Skip to main content

Advertisement

We’d like to understand how you use our websites in order to improve them. Register your interest.

Imbalanced cortisol concentrations in glycogen storage disease type I: evidence for a possible link between endocrine regulation and metabolic derangement

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). Glucose 6-phosphate (G6P) availability has been shown to modulate 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), an ER-bound enzyme catalyzing the local conversion of inactive cortisone into active cortisol. Adrenal cortex assessment has never been performed in GSDI. The aim of the current study was to evaluate the adrenal cortex hormones levels in GSDI patients.

Methods

Seventeen GSDI (10 GSDIa and 7 GSDIb) patients and thirty-four age and sex-matched controls were enrolled. Baseline adrenal cortex hormones and biochemical markers of metabolic control serum levels were analyzed. Low dose ACTH stimulation test was also performed.

Results

Baseline cortisol serum levels were higher in GSDIa patients (p = 0.042) and lower in GSDIb patients (p = 0.041) than controls. GSDIa patients also showed higher peak cortisol response (p = 0.000) and Cortisol AUC (p = 0.029). In GSDIa patients, serum cholesterol (p = 0.000), triglycerides (p = 0.000), lactate (p = 0.000) and uric acid (p = 0.008) levels were higher and bicarbonate (p = 0.000) levels were lower than controls. In GSDIb patients, serum cholesterol levels (p = 0.016) were lower and lactate (p = 0.000) and uric acid (p = 0.000) levels were higher than controls. Baseline cortisol serum levels directly correlated with cholesterol (ρ = 0.65, p = 0.005) and triglycerides (ρ = 0.60, p = 0.012) serum levels in GSDI patients.

Conclusions

The present study showed impaired cortisol levels in GSDI patients, with opposite trend between GSDIa and GSDIb. The otherwise preserved adrenal cortex function suggests that this finding might be secondary to local deregulation rather than hypothalamo-pituitary-adrenal axis dysfunction in GSDI patients. We hypothesize that 11βHSD1 might represent the link between endocrine regulation and metabolic derangement in GSDI, constituting new potential therapeutic target in GSDI patients.

Background

Glycogen storage disease type I (GSDI) is an inborn disorder of carbohydrate metabolism caused by the deficiency of microsomal glucose-6-phosphatase (G6Pase) system. It is characterized by accumulation of glycogen and fat in the liver and kidneys. Two major subtypes of GSDI have been identified: GSDIa, which is caused by mutations in the gene encoding the G6Pase alpha (G6Paseα), and GSDIb, caused by mutations in the gene encoding the glucose 6-phosphate (G6P) translocase (G6PT), which transports G6P from cytoplasm to microsomes. G6Paseα is expressed in the liver, kidney and intestine, whereas G6PT is ubiquitous. The clinical and biochemical phenotype of GSDI includes fasting hypoglycaemia, hepatomegaly, lactic acidosis, hypertriglyceridemia, hypercholesterolemia and hyperuricemia; GSDIb is also associated with neutropenia and neutrophil dysfunction, resulting in recurrent infections and predisposition to inflammatory bowel disease (IBD) [1].

G6P availability has been shown to modulate 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) activity. In GSDIa, the G6P excess in the endoplasmic reticulum (ER) (due to G6Paseα deficiency) has been associated to increased 11βHSD1 activity, while in GSDIb the lack of G6P in ER (due to G6PT deficiency) has been associated to decreased 11βHSD1 activity [2].

11βHSD1 is an ER-bound enzyme catalyzing the conversion of inactive cortisone in active cortisol. It is typically expressed in glucocorticoid receptor-rich tissues, such as the liver, adipose tissue, lung and brain [3]. 11βHSD1 requires NADPH as a cofactor generated by the hexose-6-phosphate dehydrogenase (H6PDH)-mediated conversion of G6P to 6-phosphogluconactone (6PGL) [4]. The accumulation of G6P in ER fuels the G6PT-H6PDH-11βHSD1 system, leading to increased pre-receptorial activation of glucocorticoids [5]. Therefore, the G6PT-H6PDH-11βHSD1 system is crucial in the coupling between glucose metabolism and glucocorticoid response (see Fig. 1). Interestingly, in H6PDH knock-out mice a decreased negative feedback on the hypothalamo-pituitary-adrenal (HPA) axis has been observed [6].

