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Diabetic corneal neuropathy (DCN) is a common complication of diabetes mellitus (DM). However, there are very limited therapeutic options. We investigated the effects of a peroxisome proliferator-activated receptor-alpha (PPAR)-α agonist, fenofibrate, on thirty patients (60 eyes) with type II DM. On in-vivo confocal microscopy evaluation, there was significant stimulation of corneal nerve regeneration and a reduction in nerve edema after 30 days of oral fenofibrate treatment, evidenced by the significant improvement in corneal nerve fiber density (CNFD) and corneal nerve fiber width, respectively. Corneal epithelial cells morphology also significantly improved in its cell circularity. Upon clinical examination, fenofibrate significantly improved patients’ neuropathic ocular surface status by increasing tear break-up time along with a reduction of corneal and conjunctival punctate keratopathy. Tear substance P (SP) concentrations significantly increased after treatment, suggesting an amelioration of ocular surface neuroinflammation. The changes in tear SP concentrations was also significantly associated with the improvement in CNFD. Quantitative proteomic analysis demonstrated that fenofibrate significantly upregulated and modulated the neurotrophin signalling pathway, linolenic acid, cholesterol and fat metabolism. Complement cascades, neutrophil reactions, and platelet activation were also significantly suppressed. Our results showed that fenofibrate could potentially be a novel treatment for patients with DCN.

Objective: To demonstrate differences in cardiovascular structure and function between diabetic and non-diabetic older adults. To investigate associations between acyl-carnitines and cardiovascular function as indexed by imaging measurements. Methods: A community-based cohort of older adults without cardiovascular disease underwent current cardiovascular imaging and metabolomics acyl-carnitines profiling based on current and archived sera obtained fifteen years prior to examination. Results: A total of 933 participants (women 56%, n=521) with a mean age 63±13 years were studied. Old diabetics compared to old non-diabetics had lower myocardial relaxation (0.8±0.2 vs 0.9±0.3, p=0.0039); lower left atrial conduit strain (12±4.3 vs 14±4.1, p=0.045), lower left atrial conduit strain rate (-1.2±0.4 vs -1.3±0.5, p=0.042) and lower ratio of left atrial conduit strain to left atrial booster strain (0.5±0.2 vs 0.7±0.3, p=0.0029). Higher levels of archived short chain acyl-carnitine were associated with present-day impairments in myocardial relaxation (C5:1; OR 1.03, p=0.011), worse left atrial conduit strain function (C5:1; OR 1.03, p=0.037). Increases in hydroxylated acyl-carnitines were associated with worse left atrial conduit strain [(C4-OH; OR 1.05, p=0.0017), (C16:2-OH; OR 1.18, p=0.037)]. Current, archived and changes in long chain acyl-carnitines were associated with cardiovascular functions [(C16; OR 1.02, p=0.002), (C20:3; OR 1.01, p=0.014), (C14:3; OR 1.12, p=0.033), (C18:1; OR 1.01, p=0.018), (C18:2; OR 1.01, p=0.028), (C20:4; OR 1.10, p=0.038)] (all p

Therapeutic inhibition of the sodium–glucose co-transporter 2 (SGLT2) leads to substantial loss of energy (in the form of glucose) and additional solutes (in the form of Na+ and its accompanying anions) in urine. However, despite the continuously elevated solute excretion, long-term osmotic diuresis does not occur in humans with SGLT2 inhibition. Rather, patients on SGLT2 inhibitor therapy adjust to the reduction in energy availability and conserve water. The metabolic adaptations that are induced by SGLT2 inhibition are similar to those observed in aestivation — an evolutionarily conserved survival strategy that enables physiological adaptation to energy and water shortage. Aestivators exploit amino acids from muscle to produce glucose and fatty acid fuels. This endogenous energy supply chain is coupled with nitrogen transfer for organic osmolyte production, which allows parallel water conservation. Moreover, this process is often accompanied by a reduction in metabolic rate. By comparing aestivation metabolism with the fuel switches that occur during therapeutic SGLT2 inhibition, we suggest that SGLT2 inhibitors induce aestivation-like metabolic patterns, which may contribute to the improvements in cardiac and renal function observed with this class of therapeutics. SGLT2 inhibitors induce a number of metabolic adaptations in response to increased glucose and Na+ excretion. This Perspective article describes how these adaptations suggest that SGLT2 inhibition triggers a body water-conserving mechanism, and discusses how these metabolic adjustments may contribute to the favourable cardiovascular and renal outcomes of this class of therapeutics.

