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.

Hypoglycemia-Sensing Neurons of the Ventromedial Hypothalamus Require AMPK-Induced Txn2 Expression but Are Dispensable for Physiological Counterregulation

“…However, VMN neurons are part of a multisynaptic circuit that includes an afferent and an efferent limb ( 11 ). The afferent limb comprises glucose-sensing neurons located outside of the blood-brain barrier, such as those present in the hepatoportal vein area ( 3 ) or in the nucleus of the tractus solitarius and which respond to small variations in blood glucose concentration ( 5 , 12 ), and neurons located within the blood-brain barrier, such as the GI neurons of the lateral parabrachial nucleus, which form direct synaptic contacts with VMN neurons ( 13 ).…”

“…However, supporting evidence is only circumstantial, based on various, non–cell-specific pharmacological or gene-silencing approaches ( 15 – 17 ). Thus, the relative importance in triggering the counterregulation response of VMN GI neurons and of GI neurons present at other locations of the afferent limb is not established ( 11 ).…”

Carbohydrates and the Brain: Roles and Impact

“…A fine feedback loop between the brain and various organs and tissues has been demonstrated, allowing, in normal conditions, to maintain blood glucose level rather constant around 1 g/l (7-8 mM) in the blood and ~2 mM in the brain (see below Section 5) [2,3]. The brain needs a precise and clear feedback on the metabolic state of the whole body [4]. To achieve this aim, various brain areas, especially the brainstem and the hypothalamus, integrate peripheral signals delivered by neural input from various organs, as well as by metabolites (glucose, fatty acids) and hormones (leptin, insulin, ghrelin) via the blood [2][3][4].…”

“…The brain needs a precise and clear feedback on the metabolic state of the whole body [4]. To achieve this aim, various brain areas, especially the brainstem and the hypothalamus, integrate peripheral signals delivered by neural input from various organs, as well as by metabolites (glucose, fatty acids) and hormones (leptin, insulin, ghrelin) via the blood [2][3][4]. Thus, specialized nutrients-and hormones-sensing neurons in which the firing rate varies in response to changes in extra-cellular nutrients or hormones concentration have been described.…”

Glucose Production and Glucose Disposal Integrated by an Intrinsic Inverse Coupling in Vivo: hypothesis of inter-organ reflex on glucose regulation

“…The reason why the portal protocol needed higher insulin infusion rates could be accounted for by the hepatic first-pass degradation of insulin but we couldn’t exclude the possibility of that the resistance was different if insulin acted on different side of the GP-Rd coupling. The mechanism of the GP-Rd inverse coupling is not clear but we tended to believe that it is mediated by the reflex of neural system because the coupling is real-time responded and synchronized simultaneously, in which the hypothalamus might be involved 15,18,19,20 or not be necessarily involved 21 . In conventional theory, the correlation of hepatic GP and whole-body Rd was connected and orchestrated by hormones i.e.…”