Lessons from new mouse models of glycogen storage disease type 1a in relation to the time course and organ specificity of the disease

Abstract

Patients with glycogen storage diseases type 1 (GSD1) suffer from life-threatening hypoglycaemia, when left untreated. Despite an intensive dietary treatment, patients develop severe complications, such as liver tumors and renal failure, with aging. Until now, the animal models available for studying the GSD1 did not survive after weaning. To gain further insights into the molecular mechanisms of the disease and to evaluate potential treatment strategies, we have recently developed novel mouse models in which the catalytic subunit of glucose-6 phosphatase (G6pc) is deleted in each glucose-producing organ specifically. For that, B6.G6pc(ex3lox/ex3lox) mice were crossed with transgenic mice expressing a recombinase under the control of the serum albumin, the kidney androgen protein or the villin promoter, in order to obtain liver, kidney or intestine G6pc(-/-) mice, respectively. As opposed to total G6pc knockout mice, tissue-specific G6pc deficiency allows mice to maintain their blood glucose by inducing glucose production in the other gluconeogenic organs. Even though it is considered that glucose is produced mainly by the liver, liver G6pc(-/-) mice are perfectly viable and exhibit the same hepatic pathological features as GSD1 patients, including the late development of hepatocellular adenomas and carcinomas. Interestingly, renal G6pc(-/-) mice developed renal symptoms similar to the early human GSD1 nephropathy. This includes glycogen overload that leads to nephromegaly and morphological and functional alterations in the kidneys. Thus, our data suggest that renal G6Pase deficiency per se is sufficient to induce the renal pathology of GSD1. Therefore, these new mouse models should allow us to improve the strategies of treatment on both nutritional and pharmacological points of view.

High Incidence of Serologic Markers of Inflammatory Bowel Disease in Asymptomatic Patients with Glycogen Storage Disease Type Ia

“…This supports that the intestinal abnormality alone is not sufficient to cause the disease. The role of the intestinal defect will likely be elucidated by the studies in the intestinal glucose-6-phosphatase knockout mouse model (Rajas et al 2014).…”

Recent development and gene therapy for glycogen storage disease type Ia

“…In addition, kidney-specific G6pc knockout and intestine-specific knockout mice are available to delineate molecular mechanisms underlying other long-term complications of GSD-Ia. 29,30 …”

Lipids in hepatic glycogen storage diseases: pathophysiology, monitoring of dietary management and future directions

“…The development of hepatic tumors is enhanced by a high fat enriched diet in liver-specific GSD I deficient mice (Rajas et al 2014), but it is not mentioned whether this depends on the type of fat, i.e. MCT versus long-chain triglycerides.…”

“…There are no experimental data to substantiate whether longterm dietary MCT may cause liver adenoma and hepatocellular carcinoma. The development of hepatic tumors is enhanced by a high fat enriched diet in liver-specific GSD I deficient mice (Rajas et al 2014), but it is not mentioned whether this depends on the type of fat, i.e. MCT versus long-chain triglycerides.…”