Fig. 1
figure1

Proposed pathomechanism linking endocrine regulation and metabolic imbalance in GSDI. In GSDIa G6P accumulates in both cytosol and ER within the hepatocytes. Increased G6P availability in the ER upregulates 11βHSD1 activity resulting in increased cortisol regeneration. Increased G6P in the cytosol enhances glycolysis and lipid load to mitochondria resulting in mitochondrial stress and increased cortisol synthesis (secondary to increased substrate availability). Together, these secondary metabolic disturbances lead to increased risk of insulin-resistance and metabolic syndrome. In GSDIb G6PT defect results in disrupted ER cycling in immune cells (e.g. neutrophils, lymphocytes) and subsequently decreased cortisol regeneration with the ER and potentially reduced substrates to mitochondria for cortisol synthesis. Reduced cortisol availability might contribute to chronic inflammation and higher risk for autoimmune disorders. G6P: glucose 6-phosphate, 6PG:6-phosphogluconactone, 11βHSD1:11β-hydroxysteroid dehydrogenase type 1, H6PDH: hexose-6-phosphate dehydrogenase, FAO: fatty acid oxidation

Although an inverse correlation between serum cortisol concentrations and weight SDS has been demonstrated [7, 8], adrenal cortex assessment has never been performed in GSDI patients.

The aim of the current study was to evaluate adrenal cortex function in GSDI patients unveiling possible differences between GSDIa and GSDIb patients.

Methods

Subjects

The study protocol was in accordance with the Italian regulations on privacy protection and with the Helsinki Doctrine for Human Experimentation. All studies were performed after informed consent was obtained from adult subjects or the infants’ parents. Patients were recruited over a 12 months period. Seventeen GSDI patients (6 males and 11 females) were enrolled. Ten GSDIa patients (4 males and 6 females, mean age 12.11 ± 1.52, range 6–20 years) were compared to 20 age and sex matched controls. Seven GSDIb patients (2 males and 5 females, median age 14.90 ± 2.25, range 8–23 years) were compared to 14 age and sex matched controls. The diagnosis of GSDIa and GSDIb was based on mutation analysis of the G6PC and SLC37A4 gene, respectively. All patients were on dietary treatment. Each patient received uncooked cornstarch (UCCS), nocturnal gastric drip feeding (CNGF) or a combination of the two. Dietary regimens varied among different patients according to their families’ requests and attitudes.

Thirty-four subjects with normal random blood glucose and no history of hypoglycemia were included as healthy control participants. Each GSDIa or GSDIb patient was compared to two age and sex-matched controls.

Clinical and biochemical parameters

The following clinical parameters were recorded: height, weight, body mass index (BMI), systolic and diastolic blood pressure (BP). Blood samples were obtained at 8 a.m. Fasting time ranged between 4 and 9 h. This was calculated according to patients’ usual fasting tolerance. 16/17 patients showed fasting tolerance between 4 and 6 h. One adult patient showed fasting tolerance of 9 h. To overcome the bias due to patients’ short fasting time the control subjects were asked to have blood and urine sampling after the same fasting time of his/her age and sex matched patient. Serum glucose, cholesterol, triglycerides (TG), lactate, uric acid and bicarbonate were assessed as markers of metabolic control. In order to control for possible interaction of cholesterol with triglycerides, Corrected Cholesterol (CChol) was also calculated as following: Cholesterol – (TG/5) [9].

Hormonal studies

Fasting blood samples were obtained at 8 a.m. HPA axis function was assessed by evaluating adrenocorticotropic hormone (ACTH), cortisol, androstenedione, 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone sulphate (DHEAS), renin, aldosterone serum levels as well as and 24-h Urinary Free Cortisol (UFC) levels using routine assays with commercially available kits. Cortisol, DEHAS, androstenedione, 17OHP were evaluated at baseline and after a low dose ACTH stimulation test using 1 μg Synacthen® (synthetic ACTH analogue). The timing of the ACTH stimulation test was arranged in order not to exceed patients fasting tolerance.

