Revisiting How the Brain Senses Glucose-And Why

Abstract

Glucose-sensitive neurons have long been implicated in glucose homeostasis, but how glucose-sensing information is used by the brain in this process remains uncertain. Here, we propose a model in which (1) information relevant to the circulating glucose level is essential to the proper function of this regulatory system, (2) this input is provided by neurons located outside the blood-brain barrier (BBB) (since neurons situated behind the BBB are exposed to glucose in brain interstitial fluid, rather than that in the circulation), and (3) while the efferent limb of this system is comprised of neurons situated behind the BBB, many of these neurons are also glucose sensitive. Precedent for such an organizational scheme is found in the thermoregulatory system, which we draw upon in this framework for understanding the role played by brain glucose sensing in glucose homeostasis.

Keywords: blood-brain barrier; brain; glucose-sensing.

Figure 1.. Schematic illustration of negative feedback control of glucose homeostasis by the brain.

Neurons that sense the circulating glucose level (Peripheral Glucose Sensors, which may include nerves innervating the hepatic portal vein as well as neurons in circumventricular areas such as the arcuate nucleus-median eminence (ARC-ME) and nucleus of the solitary tract-area postrema (NTS-AP)) are proposed to constitute the afferent “sensory” limb of this regulatory system. This afferent information is transmitted to Central Glucoregulatory Circuits in the hypothalamic ventromedial nucleus (VMN) and other areas on the “brain side” of the blood brain barrier (BBB). These neurons are proposed to comprise the integrative/efferent limb of the brain’s glucoregulatory system. While some of these neurons are glucose-excited (GE) or glucose-inhibited (GI), they are not anatomically-positioned to sense glucose in the circulation, and hence do not play a primary role in brain glucose sensing. Instead, these neurons are responsive both to changes in the concentration of glucose in local brain interstitial fluid (which is not closely related to the circulating level) and to input from afferent glucose-sensing neurons, and they project onto and regulate the output from neuroendocrine (including the hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenal system) and autonomic control systems. Autonomic and neuroendocrine outputs in turn affect liver, GI tract, pancreatic islets, skeletal muscle and adipose tissue in a highly-coordinated manner that ultimately determines the balance between glucose entry into and disposal from the bloodstream, which in turn determines the circulating glucose level.