Background Laparoscopic sleeve gastrectomy (LSG) has become the preferred bariatric procedure in many countries. However, there is one shortcoming of LSG in the long-term follow-up, and this is the onset of gastro-esophageal reflux disease (GERD) and erosive esophagitis (EE). Conversion to Roux-en-Y gastric bypass (RYGB) is considered an option in patients unresponsive to medical therapy. Currently, there is no evidence of EE improvement or resolution after conversion surgery. In this study, we objectively evaluate the effectiveness of RYGB in management of EE with upper endoscopy (EGD) to identify the significant variables in patients with GERD symptoms post LSG refractory to medical therapy and require conversion surgery. Methods Over a period of 11 years (2008–2019) at Singapore General Hospital, we retrospectively reviewed a prospectively collected database of a cohort of patients whom had conversion surgery to RYGB for refractory GERD and EE after LSG. Patient’s endoscopic findings and demographic and anthropometric data were analyzed. Results We identified a total of 14 patients who underwent LSG to RYGB conversions for endoscopic proven erosive esophagitis in our unit during the study period. Eight patients (57.1%) had concurrent hiatal hernia repaired. Nine (64.3%) patients were females. The median age of patients in this cohort was 44 (range 30–61) years. Mean weight and BMI were 87.7 kg (± 19.2) and 32.8 (± 3.09) kg/m2, respectively, on the day of conversion surgery. The median time between LSG and revision to RYGB was 36 (range 6–68) months. Seven patients (50%) had complete resolution of GERD symptoms after conversion, and 6 patients (42.9%) had partial resolution. Six out of 7 patients had complete resolution of EE. There were 4 anastomotic strictures (28.6%). Older patients, Indian ethnicity, present of hiatal hernia and lower weight loss after initial LSG were more likely to undergo conversion surgery. Conclusion Conversion to RYGB after LSG is clinically relevant and may be a feasible solution if patients have ongoing GERD refractory to medical therapy. Ninety-three percent of our patients achieved complete resolution of their GERD symptoms and significant improvement of erosive esophagitis with significant weight loss after conversion. This study has important implications as LSG is increasingly being performed and a proportion of these will need revision surgery for various reasons, particularly GERD which is extremely prevalent.

Background Health-related quality of life (HRQoL) measures are predictors of adverse health outcomes in older adults. Studies have demonstrated cross-sectional associations between HRQoL measures and blood-based biochemical markers. Acylcarnitines (ACs) are a class of metabolites generated in the mitochondria and are predictive of multiple geriatric syndromes. Changes in ACs reflect alterations in central carbon metabolic pathways. However, the prospective relationship between plasma ACs and declining HRQoL has not been examined. This study aimed to investigate both cross-sectional and longitudinal associations of baseline ACs with baseline and declining EuroQol-5 Dimension/EuroQol Visual Analogue Scale (EQ-5D/EQ-VAS) in community-dwelling older adults. Methods One hundred and twenty community-dwelling older adults with EQ-5D/EQ-VAS measurements at baseline and follow-up were included. We quantified ACs at baseline using targeted plasma metabolomics profiling. Multivariate regressions were performed to examine cross-sectional and longitudinal associations between the measures. Results Cross-sectionally, ACs showed no significant associations with either EQ-5D index or EQ-VAS scores. Longitudinally, multiple baseline short-chain ACs were significantly and inversely associated with declining EQ-5D index score, explaining up to 8.5% of variance in the decline. Conclusions Within a cohort of community-dwelling older adults who had high HRQoL at baseline, we showed that higher levels of short-chain ACs are longitudinally associated with declining HRQoL. These findings reveal a novel association between central carbon metabolic pathways and declining HRQoL. Notably, dysregulation in mitochondrial central carbon metabolism could be detected prior to clinically important decline in HRQoL, providing the first evidence of objective biomarkers as novel predictors to monitor HRQoL in nonpharmacological interventions and epidemiology.

