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

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

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). 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.

Methods

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.

Results

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.

Discussion

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.

Keywords

GSDIa Insulin-resistance Lipids Mitochondria Acylcarnitines Urine organic acids 

Abbreviations

ACs

Plasma acylcarnitines

C0

Free carnitine

C2

Acetylcarnitine

C3

Propionylcarnitine

C3DC

Malonylcarnitine

C4

Butyrylcarnitine

C4DC

Methylmalonylcarnitine

C5

Isovalerylcarnitine

C5DC

Glutarylcarnitine

C5:1

Tiglylcarnitine

C5OH

3OH-Isovalerylcarnitine

C6

Hexanoylcarnitine

C6DC

Adipylcarnitine

C8

Octanoylcarnitine

C8:1

Octeneylcarnitine

C10

Decanoylcarnitine

C10:1

Decenoylcarnitine

C12

Dodecanoylcarnitine

C12:1

Dodecenoylcarnitine

C14

Miristoylcarnitine

C14:1

Tetradecenoylcarnitine

C14:2

Tetradecadienoylcarnitine

C16

Palmitoylcarnitine

C16:1

Esadecenoylcarnitine

C16OH

3OH-Esadecanoylcarnitine

C18

Stearoylcarnitine

C18:1

Oleylcarnitine

C18:1OH

3OH-Oleycarnitine

CNGF

Nocturnal gastric drip feeding

FAO

Fatty acid oxidation

HOMA-IR

Homeostasis model assessment of insulin resistance

IBD

Inflammatory bowel disease

IR

Insulin-resistance

ISI

Insulin sensitivity index

QUICKI

Quantitative insulin sensitivity check index

PPP

Pentose phosphate pathway

TCA cycle

Tricarboxylic acid cycle

UCCS

Uncooked cornstarch

UOA

Urine organic acids

VAI

Visceral adiposity index

Notes

Funding

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

None.

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

10545_2018_149_MOESM1_ESM.docx (33 kb)
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
  • 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 Avanzates.c.ar.l.NaplesItaly
  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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