Metabolic Failure Research Articles

Maternal environmental enrichment protects neonatal brains from hypoxic-ischemic challenge by mitigating brain energetic dysfunction and modulating glial cell responses

There is evidence that maternal milieu and changes in environmental factors during the prenatal period may exert a lasting impact on the brain health of the newborn, even in case of neonatal brain hypoxia-ischemia (HI). The present study aimed to investigate the effects of maternal environmental enrichment (EE) on HI-induced energetic and metabolic failure, along with subsequent neural cell responses in the early postnatal period. Male Wistar pups born to dams exposed to maternal EE or standard conditions (SC) were randomly divided into Sham-SC, HI-SC, Sham-EE, and HI-EE groups. Neonatal HI was induced on postnatal day (PND) 3. The Na+,K+-ATPase activity, mitochondrial function and neuroinflammatory related-proteins were assessed at 24 h and 48 h after HI. MicroPET-FDG scans were used to measure glucose uptake at three time points: 24 h post-HI, PND18, and PND24. Moreover, neuronal preservation and glial cell responses were evaluated at PND18. After HI, animals exposed to maternal EE showed an increase in Na+,K+-ATPase activity, preservation of mitochondrial potential/mass ratio, and a reduction in mitochondrial swelling. Glucose uptake was preserved in HI-EE animals from PND18 onwards. Maternal EE attenuated HI-induced cell degeneration, white matter injury, and reduced astrocyte immunofluorescence. Moreover, the HI-EE group exhibited elevated levels of IL-10 and a reduction in Iba-1 positive cells. Data suggested that the regulation of AKT/ERK1/2 signaling pathways could be involved in the effects of maternal EE. This study evidenced that antenatal environmental stimuli could promote bioenergetic and neural resilience in the offspring against early HI damage, supporting the translational value of pregnancy-focused environmental treatments.

Robinetin Alleviates Metabolic Failure in Liver through Suppression of p300-CD38 Axis.

Metabolic abnormalities in the liver are closely associated with diverse metabolic diseases such as non-alcoholic fatty liver disease, type 2 diabetes, and obesity. The aim of this study was to evaluate the ameliorating effect of robinetin (RBN) on the significant pathogenic features of metabolic failure in the liver and to identify the underlying molecular mechanism. RBN significantly decreased triglyceride (TG) accumulation by downregulating lipogenesis-related transcription factors in AML-12 murine hepatocyte cell line. In addition, mice fed with Western diet (WD) containing 0.025% or 0.05% RBN showed reduced liver mass and lipid droplet size, as well as improved plasma insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) values. CD38 was identified as a target of RBN using the BioAssay database, and its expression was increased in OPA-treated AML-12 cells and liver tissues of WD-fed mice. Furthermore, RBN elicited these effects through its anti-histone acetyltransferase (HAT) activity. Computational simulation revealed that RBN can dock into the HAT domain pocket of p300, a histone acetyltransferase, which leads to the abrogation of its catalytic activity. Additionally, knock-down of p300 using siRNA reduced CD38 expression. The chromatin immunoprecipitation (ChIP) assay showed that p300 occupancy on the promoter region of CD38 was significantly decreased, and H3K9 acetylation levels were diminished in lipid-accumulated AML-12 cells treated with RBN. RBN improves the pathogenic features of metabolic failure by suppressing the p300-CD38 axis through its anti-HAT activity, which suggests that RBN can be used as a new phytoceutical candidate for preventing or improving this condition.

Sex and Age Differences in the Association Between Metabolic Dysfunction-Associated Fatty Liver Disease and Heart Failure: A Prospective Cohort Study.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a risk factor for heart failure (HF) occurrence, but it remains unclear whether the association between MAFLD and HF differs in different sexes and ages. A total of 96 576 participants of Kailuan Study were included. MAFLD was defined as presence of hepatic steatosis and metabolic dysfunction and classified as mild and significant by ultrasound. Hazard ratios (HRs) were calculated by Cox regression models. After a median follow-up of 14.0 years, 2939 participants developed HF. Adjusting for confounding factors, mild-MAFLD (HR, 1.27 [95% CI, 1.16-1.39]) and significant-MAFLD (HR, 1.45 [95% CI, 1.31-1.63]) were associated with a higher risk of HF in all participants, and the risk differed by sex (Pinteraction<0.05) and age (Pinteraction<0.001). Compared with non-MAFLD participants, in women, significant-MAFLD was associated with an 84% (HR, 1.84 [95% CI, 1.43-2.37]) increased risk of HF; however, in men, the risk was 36% (HR, 1.36 [95% CI, 1.20-1.53]). In participants under 45 years, mild-MAFLD and significant-MAFLD had a 55% (HR, 1.55 [95% CI, 1.07-2.25]) and 172% (HR, 2.72 [95% CI, 1.87-3.97]) increased risk of HF; however, in participants over 65 years, even significant-MAFLD did not associate with a higher risk of HF (HR, 1.11 [95% CI, 0.92-1.34]). Afterwards, we stratified all participants by both sex and age and found that the risk of MAFLD-associated HF decreased with age in men (Pinteraction<0.05) and women (Pinteraction<0.05), but the sex difference in this risk was only present in participants younger than 45 years (Pinteraction<0.05). MAFLD greatly increased the risk of HF in women, especially young women. With increasing age, MAFLD-related risk of HF decreased and the difference between men and women disappeared.

