The Exercise-Induced Improvement in hyperglycemia is Mediated by DHT Produced in the Skeletal Muscle of Zucker Diabetic Fatty Rats

Abstract

The ability of exercise to improve hyperglycemia by enhancing glucose metabolism in the skeletal muscle of type 2 diabetic patients is well established. We reported sex steroid hormones can be locally synthesized in skeletal muscle and decrease fasting blood glucose levels in obese rats. Here, we determined whether exercise-induced production of sex steroid hormones in skeletal muscle could directly reverse hyperglycemia in the Zucker diabetic fatty rat model using osmotic mini pump.Thirty Zucker diabetic fatty rats were randomly assigned to the following groups: control, exercise, or exercise with continuous infusion of 5α-reductase inhibitor.The results indicated 6 weeks of exercise significantly reduced serum insulin and fasting glucose levels compared to control group. Dehydroepiandrosterone, 5α-dehydrotestosterone, and 5α-reductase levels were all significantly higher in skeletal muscle of the exercise group. Moreover, exercise increased glucose transporter-4 translocation with a concomitant upregulation of phosphorylated phosphoinositide 3-kinase, protein kinase B and C-ζ/λ. Furthermore, significant correlations were observed between fasting glucose and muscular DHT levels. Interestingly, the observed exercise-induced improvements in serum insulin and fasting glucose levels were all suppressed by administration of 5α-reductase inhibitor.These results indicated the exercise-induced improvements in glucose metabolism signaling and glucose levels may be directly attributed to the increased levels of sex steroid hormones within skeletal muscles.

Increased Muscular 5α-Dihydrotestosterone in Response to Resistance Training Relates to Skeletal Muscle Mass and Glucose Metabolism in Type 2 Diabetic Rats

“…After 14 weeks, the 20-week-old OLETF rats were randomly divided into three groups (n = 8 each group): sedentary control (Con), resistance training (RT), or resistance training with continuous infusion of 5α-reductase inhibitor (RT+In). The 5α-reductase inhibitor (dutasteride; Sigma, Steinheim, Germany) was administrated continuously at 0.15 μL per h for 8 weeks via an implanted osmotic mini pump in subcutaneous adipose tissue (Model 2006; Alzet, Cupertino, CA) [16, 17]. The inhibitor (2 mg/kg) was dissolved into sesame oil and 200 μL was loaded into the pump [16].…”

“…The 5α-reductase inhibitor (dutasteride; Sigma, Steinheim, Germany) was administrated continuously at 0.15 μL per h for 8 weeks via an implanted osmotic mini pump in subcutaneous adipose tissue (Model 2006; Alzet, Cupertino, CA) [16, 17]. The inhibitor (2 mg/kg) was dissolved into sesame oil and 200 μL was loaded into the pump [16]. Additionally, nondiabetic, healthy, and age-matched LETO rats (n = 8) were used as controls.…”

“…Western blot analysis was performed as previously described [16, 19]. Briefly, muscle proteins (40 μg) were separated on 10% SDS-polyacrylamide gels, and then transferred to polyvinylidene difluoride (PVDF) membranes (Millipore, Billerica, MA, USA).…”

“…After these reactions, the membranes were washed three times with PBS-T. Finally, proteins were detected using an enhanced chemiluminescence plus system (GE Healthcare Biosciences) and visualized on an LAS4000 imager (GE Healthcare Biosciences) [16]. …”

“…For determination of GLUT-4 translocation, two different cellular fractions were used as previously described [16, 20, 21]. Briefly, the cells were scraped in buffer A containing (in mM) 20 Tris (pH 7.4), 1 EDTA, 0.25 EGTA, 1 DTT, 50 NaF, 25 sodium pyrophosphate, 40 β-glycerophosphate, and 250 sucrose.…”