Elsevier

Diabetes & Metabolism

Volume 39, Issue 5, October 2013, Pages 377-387
Diabetes & Metabolism

Review
Glycogen storage disease type 1 and diabetes: Learning by comparing and contrasting the two disordersApprendre en comparant le diabète et la glycogénose de type 1

https://doi.org/10.1016/j.diabet.2013.03.002Get rights and content

Abstract

Glycogen storage disease type 1 (GSD1) and diabetes may look at first like totally opposite disorders, as diabetes is characterized by uncontrolled hyperglycaemia, whereas GSD1 is characterized by severe fasting hypoglycaemia. Diabetes is due to a failure to suppress endogenous glucose production (EGP) in the postprandial state because of either a lack of insulin or insulin resistance. In contrast, GSD1 is characterized by a lack of EGP. However, both diseases share remarkably similar patterns in terms of pathophysiology such as the long-term progression of renal dysfunction and hepatic steatosis leading to renal failure and the development of hepatic tumours, respectively. Thus, much may be learned from considering the similarities between GSD1 and diabetes, especially in the metabolic pathways underlying nephropathy and fatty liver, and perhaps even more from their differences. In this review, the differences between diabetes and GSD1 are first highlighted, as both are characterized by alterations in EGP. The molecular pathways involved in liver pathologies, including steatosis, hepatomegaly (glycogenic hepatopathy) and the development of liver tumours are also compared. These pathologies are mainly due to the accumulation of lipids and/or glycogen in hepatocytes. Finally, the similar pathways leading to nephropathy in both diabetic and GSD1 patients are described. In conclusion, comparisons of these pathologies should lead to a better understanding of the crucial role of EGP in the control of glucose and energy homoeostasis. Moreover, it may highlight similar therapeutic targets for the two disorders. Thus, this review suggests that the treatment of adult patients with either GSD1 or diabetes could be carried out by the same specialists–diabetologists.

Résumé

La glycogénose de type 1 et le diabète peuvent apparaître comme deux maladies « miroir » puisque le diabète se caractérise par une hyperglycémie non contrôlée, alors que la glycogénose de type 1 se caractérise par des hypoglycémies à jeun sévères. Le diabète est dû notamment à un défaut de suppression de la production endogène de glucose (PEG) à l’état postprandial, lié à l’absence de la production d’insuline ou à une résistance à l’insuline. Au contraire, les glycogénoses de type 1 sont caractérisées par une absence de production de glucose par l’organisme. Cependant, ces deux maladies partagent un profil physiopathologique à long terme très similaire, avec une progression de la dysfonction rénale conduisant à une insuffisance rénale et une stéatose hépatique, conduisant au développement de tumeurs. La comparaison de ces deux pathologies va permettre de mettre en exergue de grandes similitudes entre les glycogénoses de type 1 et le diabète, en particulier au niveau des voies métaboliques qui sous-tendent la néphropathie et la stéatose hépatique. Dans cette revue, nous allons d’abord souligner les différences entre ces deux pathologies, qui sont toutes deux caractérisées par des défauts de la PEG. Ensuite, nous comparerons les voies moléculaires impliquées dans les pathologies hépatiques, notamment la stéatose, l’hépatomégalie (hépatopathie glycogénique) et le développement de tumeurs hépatocellulaires. Ces pathologies sont essentiellement dues à l’accumulation de lipides et/ou de glycogène dans les hépatocytes. Enfin, les voies métaboliques menant à la néphropathie des diabétiques et des patients atteints de glycogénoses de type 1 seront décrites. En conclusion, la comparaison de ces pathologies devrait nous aider à mieux comprendre le rôle crucial de la PEG dans le contrôle du glucose et l’homéostasie énergétique. De plus, cette étude devrait permettre de mettre en évidence des cibles thérapeutiques similaires dans ces deux pathologies. Ainsi, le traitement des patients atteints de diabète ou de glycogénose de type 1 pourrait être utilement effectué à l’âge adulte par les mêmes spécialistes, c’est-à-dire les diabétologues.

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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