Sodium glucose cotransporter-2 (SGLT2) inhibitors promote urinary glucose excretion, consequently reducing blood glucose. Previously we showed that 6 weeks of Dapagliflozin (Dapa) treatment improved insulin sensitivity and prevented weight gain. In addition, Dapa promoted adipose tissue (AT) beiging, lipolysis and decreased adipocyte size primarily in the visceral (VIS) depot in a canine model of mild type 2 diabetes. Little is known about the effects of Dapa on AT inflammation and ceramide synthesis in both the subcutaneous (SC) and VIS fat depots. Twelve dogs were fed a high fat diet for 6 weeks, then received a single low dose of streptozotocin (18.5mg/kg) to induce mild type 2 diabetes. Animals were then exposed to Dapa (n=6, 1.25mg/kg) or placebo (n=6) once per day for 6 weeks, while remaining on the high fat diet. At the end of the treatment, fasting plasma parameters were measured, and SC and VIS fat biopsies were obtained for molecular studies. Dapa increased adiponectin, adiponectin receptors 1 and 2 gene expression by 90%, 74% and 69% (<0.001) in VIS depot respectively. Adiponectin gene expression was upregulated by 85% in the SC (P<0.05). Inflammation markers such as TNFα and IL-6 are downregulated by 74% (P<0.05) and 86% (P<0.001) in the VIS depot respectively. In addition, genes involved in ceramide synthesis, toll like receptor 4 (TLR4) and serine palmitoyl-CoA transferase (SPTLC2) decreased by 77% and 73 % respectively (P<0.05) in the VIS depot.
In conclusion, Dapa promoted adiponectin and its receptors, decreased inflammation and enzymes involved in ceramide synthesis mainly in the VIS depot. These changes were independent of fasting glucose and insulin. Thus, for the first time we are beginning to identify mechanisms by which Dapa enhances AT function in regulating energy homeostasis and improving AT inflammation in mild type 2 diabetes canine model.
M. Kabir: None. R. N. Bergman: None. V. Gopaul: None. H. Yang: Employee; Self; AstraZeneca. C. M. Kolka: Research Support; Self; AstraZeneca.
National Institutes of Health