Divergent Effects of Atorvastatin and Pravastatin on Glucose Homeostasis in Ob/Ob Mice and the Impact of Gut Microbiota Depletion By Antibiotic Therapy

Presentation Number: SAT 585
Date of Presentation: April 1st, 2017

Janice da Costa Silva Viana*, Michella Soares Coelho, Sidney Alcântara Pereira, Bruna Teles Soares Beserra, Fernanda Cerqueira Barroso Oliveira, Angelica Amorim Amato and Francisco de Assis Rocha Neves
University of Brasilia, Brasilia, Brazil

Abstract

Statins are lipid-lowering drugs that prevent cardiovascular events in diabetic and non-diabetic patients. Additionally, statins may also impair glucose metabolism and increase the risk of type 2 diabetes (T2D), although the mechanisms underlying this effect was not fully elucidated. Modification on gut microbiota are recognized as a risk factor T2D, but the effect of statins on gut microbiota and its relation to T2D have not been explored. This study investigated the effects of statins on glucose homeostasis and if microbiota depletion modifies these effects. Male ob/ob mice on normal diet were treated with vehicle (n=10), atorvastatin (ATOR) 80 mg/kg/d (n=10) or pravastatin (PRAVA) 80 mg/kg/d (n=10), for 8 weeks (13th to 20th wk). During the last 4 weeks (17th to 20th wk), five mice from each group also received an antibiotic combination (ciprofloxacin 0.2 g/L and vancomycin 0.5 g/L in drinking water) to promote microbiota depletion. Statins were added to the diet. Weight gain, fasting blood glucose and serum levels of liver enzymes were determined, in addition to liver histology, and expression of lipogenesis (Acaca, Fas, Scd1, Srebp1) and b-oxidation-related (Acox1, Acsl1, Cpt1a, PPARa) genes. ATOR therapy reduced weight gain which was not changed when the antibiotic was associated with the treatment. Neither PRAVA nor antibiotics alone affected weight gain but combined PRAVA and antibiotics reduced weight gain. ATOR significantly increased fasting blood glucose, and this effect was abolished by antibiotic therapy. On the contrary, mice treated with PRAVA slightly decreased blood glucose levels, which was not modified by microbiota depletion. Both ATOR and PRAVA diminished serum liver enzyme levels, but this effect was not observed in mice treated with statins and antibiotics. Interesting, statin treatment decreased hepatic lipid accumulation and, the addition of antibiotic impairs this improvement. ATOR increased liver Srepb1 mRNA levels, and microbiota depletion did not change it. PRAVA also increased Srepb1 and Acaca mRNA levels which were abolished by microbiota depletion. ATOR increased liver Cpt1a expression, which was unaffected by microbiota depletion. PRAVA had no effect on the expression of b-oxidation-related genes. Our findings suggest that atorvastatin and pravastatin have different effects on glucose homeostasis and that atorvastatin-induced hyperglycemia may be dependent upon gut microbiota. They also point to beneficial actions of statins on hepatic steatosis, independently of their effects on glucose metabolism.

 

Nothing to Disclose: JDCSV, MSC, SAP, BTSB, FCBO, AAA, FDARN