Background: Glycogen storage disease type I (GSDI) is an inborn error of carbohydrate metabolism caused by mutations of either the G6PC gene (GSDIa) or the SLC37A4 gene (GSDIb). It has been recently shown that GSDIa patients are at higher risk for developing metabolic syndrome and insulin-resistance (IR). A possible role of mitochondrial dysfunction in developing IR has been proposed. Mitochondrial disorders are traditionally investigated by plasma acylcanitines (ACs) and urine organic acids (UOA) profiles. The aim of the present study was to analyze the molecules of intermediary metabolism to determine whether an alteration of mitochondrial function exists in GSDI patients and its possible role in IR. Methods. 13 GSDIa and 7 GSDIb patients, 26 and 14 age and sex-matched controls, were enrolled. Plasma ACs, UOA and surrogate markers of IR were measured. Results: GSDIa patients showed higher short-chain ACs (C0, C2, C3,C4, C6DC) and long-chain ACs (C14, C16, C16:1, C16OH, C18, C18OH) levels and urinary excretion of lactate, pyruvate, ethylmalonate, fumarate, malate, 3-methylglutaconate, 3-methylglutarate, suberate, aconitate, sebacate, 2-ketoglutarate, 4-octenedioate than controls (p < 0.05). GSDIb patients showed higher C0 and C4 levels than controls (p <0.05). In GSDIa patients C12 and C16 levels correlated with Insulin serum levels, HOMA, QUICKI and ISI (p < 0.05); long-chain ACs levels correlated with cholesterol, triglycerides and VAI (p< 0.05). Discussion: Increased plasma long-chain ACs and abnormal UOA profile suggest overload of mitochondrial lipid oxidation and Krebs cycle/respiratory chain inefficiency leading to mitochondrial stress. Correlation data are consistent with the reported hypothesis that IR is associated to mitochondrial dysfunction. It can be hypothesized that inefficient beta-oxidation generates chain-shortened ACs that may affect insulin signaling pathway, leading to IR.
Plasma acylcarnitines and urine organic acids profiles provide evidence for possible mitochondrial dysfunction in glycogen storage disease type Ia / Rossi, Alessandro; Ruoppolo, Margherita; Formisano, Pietro; Villani, GUGLIELMO ROSARIO DOMENI; Albano, L.; Gallo, G.; Moccia, A.; Parenti, Giancarlo; Strisciuglio, Pietro; Melis, Daniela. - (2016). (Intervento presentato al convegno Annual Symposium SSIEM (Society for the study of Inborn Errors of Metabolism) tenutosi a Roma nel 6-9 settembre 2016).
Plasma acylcarnitines and urine organic acids profiles provide evidence for possible mitochondrial dysfunction in glycogen storage disease type Ia
ROSSI, ALESSANDRO;RUOPPOLO, MARGHERITA;FORMISANO, PIETRO;VILLANI, GUGLIELMO ROSARIO DOMENI;PARENTI, GIANCARLO;STRISCIUGLIO, PIETRO;MELIS, DANIELA
2016
Abstract
Background: Glycogen storage disease type I (GSDI) is an inborn error of carbohydrate metabolism caused by mutations of either the G6PC gene (GSDIa) or the SLC37A4 gene (GSDIb). It has been recently shown that GSDIa patients are at higher risk for developing metabolic syndrome and insulin-resistance (IR). A possible role of mitochondrial dysfunction in developing IR has been proposed. Mitochondrial disorders are traditionally investigated by plasma acylcanitines (ACs) and urine organic acids (UOA) profiles. The aim of the present study was to analyze the molecules of intermediary metabolism to determine whether an alteration of mitochondrial function exists in GSDI patients and its possible role in IR. Methods. 13 GSDIa and 7 GSDIb patients, 26 and 14 age and sex-matched controls, were enrolled. Plasma ACs, UOA and surrogate markers of IR were measured. Results: GSDIa patients showed higher short-chain ACs (C0, C2, C3,C4, C6DC) and long-chain ACs (C14, C16, C16:1, C16OH, C18, C18OH) levels and urinary excretion of lactate, pyruvate, ethylmalonate, fumarate, malate, 3-methylglutaconate, 3-methylglutarate, suberate, aconitate, sebacate, 2-ketoglutarate, 4-octenedioate than controls (p < 0.05). GSDIb patients showed higher C0 and C4 levels than controls (p <0.05). In GSDIa patients C12 and C16 levels correlated with Insulin serum levels, HOMA, QUICKI and ISI (p < 0.05); long-chain ACs levels correlated with cholesterol, triglycerides and VAI (p< 0.05). Discussion: Increased plasma long-chain ACs and abnormal UOA profile suggest overload of mitochondrial lipid oxidation and Krebs cycle/respiratory chain inefficiency leading to mitochondrial stress. Correlation data are consistent with the reported hypothesis that IR is associated to mitochondrial dysfunction. It can be hypothesized that inefficient beta-oxidation generates chain-shortened ACs that may affect insulin signaling pathway, leading to IR.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
