Lima, Perú, para revisar la literatura disponible, discutir el papel de la prediabetes en la diabetes mellitus tipo 2 y la enfermedad cardiovascular, analizar la información recolectada y formular conclusiones para el diagnóstico y el tratamiento de la prediabetes en América Latina.Se analizaron el diagnóstico, el tamizaje y el tratamiento de la prediabetes, inclusive los cambios en el estilo de vida, el tratamiento farmacológico y la relación costo-eficacia. Se emitieron cinco conclusiones para América Latina: la prediabetes es un problema clínico y de salud pública; los sistemas de atención de la salud actualmente no diagnostican o no tratan la prediabetes; el uso de herramientas de detección del riesgo de prediabetes es necesario en toda la región; el tratamiento incluye cambios en el estilo de vida, educación multidisciplinaria y metformina; y se debe brindar apoyo para llevar registros de historias clínicas y realizar estudios adicionales.El panel de expertos concluyó que en América Latina el tratamiento preventivo basado en cambios en el estilo de vida y administración de metformina son intervenciones eficaces en relación al costo. Es importante mejorar la identificación y el manejo de la prediabetes en el nivel de atención primaria.Entender o estado do diagnóstico e tratamento do prediabetes na América Latina e avaliar o uso de metformina para prevenção de diabetes neste contexto.Um painel de 15 especialistas em diabetes de sete países da América Latina reuniu-se de 14 a 15 de agosto de 2014 em Lima, Peru, para analisar a literatura disponível, discutir o papel do prediabetes em diabetes mellitus tipo 2 e doenças cardiovasculares, analisar informações coletadas e fazer conclusões para o diagnóstico e tratamento do prediabetes na América Latina.O diagnóstico, rastreio e tratamento pré-diabetes, incluindo mudanças de estilo de vida, tratamento farmacológico e custo-efetividade foram discutidos. Foram emitidas cinco conclusões resultantes para a América Latina: o prediabetes é um problema clínico e de saúde pública; os sistemas de saúde atualmente não diagnosticam/tratam prediabetes; o uso de ferramentas de detecção de risco de prediabetes é necessário em toda a região; o tratamento inclui mudanças de estilo de vida, educação multidisciplinar e metformina; e devem ser suportados registros de pacientes e outros estudos.O painel de especialistas concluiu que na América Latina, o tratamento preventivo através de mudanças de estilo de vida e metformina são intervenções efetivas em relação ao custo. É importante melhorar a identificação e gestão do prediabetes no nível de atenção primária.

Background Low‐density lipoprotein ( LDL ) with apolipoprotein C‐ III (apoC‐ III ) is the lipoprotein species that most strongly predicts initial and recurring coronary heart disease ( CHD ) events in several cohorts. Thus, a large portion of the CHD risk conferred by LDL may be attributable to LDL that contains apoC‐ III . Very‐low‐density lipoprotein ( VLDL ) and LDL with apoC‐ III have varying amounts of apoE. We hypothesized that a high content of apoE lessens the adverse influence of apoC‐ III on the risk of CHD because it promotes the clearance of VLDL and LDL from plasma. Methods and Results We studied 2 independent cohorts, the Nurses' Health Study, composed of women, and the Health Professionals Follow‐up Study, composed of men. These cohorts contributed to this study 322 women and 418 men initially free of CVD who developed a fatal or nonfatal myocardial infarction during 10 to 14 years of follow‐up and matched controls who remained free of CHD . The apoE content of LDL with apoC‐ III was inversely associated with CHD after multivariable adjustment (relative risk for top versus bottom quintile 0.53, 95% CI 0.35 to 0.80). The apoE content of VLDL with apoC‐ III had a similar inverse association with CHD . The highest risks were associated with a high apoB concentration and a low apoE content of LDL with apoC‐III or of VLDL+LDL with apoC‐III. The observed associations were in both male and female cohorts and independent of traditional CHD risk factors and of C‐reactive protein. Conclusions An increased apoE content in VLDL and LDL with apoC‐ III was associated with a lower risk of CHD . Strategies to enrich VLDL and LDL in apoE are worth exploring for the prevention of CHD .

Background: Plasma concentrations of some lysophospholipids correlate with metabolic alterations in humans, but their poten tial 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 secre tion. Fifteen participants additionally underwent a hyperinsulinemic-euglycemic clamp for estimation of insulin-stimulated glu cose 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.