Induced acute hyperglycemia modifies the barrier function of the intestinal epithelium by tissue inflammation and tight junction disruption resulting in hydroelectrolytic secretion in an animal model.

Diabetic-metabolic syndrome (MetS-D) has a high prevalence worldwide, in which an association with the rupture of the intestinal epithelium barrier function (IEBF) has been pointed out, but the functional and morphological properties are still not well understood. This study aimed to evaluate the impact of acute hyperglycemia diabetes on intestinal tight junction proteins, metabolic failure, intestinal ion and water transports, and IEBF parameters. Diabetes was induced in male Rattus norvegicus (200-310 g) with 0.5 mL of streptozotocin (70 mg/kg). Glycemic and clinical parameters were evaluated every 7 days, and intestinal parameters were evaluated on the 14th day. The MetS-D animals showed a clinical pattern of hyperglycemia, with increases in the area of villi and crypts, lactulose:mannitol ratio, myeloperoxidase (MPO) activity, and intestinal tissue concentrations of malondialdehyde (MDA), but showed a reduction in reduced glutathione (GSH) when these parameters were compared to the control. The MetS-D group had increased secretion of Na+, K+, Cl-, and water compared to the control group in ileal tissue. Furthermore, we observed a reduction in mRNA transcript of claudin-2, claudin-15, and NHE3 and increases of SGLT-1 and ZO-1 in the MetS-D group. These results showed that MetS-D triggered intestinal tissue inflammation, oxidative stress, complex alterations in gene regulatory protein transcriptions of intestinal transporters and tight junctions, damaging the IEBF and causing hydroelectrolyte secretion.

Maternally Inherited Essential Hypertension May Be Associated with the Mutations in Mitochondrial tRNAGlu Gene.

Mitochondrial DNA (mtDNA) mutations are associated with essential hypertension (EH), but the molecular mechanism remains largely unknown. The aim of this study is to explore the association between mtDNA mutations and EH. Two maternally inherited families with EH are underwent clinical, genetic and biochemical assessments. mtDNA mutations are screened by PCR-Sanger sequencing and phylogenetic, and bioinformatics analyses are performed to evaluate the pathogenicity of mtDNA mutations. We also generate cytoplasmic hybrid (cybrid) cell lines to analysis mitochondrial functions. Matrilineal relatives exhibit variable degree of clinical phenotypes. Molecular analysis reveals the presence of m.A14693G and m.A14696G mutations in two pedigrees. Notably, the m.A14693G mutation occurs at position 54 in the TψC loop of tRNAGlu, a position which is critical for post-transcriptionally modification of tRNAGlu. While the m.A14696G mutation creates a novel base-pairing (51C-64G). Bioinformatic analysis shows that these mutations alter tRNAGlu secondary structure. Additionally, patients with tRNAGlu mutations exhibit markedly decreased in mtDNA copy number, mitochondrial membrane potential (MMP) and ATP, whereas the levels of reactive oxygen species (ROS) increase significantly. The m.A14696G and m.A14693G mutations lead to failure in tRNAGlu metabolism and cause mitochondrial dysfunction that is responsible for EH.

Dual barrier system against xenomitochondrial contamination in mouse embryos

Heteroplasmic mammalian embryos between genetically distant species fail to develop to term, preventing transmission of xenomitochondrial DNA to progeny. However, there is no direct evidence indicating the mechanisms by which species specificity of the mitochondrial genome is ensured during mammalian development. Here, we have uncovered a two-step strategy underlying the prevention of xenomitochondrial DNA transmission in mouse embryos harboring bovine mitochondria (mtB-M embryos). First, mtB-M embryos showed metabolic disorder by transient increase of reactive oxygen species at the 4-cell stage, resulting in repressed development. Second, trophoblasts of mtB-M embryos led to implantation failure. Therefore, we tested cell aggregation with tetraploid embryos to compensate for the placentation of mtB-M embryos. The 14 mtB-M embryos harboring bovine mtDNAs developed to term at embryonic day 19.5. Taken together, our results show that contamination of bovine mtDNA is prohibited by embryonic lethality due to metabolic disruption and failure of placentation, suggesting these represent xenomitochondrial elimination mechanisms in mammalian embryos.

