Neural Responses to Mechanical Stimulation in Thin Muscle Afferents and Dorsal Root Ganglia are Sensitized by Insulin
Authors: Hotta Norio , Katanosaka Kimiaki , Mizumura Kazue , Mitchell Jere H. , Smith Scott A. , Mizuno Masaki 
Published: June 2021

In patients with type 2 diabetes mellitus (T2D), the circulatory responses to physical activity are abnormally exaggerated. Recent studies in patients with T2D have suggested that this exaggerated cardiovascular response is mediated, in part, by the exercise pressor reflex (EPR) which is a primary contributor to autonomic cardiovascular control during exercise. However, the mechanisms underlying this abnormal EPR function in T2D remain unknown. The pathophysiology of T2D is characterized by insulin resistance induced hyperinsulinemia. Further, evidence suggests that insulin increases the sensitivity of transient receptor potential vanilloid receptors localized to muscle afferent neurons that contribute to EPR activation. Importantly, sensitization of muscle receptors associated with the mechanically sensitive component of the EPR (i.e. the muscle mechanoreflex) has been shown to mediate reflex overactivity in other cardiovascular disease states such as heart failure and hypertension. Given this information, it is logical to suggest that excess levels of insulin may potentiate mechanoreflex function in T2D.

PURPOSE

To examine the effect of insulin on neuronal responses to mechanical stimulation in thin muscle afferents and dorsal root ganglia (DRG) of normal healthy rodents. We hypothesized that insulin sensitizes the activity of mechanically sensitive afferent neurons.

METHODS

Mechanically activated neurons were assessed before (control) and after exposure to insulin 1) by single‐fiber recordings from rat muscle‐nerve preparations in vitro and 2) by whole cell patch‐clamp recordings from cultured mice DRG neurons. The magnitude of the response to mechanical stimulation as well as the mechanical threshold were assessed.

RESULTS

Compared to control, the mechanical threshold of thin muscle afferents was significantly decreased after insulin administration (58±16 vs. 15±17 mN, n=8, P<0.05) while the response magnitude was not changed (66±22 vs. 68±16 spikes, n=8). In DRG cell culture, mechanically activated current was significantly augmented by insulin (−93 ±12 vs. −190±43 pA, n=16, P<0.05) whereas the mechanical threshold was significantly decreased (4.6±0.4 vs. 2.6±0.3 steps, n=17, P<0.05). Further, after pretreatment of DRG insulin receptors with the inhibitor GSK1838705, insulin failed to augment the mechanically activated current (−91±19 vs. −92±19 pA, n=14) or to reduce the mechanical threshold (3.5 ± 0.4 vs. 3.4 ± 0.5 steps, n=11).

CONCLUSIONS

These data demonstrate that thin muscle afferent and DRG neuronal responses to mechanical stimulation are sensitized by the presence of insulin in normal healthy animals. Importantly, the findings provide support for the concept that chronic hyperinsulinemia enhances skeletal muscle mechanoreflex function in T2D contributing to the abnormal cardiovascular response during exercise in this disease.

Support or Funding Information

Supported by the Lawson & Rogers Lacy Research Fund in Cardiovascular Disease and JSPS KAKENHI JP17K01769

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.