Overview of brain control of glucose homeostasis in normal physiology
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page 129-131
2025-10-27
46
Following a meal, ingested glucose and other nutrients enter the circulation from the gastrointestinal tract, eliciting a multitude of responses that both increase glucose disposal and inhibit endogenous glucose production to minimize the resultant blood glucose excursion. Insulin is a key mediator of these responses, promoting glucose disposal into muscle, fat, and other insulin- sensitive tis sues, while simultaneously restraining endogenous glucose production by the liver. Meal- induced insulin secretion is stimulated by (i) rising plasma levels of glucose and other nutrients; (ii) release of incretin peptides, such as glucagon- like peptide 1 (GLP- 1), from the gastrointestinal tract; and (iii) adjustments of autonomic tone to pancreatic islets. In addition to coordinating the timing and magnitude of the insulin secretory response, the brain can also activate insulin- independent mechanisms that lower blood glucose levels, including both suppression of endogenous glucose production and increase in hepatic glucose uptake (Figure 1). These dynamic interactions illustrate how cooperation between brain, pancreas, liver, and other tissues limits plasma glucose excursion in the post- prandial state. Equally important to glucose homeostasis is maintenance of stable glycaemia in the basal state (i.e. in the absence of ingested nutrients). Unlike the response to a meal, however, insulin- independent mechanisms predominate in the control of glucose disposal in the basal state (i.e. in the absence of nutrient entry from the gastrointestinal tract).
Fig1. Autonomic control of glucose homeostasis. Pancreatic islets receive autonomic input originating with neurons in the hypothalamus, midbrain, and brainstem nuclei that in turn regulate the parasympathetic (PNS) and sympathetic (SNS) nervous system outflow. Glucagon secretion is increased by activation of either PNS or SNS, whereas insulin secretion is stimulated by the former and inhibited by the latter. Sympathetic fibres supplying the liver also affect both hepatic glucose production (HGP) and uptake. In response to hypoglycaemia, therefore, activation of SNS outflow to the liver and pancreas increases both glucagon secretion and HGP, whereas insulin secretion is inhibited. Conversely, insulin release in response to both food consumption and the mere anticipation of a meal is stimulated by activation of PNS supply to pancreatic islets. Source: Figure generated using http://Biorender.com.
Autonomic control of pancreatic islet function
Brain–islet connections involving both the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) (Figure 1) [5] can rapidly influence both insulin and glucagon secretion in response to changes in the level of circulating nutrients and other stimuli under physiological conditions.
Recent 3D imaging of cleared human pancreatic islets shows dense innervation by both SNS and PNS fibres and, whereas insulin secretion during a meal is augmented by an associated increase of PNS outflow, glucagon section during hypoglycaemia is enhanced by both PNS and SNS outflow to the islet (Figure 1). The liver is also richly supplied with SNS fibres, activation of which stimulates hepatic glucose production, thereby helping to restore normoglycaemia; these fibres are also activated in response to hypoglycaemia. This increased hepatic glucose pro duction is facilitated by increased SNS outflow to pancreatic islets, which potently inhibits insulin secretion in addition to enhancing glucagon release.
The brain also participates in control of islet function under more physiological conditions. For example, the cephalic phase of insulin release involves insulin secretion induced by increased PNS outflow to the pancreas that is triggered by feeding cues before feeding begins and blood glucose levels begin to rise (Figure 1). This response is mediated primarily by vagal cholinergic signals, is malleable to changing environmental stimuli, and is a large contributor to whole- body glucose tolerance following a meal. Complementing this response is augmented post- prandial insulin secretion resulting from a meal- induced increase of PNS tone.