Statistical analysis

“Peak cortisol” was defined as the maximum observed cortisol value measured following ACTH administration regardless of when it occurred. Area under the curve (AUC) was calculated by trapezoid formula. All data in the text or shown in the figures are expressed as mean ± SE. Statistical analysis was performed using Statistical Package for Social Science (SPSS 10 for Windows Update; SPSS Inc., Chicago, Illinois, USA). The comparisons between numerical variables were performed by Student’s t-test corrected for Fisher’s exact test. The normality of the distribution was checked by the Shapiro–Wilk test. One-way ANCOVA with Bonferroni-adjusted post hoc tests analysis was performed to control cortisol concentrations for covariates (cholesterol, triglycerides and CChol). Correlation study was performed by Spearman’s rank correlation. Cholesterol, TG and CChol were further assessed in multivariable linear regression analysis. The predictive capability of the multivariable regression model was checked by the F-test. Statistical significance was set at p < 0.05.

Results

Clinical and biochemical parameters (Table 1 and Additional file 1)

GSDIa patients showed increased cholesterol (p = 0.000), TG (p = 0.000), lactate (p = 0.000) and uric acid (p = 0.008) serum levels and reduced bicarbonate serum levels (p = 0.000) compared to controls. GSDIb patients showed reduced cholesterol (p = 0.016), CChol (p = 0.010) and bicarbonate (p = 0.002) serum levels and increased lactate (p = 0.000) and uric acid (p = 0.000) serum levels (p = 0.002) compared to controls. GSDIb patients showed lower height (p = 0.040) and height centile (p = 0.002) and weight centile (p = 0.030) than controls. Glucose concentrations ranged 4.4–7.8 mmol/L in GSDIa patients and 4.0–8.1 mmol/L in GSDIb patients (Additional file 1A). No significant difference in the remaining parameters was observed between GSDIa and GSDIb patients and controls.

Table 1 Clinical and biochemical markers of metabolic control in GSDI patients and control subjects

Hormonal studies

Baseline serum hormone levels and UFC are shown in Table 2 and Additional file 1. Serum cortisol levels were higher in GSDIa patients (p = 0.042, Fig. 2a) and lower in GSDIb patients (p = 0.041, Fig. 2b) than controls. GSDIa patients showed higher 60 min (p = 0.019, Fig. 2a) and 90 min (p = 0.000, Fig. 2a) cortisol levels after ACTH stimulation and higher peak cortisol response (p = 0.000, Fig. 2c) as well as cortisol area under the curve (AUC) (21,536 ± 884 vs 18,716 ± 764, p = 0.029) than controls. No significant difference in the remaining serum hormone levels, AUC and UFC were observed between GSDIa or GSDIb patients and controls. After controlling for covariates, no significant difference in 30 min and 60 min cortisol levels was observed between patients and controls (GSDIa: p = 0.645, GSDIb: p = 0.850); 90 min cortisol levels were significantly higher in GSDIa patients than controls (p = 0.007).

Table 2 Baseline hormone serum levels in GSDI patients and control subjects
Fig. 2
figure2

a Baseline and ACTH-stimulated cortisol levels in GSDIa patients () and controls (■). b Baseline and ACTH-stimulated cortisol levels in GSDIb patients (▲) and controls (). c Peak ACTH-stimulated cortisol levels in GSDIa and GSDIb patients and controls. * p < 0.05, *** p < 0.001. T30: 30 min after ACTH analogue administration, T60: 60 min after ACTH analogue administration, T90: 90 min after ACTH analogue administration

Correlation study

Baseline cortisol serum levels directly correlated with cholesterol (ρ = 0.65, p = 0.005) and TG (ρ = 0.60, p = 0.012) serum levels in GSDI patients (Fig. 3). A direct correlation between cholesterol and triglycerides was found (ρ = 0.77, p = 0.000). Multivariate analysis (F-test, p = 0.031) showed no significance for cholesterol (β = 0.50, p = 0.149), TG (β = 0.32, p = 0.640) and CChol (β = 0.39, p = 0.150).

