ReviewGlycogen storage disease type 1 and diabetes: Learning by comparing and contrasting the two disordersApprendre en comparant le diabète et la glycogénose de type 1
Section snippets
A rare disease compared with an epidemic
Glycogen storage disease type 1 (GSD1), also known as von Gierke disease, is an autosomal-recessive metabolic disorder with an estimated incidence of one in 100,000 live births. The genetic disorder is caused by a deficiency of glucose-6-phosphatase (G6Pase) activity leading to loss of endogenous glucose production (EGP) [1], [2], [3]. G6Pase is an enzyme complex that hydrolyzes glucose-6-phosphate (G6P) into glucose and inorganic phosphate in the terminal step of both gluconeogenesis and
Altered endogenous glucose production
Glucose homoeostasis is notably achieved by coordination of the signalling pathways that regulate glycogen synthesis, glycogenolysis and gluconeogenesis. During nutrient intake, glucose is taken up from the circulation and stored in hepatocytes and muscle as glycogen. In the postabsorptive state, glycogen phosphorylase catalyzes the release of glucose from liver glycogen chains to maintain blood glucose. As this glycogen store is depleted, de novo glucose is synthesized from lactate, amino
Hepatic steatosis
Non-alcoholic fatty liver disease (NAFLD) refers to a wide spectrum of disorders characterized by hepatic fat accumulation. Although often considered benign, it is now recognized that hepatic steatosis can progress to chronic liver inflammation, or steatohepatitis, a severe condition of inflamed fatty liver that can further progress to fibrosis and cirrhosis and, finally, the development of hepatocellular carcinoma (HCC) [33]. Several mechanisms can account for the excess hepatic triglyceride
Liver cancer
In the liver, long-term complications of G6Pase deficiency include focal nodular hyperplasia and, more often, hepatocellular adenoma (HCA) with a risk of malignant transformation [10], [60]. Despite massive hepatic steatosis, neither fibrosis nor cirrhosis has been observed in GSD1 patients. This could be explained by the limited β-oxidation-induced oxidative stress and a strong antioxidative defence [61]. HCA develops predominantly during and after puberty, and more than 70% of GSD1 adult
Hepatomegaly
As already mentioned, the massive accumulation of G6P leads to high glycogen stores and hepatomegaly in GSD1. More commonly, the presence of a protruding abdomen due to marked hepatomegaly at around 3 months of age is the first symptom, although in some cases the liver may already be enlarged at birth. The size of the liver increases gradually and its lower border may extend to well below the umbilicus. However, it should be emphasized that hepatomegaly may be missed on physical examination as
Renal disease
Chronic renal disease was recognized as a major complication of GSD1a in the late 1980s. Almost all GSD1a patients above 20 years of age manifest kidney complications, including proteinuria. Many also have hypertension, renal stones, nephrocalcinosis, altered creatinine clearance and, eventually, renal failure. Unfortunately, intensive dietary therapy in GSD1a patients fails to prevent the long-term complications of renal disease. In fact, renal disease in GSD1a follows a similar clinical
Is G6Pase a therapeutic target for glucose control in type 2 diabetes?
On comparing these two pathological conditions, inhibiting hepatic G6Pase activity in the liver appears to be an attractive approach for treating diabetes. However, there are two major limitations. As GSD1 patients develop hypoglycaemia and fatty liver, it might be expected that moderate inhibition of hepatic G6Pase could lead to marked perturbations in the expression of various genes involved in lipogenesis, but this could exacerbate hepatic steatosis in type 2 diabetes patients and lead to
Disclosure of interest
The authors declare that they have no conflicts of interest concerning this article.
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