glycogen and dapagliflozin

Glycogen storage disease XI, also known as Fanconi-Bickel syndrome (FBS), is a rare autosomal recessive disorder caused by mutations in the

Topics: Animals; Fanconi Syndrome; Glucose; Glycogen; Humans; Kidney; Mice; Sodium-Glucose Transporter 2 Inhibitors

Mutations in. We utilized an inducible mouse model of GSD1b, TM-G6PT. In proximal tubule cells, G6PT suppression stimulates the upregulation and activity of hexokinase-I, which increases availability of the reabsorbed glucose for intracellular metabolism. Dapagliflozin prevented glycogen accumulation and improved kidney morphology by promoting a metabolic switch from glycogen synthesis toward lysis and by restoring expression levels of the main proximal tubule functional markers.. We provide proof of concept for the efficacy of dapagliflozin in preserving kidney function in GSD1b mice. Our findings could represent the basis for repurposing this drug to treat patients with GSD1b.

Topics: Animals; Disease Models, Animal; Glucose; Glycogen; Glycogen Storage Disease Type I; Kidney; Kidney Tubules, Proximal; Mice; Sodium-Glucose Transporter 2

Selective sodium glucose cotransporter-2 inhibitor (SGLT2i) treatment promotes urinary glucose excretion, thereby reducing blood glucose as well as body weight. However, only limited body weight reductions are achieved with SGLT2i treatment. Hyperphagia is reportedly one of the causes of this limited weight loss. However, the effects of SGLT2i treatment on systemic energy expenditure have not been fully elucidated. Herein, we investigated the acute effects of dapagliflozin, a SGLT2i, on systemic energy expenditure in mice. Eighteen hours after dapagliflozin treatment oxygen consumption and brown adipose tissue (BAT) expression of ucp1, a thermogenesis-related gene, were significantly decreased as compared to those after vehicle treatment. In addition, dapagliflozin significantly suppressed norepinephrine (NE) turnover in BAT and c-fos expression in the rostral raphe pallidus nucleus (rRPa) which contains the sympathetic premotor neurons responsible for thermogenesis. These findings indicate that the dapagliflozin-mediated acute decrease in energy expenditure involves a reduction in BAT thermogenesis via decreased sympathetic nerve activity from the rRPa. Furthermore, common hepatic branch vagotomy abolished the reductions in ucp1 expression and NE contents in BAT and c-fos expression in the rRPa. In addition, alterations in hepatic carbohydrate metabolism, such as decreases in glycogen contents and upregulation of phosphoenolpyruvate carboxykinase, manifested prior to the suppression of BAT thermogenesis, e.g. 6 hours after dapagliflozin treatment. Collectively, these results suggest that SGLT2i treatment acutely suppresses energy expenditure in BAT via regulation of an inter-organ neural network consisting of the common hepatic vagal branch and sympathetic nerves.

Topics: Adipose Tissue, Brown; Animals; Benzhydryl Compounds; Carbohydrate Metabolism; Energy Metabolism; Gene Expression Regulation; Glucosides; Glycogen; Ion Channels; Liver; Male; Mice; Midbrain Raphe Nuclei; Mitochondrial Proteins; Proto-Oncogene Proteins c-fos; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Synaptic Transmission; Thermogenesis; Uncoupling Protein 1; Vagus Nerve