Background: The kynurenine pathway (KP) is the major catabolic pathway for tryptophan degradation. The KP plays an important role as the sole de novo nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway in normal human physiology and functions as a counter-regulatory mechanism to mitigate immune responses during inflammation. Although the KP has been implicated in a variety of disorders including Huntington’s disease, seizures, cardiovascular disease, and osteoporosis, its role in renal diseases is seldom discussed. Summary: This review summarizes the roles of the KP and its metabolites in acute kidney injury (AKI) and chronic kidney disease (CKD) based on current literature evidence. Metabolomics studies demonstrated that the KP metabolites were significantly altered in patients and animal models with AKI or CKD. The diagnostic and prognostic values of the KP metabolites in AKI and CKD were highlighted in cross-sectional and longitudinal human observational studies. The biological impact of the KP on the pathophysiology of AKI and CKD has been studied in experimental models of different etiologies. In particular, the activation of the KP was found to confer protection in animal models of glomerulonephritis, and its immunomodulatory mechanism may involve the regulation of T cell subsets such as Th17 and regulatory T cells. Manipulation of the KP to increase NAD+ production or diversion toward specific KP metabolites was also found to be beneficial in animal models of AKI. Key Messages: KP metabolites are reported to be dysregulated in human observational and animal experimental studies of AKI and CKD. In AKI, the magnitude and direction of changes in the KP depend on the etiology of the damage. In CKD, KP metabolites are altered with the onset and progression of CKD all the way to advanced stages of the disease, including uremia and its related vascular complications. The activation of the KP and diversion to specific sub-branches are currently being explored as therapeutic strategies in these diseases, especially with regards to the immunomodulatory effects of certain KP metabolites. Further elucidation of the KP may hold promise for the development of biomarkers and targeted therapies for these kidney diseases.

Introduction: Concomitant risk factors challenge the mechanistic understanding of cardiac aging. We determined the degree to which the left atrial function could be distinguished by advanced cardiac magnetic resonance (CMR) imaging in older adults and assessed associations between the left atrial function and the plasma biomarkers related to biological aging and cardiovascular disease [serum monocyte chemoattractant protein-1 (MCP1), matrix metallopeptidase 9 (MMP-9), B-type natriuretic peptides (BNPs), galectin-3 (Gal-3), high-sensitivity cardiac troponin I (hsTn1), high-sensitivity C-reactive protein (hs-CRP), and soluble urokinase plasminogen activator receptor (sUPAR)]. Methods: Among a cross-sectional population-based cohort of older adults, longitudinal LA strain including reservoir strain (ϵs), conduit strain (ϵe), and booster strain (ϵa) as well as peak strain rates (SRs, SRe, SRa) were determined using CMR and studied in association with blood biomarkers. Results: We studied 243 community adults (42.8% female, mean age 70.3 ± 9.5 years). In bivariate analysis, ϵe and SRe were reduced in gradation with increasing risk factors (all p values

Data on attitudes and perceptions towards obesity are lacking in Asia. Participants who attended an obesity public forum were surveyed concerning obesity and its treatment options. Although obesity is generally accepted as a disease with biological underpinnings such as hormonal imbalances and slow metabolic rate, it is also regarded as an issue of personal responsibility. 65.1% believed that weight-loss medications are dangerous. 20.6% thought that pharmacotherapy is effective for weight loss, whereas 41.1% were unsure. Most believed that bariatric surgery could improve health (81.9%) and diabetes control (74.0%) although 64.1% were unsure of its risks.

Background: Bile acids (BAs) are traditionally associated with lipid absorption and phase II detoxification by forming various BA conjugates. Recently, it has been discovered that BAs also regulate glucose metabolism, and the increase in BAs in patients following bariatric surgery may contribute to the post-surgery improvement in insulin resistance (IR). However, while Roux-en-Y gastric bypass can increase BA concentrations post-surgery, this may not be the case after laparoscopic sleeve gastrectomy (LSG). We hypothesized that the profiling of BAs that include the conjugated BA species could detect post-surgery BA changes after LSG. To test our hypothesis, we performed comprehensive profiling of BAs in Asian individuals with morbid obesity at baseline, and at 6 months following LSG. Methods: Fourteen subjects scheduled for LSG were recruited. Anthropometric measurements, oral glucose tolerance test, and biochemistry tests were performed at baseline and at 6 months after LSG. BAs were profiled using liquid chromatography–mass spectrometry. Results: At 6 months, subjects lost significant weight from 117.4±5.4 to 92.1±3.8 kg and demonstrated significant improvement in IR. HOMA-IR decreased from 6.2±0.7 to 2.0±0.2 and the Matsuda index increased from 1.9±0.3 to 3.3±0.3. We did not detect any significant post-operative change in the levels of total BAs (5237.1±1219.4 vs. 3631.7±457.9, p=0.181) or non-sulfated BAs after LSG. However, sulfated BA species increased significantly after LSG. Conclusion: Our study showed that the serum concentrations of sulfated BA species in morbidly obese Asian individuals increased significantly 6 months after LSG; the increase in sulfated BAs after LSG might contribute to the post-surgery improvement of metabolic health.

