Journal of Inherited Metabolic Disease

, Volume 41, Issue 6, pp 985–995 | Cite as

Insulin-resistance in glycogen storage disease type Ia: linking carbohydrates and mitochondria?

  • Alessandro RossiEmail author
  • Margherita Ruoppolo
  • Pietro Formisano
  • Guglielmo Villani
  • Lucia Albano
  • Giovanna Gallo
  • Daniela Crisci
  • Augusta Moccia
  • Giancarlo Parenti
  • Pietro Strisciuglio
  • Daniela Melis
Original Article



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). GSDIa patients are at higher risk of developing insulin-resistance (IR). Mitochondrial dysfunction has been implicated in the development of IR. Mitochondrial dysfunction can demonstrate abnormalities in plama acylcarnitines (ACs) and urine organic acids (UOA). The aim of the study was to investigate the presence of mitochondrial impairment in GSDI patients and its possible connection with IR.


Fourteen GSDIa, seven GSDIb patients, 28 and 14 age and sex-matched controls, were enrolled. Plasma ACs, UOA, and surrogate markers of IR (HOMA-IR, QUICKI, ISI, VAI) were measured.


GSDIa patients showed higher short-chain ACs and long-chain ACs levels and increased urinary excretion of lactate, pyruvate, 2-ketoglutarate, 3-methylglutaconate, adipate, suberate, aconitate, ethylmalonate, fumarate, malate, sebacate, 4-octenedioate, 3OH-suberate, and 3-methylglutarate than controls (p < 0.05). GSDIb patients showed higher C0 and C4 levels and increased urinary excretion of lactate, 3-methylglutarate and suberate than controls (p < 0.05). In GSDIa patients C18 levels correlated with insulin serum levels, HOMA-IR, QUICKI, and ISI; long-chain ACs levels correlated with cholesterol, triglycerides, ALT serum levels, and VAI.


Increased plasma ACs and abnormal UOA profile suggest mitochondrial impairment in GSDIa. Correlation data suggest a possible connection between mitochondrial impairment and IR. We hypothesized that mitochondrial overload might generate by-products potentially affecting the insulin signaling pathway, leading to IR. On the basis of the available data, the possible pathomechanism for IR in GSDIa is proposed.


GSDIa Insulin-resistance Lipids Mitochondria Acylcarnitines Urine organic acids 



Plasma acylcarnitines


Free carnitine






















































Nocturnal gastric drip feeding


Fatty acid oxidation


Homeostasis model assessment of insulin resistance


Inflammatory bowel disease




Insulin sensitivity index


Quantitative insulin sensitivity check index


Pentose phosphate pathway

TCA cycle

Tricarboxylic acid cycle


Uncooked cornstarch


Urine organic acids


Visceral adiposity index



This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest


Informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients (or their legal guardians) for being included in the study.

Supplementary material

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ESM 1 (DOCX 33 kb)
10545_2018_149_MOESM2_ESM.docx (195 kb)
Suppl. Fig. 1 (DOCX 194 kb)
10545_2018_149_MOESM3_ESM.docx (41 kb)
Suppl. Fig. 2 (DOCX 41 kb)


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Copyright information

© SSIEM 2018

Authors and Affiliations

  • Alessandro Rossi
    • 1
    Email author return OK on get
  • Margherita Ruoppolo
    • 2
    • 3
  • Pietro Formisano
    • 4
  • Guglielmo Villani
    • 2
    • 3
  • Lucia Albano
    • 2
    • 3
  • Giovanna Gallo
    • 2
    • 3
  • Daniela Crisci
    • 2
    • 3
  • Augusta Moccia
    • 4
  • Giancarlo Parenti
    • 1
    • 5
  • Pietro Strisciuglio
    • 1
  • Daniela Melis
    • 1
  1. 1.Department of Translational Medical Science, Section of PediatricsFederico II UniversityNaplesItaly
  2. 2.Department of Molecular Medicine and Medical BiotechnologyFederico II UniversityNaplesItaly
  3. 3.CEINGE Biotecnologie
  4. 4.Department of Translational Medical Science, Section of Clinical PathologyFederico II UniversityNaplesItaly
  5. 5.Telethon Institute of Genetics and MedicinePozzuoliItaly

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