Sex hormone-binding globulin improves lipid metabolism and reduces inflammation in subcutaneous adipose tissue of metabolic syndrome-affected horses.

Equine metabolic syndrome (EMS) is a steadily growing endocrine disorder representing a real challenge in veterinary practice. As a multifactorial condition, EMS is characterized by three main metabolic abnormalities including insulin resistance, increased adiposity or obesity and hoof laminitis. Adipose tissue dysfunction is recognized as a core pathophysiological determinant of EMS, as it strongly participates to lipotoxicity and systemic metaflammation, both of which have been closely linked to the development of generalized insulin resistance. Besides, sex hormone binding globulin (SHBG) is an important sex steroids transporters that has been recently proposed as an important metabolic mediator. Therefore, the aim of this study was to verify whether SHBG treatment may ameliorate subcutaneous adipose tissue metabolic failure under EMS condition in terms of lipidome homeostasis, lipid metabolism programs, insulin signalling and local inflammation. Subcutaneous adipose tissue (SAT) biopsies were collected post-mortem from healthy (n = 3) and EMS (n = 3) slaughtered horses. SHBG protein has been applied to SAT samples from EMS horses for 24h at a final concentration of 50nM, while control groups (healthy and untreated EMS) were cultured in the presence of SHBG-vehicle only. Tissues from all groups were afterwards secured for downstream analysis of gene expression using RT-qPCR, protein levels by Western blot and ELISA assay and lipidomics through GC-MS technique. Obtained results showcased that SHBG intervention efficiently normalized the altered fatty acids (FAs) profiles by lowering the accumulation of saturated and trans FAs, as well as the pro-inflammatory arachidonic and linoleic acids. Moreover, SHBG showed promising value for the regulation of adipocyte lipolysis and engorgement by lowering the levels of perilipin-1. SHBG exerted moderated effect toward SCD1 and FASN enzymes expression, but increased the LPL abundance. Interestingly, SHBG exhibited a negative regulatory effect on pro-adipogenic stimulators and induced higher expression of KLF3, IRF3 and β-catenin, known as strong adipogenesis repressors. Finally, SHBG protein showed remarkable ability in restoring the insulin signal transduction, IR/IRS/Pi3K/AKT phosphorylation events and GLUT4 transporter abundance, and further attenuate pro-inflammatory response by lowering IL-6 tissue levels and targeting the PDIA3/ERK axis. Overall, the obtained data clearly demonstrate the benefice of SHBG treatment in the regulation of adipose tissue metabolism in the course of EMS and provide new insights for the development of molecular therapies with potential translational application to human metabolic disorders.

Identification of a Novel Mechanism Fostering the Alterations of Brain Energy Metabolism: a Link Between AD and T2DM

AbstractBackgroundBrain insulin resistance (bIR) is associated with mitochondrial stress, failure of energy metabolism, synaptic loss and ultimately neurodegeneration both in Alzheimer’s disease (AD) and Type 2‐Diabetes Mellitus (T2DM). Our group previously demonstrated that loss of BVR‐A is an early event triggering bIR in AD. Hence, we tested the hypothesis that reduced BVR‐A levels link bIR and mitochondrial defects resulting in AD‐like neuropathology in T2DM.MethodAlterations of insulin signalling, autophagic flux, oxidative stress levels and AD hallmarks were analyzed in the hippocampus of wild‐type and the goto‐kakizaki (GK) model of T2DM rats. Hippocampal mitochondrial function was evaluated by measuring oxygen consumption rate (OCR), mitochondrial complexes, mitochondrial unfolded protein response (UPRmt) and oxidative stress levels. These data were correlated with peripheral metabolic measurements (fasting glucose, insulin and OGTT) and cognitive tasks (spatial memory). To confirm the role of BVR‐A, similar analyses were performed in the hippocampus of WT and BVR‐A KO mice fed a high fat diet (HFD, 60% kcal from fat) for 1, 3 or 8 weeks. Additional mechanistic insights were gained by evaluating mitochondrial function (sea‐horse) and the above‐mentioned intracellular pathways in response to insulin, in neuronal cells lacking BVR‐A.ResultGK rats displayed a diabetic phenotype and impaired spatial memory. Reduced BVR‐A levels along with IRS1 hyper‐activation and loss of Akt‐mediated inhibition of GSK3ß were observed in the hippocampus, consistent with the regulatory role for BVR‐A. As result, hyperactive GSK3ß accumulated in hippocampal mitochondria fostering their impairment characterized by reduced OCR and activation of UPRmt. Similar alterations in BVR‐A KO mice and in neuronal cells lacking BVR‐A were observed, reinforcing the role for BVR‐A in regulating mitochondrial bioenergetics in response to insulin. HFD regimen promoted worse outcomes in BVR‐A KO mice with respect to WT. Remarkably, gender‐differences were observed whereby female mice show earlier and greater alterations with respect to male mice.ConclusionThese results suggest that early BVR‐A loss triggers bIR and the hyper‐action of GSK3ß, that, in turn, drives the development of mitochondrial stress in T2DM brain. These alterations accelerate the impairment of energy metabolism and development of AD‐like neuropathology in T2DM.