Induced pluripotent stem cells derived cells (iPSCs) not only can be used for personalized cell transfer therapy, but also can be used for modeling diseases for drug screening and discovery in vitro. Although prior studies have characterized the function of rodent iPSCs derived endothelial cells (ECs) in diabetes or metabolic syndrome, feature phenotypes are largely unknown in hiPSC-ECs from patients with diabetes. Here, we used hiPSC lines from patients with type 2 diabetes mellitus (T2DM) and differentiated them into ECs (dia-hiPSC-ECs). We found that dia-hiPSC-ECs had disrupted glycine homeostasis, increased senescence, and impaired mitochondrial function and angiogenic potential as compared with healthy hiPSC-ECs. These signature phenotypes will be helpful to establish dia-hiPSC-ECs as models of endothelial dysfunction for understanding molecular mechanisms of disease and for identifying and testing new targets for the treatment of endothelial dysfunction in diabetes.

Aim We have reported earlier that a high salt intake triggered an aestivation‐like natriuretic‐ureotelic body water conservation response that lowered muscle mass and increased blood pressure. Here, we tested the hypothesis that a similar adaptive water conservation response occurs in experimental chronic renal failure. Methods In four subsequent experiments in Sprague Dawley rats, we used surgical 5/6 renal mass reduction (5/6 Nx) to induce chronic renal failure. We studied solute and water excretion in 24‐hour metabolic cage experiments, chronic blood pressure by radiotelemetry, chronic metabolic adjustment in liver and skeletal muscle by metabolomics and selected enzyme activity measurements, body Na+, K+ and water by dry ashing, and acute transepidermal water loss in conjunction with skin blood flow and intra‐arterial blood pressure. Results 5/6 Nx rats were polyuric, because their kidneys could not sufficiently concentrate the urine. Physiological adaptation to this renal water loss included mobilization of nitrogen and energy from muscle for organic osmolyte production, elevated norepinephrine and copeptin levels with reduced skin blood flow, which by means of compensation reduced their transepidermal water loss. This complex physiologic‐metabolic adjustment across multiple organs allowed the rats to stabilize their body water content despite persisting renal water loss, albeit at the expense of hypertension and catabolic mobilization of muscle protein. Conclusion Physiological adaptation to body water loss, termed aestivation, is an evolutionary conserved survival strategy and an under‐studied research area in medical physiology, which besides hypertension and muscle mass loss in chronic renal failure may explain many otherwise unexplainable phenomena in medicine.

The initial sensing of dietary methionine restriction (MR) occurs in the liver where it activates an integrated stress response (ISR) that quickly reduces methionine utilization. The ISR program is regulated in part by ATF4, but ATF4’s prototypical upstream regulator, eIF2α, is not acutely activated by MR. Bioinformatic analysis of RNAseq and metabolomics data from liver samples harvested 3 h and 6 h after initiating MR shows that general translation is inhibited at the level of ternary complex formation by an acute 50% reduction of hepatic methionine that limits formation of initiator methionine tRNA. The resulting ISR is induced by selective expression of ATF4 target genes that mediate adaptation to reduced methionine intake and return hepatic methionine to control levels within 4 days of starting the diet. Complementary in vitro experiments in HepG2 cells after knockdown of ATF4, or inhibition of mTOR or Erk1/2 support the conclusion that the early induction of genes by MR is partially dependent on ATF4 and regulated by both mTOR and Erk1/2. Taken together, these data show that initiation of dietary MR induces an mTOR- and Erk1/2-dependent stress response that is linked to ATF4 by the sharp, initial drop in hepatic methionine and resulting repression of translation pre-initiation.