Autonomic mechanisms also control post- prandial glucagon secretion, with local glucagon release in the islet enhancing the responsiveness of insulin- secreting β cells to glucose. These islet responses are likely coordinated by specific glucoregulatory neuronal populations within the hindbrain, midbrain, and hypothalamus that project via multisynaptic relays into the pancreas. Experimental impairment of neuronal glucose sensing within the mediobasal hypothalamus produces distinct effects on glucose homeostasis through these brain–islet multisynaptic relays, which further implicates autonomic input to the islet in its response to both feeding and hypoglycaemia. Although the liver is a major target for the actions of both insulin and glucagon (which suppress and increase hepatic glucose output, respectively), the brain also regulates glucose handling by the liver not only during hypoglycaemia, but in response to sustained hyperglycaemia as well. Specifically, both human and rodent studies suggest that intact brain KATP channel activity is required for the effect of clamped hyperglycaemia to suppress hepatic glucose production.
Circadian control of metabolism
The suprachiasmatic nucleus (referred to as the master circadian pacemaker) contains neurons whose activity is governed by a system of clock genes that is entrained to the light–dark cycle to turn on and off in a circadian manner. This repeating pattern of suprachiasmatic nucleus neuron activation in turn aligns many behaviours and metabolic functions to the circadian clock. For example, hepatic insulin sensitivity (i.e. responsiveness to insulin- mediated suppression of hepatic glucose output) decreases during sleep and increases on waking, in anticipation of the onset of feeding, and a specific subset of neurons producing γ-aminobutyric acid (GABA) in the suprachiasmatic nucleus whose rhythmic firing underlies circadian variation in hepatic insulin sensitivity was recently identified. Since normal glucose tolerance depends on proper coupling of insulin secretion to insulin sensitivity, and since mechanisms under lying this coupling remain to be established, it will be interesting to determine if the brain also governs adaptive β- cell response to daily variation in insulin sensitivity. Such a finding would extend previous work linking the brain to adaptive changes of both insulin secretion and insulin sensitivity during cold exposure (discussed later).
How does the brain sense physiological changes in blood glucose?
Although it makes teleological sense for the brain to sense circulating glucose levels (analogous to the recently discovered Drosophila glucose- sensing neuron pair), precisely how this process occurs remains uncertain. The balance of available literature points to a distributed network of neurons that convey afferent information to the brain regarding both glucose availability and need. Although this brain glucose sensing process can, in theory, involve glucose- responsive neurons (or glia) in brain parenchyma, many of these neurons are exposed only to glucose levels in brain interstitial fluid and not to levels in the circulation. Reliance on glucose sensing by cells exposed only to brain interstitial fluid is unlikely to explain all the effects observed in vivo, given that the glucose level in brain interstitial fluid is much lower than in plasma, and that following a change in the plasma level, changes in brain interstitial fluid occur relatively slowly. For these reasons, information regarding the blood glucose level is likely communicated to the brain via a distributed system of neurons (and perhaps glial cells) that are anatomically well placed to sense the circulating glucose level. These include neurons located in the vasculature (including the hepatic portal vein, where they are well placed to detect glucose absorbed from the gastrointestinal tract), the gastrointestinal tract itself, and brain areas known as circumventricular organs that are characterized by an incompletely developed blood–brain barrier. Particularly relevant among the latter are the median eminence of the hypothalamus and area postrema of the hindbrain; neurons in these brain areas that are exposed to the circulation may provide the brain with the real- time afferent information needed to mount adaptive responses important for normal glucose homeostasis.
What, then, might be the primary role in whole- body glucose homeostasis played by cells that sense glucose locally in brain interstitial fluid? While the answer is unknown, many of these parenchymal cells are located within glucoregulatory neurocircuits downstream of peripheral glucose sensors that respond to changes of glycaemia, in addition to detecting changes in brain interstitial fluid glucose levels directly. It is possible, for example, that brain interstitial fluid glucose levels offer a baseline against which afferent information relevant to the circulating level conveyed from peripheral sources can be compared. Additional study is required to clarify the roles of direct and indirect brain glucose- sensing mechanisms in glucose homeostasis; both may in fact contribute, as these possibilities are not mutually exclusive.
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