Fig. 3
figure3

Correlation between baseline cortisol levels and cholesterol (, ρ = 0.65, p < 0.01) and triglycerides (▲, ρ = 0.60, p < 0.05) levels in GSDI patients. * p < 0.05, **p < 0.01, *** p < 0.001

Discussion

An endocrine involvement has been extensively reported in GSDI [7, 8, 10,11,12]. Interestingly, most of the typical findings in GSDI (short stature, delayed puberty, hypothyroidsm, polycystic ovaries, osteoporosis) are similar to those of Cushing’s syndrome, suggesting a possible impairment in glucocorticoid metabolism in GSDI. To the best of our knowledge, systematic adrenal cortex assessment has never been performed in GSDI. In order to gather information on the function of the adrenal cortex, data concerning adrenal cortex hormones (both at baseline and after ACTH challenge) were collected in GSDIa and GSDIb patients. GSDIa patients showed higher baseline and ACTH-stimulated cortisol levels with GSDIb patients showing decreased baseline cortisol levels. The opposite cortisol profile between GSDIa and GSDIb points to a possible role of the metabolic defect per se in the endocrine imbalance. The results of the current study suggest that imbalanced cortisol levels in GSDI might be due to local deregulation rather than HPA axis activation. Cortisol role as a counter-regulatory hormone in glucose homeostasis should also be taken into account. No patient showed low blood glucose concentrations in the present study. Two GSDIb patients showed glucose concentration slightly above 4.0 mmol/L (Additional file 1A). Notably, GSDIb patients showed lower cortisol levels than controls in the present study. Glucose concentrations were not routinely measured at the end of the ACTH stimulation test based on the following considerations: 1) the timing of the ACTH stimulation test was arranged in order not to exceed patients fasting tolerance and 2) the administration of ACTH stimulates the release of cortisol from the adrenal cortex and no glucose lowering effect was expected. Indeed, data on glucose concentration at the end of the ACTH stimulation test available in four patients showed a relatively stable trend (Additional file 2). No correlation was found between glucose concentrations and cortisol levels at the end of the ACTH stimulation test in those patients (p = 0.800) suggesting that glucose concentration likely did not affect cortisol levels in the present study.

The regulation of adrenal cortex function is under control of HPA axis [13]. Nonetheless, 11βHSD1 has recently emerged as a local regulator mechanism [4]. An important biological function of liver 11βHSD1 (different from tissue-specific pre-receptoral metabolism) is a systemic shift of the cortisol:cortisone equilibrium towards active cortisol promoting the crucial metabolic and circulatory effects of cortisol [14]. Glucocorticoid excess is known to cause obesity and diabetes [15]. The considerable similarities between Cushing’s syndrome and metabolic syndrome (MS) have driven investigations on possible pathogenic role of glucocorticoids. Among all possible determinants (e.g. HPA axis, intracellular receptors density, prereceptorial metabolism), 11βHSD1 has emerged as the most plausible mechanism [16, 17]. The hepatic 11βHSD1 plays a key role in the development of MS [18, 19]. Conversely, 11βHSD1 knock-out mice are resistant to the development of MS [20, 21]. 11βHSD1 is nowadays a promising therapeutic target and a number of 11βHSD1 inhibitors are in development as potentially effective in the treatment of MS and diabetes [22, 23]. Interestingly, the G6P excess in the liver ER has been associated to increased 11βHSD1 activity in GSDIa [2]. The increased 11βHSD1 activity might play a role in the increased prevalence of insulin-resistance (IR) and MS reported in GSDIa patients [24].

Biochemically, glucocorticoid synthesis involves the shuttling of precursors between mitochondria and the ER, with cholesterol entering the mitochondria as first step [25]. Most steroidogenic cholesterol is derived from circulating lipoproteins, but it may be also produced de novo within the ER [26]. Interestingly, increased G6P levels in ER [27] and mitochondrial dysfunction [28] have been suggested to be the cause and the effect of hypercholesterolemia in GSDIa, respectively. Notably, G6Pase activity has been shown in zona reticularis and zona fasciculata that are actively involved in cortisol synthesis [29]. The increase of cortisol synthesis might in principle represent a mechanism to divert cholesterol excess within the mitochondria in GSDIa. Correlation data support this hypothesis. Despite not statistically significant, these data suggest that the combination of cholesterol and TG would best explain the cortisol levels in GSDI patients. The lack of significance at multivariate analysis might be due to small sample size and high correlation between the two independent variables.