Glioblastoma (GBM) is a uniformly lethal disease driven by glioma stem cells (GSCs). Here, we use a chemical biology approach to unveil previously unknown GBM dependencies. By studying sulconazole (SN) with anti-GSC properties, we find that SN disrupts biotin distribution to the carboxylases and histones. Transcriptomic and metabolomic analyses of SN-treated GSCs reveal metabolic alterations that are characteristic of biotin-deficient cells, including intracellular cholesterol depletion, impairment of oxidative phosphorylation, and energetic crisis. Furthermore, SN treatment reduces histone biotinylation, histone acetylation, and expression of superenhancer-associated GSC critical genes, which are also observed when biotin distribution is genetically disrupted by holocarboxylase synthetase (HLCS) depletion. HLCS silencing impaired GSC tumorigenicity in an orthotopic xenograft brain tumor model. In GBM, high HLCS expression robustly indicates a poor prognosis. Thus, the dependency of GBM on biotin distribution suggests that the rational cotargeting of biotin-dependent metabolism and epigenetic pathways may be explored for GSC eradication. National Research Foundation (NRF) National University of Singapore (NUS), Temasek Laboratories Published version This work was supported by the National Research Foundation Fellowship NRF-NRFF2017-01 (D.S.T.O.), National University of Singapore (NUS) start-up grant (D.S.T.O. and M.J.K.), NUS President’s Assistant Professorship (D.S.T.O.), and NUS Research Scholarships (M.J.Y.A., B.W.L.L., Y.H.C., and R.T.M.). S.K. and C.S.V. thank A*STAR and NSCC for support.

Ceramide production takes place throughout the body and plays a key role in the maintenance of normal physiology. However, ceramide levels are altered during disease states, particularly considering the development of diabetes and dyslipidemia. Ceramide production is also associated with atherosclerotic plaque instability. Recent studies revealed that patients with unstable coronary artery disease (CAD) presented increased plasma ceramide levels (especially C16, C18, and C24:1). These molecules are currently considered emerging biomarkers of cardiovascular diseases (CVD), being used for predicting atherosclerotic plaque instability and adverse cardiovascular events independently from traditional risk factors. With the aim of describing and discussing the role of ceramides in the stratification of cardiovascular diseases, this narrative review contextualizes the importance of this biomarker in the present cardiology scenario.A produção de ceramida ocorre em todo o corpo e desempenha um papel importante na manutenção da fisiologia normal. No entanto, os níveis de ceramidas são alterados em estados de doença, principalmente durante o desenvolvimento de diabetes e dislipidemia. A produção de ceramidas também está associada à instabilidade das placas ateroscleróticas. Estudos recentes revelam que pacientes com doença arterial coronariana instável apresentam níveis plasmáticos aumentados de ceramidas (principalmente C16, C18 e C24:1). Atualmente, são consideradas biomarcadores emergentes nas doenças cardiovasculares, sendo utilizadas na predição de instabilidade da placa aterosclerótica e eventos cardiovasculares adversos de forma independente aos fatores de risco tradicionais. Com o objetivo de descrever e discutir o papel das ceramidas na estratificação das doenças cardiovasculares, o desenvolvimento desta revisão narrativa contextualiza a importância desse biomarcador no cenário atual da cardiologia.

Background The adverse consequences of diabetes mellitus on cardiovascular health is well-established. However, few studies have studied the impact of diabetes on ageing. In our previous investigations, we identified distinct patterns of myocardial ageing among older adults otherwise asymptomatic for clinical cardiovascular disease. In this analysis, we hypothesize that glycated hemoglobin (HbA1c) may be differentially associated with these distinct signatures of myocardial ageing, thereby providing greater precision towards future preventative trials. Methods We performed extensive cardiovascular examinations on a cohort of asymptomatic aged community adults. Transthoracic echocardiography measured left ventricular structure and function. LV filling pressure was measured as the ratio between early mitral inflow velocity and mitral annular early diastolic velocity. Longitudinal left atrial (LA) strain comprising reservoir strain (ɛs), conduit strain (ɛe) and booster strain (ɛa) and their corresponding peak strain rates (SRs, SRe, SRa) were measured using cardiac magnetic resonance (CMR) feature tracking technique. Blood sampling for biomarkers were performed simultaneously with cardiovascular examinations. Results Among n=515 community adults in sinus rhythm and without cardiovascular disease [mean age 73±4 years, 255 (50%) females], 116 (23%) had diabetes. Age (73 vs 73 years) and heart rate (72 vs 75 beats per minute) were similar between diabetic and non-diabetic older adults. Diabetic older adults are mostly male (59% vs 48%, p=0.046), had larger body mass indices (24 vs 23 kg/m2, p=0.027), and greater burdens of hypertension (81% vs 41%, p Conclusion Our detailed examinations revealed distinct associations between glycated hemoglobin and myocardial functions that additionally varied in magnitude. As a contemporary biomarker, glycated hemoglobin may be useful for stratifying risks associated with myocardial ageing, particularly in ageing-related left atrial myopathies. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): National Medical Research Council of Singapore; Singhealth Foundation