Inward Operation of Sodium-Bicarbonate Cotransporter 1 Promotes Astrocytic Na+ Loading and Loss of ATP in Mouse Neocortex during Brief Chemical Ischemia.

Ischemic conditions cause an increase in the sodium concentration of astrocytes, driving the breakdown of ionic homeostasis and exacerbating cellular damage. Astrocytes express high levels of the electrogenic sodium-bicarbonate cotransporter1 (NBCe1), which couples intracellular Na+ homeostasis to regulation of pH and operates close to its reversal potential under physiological conditions. Here, we analyzed its mode of operation during transient energy deprivation via imaging astrocytic pH, Na+, and ATP in organotypic slice cultures of the mouse neocortex, complemented with patch-clamp and ion-selective microelectrode recordings and computational modeling. We found that a 2 min period of metabolic failure resulted in a transient acidosis accompanied by a Na+ increase in astrocytes. Inhibition of NBCe1 increased the acidosis while decreasing the Na+ load. Similar results were obtained when comparing ion changes in wild-type and Nbce1-deficient mice. Mathematical modeling replicated these findings and further predicted that NBCe1 activation contributes to the loss of cellular ATP under ischemic conditions, a result confirmed experimentally using FRET-based imaging of ATP. Altogether, our data demonstrate that transient energy failure stimulates the inward operation of NBCe1 in astrocytes. This causes a significant amelioration of ischemia-induced astrocytic acidification, albeit at the expense of increased Na+ influx and a decline in cellular ATP.

Galectin-4 is associated with diabetes and obesity in a heart failure population

An association between high Galectin-4 (Gal-4) and prevalence of diabetes in subjects with heart failure (HF) has previously been reported. The purpose of this study was to confirm these findings, as well as to further investigate this association, in a Swedish HF population. In addition, a second aim was to explore Gal-4’s association with obesity and biomarkers of metabolism and heart failure. Gal-4 was measured using a proximity extension array technique in 324 hospitalized HF patients within the Swedish HeArt and bRain failure investigation trial cohort. Obesity was defined as BMI ≥ 30. Multivariable logistic regression models were used to explore associations between Gal-4 and diabetes/obesity, and linear regression models were used to explore the associations between Gal-4 and biomarkers. A total of 309 participants (29.1% female; mean age 74.8 years) provided complete data for the analysis of associations between Gal-4 and diabetes. Additionally, for the analysis of heart failure phenotype, complete data was available for 230 subjects. Gal-4 was positively associated with prevalent diabetes (OR 2.60; CI 95% 1.56–4.32). In multivariable models, Gal-4 levels were significantly associated with obesity, but only for subjects with diabetes (OR 2.48; 1.09–5.62). Additionally, Gal-4 demonstrated a significant association with the incretin Glucose-dependent insulinotropic polypeptide (GIP), as well as with biomarkers of HF. In the stratified analyses, the association between Gal-4 and diabetes was prominent in patients with reduced ejection fraction (n = 160, OR 3.26; 95%CI 1.88–5.66), while it was not observed in those without (n = 70, 1.96 (0.75–5.10)). In this cross-sectional, observational study, higher Gal-4 levels in HF patients were associated with higher GIP levels. Further, increased levels of Gal-4 were associated with increased likelihood of diabetes, and obesity. This association was particularly pronounced in individuals with HF characterized by reduced ejection fraction. Additionally, Gal-4 levels were significantly elevated in heart failure patients with diabetes and obesity.

