Diabetes and the associated hyper- and hypo-glycemia damage blood vessels in the brain, worsening cognitive function and increasing the risk of developing dementia.  Type 2 diabetes mellitus is characterized by insulin resistance.  The “resistance” to insulin is largely a result of poor insulin delivery to the target cells with blood flow being the primary regulator of insulin mediated glucose update.  Blood flow to skeletal muscle is tightly regulated by both the vasoconstrictive, sympathetic and vasodilatory, parasympathetic nervous systems. 

We are taking advantage of the interorgan communication facilitated by the peripheral nervous system to manipulate blood flow to improve glucose homeostasis. 

The baroreceptor reflex is defined as the sensing of pressure in the aortic arch and compensatory changes in vascular tone and heart rate to maintain blood pressure.  Using a mouse with improved cardiac contractility, we activated the baroreceptor reflex, to induce vasodilation and improve glucose homeostasis in diet-induced obese mice. 

Fatty liver is associated with hypertension and insulin resistance.  We previously established that the fatty liver produces GABA, which inhibits activity of the vagal nerve resulting in hyperinsulinemia and insulin resistance.  Inhibiting liver GABA production improves insulin sensitivity, prevents obesity and angiotensin II induced hypertension, and increases vasodilatory cGMP in skeletal muscle.  GABA signaling onto the hepatic vagal nerve increases peroneal nerve activity and sympathetic tone at skeletal muscle.  This established the key role of hepatic vagal afferent signaling in regulating insulin and glucose delivery to skeletal muscle.   

Together our studies establish the potential to target the afferent peripheral nervous system signaling to modulate microvascular blood flow, systemic blood pressure, and metabolic health.