Glycogen storage disease type 1 and diabetes: Learning by comparing and contrasting the two disorders

Increased plasma ACs and abnormal UOA profile suggest mitochondrial impairment in GSDIa. Correlation data suggest a possible connection between mitochondrial impairment and IR. We hypothesized that mitochondrial overload might generate by-products potentially affecting the insulin signaling pathway, leading to IR. On the basis of the available data, the possible pathomechanism for IR in GSDIa is proposed.

Section: Discussionmentioning

confidence: 84%

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

Rossi

Ruoppolo

Formisano

et al. 2018

“…Currently there are conflicting experimental data (Ubels et al 2002;Bernier et al 2009) and no convincing epidemiological data substantiating strong associations between metabolic syndrome, type 2 diabetes and GSD. Close clinical monitoring for cardiovascular diseases, chronic kidney disease and diabetes in ageing GSD patients (regardless what subtype) seems to be justified, because these disorders share many metabolic pathways (Rajas et al 2013).…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

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

Derks

Rijn

2015

Hepatic glycogen storage diseases (GSD) underscore the intimate relationship between carbohydrate and lipid metabolism. The hyperlipidemias in hepatic GSD reflect perturbed intracellular metabolism, providing biomarkers in blood to monitor dietary management. In different types of GSD, hyperlipidemias are of a different origin. Hypertriglyceridemia is most prominent in GSD type Ia and associated with long-term outcome morbidity, like pancreatitis and hepatic adenomas. In the ketotic subtypes of GSD, hypertriglyceridemia reflects the age-dependent fasting intolerance, secondary lipolysis and increased mitochondrial fatty acid oxidation. The role of high protein diets is established for ketotic types of GSD, but non-traditional dietary interventions (like medium-chain triglycerides and the ketogenic diet) in hepatic GSD are still controversial and necessitate further studies. Patients with these rare inherited disorders of carbohydrate metabolism meet several criteria of the metabolic syndrome, therefore close monitoring for cardiovascular diseases in ageing GSD patients may be justified.

“…In addition, L.G6pc −/− mice could be used to test drugs targeting the development of hepatic tumors. Interestingly, the molecular mechanisms involved in GSD1a nephropathy are very similar to those of diabetic patients (Mundy and Lee 2002;Rajas et al 2013). Therefore, K.G6pc −/− mice could be a useful tool in future studies of the pharmacological treatment of EMT and/or kidney failure developed by patients with either GSD1 or diabetes.…”

Section: Lessons From the Tissue-specific G6pc Knockout Mouse Modelsmentioning

confidence: 92%

“…The characterization of renal K-G6pc −/− metabolism allowed us to highlight similarities of molecular pathways involved in the development of EMT in both GSD1 and diabetes (Mundy and Lee 2002;Rajas et al 2013). Indeed, the accumulation of lipids or lipid derivatives leads to the activation of renin-angiotensin system and subsequently of the TGFβ1 pathway.…”

Section: Kidney G6pc Knockout Micementioning

confidence: 99%

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

Rajas

Clar

Gautier‐Stein

et al. 2014

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.