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Background: Growth differentiation factor 15 (GDF15) is a mitokine, the role of which, total or H-specific, in modulating energy metabolism and homeostasis in obesity-related diseases, such as metabolic dysfunction associated steatotic liver disease (MASLD), has not been fully elucidated in adult humans. We aimed to investigate the fasting and stimulated levels of GDF15, total and H-specific, glucose-dependent insulinotropic polypeptide (GIP) and C-peptide, in two physiology interventional studies: one focusing on obesity, and the other on MASLD., Methods: Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed., Results: In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders., Conclusion: Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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).)

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.)

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.)

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.)

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.