Abstract 14802: Chronic Tadalafil Therapy Improves Fasting Glucose Levels And Downregulates Microrna-103 And -107 In Obese Diabetic Mice

Abstract

Background: MicroRNAs (MiRs) are small non-coding RNAs that regulate gene expression in a sequence dependent manner. Two related miRs (miR-103/107) are powerful negative regulators of insulin sensitivity and glucose metabolism and are upregulated in animal models of insulin resistance and obesity. Likewise in diabetic mice, antisense-mediated silencing of both miRs has shown to improve insulin signaling and glucose homeostasis. We hypothesized that chronic therapy with the phosphodiesterase-5 inhibitor (PDE-5i), tadalafil (TAD), improves fasting glucose levels, reduces body weight and downregulates miR-103/107 in db/db mice.

Methods and Results: Eight db/db mice underwent treatment with TAD (1 mg/Kg i.p., n=5) or 10% DMSO (n=3) for 28 days. Body weight and fasting glucose levels were determined weekly. Three C57BL/6 mice were used as non-diabetic controls. Upon completion, mice were sacrificed, hearts were homogenized and total RNA was isolated. After concentration and purity was checked, total RNA was subjected to reverse transcription using miR specific primers. Real time PCR was performed using miR assay probes to determine expression. MiR levels were standardized against small nucleolar RNA (sno-RNA)-202. TAD showed a significant decrease in glucose levels (276±36.4 mg/dL vs. 491±29.3 mg/dL; p<0.01), but not a decrease in weight compared to the DMSO group (45.4±2.2 g vs. 47.8±2.7 g). Both miR-103/107 increased in the hearts of diabetic mice compared to control [Fig. 1]. Interestingly, TAD rerapy downregulated both miRs to levels comparable to those found in the healthy non-diabetic controls.

Conclusion: This study provides the first evidence of increased expression of miR-103/107 in diabetic hearts which is downregulated by TAD. Moreover, chronic TAD therapy may improve fasting blood glucose levels through downregulation of miR-103/107 and this may be a novel, clinically relevant approach to improving insulin sensitivity in diabetics.