Glucose clearance and uptake is increased in the SOD1G93A mouse model of amyotrophic lateral sclerosis through an insulin-independent mechanism

Metabolic disturbances are associated with the progression of the neurodegenerative disorder, amyotrophic lateral sclerosis (ALS). However, the molecular events that drive energy imbalances in ALS are not completely understood. In this study, we aimed to elucidate deficits in energy homeostasis in the SOD1(G93A) mouse model of ALS. SOD1(G93A) mice and their wild-type littermates underwent indirect calorimetry and intraperitoneal glucose/insulin tolerance tests at both the onset and mid-symptomatic stages of the disease. Glucose uptake and the plasma glucoregulatory hormone profiles were analyzed. Pancreatic islet cell mass and function were assessed by measuring hormone concentrations and secretion in isolated islets, and pancreatic alpha- and beta-cell immunoreactive areas. Finally, we profiled liver glycogen metabolism by measuring glucagon concentrations and liver metabolic gene expressions. We identified that mid-symptomatic SOD1(G93A) mice have increased oxygen consumption and faster exogenous glucose uptake, despite presenting with normal insulin tolerance. The capacity for pancreatic islets to secrete insulin appears intact, however, islet cell insulin concentrations and beta-cell mass were reduced. Fasting glucose homeostasis was also disturbed, along with increased liver glycogen stores, despite elevated circulating glucagon, suggesting that glucagon signaling is impaired. Metabolic gene expression profiling of livers indicated that glucose cannot be utilized efficiently in SOD1(G93A) mice. Overall, we demonstrate that glucose homeostasis and uptake are altered in SOD1(G93A) mice, which is linked to an increase in insulin-independent glucose uptake, and a loss of beta-cells, insulin production, and glucagon sensitivity. This suggests that the hormonal regulation of glucose concentrations may contribute to the progression of disease in this ALS mouse model.