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Unexplained hypoglycemia during continuous nocturnal gastric drip-feeding in a patient with glycogen storage disease type ia: is it a dumping-like syndrome?

ABSTRACT: A 5 years old boy affected with Glycogen Storage Disease type Ia (GSD-Ia) with previous optimal metabolic control developed severe erratic hypoglycemic episodes during continuous nocturnal gastric drip-feeding (CNGDF) administered by nasogastric tube. The episodes of hypoglycemia were not related to pump failure or human errors or wrong position of the tube in the gastrointestinal tract. Hyperinsulinism was also considered in this patient but it was excluded mainly because hypoglycemia was only nocturnal. Moreover, hypoglycemic episodes disappeared when CNGDF was stopped and he was fed with normal meals. The fact that hypoglycemia resolved after stopping CNGDF when nocturnal meals were introduced led us to hypothesize that CNGDF rich with simple carbohydrates might have been the cause of a sort of dumping-like syndrome. Dumping syndrome (DS) develops when a large amount of carbohydrate reaches the small intestine due to rapid gastric emptying (Tack et al. 2009; Hejazi et al. 2010). We suppose that CNGDF induced a disturbance of gastric motility with a gastric accumulation of fluids at a certain time of the night followed by a rapid voiding of the stomach leading to DS.

SUBMITTER: Brambilla A

PROVIDER: S-EPMC3565651 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Unexplained hypoglycemia during continuous nocturnal gastric drip-feeding in a patient with glycogen storage disease type ia: is it a dumping-like syndrome?

Brambilla A A Pozzoli A A Furlan F F Parini R R

JIMD reports 20120713

A 5 years old boy affected with Glycogen Storage Disease type Ia (GSD-Ia) with previous optimal metabolic control developed severe erratic hypoglycemic episodes during continuous nocturnal gastric drip-feeding (CNGDF) administered by nasogastric tube. The episodes of hypoglycemia were not related to pump failure or human errors or wrong position of the tube in the gastrointestinal tract. Hyperinsulinism was also considered in this patient but it was excluded mainly because hypoglycemia was only ...[more]

PMID: 23430516

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Project description:Background: Glycogen storage disease type Ia (GSD Ia), also known as von Gierke disease, is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, the enzyme that catalyzes the final step of gluconeogenesis and glycogenolysis. The accumulation of glucose-6-phosphate leads to increased glycogen and triglyceride levels in the liver. Patients with GSD Ia can develop steatohepatitis, cirrhosis, and increased risk for hepatocellular adenomas and carcinomas. We previously showed that animal models of GSD Ia had defective autophagy and dysfunctional mitochondria. In this study, we examined the effect of VK2809, a liver-specific thyroid hormone receptor ? agonist, on hepatic steatosis, autophagy, and mitochondrial biogenesis in a mouse model of GSD Ia. Methods: G6pc-/--deficient (GSD Ia) mice were treated with VK2809 or vehicle control by daily intraperitoneal injection for four days. The hepatic triglyceride and glycogen were determined by biochemical assays. Autophagy and mitochondrial biogenesis were measured by Western blotting for key autophagy and mitochondrial markers. Results: VK2809 treatment decreased hepatic mass and triglyceride content in GSD Ia mice. VK2809 stimulated hepatic autophagic flux as evidenced by increased microtubule-associated protein light chain 3-II (LC3B-II), decreased p62 protein levels, activation of AMP-activated protein kinase (AMPK), inhibition of the mammalian target of rapamycin (mTOR) signaling, enhancement of protein levels of ATG5-ATG12, and increased lysosomal protein expression. VK2809 also increased the expression of carnitine palmitoyltransferase 1a (CPT1?) and fibroblast growth factor 21 (FGF21), as well as mitochondrial biogenesis to promote mitochondrial ?-oxidation. Conclusions: In summary, VK2809 treatment decreased hepatic triglyceride levels in GSD Ia mice through its simultaneous restoration of autophagy, mitochondrial biogenesis, and ?-oxidation of fatty acids. Liver-specific thyromimetics represent a potential therapy for hepatosteatosis in GSD Ia as well as nonalcoholic fatty liver disease.

Project description:A deficiency in glucose-6-phosphatase-α (G6Pase-α) in glycogen storage disease type Ia (GSD-Ia) leads to impaired glucose homeostasis and metabolic manifestations including hepatomegaly caused by increased glycogen and neutral fat accumulation. A recent report showed that G6Pase-α deficiency causes impairment in autophagy, a recycling process important for cellular metabolism. However, the molecular mechanism underlying defective autophagy is unclear. Here we show that in mice, liver-specific knockout of G6Pase-α (L-G6pc-/-) leads to downregulation of sirtuin 1 (SIRT1) signaling that activates autophagy via deacetylation of autophagy-related (ATG) proteins and forkhead box O (FoxO) family of transcriptional factors which transactivate autophagy genes. Consistently, defective autophagy in G6Pase-α-deficient liver is characterized by attenuated expressions of autophagy components, increased acetylation of ATG5 and ATG7, decreased conjugation of ATG5 and ATG12, and reduced autophagic flux. We further show that hepatic G6Pase-α deficiency results in activation of carbohydrate response element-binding protein, a lipogenic transcription factor, increased expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), a lipid regulator, and suppressed expression of PPAR-α, a master regulator of fatty acid β-oxidation, all contributing to hepatic steatosis and downregulation of SIRT1 expression. An adenovirus vector-mediated increase in hepatic SIRT1 expression corrects autophagy defects but does not rectify metabolic abnormalities associated with G6Pase-α deficiency. Importantly, a recombinant adeno-associated virus (rAAV) vector-mediated restoration of hepatic G6Pase-α expression corrects metabolic abnormalities, restores SIRT1-FoxO signaling, and normalizes defective autophagy. Taken together, these data show that hepatic G6Pase-α deficiency-mediated down-regulation of SIRT1 signaling underlies defective hepatic autophagy in GSD-Ia.

Dataset Information

Unexplained hypoglycemia during continuous nocturnal gastric drip-feeding in a patient with glycogen storage disease type ia: is it a dumping-like syndrome?

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Unexplained hypoglycemia during continuous nocturnal gastric drip-feeding in a patient with glycogen storage disease type ia: is it a dumping-like syndrome?

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