Estimating the extent to which chronic kidney disease mediates the association between metabolic syndrome and heart failure: the Atherosclerosis Risk in Communities (ARIC) Study

Abstract Background/Introduction Metabolic Syndrome (MetS) is linked to increased risk of developing heart failure (HF), underscoring a need to implement more aggressive lifestyle and pharmacotherapeutic HF prevention strategies. Chronic kidney disease (CKD) is associated with MetS and is a risk factor for HF; however, therapies protective against both kidney function decline and HF risk such as ACEi/ARBs and SGLT2i are underutilized among individuals with MetS. A potential contributor to this underutilization is that creatinine (Cr)- based estimates of glomerular filtration rate (eGFR) may underestimate the role of CKD as a mediator of HF risk relative to Cystatin-C (CysC) based eGFR. Purpose To compare estimations of the relationship between MetS and kidney function, and of the extent to which eGFR mediates the link between MetS and incident HF, using CysC-based versus Cr-based eGFR. Methods Among ARIC Visit 4 (1996-1998) participants without baseline HF, we used linear regression to assess the cross-sectional association of MetS severity (measured using an established z-score, modeled in quartiles and continuously) with eGFR, with comparisons across 3 different eGFR equations (CKD-Cr 2021, CKD-Cr-CysC 2021 and CKD-CysC 2012). In prospective analyses, we used Cox regression and mediation analyses to estimate the extent to which kidney function mediated the association between MetS and incident HF after Visit 4 through 12/31/2019, with comparisons across the 3 eGFR equations. Results Among 8,582 participants (mean age 63.1 years, 56.9% women, 18.4% Black adults), 1,803 developed HF over a median follow-up of 21 years. MetS was more strongly associated with eGFR when using eGFR estimates that included CysC, with the 4th vs 1st quartile of MetS Z-score associated with an adjusted eGFR difference of -2.55 ml/min/1.73m2 (95% CI -3.36 to -1.73) for CKD-Cr, -8.07 ml/min/1.73m2 (95% CI -8.95 to -7.19) for CKD-Cr-CysC and -10.74 ml/min/1.73m2 (95% CI -11.67 to -9.80) for CKD-CysC. In prospective analyses, we also estimated greater mediation by kidney function of the association between MetS and incident HF when using eGFR equations that included CysC. The strength of the association between MetS and HF potentially mediated by kidney function increased from 3.0% to 15.2% to 24.2%, respectively, when using eGFR-Cr vs eGFR-Cr-CysC vs eGFR-CysC (Table and Figure). These estimates were not significantly attenuated after additional adjustment for coronary heart disease and C-reactive protein. Conclusion(s) The degree of kidney function reduction associated with MetS, and the subsequent implications of kidney dysfunction for HF risk in those with MetS, are underestimated using eGFR-Cr equations compared to eGFR equations including CysC. Greater appreciation by clinicians of the impact of kidney disease on HF risk among individuals with MetS could help increase utilization of kidney-protective therapies that can lower HF risk.

Advances in Metabolic Remodeling and Intervention Strategies in Heart Failure.

The heart is the most energy-demanding organ throughout the whole body. Perturbations or failure in energy metabolism contributes to heart failure (HF), which represents the advanced stage of various heart diseases. The poor prognosis and huge economic burden associated with HF underscore the high unmet need to explore novel therapies targeting metabolic modulators beyond conventional approaches focused on neurohormonal and hemodynamic regulators. Emerging evidence suggests that alterations in metabolic substrate reliance, metabolic pathways, metabolic by-products, and energy production collectively regulate the occurrence and progression of HF. In this review, we provide an overview of cardiac metabolic remodeling, encompassing the utilization of free fatty acids, glucose metabolism, ketone bodies, and branched-chain amino acids both in the physiological condition and heart failure. Most importantly, the latest advances in pharmacological interventions are discussed as a promising therapeutic approach to restore cardiac function, drawing insights from recent basic research, preclinical and clinical studies.