GSDIb is typically associated with neutropenia, neutrophil dysfunction and predisposition to inflammatory bowel disease (IBD) [1]. Increased prevalence of autoimmune disorders has been reported [10, 30]. In GSDIb the lack of G6P in ER has been associated to decreased 11βHSD1 activity [2]. 11βHSD1 is widely expressed in immune cells [31]. 11βHSD1 expression has been associated with a switch in energy metabolism suggesting that 11βHSD1 deficiency might worsen tissue damage in the case of chronic inflammation [32, 33]. Indeed, 11βHSD1-deficient mice showed delayed resolution of the inflammation [34]. Glucocorticoids are also essential regulators of T-cells development [35]. The engagement of glucocorticoid receptor has been recently shown as crucial determinant conferring protection from autoimmunity during pregnancy in mice [36]. Regulatory T cells (Tregs) are particularly responsive to glucocorticoid signals [37] and impairment of Tregs has been described in a number of autoimmune diseases [38]. Interestingly, disrupted Tregs function has been reported in GSDIb patients [39]. We hypothesize that reduced 11βHSD1 activity in GSDIb patients’ immune cells could impair energy metabolism and cell function and play a role in delayed resolution of inflammation and development of autoimmune disorders.

Conclusions

Opposite cortisol levels were found in GSDIa (increased) and GSDIb (decreased) patients. The findings of the current study suggest that imbalanced cortisol concentrations might be due to local deregulation rather than HPA axis activation in GSDI. 11βHSD1 activity modulation by G6P availability could explain the opposite cortisol profile in GSDIa and GSDIb patients. We speculate that glucocorticoid deregulation might play a role in the development of the emerging complications in GSDIa (namely IR and MS) and GSDIb (delayed inflammation, autoimmune disorders) patients (Fig. 1). The results of the current study suggest that adrenal evaluation should be considered to define the pathophysiology of complications in GSDI and possibly provide additional disease biomarker. It is noteworthy that the dysregulation of cortisol secretion is opposite in GSDIa and GSDIb. Future studies dissecting the connection between G6Pase system and 11βHSD1 are warranted in order to identify new potential therapeutic targets in GSDI patients.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ER:

Endoplasmic reticulum

G6P:

Glucose 6-phosphate

G6Pase:

Glucose-6-phosphatase

11βHSD1:

11β-hydroxysteroid dehydrogenase type 1

HPA axis:

Hypothalamo-Pituitary-Adrenal Axis

References

  1. 1.

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

  2. 2.

    Walker EA, Ahmed A, Lavery GG, Tomlinson JW, Kim SY, Cooper MS, et al. 11beta-Hydroxysteroid Dehydrogenase Type 1 Regulation by Intracellular Glucose 6-Phosphate Provides Evidence for a Novel Link between Glucose Metabolism and Hypothalamo-Pituitary-Adrenal Axis Function. J Biol Chem. 2007;282(37):27030–6.

  3. 3.

    White PC, Rogoff D, McMillan DR. Physiological roles of 11 beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase. Curr Opin Pediatr. 2008;20(4):453–7.

  4. 4.

    Seckl JR, Walker BR. Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action. Endocrinology. 2001;142(4):1371–6.

  5. 5.

    Bánhegyi G, Csala M, Benedetti A. Hexose-6-phosphate dehydrogenase: linking endocrinology and metabolism in the endoplasmic reticulum. J Mol Endocrinol. 2009;42(4):283–9.

  6. 6.

    Rogoff D, Ryder JW, Black K, Yan Z, Burgess SC, McMillan DR, et al. Abnormalities of glucose homeostasis and the hypothalamic-pituitary-adrenal axis in mice lacking hexose-6-phosphate dehydrogenase. Endocrinology. 2007;148(10):5072–80.

  7. 7.

    Mundy HR, Hindmarsh PC, Matthews DR, Leonard JV, Lee PJ. The regulation of growth in glycogen storage disease type 1. Clin Endocrinol. 2003;58:332–9.

  8. 8.

    Dunger DB, Holder AT, Leonard JV, Okae J, Preece MA. Growth and Endocrine Changes in the Hepatic Glycogenoses. Eur J Pediatr. 1982;138:226–30.

  9. 9.

    Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502.

  10. 10.

    Melis D, Pivonello R, Parenti G, Della Casa R, Salerno M, Lombardi G, et al. Increased prevalence of thyroid autoimmunity and hypothyroidism in patients with glycogen storage disease type I. J Pediatr. 2007;150(3):300–5 305.e1.

  11. 11.

    Lee PJ, Patel A, Hindmarsh PC, Mowat AP, Leonard JV. The prevalence of polycystic ovaries in the hepatic glycogen storage diseases: its association with hyperinsulinism. Clin Endocrinol (Oxf). 1995;42(6):601–6.

  12. 12.

    Melis D, Della Casa R, Balivo F, Minopoli G, Rossi A, Salerno M, et al. Involvement of endocrine system in a patient affected by glycogen storage disease 1b: speculation on the role of autoimmunity. Ital J Pediatr. 2014;40(1):30.

  13. 13.

    Arnett MG, Muglia LM, Laryea G, Muglia LJ. Genetic Approaches to Hypothalamic-Pituitary-Adrenal Axis Regulation. Neuropsychopharmacology. 2016;41(1):245–60.

  14. 14.

    Vogesera M, Zachovalb R, Felbingerc TW, Jacoba K. Increased Ratio of Serum Cortisol to Cortisone in Acute-Phase Response. Horm Res. 2002;58:172–5.

  15. 15.

    Pivonello R, De Leo M, Vitale P, Cozzolino A, Simeoli C, De Martino MC, et al. Pathophysiology of diabetes mellitus in Cushing’s syndrome. Neuroendocrinology. 2010;92(Suppl 1):77–81.

  16. 16.

    Wake DJ, Walker BR. 11 beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome. Mol Cell Endocrinol. 2004;215(1–2):45–54.

  17. 17.

    Wamil M, Seckl JR. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 as a promising therapeutic target. Drug Discov Today. 2007;12(13–14):504–20.

  18. 18.

    Czegle I, Csala M, Mandl J, Benedetti A, Karádi I, Bánhegyi G. G6PT-H6PDH-11βHSD1 triad in the liver and its implication in the pathomechanism of the metabolic syndrome. World J Hepatol. 2012;4(4):129–38.

  19. 19.

    Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001;294(5549):2166–70.

  20. 20.

    Kotelevtsev Y, Holmes MC, Burchell A, Houston PM, Schmoll D, Jamieson P, et al. 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proc Natl Acad Sci U S A. 1997;94(26):14924–9.

  21. 21.

    Du H, Liu L, Wang Y, Nakagawa Y, Lyzlov A, Lutfy K, et al. Specific reduction of G6PT may contribute to downregulation of hepatic 11β-HSD1 in diabetic mice. J Mol Endocrinol. 2013;50(2):167–78.

  22. 22.

    Boyle CD, Kowalski TJ. 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: a review of recent patents. Expert Opin Ther Pat. 2009;19(6):801–25.

  23. 23.

    Anagnostis P, Katsiki N, Adamidou F, Athyros VG, Karagiannis A, Kita M, et al. 11beta-Hydroxysteroid dehydrogenase type 1 inhibitors: novel agents for the treatment of metabolic syndrome and obesity-related disorders? Metabolism. 2013;62(1):21–33.

  24. 24.

    Melis D, Rossi A, Pivonello R, Salerno M, Balivo F, Spadarella S, et al. 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. 2015;10:91.

  25. 25.

    Miller WL. Steroid hormone synthesis in mitochondria. Mol Cell Endocrinol. 2013;379:62–73.

  26. 26.

    Porter FD, Herman GE. Malformation syndromes caused by disorders of cholesterol synthesis. J. Lipid Res. 2011;52:6–34.

  27. 27.

    Bandsma RH, Smit GP, Kuipers F. Disturbed lipid metabolism in glycogen storage disease type 1. Eur J Pediatr. 2002;161(Suppl 1):S65–9.

  28. 28.

    Rossi A, Ruoppolo M, Formisano P, Villani G, Albano L, Gallo G, et al. Insulin-resistance in glycogen storage disease type Ia: linking carbohydrates and mitochondria? J Inherit Metab Dis. 2018;41(6):985–95.

  29. 29.

