ESE Young Investigator Award
Milano Felipe dos Santos Ferreira Marques, Rosana Cristina Tieko Mori, Maristela Mitiko Okamoto & Ubiratan Fabres Machado
Introduction: GLUT4 protein is the most important isoform of glucose transporters in skeletal muscle. Reduction in its content and/or translocation is related to insulin resistance and type 2 diabetes mellitus. In skeletal muscle cells there is also an ATP-sensitive potassium (KATP) channel with two subunits, sulfonylurea receptor type 2A, ABCC9 (SUR2A) and KIR6.2 (KCNJ11). In pancreatic B cells, this channel triggers insulin secretion in response to the rise in glucose levels, but in skeletal muscle its role is still unknown. Considering these aspects the aim of this study was to investigate whether KATP channel can influence glucose uptake in skeletal muscle by regulating GLUT4 expression and/or translocation.
Methods: Insulin resistance was induced in male Wistar rats by neonatal treatment with monosodium glutamate (MSG) (4 mg/g per day, s.c). At the age of three months, both control (C) and MSG treated animals received glimepiride (0.1 mg/kg per day, in the drinking water) for 4 weeks, and were divided into non-treated (C and MSG) and glimepiride treated (CG and MSG-G) groups. Animals were submitted to insulin tolerance test (ITT) and samples of glycolytic (EDL-extensor digitorium longus) and oxidative (soleus) skeletal muscles were excised for quantification of SUR2A, KIR6.2 and GLUT4 mRNA expression by real time RT-PCR.
Results: In ITT, MSG obese rats showed a significant decrease in glucose decay in response to insulin (30%, P<0.05 versus C and MSG/G) and the glimepiride treatment improved the insulin sensitivity to the control level. In soleus muscle, a ~45% increase in SUR2A mRNA level was observed in MSG/G obese rats (P<0.01 versus MSG and C), but in EDL no difference occurred among groups. In EDL, GLUT4 mRNA was 40% reduced in MSG rats (P<0.01 versus C), and increased back to control level after glimepiride treatment in MSG/G rats (P<0.01 versus MSG). In soleus muscle, an increase of 15% in GLUT4 mRNA was found in MSG obese rats (P<0.01 versus C). After treatment with glimepiride, a further 17% increase in GLUT4 mRNA occurred (MSG/G versus MSG, P<0.05). No significant differences (P>0.05) in mRNA expression of KIR6.2 (EDL and soleus) were found.
Conclusion: In insulin resistant animals, glimepiride increased insulin sensitivity which could be associated to enhanced GLUT4 and SUR2A genes expression in soleus muscle.
Financial support: Fapesp (# 2008/57798-6).