Second-Line Pharmaceutical Treatments for Patients with Type 2 Diabetes

Assessing the relative effectiveness and safety of additional treatments when metformin monotherapy is insufficient remains a limiting factor in improving treatment choices in type 2 diabetes. To determine whether data from electronic health records across the University of California Health system could be used to assess the comparative effectiveness and safety associated with 4 treatments in diabetes when added to metformin monotherapy. This multicenter, new user, multidimensional propensity score-matched retrospective cohort study with leave-one-medical-center-out (LOMCO) sensitivity analysis used principles of emulating target trial. Participants included patients with diabetes receiving metformin who were then additionally prescribed either a sulfonylurea, dipeptidyl peptidase-4 inhibitor (DPP4I), sodium-glucose cotransporter-2 inhibitor (SGLT2I), or glucagon-like peptide-1 receptor agonist (GLP1RA) for the first time and followed-up over a 5-year monitoring period. Data were analyzed between January 2022 and April 2023. Treatment with sulfonylurea, DPP4I, SGLT2I, or GLP1RA added to metformin monotherapy. The main effectiveness outcome was the ability of patients to maintain glycemic control, represented as time to metabolic failure (hemoglobin A1c [HbA1c] ≥7.0%). A secondary effectiveness outcome was assessed by monitoring time to new incidence of any of 28 adverse outcomes, including diabetes-related complications while treated with the assigned drug. Sensitivity analysis included LOMCO. This cohort study included 31 852 patients (16 635 [52.2%] male; mean [SD] age, 61.4 [12.6] years) who were new users of diabetes treatments added on to metformin monotherapy. Compared with sulfonylurea in random-effect meta-analysis, treatment with SGLT2I (summary hazard ratio [sHR], 0.75 [95% CI, 0.69-0.83]; I2 = 37.5%), DPP4I (sHR, 0.79 [95% CI, 0.75-0.84]; I2 = 0%), GLP1RA (sHR, 0.62 [95% CI, 0.57-0.68]; I2 = 23.6%) were effective in glycemic control; findings from LOMCO sensitivity analysis were similar. Treatment with SGLT2I showed no significant difference in effectiveness compared with GLP1RA (sHR, 1.26 [95% CI, 1.12-1.42]; I2 = 47.3%; no LOMCO) or DPP4I (sHR, 0.97 [95% CI, 0.90-1.04]; I2 = 0%). Patients treated with DPP4I and SGLT2I had fewer cardiovascular events compared with those treated with sulfonylurea (DPP4I: sHR, 0.84 [95% CI, 0.74-0.96]; I2 = 0%; SGLT2I: sHR, 0.78 [95% CI, 0.62-0.98]; I2 = 0%). Patients treated with a GLP1RA or SGLT2I were less likely to develop chronic kidney disease (GLP1RA: sHR, 0.75 [95% CI 0.6-0.94]; I2 = 0%; SGLT2I: sHR, 0.77 [95% CI, 0.61-0.97]; I2 = 0%), kidney failure (GLP1RA: sHR, 0.69 [95% CI, 0.56-0.86]; I2 = 9.1%; SGLT2I: sHR, 0.72 [95% CI, 0.59-0.88]; I2 = 0%), or hypertension (GLP1RA: sHR, 0.82 [95% CI, 0.68-0.97]; I2 = 0%; SGLT2I: sHR, 0.73 [95% CI, 0.58-0.92]; I2 = 38.5%) compared with those treated with a sulfonylurea. Patients treated with an SGLT2I, vs a DPP4I, GLP1RA, or sulfonylurea, were less likely to develop indicators of chronic hepatic dysfunction (sHR vs DPP4I, 0.68 [95% CI, 0.49-0.95]; I2 = 0%; sHR vs GLP1RA, 0.66 [95% CI, 0.48-0.91]; I2 = 0%; sHR vs sulfonylurea, 0.60 [95% CI, 0.44-0.81]; I2 = 0%), and those treated with a DPP4I were less likely to develop new incidence of hypoglycemia (sHR, 0.48 [95% CI, 0.36-0.65]; I2 = 22.7%) compared with those treated with a sulfonylurea. These findings highlight familiar medication patterns, including those mirroring randomized clinical trials, as well as providing new insights underscoring the value of robust clinical data analytics in swiftly generating evidence to help guide treatment choices in diabetes.

The PTP1B Inhibitor Trodusquemine (MSI-1436) Improves Glucose Uptake in Equine Metabolic Syndrome Affected Liver through Anti-Inflammatory and Antifibrotic Activity.

