Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

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

References

  • Aguer C, McCoin CS, Knotts TA, Thrush AB, Ono-Moore K, McPherson R et al (2015) Acylcarnitines: potential implications for skeletal muscle insulin resistance. FASEB J 29(1):336–345

    Article  CAS  PubMed  Google Scholar 

  • Amato MC, Giordano C (2014) Visceral adiposity index: an indicator of adipose tissue dysfunction. Int J Endocrinol 2014:730827

    Article  PubMed  PubMed Central  Google Scholar 

  • Bandsma RH, Smit GP, Kuipers F (2002) Disturbed lipid metabolism in glycogen storage disease type 1. Eur J Pediatr 161(Suppl 1):S65–S69

    Article  CAS  PubMed  Google Scholar 

  • Bhattacharya K (2011) Dietary dilemmas in the management of glycogen storage disease type I. J Inherit Metab Dis 34(3):621–629

    Article  CAS  PubMed  Google Scholar 

  • Bhattacharya K, Mundy H, Lilburn MF, Champion MP, Morley DW, Maillot F (2015) A pilot longitudinal study of the use of waxy maize heat modified starch in the treatment of adults with glycogen storage disease type I: a randomized double-blind cross-over study. Orphanet J Rare Dis 10:18

    Article  PubMed  PubMed Central  Google Scholar 

  • Das AM, Lücke T, Meyer U, Hartmann H, Illsinger S (2010) Glycogen storage disease type 1: impact of medium-chain triglycerides on metabolic control and growth. Ann Nutr Metab 56(3):225–232

    Article  CAS  PubMed  Google Scholar 

  • Derks TG, van Rijn M (2015) Lipids in hepatic glycogen storage diseases: pathophysiology, monitoring of dietary management and future directions. J Inherit Metab Dis 38(3):537–543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Derks TG, Martens DH, Sentner CP, Van Rijn M, de Boer F, Smit GP et al (2013) Dietary treatment of glycogen storage disease type Ia: uncooked cornstarch and/or continuous nocturnal gastric drip-feeding? Mol Genet Metab 109(1):1–2

    Article  CAS  PubMed  Google Scholar 

  • Farah BL, Sinha RA, Wu Y, Shing BK, Lim A, Hirayama M et al (2017) Hepatic mitochondrial dysfunction is a feature of glycogen storage disease type Ia (GSDIa). Sci Rep 7:44408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hancox RJ, Landhuis CE (2011) Correlation between measures of insulin resistance in fasting and non-fasting. Diabetol Metab Syndr 3(1):23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones JG, Garcia P, Barosa C, Delgado TC, Diogo L (2009) Hepatic anaplerotic outflow fluxes are redirected from gluconeogenesis to lactate synthesis in patients with type 1a glycogen storage disease. Metab Eng 11(3):155–162

    Article  CAS  PubMed  Google Scholar 

  • Jun HS, Weinstein DA, Lee YM, Mansfield BC, Chou JY (2014) Molecular mechanisms of neutrophil dysfunction in glycogen storage disease type Ib. Blood 123(18):2843–2853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kelley DE, He J, Menshikova EV, Ritov VB (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51(10):2944–2950

    Article  CAS  PubMed  Google Scholar 

  • Kishnani PS, Austin SL, Abdenur JE, Arn P, Bali DS, Boney A et al (2014) Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med 16(11):e1

    Article  CAS  PubMed  Google Scholar 

  • Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O et al (2008) Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7(1):45–56

    Article  CAS  PubMed  Google Scholar 

  • Kumps A, Duez P, Mardens Y (2002) Metabolic, nutritional, iatrogenic, and artifactual sources of urinary organic acids: a comprehensive table. Clin Chem 48(5):708–717

    CAS  PubMed  Google Scholar 

  • Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7):412–419

    Article  CAS  PubMed  Google Scholar 

  • McCoin CS, Knotts TA, Adams SH (2015) Acylcarnitines--old actors auditioning for new roles in metabolic physiology. Nat Rev Endocrinol 11(10):617–625

    Article  PubMed  PubMed Central  Google Scholar 

  • Melis D, Rossi A, Pivonello R, Salerno M, Balivo F, Spadarella S et al (2015) Glycogen storage disease type Ia (GSDIa) but not glycogen storage disease type Ib (GSDIb) is associated to an increased risk of metabolic syndrome: possible role of microsomal glucose 6-phosphate accumulation. Orphanet J Rare Dis 10:91

    Article  PubMed  PubMed Central  Google Scholar 

  • Melis D, Rossi A, Pivonello R, Del Puente A, Pivonello C, Cangemi G et al (2016) Reduced bone mineral density in glycogen storage disease type III: evidence for a possible connection between metabolic imbalance and bone homeostasis. Bone 86:79–85

    Article  CAS  PubMed  Google Scholar 

  • Montgomery MK, Turner N (2015) Mitochondrial dysfunction and insulin resistance: an update. Endocr Connect 4(1):R1–R15

    Article  CAS  PubMed  Google Scholar 

  • Muniyappa R, Lee S, Chen H, Quon MJ (2008) Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab 294(1):E15–E26

    Article  CAS  PubMed  Google Scholar 

  • Muoio DM, Newgard CB (2008) Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 9(3):193–205

