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

Rossi, Alessandro; Ruoppolo, Margherita; Formisano, Pietro; Villani, Guido; Albano, Lucia; Gallo, Giovanna; Crisci, Daniela; Moccia, Augusta; Parenti, Giancarlo; Strisciuglio, Pietro; Melis, Daniela

doi:10.1007/s10545-018-0149-4

Cited by 26 publications

(30 citation statements)

References 36 publications

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“…As well-known and showed in Fig. 2, chronic inflammation contributes to the pathogenesis of insulin resistance and compensatory hyperinsulinemia that in turn plays a role in the development of the typical increased amplitude and frequency of GnRH and LH pulse secretion seen in PCOS [129][130][131]. The fact that BPA was associated with a decrease of antral follicle count in infertile women with PCOS suggests that BPA may impair ovarian reserve [132].…”

Section: Observational Studies In Humansmentioning

confidence: 69%

Bisphenol A: an emerging threat to female fertility

Pivonello

Muscogiuri

Nardone

et al. 2020

Reprod Biol Endocrinol

156

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Bisphenol-A (BPA) has been reported to be associated to female infertility. Indeed, BPA has been found to be more frequently detected in infertile women thus leading to hypothesize a possible effect of BPA on natural conception and spontaneous fecundity. In addition, in procedures of medically assisted reproduction BPA exposure has been found to be negatively associated with peak serum estradiol levels during gonadotropin stimulation, number of retrieved oocytes, number of normally fertilized oocytes and implantation. BPA deleterious effects are more critical during perinatal exposure, causing dysregulation of hypothalamic-pituitary-ovarian axis in pups and adults, with a precocious maturation of the axis through a damage of GnRH pulsatility, gonadotropin signaling and sex steroid hormone production. Further, BPA exposure during early lifestage may have a transgenerational effect predisposing the subsequent generations to the risk of developing BPA related disease. Experimental studies suggested that prenatal, perinatal and postnatal exposure to BPA can impair several steps of ovarian development, induce ovarian morphology rearrangement and impair ovarian function, particularly folliculogenesis, as well as can impair uterus morphology and function, in female adult animal and offspring. Finally, studies carried out in animal models have been reported the occurrence of endometriosis-like lesions after BPA exposure. Moreover, BPA exposure has been described to encourage the genesis of PCOS-like abnormalities through the impairment of the secretion of sex hormones affecting ovarian morphology and functions, particularly folliculogenesis. The current manuscript summarizes the evidence regarding the association between BPA exposure and female infertility, reviewing both clinical and preclinical studies.

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Section: Observational Studies In Humansmentioning

confidence: 69%

Bisphenol A: an emerging threat to female fertility

Pivonello

Muscogiuri

Nardone

et al. 2020

Reprod Biol Endocrinol

156

View full text Add to dashboard Cite

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“…For example, elevated plasma levels of C3 and C5 acylcarnitines, the phenomenon linked to the ALDH1L2 loss, could be associated with obesity, metabolic syndrome, insulin resistance, and type 2 diabetes [ 49 , 50 ]. Such an increase was shown to reflect decreased mitochondrial function or mitochondrial impairment [ 51 , 52 ]. Also, plasma concentrations of butyrylcarnitine and methylbutyrylcarnitine were higher in NASH [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, increased plasma acylcarnitines were identified as predictive markers of mitochondrial disfunction in type 2 diabetes [ 55 ] which could be associated with incomplete β-oxidation of fatty acids [ 56 ]. Mechanistically, mitochondrial overload might generate by-products, which would affect the insulin signaling pathway, thus leading to insulin resistance [ 52 ]. In agreement with this hypothesis, mitochondrial β-oxidation is altered in patients with type 2 diabetes [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder

et al. 2020

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Background Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 simultaneously producing NADPH. We have recently reported that the lack of the enzyme due to compound heterozygous mutations was associated with neuro-ichthyotic syndrome in a male patient. Here, we address the role of ALDH1L2 in cellular metabolism and highlight the mechanism by which the enzyme regulates lipid oxidation. Methods We generated Aldh1l2 knockout (KO) mouse model, characterized its phenotype, tissue histology, and levels of reduced folate pools and applied untargeted metabolomics to determine metabolic changes in the liver, pancreas, and plasma caused by the enzyme loss. We have also used NanoString Mouse Inflammation V2 Code Set to analyze inflammatory gene expression and evaluate the role of ALDH1L2 in the regulation of inflammatory pathways. Results Both male and female Aldh1l2 KO mice were viable and did not show an apparent phenotype. However, H&E and Oil Red O staining revealed the accumulation of lipid vesicles localized between the central veins and portal triads in the liver of Aldh1l2-/- male mice indicating abnormal lipid metabolism. The metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Specifically, drastically increased plasma acylcarnitine and acylglycine conjugates were indicative of impaired β-oxidation in the liver. Our metabolomics data further showed that mechanistically, the regulation of lipid metabolism by ALDH1L2 is linked to coenzyme A biosynthesis through the following steps. ALDH1L2 enables sufficient NADPH production in mitochondria to maintain high levels of glutathione, which in turn is required to support high levels of cysteine, the coenzyme A precursor. As the final outcome, the deregulation of lipid metabolism due to ALDH1L2 loss led to decreased ATP levels in mitochondria. Conclusions The ALDH1L2 function is important for CoA-dependent pathways including β-oxidation, TCA cycle, and bile acid biosynthesis. The role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous diseases. On a broader scale, our study links folate metabolism to the regulation of lipid homeostasis and the energy balance in the cell.

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“…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].…”

Section: Discussionmentioning

confidence: 99%

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

Rossi

Simeoli

Salerno

et al. 2020

Orphanet J Rare Dis

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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.

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

Cited by 26 publications

References 36 publications

Bisphenol A: an emerging threat to female fertility

Bisphenol A: an emerging threat to female fertility

Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder

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

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