Summary: Hypertrophic cardiomyopathy (HCM) is a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to physiological or pathological stress, prolonged hypertrophy can lead to heart failure. Here we demonstrate that Prdm16 is dispensable for cardiac development. However, it is required in the adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age. Cardiac-specific deletion of Prdm16 results in cardiac hypertrophy, excessive ventricular fibrosis, mitochondrial dysfunction, and impaired metabolic flexibility, leading to heart failure. We demonstrate that Prdm16 and euchromatic histone-lysine N-methyltransferase factors (Ehmts) act together to reduce expression of fetal genes reactivated in pathological hypertrophy by inhibiting the functions of the pro-hypertrophic transcription factor Myc. Although young Prdm16 knockout mice show normal cardiac function, they are predisposed to develop heart failure in response to metabolic stress. Our study demonstrates that Prdm16 protects the heart against age-dependent cardiac hypertrophy and heart failure.

IntroductionWe evaluated whether concentrations of serum acylcarnitines and amino acids are associated with risk of type 2 diabetes and can improve predictive diabetes models in an Asian population.Research design and methodsWe used data from 3313 male and female participants from the Singapore Prospective Study Program cohort who were diabetes-free at baseline. The average age at baseline was 48.0 years (SD: 11.9 years), and participants were of Chinese, Malay, and Indian ethnicity. Diabetes cases were identified through self-reported physician diagnosis, fasting glucose and glycated hemoglobin concentrations, and linkage to national disease registries. We measured fasting serum concentrations of 45 acylcarnitines and 14 amino acids. The association between metabolites and incident diabetes was modeled using Cox proportional hazards regression with adjustment for age, sex, ethnicity, height, and parental history of diabetes, and correction for multiple testing. Metabolites were added to the Atherosclerosis Risk in Communities (ARIC) predictive diabetes risk model to assess whether they could increase the area under the receiver operating characteristic curve (AUC).ResultsParticipants were followed up for an average of 8.4 years (SD: 2.1 years), during which time 314 developed diabetes. Branched-chain amino acids (HR: 1.477 per SD; 95% CI 1.325 to 1.647) and the alanine to glycine ratio (HR: 1.572; 95% CI 1.426 to 1.733) were most strongly associated with diabetes risk. Additionally, the acylcarnitines C4 and C16-OH, and the amino acids alanine, combined glutamate/glutamine, ornithine, phenylalanine, proline, and tyrosine were significantly associated with higher diabetes risk, and the acylcarnitine C8-DC and amino acids glycine and serine with lower risk. Adding selected metabolites to the ARIC model resulted in a significant increase in AUC from 0.836 to 0.846.ConclusionsWe identified acylcarnitines and amino acids associated with risk of type 2 diabetes in an Asian population. A subset of these modestly improved the prediction of diabetes when added to an established diabetes risk model.

Activation of the renin-angiotensin system (RAS) is a major contributor to the pathogenesis of diabetic nephroathy (DN). However, the precise mechanisms of renoprotection associated with RAS blockade in DN are not entirely clear. The aim of this study is to examine whether metabolic effects of RAS blockade might contribute to renoprotection. We utilized a mouse model of DN combining severe type I diabetes (the Akita mutation) with a single-copy renin transgene (ReninTG) driven by the albumin promoter. Akita-ReninTG mice on a 129/Sv background (DN-susceptible mice) develop clinical features of human DN including high-grade albuminuria, renal interstitial inflammation and glomerulosclerosis, while Akita-ReninTG mice on a C57BL/6 background (DN-resistant mice) do not develop significant kidney disease. These two experimental groups were treated with the angiotensin receptor blocker (ARB) losartan 10 mg/kg/day for 12 weeks, and metabolic profiles in kidney tissues were examined using a targeted metabolomics assay. The DN-susceptible mice exhibited high-grade albuminuria that was significantly attenuated by ARB (Vehicle vs ARB: 1480±562 vs 193±42 μg/day, p =0.045), while DN-resistant mice had minimal albuminuria that was not affected by ARB (Vehicle vs ARB: 80±14 vs 75±14 μg/day, p =0.801). The metabolomics profiles of the DN-resistant mice were similar to C57BL/6 wild-type controls. By contrast, DN-susceptible mice exhibited broad reductions in even-chain acyl-carnitines and an abnormal profile of TCA cycle intermediates compared to 129/Sv wild-type controls, suggesting substantial impairments of renal mitochondrial fuel oxidation including altered fatty acid metabolism. RAS blockade had broad effects to correct this profile by increasing acetyl-carnitines generated from acetyl-CoA and concomitantly normalizing expression of genes associated with mitochondrial fatty acid metabolism including PPAR-α, PGC-1α, CPT1 and CPT2. ARB treatment restored TCA cycle activity to normal. These findings suggest that effects of RAS blockade re-establish normal fuel metabolism and mitochondrial fatty acid oxidation in kidney and may contribute to renoprotection.