Hyperactivation of protein tyrosine phosphatase (PTP1B) has been associated with several metabolic malfunctions ranging from insulin resistance, metaflammation, lipotoxicity, and hyperglycaemia. Liver metabolism failure has been proposed as a core element in underlying endocrine disorders through persistent inflammation and highly fibrotic phenotype. In this study, the outcomes of PTP1B inhibition using trodusquemine (MSI-1436) on key equine metabolic syndrome (EMS)-related alterations including inflammation, fibrosis, and glucose uptake have been analyzed in liver explants collected from EMS-affected horses using various analytical techniques, namely, flow cytometry, RT-qPCR, and Western blot. PTP1B inhibition using trodusquemine resulted in decreased proinflammatory cytokines (IL-1β, TNF-α, and IL-6) release from liver and PBMC affected by EMS and regulated expression of major proinflammatory microRNAs such as miR-802 and miR-211. Moreover, MSI-1436 enhanced the anti-inflammatory profile of livers by elevating the expression of IL-10 and IL-4 and activating CD4+CD25+Foxp3+ regulatory T cells in treated PBMC. Similarly, the inhibitor attenuated fibrogenic pathways in the liver by downregulating TGF-β/NOX1/4 axis and associated MMP-2/9 overactivation. Interestingly, PTP1B inhibition ameliorated the expression of TIMP-1 and Smad7, both important antifibrotic mediators. Furthermore, application of MSI-1436 was found to augment the abundance of glycosylated Glut-2, which subsequently expanded the glucose absorption in the EMS liver, probably due to an enhanced Glut-2 stability and half-life onto the plasma cell membranes. Taken together, the presented data suggest that the PTP1B inhibition strategy and the use of its specific inhibitor MSI-1436 represents a promising option for the improvement of liver tissue integrity and homeostasis in the course of EMS and adds more insights for ongoing clinical trials for human MetS management.

Platelets of COVID-19 patients display mitochondrial dysfunction, oxidative stress, and energy metabolism failure compatible with cell death

BackgroundAlterations in platelet function have been implicated in the pathophysiology of COVID-19 since the beginning of the pandemic. While early reports linked hyperactivated platelets to thromboembolic events in COVID-19, subsequent investigations demonstrated hyporeactive platelets with a procoagulant phenotype. Mitochondria are important for energy metabolism and the function of platelets. ObjectivesHere, we sought to map the energy metabolism of platelets in a cohort of noncritically ill COVID-19 patients and assess platelet mitochondrial function, activation status, and responsiveness to external stimuli. MethodsWe enrolled hospitalized COVID-19 patients and controls between October 2020 and December 2021. Platelets function and metabolism was analyzed by flow cytometry, metabolomics, glucose fluxomics, electron and fluorescence microscopy and western blot. ResultsPlatelets from COVID-19 patients showed increased phosphatidylserine externalization indicating a procoagulant phenotype and hyporeactivity to ex vivo stimuli, associated with profound mitochondrial dysfunction characterized by mitochondrial depolarization, lower mitochondrial DNA–encoded transcript levels, an altered mitochondrial morphology consistent with increased mitochondrial fission, and increased pyruvate/lactate ratios in platelet supernatants. Metabolic profiling by untargeted metabolomics revealed NADH, NAD+, and ATP among the top decreased metabolites in patients’ platelets, suggestive of energy metabolism failure. Consistently, platelet fluxomics analyses showed a strongly reduced utilization of 13C-glucose in all major energy pathways together with a rerouting of glucose to de novo generation of purine metabolites. Patients’ platelets further showed evidence of oxidative stress, together with increased glutathione oxidation and synthesis. Addition of plasma from COVID-19 patients to normal platelets partially reproduced the phenotype of patients’ platelets and disclosed a temporal relationship between mitochondrial decay and (subsequent) phosphatidylserine exposure and hyporeactivity. ConclusionThese data link energy metabolism failure in platelets from COVID-19 patients with a prothrombotic platelet phenotype with features matching cell death.

Optimization of Nutrition after Brain Injury: Mechanistic and Therapeutic Considerations.

Emerging science continues to establish the detrimental effects of malnutrition in acute neurological diseases such as traumatic brain injury, stroke, status epilepticus and anoxic brain injury. The primary pathological pathways responsible for secondary brain injury include neuroinflammation, catabolism, immune suppression and metabolic failure, and these are exacerbated by malnutrition. Given this, there is growing interest in novel nutritional interventions to promote neurological recovery after acute brain injury. In this review, we will describe how malnutrition impacts the biomolecular mechanisms of secondary brain injury in acute neurological disorders, and how nutritional status can be optimized in both pediatric and adult populations. We will further highlight emerging therapeutic approaches, including specialized diets that aim to resolve neuroinflammation, immunodeficiency and metabolic crisis, by providing pre-clinical and clinical evidence that their use promotes neurologic recovery. Using nutrition as a targeted treatment is appealing for several reasons that will be discussed. Given the high mortality and both short- and long-term morbidity associated with acute brain injuries, novel translational and clinical approaches are needed.

