1H-NMR-Based Metabolomics in Autism Spectrum Disorder and Pediatric Acute-Onset Neuropsychiatric Syndrome

We recently described a unique plasma metabolite profile in subjects with pediatric acute-onset neuropsychiatric syndrome (PANS), suggesting pathogenic models involving specific patterns of neurotransmission, neuroinflammation, and oxidative stress. Here, we extend the analysis to a group of patients with autism spectrum disorder (ASD), as a consensus has recently emerged around its immune-mediated pathophysiology with a widespread involvement of brain networks. This observational case-control study enrolled patients referred for PANS and ASD from June 2019 to May 2020, as well as neurotypical age and gender-matched control subjects. Thirty-four PANS outpatients, fifteen ASD outpatients, and twenty-five neurotypical subjects underwent physical and neuropsychiatric evaluations, alongside serum metabolomic analysis with 1H-NMR. In supervised models, the metabolomic profile of ASD was significantly different from controls (p = 0.0001), with skewed concentrations of asparagine, aspartate, betaine, glycine, lactate, glucose, and pyruvate. Metabolomic separation was also observed between PANS and ASD subjects (p = 0.02), with differences in the concentrations of arginine, aspartate, betaine, choline, creatine phosphate, glycine, pyruvate, and tryptophan. We confirmed a unique serum metabolomic profile of PANS compared with both ASD and neurotypical subjects, distinguishing PANS as a pathophysiological entity per se. Tryptophan and glycine appear as neuroinflammatory fingerprints of PANS and ASD, respectively. In particular, a reduction in glycine would primarily affect NMDA-R excitatory tone, overall impairing downstream glutamatergic, dopaminergic, and GABAergic transmissions. Nonetheless, we found metabolomic similarities between PANS and ASD that suggest a putative role of N-methyl-D-aspartate receptor (NMDA-R) dysfunction in both disorders. Metabolomics-based approaches could contribute to the identification of novel ASD and PANS biomarkers

Impatto dei trigliceridi per se su insulino-sensibilità e funzione beta-cellulare nell'uomo: uno studio di intervento con bezafibrato

L’ipertrigliceridemia è una dislipidemia frequente e una conseguenza riconosciuta della sindrome metabolica e dell’insulino-resistenza. Tuttavia, evidenze crescenti suggeriscono che essa possa contribuire direttamente alla disregolazione dell’omeostasi glucidica ed essere un importante mediatore della lipotossicità, persino più che gli acidi grassi, sia sugli organi periferici che sulle cellule β-pancreatiche. Infatti, studi epidemiologici e di intervento suggeriscono che l’ipertrigliceridemia cronica riduca l’insulino-sensibilità, la clearance insulinica e la funzione β-cellulare intrinseca e aumenti l’insulino-secrezione, aumentando globalmente il rischio di sviluppo di diabete mellito di tipo 2 (DM2). Se questo è vero, tali effetti negativi potrebbero essere attivamente contrastati dai fibrati, farmaci ipolipemizzanti ad alta potenza. Nel nostro studio abbiamo trattato pazienti con normale tolleranza glucidica (NGT) affetti esclusivamente da ipertrigliceridemia (n=23) per sei settimane con bezafibrato e valutato i maggiori meccanismi responsabili dell’omeostasi glucidica al basale e post-trattamento. Il trattamento di breve termine con bezafibrato ha ridotto i livelli plasmatici di glucosio e insulina a digiuno, migliorato la tolleranza glucidica e l’insulino-resistenza whole body, mentre ha sortito solo un modesto effetto sulla funzione β-cellulare intrinseca e alcun effetto sulla clearance insulinica e sulla produzione endogena di glucosio (EGP), che appariva severamente compromessa al basale. In conclusione, i nostri risultati suggeriscono che un trattamento di breve termine con bezafibrato possa migliorare il controllo glucidico, l’insulino-sensibilità e, modestamente, la funzione β-cellulare intrinseca in pazienti con ipertrigliceridemia cronica, verosimilmente contribuendo a ridurre, se prolungato nel tempo, il rischio di progressione a DM2. Tuttavia, anche in corso di terapia di lungo termine con bezafibrato, gli effetti protettivi sulla funzione β-cellulare intrinseca potrebbero essere modesti per il suo deterioramento cronico dovuto allo stimolo secretorio persistente esercitato da parte di un’EGP patologica, suggerendo la presenza di una funzionalità metabolica epatica altamente compromessa nei soggetti con ipertrigliceridemia cronica, anche laddove questi siano normali per tolleranza al glucosio. Hypertriglyceridemia is a common dyslipidemia and a known consequence of metabolic syndrome and insulin resistance. Emerging evidence suggests that it is able to contribute itself to dysregulation of glucose homeostasis and could be an important mediator of lipotoxicity, even more than fatty acids, both on peripheral organs and on pancreatic beta-cells. In fact, epidemiological studies support the concept that chronic hypertriglyceridemia reducing insulin sensitivity, insulin clearance and beta-cell function and increasing insulin secretion, would increase the risk of type 2 diabetes. If this is true, these negative effects should be reversed or ameliorated by fibrates, a potent triglyceride lowering drug. In our study, we treated NGT patients with hypertriglyceridemia (n= 23) with bezafibrate for six weeks and evaluated the major mechanisms responsible for glucose homeostasis. Bezafibrate reduced fasting plasma glucose and insulin concentrations, improved glucose tolerance and insulin resistance, while had a modest effect on beta-cell function and none on insulin clearance and endogenous glucose production (EGP), which appeared compromised at baseline. In conclusion, our results confirm that lowering plasma triglyceride levels could be a strategy to ameliorate glucose control, in patients with chronic hypertriglyceridemia, eventually reducing the risk of T2D. The lack of effects on beta-cell function and particularly on EGP suggest the presence in these patients of a chronic damage