Therapeutic inhibition of the sodium-glucose co-transporter 2 (SGLT2) leads to substantial loss of energy (in the form of glucose) and additional solutes (in the form of Na

BACKGROUND Plasma concentrations of branched-chain amino acids (BCAAs) are elevated in obese individuals with insulin resistance (IR) and decrease after bariatric surgery. However, the metabolic mechanisms are unclear. OBJECTIVES Our objectives are to compare leucine kinetics between morbidly obese and healthy-weight individuals cross-sectionally, and to prospectively evaluate changes in the morbidly obese after sleeve gastrectomy. We hypothesized that leucine oxidation is slower in obese individuals and increases after surgery. METHODS Ten morbidly obese [BMI (in kg/m2) ≥32.5, age 21-50 y] and 10 healthy-weight participants (BMI

Background Hand grip strength (HGS) has been proposed as a robust predictor for frailty and sarcopenia. Hence, identifying biomarkers for declining HGS accompanying aging could deepen our understanding of the biological underpinnings, informing pre-emptive intervention. Acylcarnitines (ACs) are metabolites generated by fatty acid metabolism in the mitochondria and are dysregulated in multiple disorders affecting the musculature. However, they have not been comprehensively profiled and examined regarding their utility in predicting variability in declining HGS, longitudinally. Thus, we aimed to: 1) validate previous findings on insignificant cross-sectional association between ACs and HGS, and 2) examine whether baseline ACs were associated with both decline and variability in HGS over 18 months, in community-dwelling older adults. Methods We included participants who had HGS measured with dynamometer longitudinally (N = 121). We quantified ACs by targeted plasma metabolomics profiling. Multivariable linear regressions were then performed. Results Cross-sectionally, ACs were not significantly associated with HGS. Longitudinally, baseline short-chain dicarboxylic and hydroxylated acylcarnitines (AC-DC/−OH) levels were inversely associated with and significantly explained the variability in 18-month decline in HGS. A specific AC species, the C4−OH, accounted for most of the variance explained. Conclusions We showed novel biomarkers for declining HGS, furthering molecular understanding and informing nutritional pre-emptive programs.