Genistein enhances NAD+ biosynthesis by upregulating nicotinamide phosphoribosyltransferase in adipocytes

A decrease in the NAD+ level in adipocytes causes adipose-tissue dysfunction, leading to systemic glucose, and lipid metabolism failure. Therefore, it is necessary to develop small molecules and nutraceuticals that can increase NAD+ levels in adipocytes. Genistein, a nutraceutical derived from soybeans, has various physiological activities and improves glucose and lipid metabolism. In this study, we aimed to unravel the effects of genistein on the NAD+ level in adipocytes and the underlying molecular mechanisms. Genistein enhanced NAD+ biosynthesis by increasing the expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis. A pull-down assay using genistein-immobilized beads revealed prohibitin 1 (PHB1) as a target protein of genistein. The knockdown of Phb1 suppressed the genistein-induced increase in NAMPT expression and NAD+ level in adipocytes. Genistein-bound PHB1 contributed to the stabilization of the transcription factor CCAAT/enhancer-binding protein β through the activation of extracellular signal-regulated kinase, resulting in increased NAMPT expression at the transcriptional level. Genistein induced the dephosphorylation of peroxisome proliferator-activated receptor at serine 273 and increased the level of the insulin-sensitizing adipokine adiponectin in adipocytes, whereas the knockdown of Nampt and Phb1 abolished these genistein-mediated effects. Our results proved the potential efficacy of genistein in increasing the NAD+ level and restoring metabolic function in adipocytes. Furthermore, we identified PHB1, localized to the plasma membrane, as a novel candidate target protein for increased expression of NAMPT in adipocytes. Overall, these findings will assist in developing NAD+-boosting nutraceuticals to alleviate metabolic dysfunctions in adipose tissues.

Prognostic Nutritional Index (PNI) as a Predictor in Patients with Metabolic Syndrome and Heart Failure.

There is a lack of research on nutritional status and poor prognosis in patients with metabolic syndrome and heart failure. This study evaluated the relationship between nutritional status as defined by the PNI and adverse outcomes in patients with metabolic syndrome and heart failure. A total of 1048 heart failure patients with metabolic syndrome admitted to the Heart Center of the First Affiliated Hospital of Xinjiang Medical University from January 2015 to December 2019 were consecutively. PNI was used to assess their nutritional status. A total of 51.0% of the patients were in the nonmalnutrition group (PNI≥45), 27.9% were in the mild malnutrition group (40≤PNI<45), and 21.1% of patients were in the malnutrition group (PNI<40). At 36 months of follow-up, after adjusting for other confounding factors, malnutrition (PNI<40) was independently associated with all-cause death (HR: 1.787, 95% CI: 1.451-2.201, P<0.001) and cardiovascular death (HR: 1.837, 95% CI: 1.467-2.301, P<0.001). PNI showed additional prognostic predictive value when included in the established risk factor model, both for all-cause death (AUC: 0.620, 95% CI: 0.579-0.661, P<0.001) and cardiovascular death (AUC: 0.596, 95% CI: 0.555-0.636, P<0.001). In patients with metabolic syndrome and heart failure, malnutrition assessed by PNI is an independent predictor for all-cause death and cardiovascular death, and PNI is negatively correlated with the occurrence of adverse outcomes.

Comparative effectiveness of second line glucose lowering drug treatments using real world data: emulation of a target trial

ObjectiveTo build on the recently completed GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) randomised trial examining the comparative effectiveness of second line glucose lowering drugs in achieving...

Impaired BCAA catabolism in adipose tissues promotes age-associated metabolic derangement.

Adipose tissues are central in controlling metabolic homeostasis and failure in their preservation is associated with age-related metabolic disorders. The exact role of mature adipocytes in this phenomenon remains elusive. Here we describe the role of adipose branched-chain amino acid (BCAA) catabolism in this process. We found that adipocyte-specific Crtc2 knockout protected mice from age-associated metabolic decline. Multiomics analysis revealed that BCAA catabolism was impaired in aged visceral adipose tissues, leading to the activation of mechanistic target of rapamycin complex (mTORC1) signaling and the resultant cellular senescence, which was restored by Crtc2 knockout in adipocytes. Using single-cell RNA sequencing analysis, we found that age-associated decline in adipogenic potential of visceral adipose tissues was reinstated by Crtc2 knockout, via the reduction of BCAA-mTORC1 senescence-associated secretory phenotype axis. Collectively, we propose that perturbation of BCAA catabolism by CRTC2 is critical in instigating age-associated remodeling of adipose tissue and the resultant metabolic decline in vivo.