    Article  CAS  PubMed  Google Scholar 

  • Nagasaka H, Hirano K, Ohtake A, Miida T, Takatani T, Murayama K et al (2007) Improvements of hypertriglyceridemia and hyperlacticemia in Japanese children with glycogen storage disease type Ia by medium-chain triglyceride milk. Eur J Pediatr 166(10):1009–1016

    Article  PubMed  Google Scholar 

  • Oosterveer MH, Schoonjans K (2014) Hepatic glucose sensing and integrative pathways in the liver. Cell Mol Life Sci 71(8):1453–1467

    Article  CAS  PubMed  Google Scholar 

  • Rajas F, Labrune P, Mithieux G (2013) Glycogen storage disease type 1 and diabetes: learning by comparing and contrasting the two disorders. Diabetes Metab 39(5):377–387

    Article  CAS  PubMed  Google Scholar 

  • Rake JP, Visser G, Labrune P, Leonard JV, Ullrich K, Smit GP (2002) Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European study on glycogen storage disease type I (ESGSD I). Eur J Pediatr 161(Suppl 1):S20–S34

    Article  CAS  PubMed  Google Scholar 

  • Ruoppolo M, Campesi I, Scolamiero E, Pecce R, Caterino M, Cherchi S et al (2014) Serum metabolomic profiles suggest influence of sex and oral contraceptive use. Am J Transl Res 6(5):614–624

    CAS  PubMed  PubMed Central  Google Scholar 

  • Satapati S, Sunny NE, Kucejova B, Fu X, He TT, Mendez-Lucas A et al (2012) Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. J Lipid Res 53(6):1080–1092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schooneman MG, Ten Have GA, van Vlies N, Houten SM, Deutz NE, Soeters MR (2015) Transorgan fluxes in a porcine model reveal a central role for liver in acylcarnitine metabolism. Am J Physiol Endocrinol Metab 309(3):E256–E264

    Article  CAS  PubMed  Google Scholar 

  • Scolamiero E, Cozzolino C, Albano L, Ansalone A, Caterino M, Corbo G et al (2015) Targeted metabolomics in the expanded newborn screening for inborn errors of metabolism. Mol BioSyst 11(6):1525–1535

    Article  CAS  PubMed  Google Scholar 

  • Spaziani S, Imperlini E, Mancini A, Caterino M, Buono P, Orrù S (2014) Insulin-like growth factor 1 receptor signaling induced by supraphysiological doses of IGF-1 in human peripheral blood lymphocytes. Proteomics 14(13–14):1623–1629

    Article  CAS  PubMed  Google Scholar 

  • Villani GR, Gallo G, Scolamiero E, Salvatore F, Ruoppolo M (2017) "Classical organic acidurias": diagnosis and pathogenesis. Clin Exp Med 17(3):305–323

    Article  CAS  PubMed  Google Scholar 

  • Wolfsdorf JI, Plotkin RA, Laffel LM, Crigler JF Jr (1990) Continuous glucose for treatment of patients with type 1 glycogen-storage disease: comparison of the effects of dextrose and uncooked cornstarch on biochemical variables. Am J Clin Nutr 52(6):1043–1050

    Article  CAS  PubMed  Google Scholar 

  • Xu G, Hansen JS, Zhao XJ, Chen S, Hoene M, Wang XL et al (2016) Liver and muscle contribute differently to the plasma Acylcarnitine pool during fasting and exercise in humans. J Clin Endocrinol Metab 101(12):5044–5052

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

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

Author information

Authors and Affiliations

  1. Department of Translational Medical Science, Section of Pediatrics, Federico II University, Via Sergio Pansini, 5, 80131, Naples, Italy

    Alessandro Rossi, Giancarlo Parenti, Pietro Strisciuglio & Daniela Melis

  2. Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy

    Margherita Ruoppolo, Guglielmo Villani, Lucia Albano, Giovanna Gallo & Daniela Crisci

  3. CEINGE Biotecnologie Avanzates.c.ar.l., Naples, Italy

    Margherita Ruoppolo, Guglielmo Villani, Lucia Albano, Giovanna Gallo & Daniela Crisci

  4. Department of Translational Medical Science, Section of Clinical Pathology, Federico II University, Naples, Italy

    Pietro Formisano & Augusta Moccia

  5. Telethon Institute of Genetics and Medicine, Pozzuoli, Italy

    Giancarlo Parenti

Authors
  1. Alessandro Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Margherita Ruoppolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pietro Formisano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guglielmo Villani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lucia Albano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giovanna Gallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniela Crisci
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Augusta Moccia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giancarlo Parenti
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pietro Strisciuglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Daniela Melis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alessandro Rossi.

Ethics declarations

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.

Additional information

Communicated by: Verena Peters

Electronic supplementary material

ESM 1

(DOCX 33 kb)

Suppl. Fig. 1

(DOCX 194 kb)

Suppl. Fig. 2

(DOCX 41 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rossi, A., Ruoppolo, M., Formisano, P. et al. Insulin-resistance in glycogen storage disease type Ia: linking carbohydrates and mitochondria?. J Inherit Metab Dis 41, 985–995 (2018). https://doi.org/10.1007/s10545-018-0149-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-018-0149-4

Keywords

Search

Navigation