Key Points Question Are bariatric interventions associated with serum micronutrients and metabolic hormones changes in the years after intervention, and do trajectories differ between laparoscopic sleeve gastrectomy vs gastric bypass procedures? Findings In this comparative effectiveness study of 499 patients who underwent sleeve gastrectomy and 189 patients who underwent one-anastomosis or Roux-en-Y gastric bypass, parameters associated with calcium metabolism did not differ between the groups. The extent of hemoglobin suppression was greater among patients who underwent gastric bypass compared with those who underwent laparoscopic sleeve gastrectomy, but the difference was not explained by differences in iron stores or vitamin B levels. Meaning The findings of this study suggest that micronutrient deficiencies after bariatric interventions are differentially associated with types of bariatric procedures., This comparative effectiveness study examines the association of bariatric interventions with micronutrient deficiencies and endocrine disturbances., Importance Few studies have described the longitudinal trajectories of serum levels of micronutrients whose deficiencies are associated with serious sequelae following bariatric procedures, such as anemia, osteoporotic fractures, and neuropathies. Furthermore, previous studies comparing laparoscopic sleeve gastrectomy (LSG) vs Roux-en-Y gastric bypass (LRYGB) or one-anastomosis gastric bypass (OAGB) procedures may have been limited by selection and confounding biases. Objective To appraise the spectrum and temporal course of micronutrient deficiencies associated with bone metabolism and erythropoiesis after LSG vs OAGB or LRYGB procedures, using the propensity score as a balancing score. Design, Setting, and Participants This prospective, longitudinal comparative effectiveness study was conducted at a high-volume bariatric unit in Singapore from September 1, 2008, to November 30, 2017, with a cutoff date for analysis of September 2018. Patients who underwent adjustable gastric banding, biliopancreatic diversion procedures, and intragastric balloon procedures were excluded. All other patients who underwent bariatric procedures were included. Data were analyzed from September 23 to 30, 2018. Main Outcomes and Measures Serial assessment of 13 biochemical parameters at 12 time points for up to 5 years after bariatric procedure. Inverse probability-of-treatment weights were used to obtain estimates of the mean associations of variables assessed with the bariatric surgical interventions. Longitudinal trajectories were analyzed using mixed-effects generalized linear models to apportion the temporal variation of serum micronutrients into fixed-effects and random-effects components. Results A total of 688 patients were included in this study, of whom 499 underwent LSG (mean [SD] age, 41.5 [11.3] years; 318 [63.7%] women) and 189 underwent OAGB or LRYGB (mean [SD] age, 48.6 [9.4] years; 112 [59.3%] women). There were no differences during follow-up among patients who underwent LSG vs those who underwent OAGB or LRYGB in intact parathyroid hormone levels (mean difference, 7.05 [95% CI, −28.67 to 42.77] pg/mL; P = .70), serum 25-hydroxyvitamin D levels (mean difference, −0.72 [95% CI, −1.56 to 0.12] ng/mL; P = .09), or phosphate levels (mean difference, 0.006 [95% CI, −0.052 to 0.064] mg/dL; P = .83). Hemoglobin levels were a mean 0.63 (95% CI, 0.41 to 0.85) g/dL higher among patients who underwent LSG compared with those who underwent OAGB or LRYGB (P

Scope Coffee and tea are among the most popular beverages in the world. However, the association between habitual coffee, green tea, and black tea consumption with metabolomics profiles in Asian populations remain largely unknown. Methods and results 158 metabolites (14 amino acids, 45 acylcarnitines, and 99 sphingolipids) in the blood plasma of participants are measured from the population-based Singapore Prospective Study Program cohort using mass spectrometry (MS). Linear regression models are used to obtain the estimates for the association between coffee and tea consumption with metabolite levels, adjusted for potential confounders and false discovery rate (FDR). Coffee consumption is significantly associated with higher levels of 63 sphingolipids (29 sphingomyelins, 32 ceramides, a sphingosine-1-phosphate, and a sphingosine) and lower levels of 13 acylcarnitines and alanine. Black tea consumption is significantly associated with higher levels of eight sphingolipids, and lower levels of an amino acid, whereas green tea is significantly inversely associated with four metabolites (C8:1-OH acylcarnitine, ganglioside GM3 d18:1/16:0, sphingomyelins d18:2/18:0 and d18:1/14:0). Conclusions Coffee, black tea, and green tea consumption are associated with plasma levels of certain classes of sphingolipids and acylcarnitines in an Asian population, particularly sphingomyelins, which may mediate the health benefits of these beverages.

Little is known about pathophysiology of sarcopenia in diabetes. We aimed to study amino acid profile associated with skeletal muscle mass loss longitudinally in Type 2 Diabetes Mellitus (T2DM).This is a prospective study of 1140 patients aged 56.6 ± 10.6 years from the SMART2D cohort. Skeletal muscle mass was measured using bio-impedance analysis at baseline and follow-up. Amino acids were measured by mass spectrometry.Over a period of up to 7.9 years, 43.9% experienced skeletal muscle mass loss. Lower baseline valine, leucine and isoleucine levels were associated with decreased skeletal muscle mass index (SMI) with corresponding coefficient 0.251(95 %CI 0.009 to 0.493), 0.298(95 %CI 0.051 to 0.544)) and 0.366(95 %CI 0.131 to 0.600). Higher baseline valine, leucine, isoleucine, alanine and tryptophan levels were associated with reduced odds of muscle mass loss with corresponding odds ratio (OR)0.797 (95 %CI 0.690 to 0.921), 0.825 (95 %CI 0.713 to 0.955), 0.826 (95 %CI 0.718-0.950), 0.847 (95 %CI 0.739-0.969) and 0.835 (95 %CI 0.720-0.979).The branched-chain amino acids valine, leucine and isoleucine were positively associated with change in SMI and reduced odds of muscle mass loss longitudinally. Further studies should be conducted to elucidate the pathophysiological mechanisms underlying the relationship between these amino acids and muscle mass loss in T2DM.