Intracerebroventricular injection of insulin normalizes the augmented exercise pressor reflex in type II diabetic rats
Authors: Estrada Juan , Ishizawa Rie , Kim Han-Kyul , Fukazawa Ayumi , Iwamoto Gary , Smith Scott , Vongpatanasin Wanpen , Mizuno Masaki 
Published: May 2023

Type 2 diabetes mellitus (T2D) leads to alterations in insulin signaling and autonomic function, including abnormal cardiovascular response to exercise. Cardiovascular control during exercise is in part mediated by the exercise pressor reflex (EPR). The EPR transmits information from primary sensory neurons in working skeletal muscle to cardiovascular control centers in the brain, resulting in reflexively increased blood pressure (BP). Insulin receptors are expressed on neurons in these cardiovascular control centers. Thus, it is logical to suggest that insulin signaling could be disrupted in these neurons in T2D. We hypothesized that the augmented cardiovascular and sympathetic responses to exercise in T2D may be attenuated by administration of insulin into the brain. Purpose: This study was conducted to demonstrate that insulin administration into the central nervous system of rats acutely attenuates the augmented BP and sympathetic responses to muscle contraction in rats with T2D. Methods: T2D and control rats were generated by feeding Sprague-Dawley rats either a high fat diet (T2D, n=10) or normal diet (control, n=7) for 12-16 wks. Before beginning the diet, either two low doses of i.p. streptozotocin (T2D, 35mg/kg week 1, 25mg/kg week 2) or two i.p. saline injections (control) were administered. A precollicular decerebration was performed, and the left L4 and L5 ventral roots were electrically stimulated to evoke hindlimb skeletal muscle contractions. Renal sympathetic nerve activity (RSNA) and BP responses to activation of the EPR were assessed before, and post 1 and 2hr intracerebroventricular (ICV) insulin injection (500mU, 50nL). Fasting blood glucose was measured before experiments. Data were evaluated by Two-way Repeated Measures ANOVA or Student’s t-test. Results: Fasting blood glucose was significantly higher in T2D as compared to control rats (T2D 150±55 mg/dL vs 100±16 mg/dL, P=0.0353). In the T2D group, the BP and RSNA responses to contraction were significantly attenuated at 1hr post-ICV insulin (ΔMAP Pre [36±14 mmHg] vs 1hr post [21±14 mmHg], P=0.0002; ΔRSNA Pre [107.5±40%], vs 1hr post [75.4±46%], P=0.0043), and then further attenuated at 2hr post (ΔMAP 1hr [21±14 mmHg] vs 2hr [11±6 mmHg], P= 0.0155; ΔRSNA 1hr [75.4±46%] vs 2hr [51±35%], P=0.0363). There were no differences in pressor or sympathetic responses observed in the control group post-ICV insulin. Conclusion: The data demonstrate that brain insulin normalizes the potentiated BP and RSNA responses to muscle contraction in T2D rats. Thus, impaired insulin signaling within cardiovascular control centers of the brain may underlie the augmented EPR in T2D rats. Central insulin treatment may potentially restore normal autonomic function in part by decreasing neuronal excitability in T2D. Supported by NIH-NHLBI, Lawson & Rogers Lacy Research Fund This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.