    Hume R, Voice M, Pazouki S, Giunti R, Benedetti A, Burchell A. The human adrenal microsomal glucose-6-phosphatase system. J Clin Endocrinol Metab. 1995;80(6):1960–6.

  30. 30.

    Melis D, Balivo F, Della Casa R, Romano A, Taurisano R, Capaldo B, et al. Myasthenia gravis in a patient affected by glycogen storage disease type Ib: a further manifestation of an increased risk for autoimmune disorders? J Inherit Metab Dis. 2008;31(Suppl 2):S227–31.

  31. 31.

    Coutinho AE, Kipari TM, Zhang Z, Esteves CL, Lucas CD, Gilmour JS, et al. 11β-Hydroxysteroid Dehydrogenase Type 1 Is Expressed in Neutrophils and Restrains an Inflammatory Response in Male Mice. Endocrinology. 2016;157(7):2928–36. 4.

  32. 32.

    Coutinho AE, Gray M, Brownstein DG, Salter DM, Sawatzky DA, Clay S, et al. 11β-Hydroxysteroid dehydrogenase type 1, but not type 2, deficiency worsens acute inflammation and experimental arthritis in mice. Endocrinology. 2012;153(1):234–40.

  33. 33.

    Chapman KE, Coutinho AE, Zhang Z, Kipari T, Savill JS, Seckl JR. Changing glucocorticoid action: 11β-hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation. J Steroid Biochem Mol Biol. 2013;137:82–92.

  34. 34.

    Chapman KE, Coutinho AE, Gray M, Gilmour JS, Savill JS, Seckl JR. The role and regulation of 11beta-hydroxysteroid dehydrogenase type 1 in the inflammatory response. Mol Cell Endocrinol. 2009;301(1–2):123–31.

  35. 35.

    Ashwell JD, King LB, Vacchio MS. Cross-talk between the T cell antigen receptor and the glucocorticoid receptor regulates thymocyte development. Stem Cells. 1996;14(5):490–500.

  36. 36.

    Nie H, Zheng Y, Li R, Guo TB, He D, Fang L, et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat Med. 2013;19(3):322–8.

  37. 37.

    Ugor E, Prenek L, Pap R, Berta G, Ernszt D, Najbauer J, et al. Glucocorticoid hormone treatment enhances the cytokine production of regulatory T cells by upregulation of Foxp3 expression. Immunobiology. 2018;223(4–5):422–31.

  38. 38.

    Engler JB, Kursawe N, Solano ME, Patas K, Wehrmann S, Heckmann N, et al. Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy. Proc Natl Acad Sci U S A. 2017;114(2):E181–90.

  39. 39.

    Melis D, Carbone F, Minopoli G, La Rocca C, Perna F, De Rosa V, et al. Cutting Edge: Increased Autoimmunity Risk in Glycogen Storage Disease Type 1b Is Associated with a Reduced Engagement of Glycolysis in T Cells and an Impaired Regulatory T Cell Function. J Immunol. 2017;198(10):3803–8.

Download references

Acknowledgements

Not applicable.

Funding

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

Author information

Affiliations

Authors

Contributions

AR wrote the first draft of the manuscript and neither an honorarium or grant, or other forms of payment was given to anyone to produce the manuscript. All authors made substantial contributions to the conception or design of the work or the acquisition, analysis or interpretation of data. AR, CS, MS, RF, RDC, PS were involved in the clinical investigation and follow-up of the patients. AC, GP, RP and DM critically reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Daniela Melis.

Ethics declarations

Ethics approval and consent to participate

The study was performed in accordance with the Declaration of Helsinki and approved by The the Medical Ethics Committee of the University of Naples “Federico II” (n. 151/05). All studies were performed after informed consent was obtained from adult subjects or the infants’ parents.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rossi, A., Simeoli, C., Salerno, M. et al. Imbalanced cortisol concentrations in glycogen storage disease type I: evidence for a possible link between endocrine regulation and metabolic derangement. Orphanet J Rare Dis 15, 99 (2020). https://doi.org/10.1186/s13023-020-01377-w

Download citation

Keywords

  • Cortisol
  • 11βHSD1
  • Cholesterol
  • Insulin-resistance
  • Autoimmune