Exaggerated sympathetic and pressor responses to exercise pressor reflex activation are attenuated by intracerebroventricular insulin administration in type 2 diabetic rats

Abstract

The cardiovascular response to exercise is abnormally exaggerated in patients with type 2 diabetes mellitus (T2D). We have previously demonstrated that stimulation of the exercise pressor reflex (EPR) during muscle contraction elicits exaggerated increases in renal sympathetic nerve activity (RSNA) contributing significantly to this heightened circulatory responsiveness. However, the mechanisms underlying this EPR dysfunction remain to be elucidated. Evidence suggests that the availability of brain insulin is reduced in T2D. Given that sympathetic activity is primarily regulated within the brain, we hypothesized that a decrease in brain insulin contributes to EPR‐induced sympathetic overactivity in this disease. To test this hypothesis, we measured changes in RSNA and mean arterial pressure (MAP) during stimulation of the EPR in decerebrated Sprague‐Dawley rats given either a normal diet (control) or a high fat diet (in combination with a one‐time low dose of streptozotocin to produce T2D) for 14–16 weeks. Compared to normal diet‐fed rats, animals receiving the high fat diet had significantly increased plasma insulin (1.6±0.2 vs. 4.1±0.4 ng/mL, P<0.05) as well as fasting blood glucose (94±5 vs. 120±5 mg/dL, P<0.05). Compared to control animals, stimulation of the EPR by electrically‐induced muscle contraction evoked significantly greater increases in RSNA (Δ = 36±10 vs. 122±20 %, P<0.05) and MAP (Δ = 15±1 vs. 49±5 mmHg, P<0.05) in T2D rats. Intracerebroventricular insulin administration significantly attenuated the exaggerated sympathetic (Δ = 111±20 vs. 50±17 %, P=0.05) and pressor responses (Δ = 49±5 vs. 12±4 mmHg, P<0.05) to EPR activation in T2D rats but did not have a significant effect in control animals (RSNA: Δ = 43±2 vs. 33±13 %; MAP: Δ = 15±1 vs. 7±4 mmHg). These findings suggest that the heightened cardiovascular response to exercise in T2D may be mediated by EPR‐induced sympathetic dysfunction resulting as a consequence of decreased insulin availability within the brain.Support or Funding InformationSupported by the Lawson & Rogers Lacy Research Fund in Cardiovascular Disease.