CNS GLP-1 regulation of peripheral glucose homeostasis
Introduction
In response to a meal, a complex network of physiological responses, including neural and endocrine signals, regulate the digestion, absorption, and storage of ingested nutrients. Many of these signals are generated in response to the physiochemical properties of ingested food passing through the gut. The importance of these signals was first hypothesized by McIntyre et al. [1] in 1964 after observing that the glucose clearance and insulin levels were much greater following oral vs. intravenous administration of the same dose of glucose in human subjects. The authors hypothesized that this incretin effect (greater secretion of insulin in response to oral vs. intravenous glucose) was due to the secretion of hormones from the gut stimulated by a glucose load. The first incretin found was glucose-dependent insulintropic polypeptide (GIP), and a decade later, glucagon-like peptide-1 (GLP-1) was discovered [2]. Both hormones are released from the gut, GIP from the duodenal K cells, and GLP-1 from the L-cells. Although both hormones stimulate insulin secretion, beta cell sensitivity to GIP but not GLP-1 is reduced over time. This has proven to be advantageous clinically as two recently approved treatments for type 2 diabetes mellitus activate GLP-1 signaling to improve glucose homeostasis.
GLP-1 is also made in a discrete population of neurons in the hindbrain [3], [4]. The physiological function of CNS GLP-1 receptor (GLP-1r) has been linked to the control of food intake, endocrine and behavioral responses to stress, and visceral illness [5], [6], [7]. The function of the central and peripheral GLP-1 signaling systems are generally held to be separate; i.e. peripheral GLP-1 regulates glucose homoestasis while central GLP-1 regulates food intake. This review challenges this dogma by providing recent evidence linking the CNS GLP-1 system to glucose homeostasis as well and proposes a model that integrates the role of CNS and peripheral GLP-1 systems in regulation of glucose homeostasis.
Section snippets
Model for integration of peripheral and CNS GLP-1 systems in regulation of glucose homeostasis
The importance of GLP-1 in regulation of glucose homeostasis is illustrated by the widespread clinical use of drugs that activate the GLP-1 system to treat type 2 diabetes mellitus. The generally accepted model for GLP-1 regulation of glucose homeostasis is that following the ingestion nutrients, GLP-1 is secreted from the intestine and acts directly on the β-cells to stimulate insulin secretion which in turn modulates glucose homeostasis. Recent data demonstrate increases in vagal afferent
The role of peripheral GLP-1 in glucose homeostasis
GLP-1 is cleaved from preproglucagon in mucosal endocrine cells (L-cells) located predominantly in the distal intestinal tract [14], [15]. To date, only one GLP-1r has been described and thus far, there are no other naturally occurring mammalian ligands for the GLP-1r. Following the ingestion of glucose, fat, or mixed nutrient meals, GLP-1 increases several fold within 20–30 min and remains elevated for up to 4 h [16]. As stated above, GLP-1 augments nutrient-induced insulin release [2], [17],
The CNS GLP-1 system
In addition to being secreted from the intestine, GLP-1 is also a neurotransmitter synthesized in a discrete population of neurons found in the nucleus of the solitary tract (NTS) within the hindbrain [3], [14], [28]. These GLP-1 cells have rich axonal innervation to the hypothalamus and the central nucleus of the amygdala [28], [29]. After third ventricular administration of GLP-1, c-fos like immunoreactivity, a marker for neuronal activation, is increased in the paraventricular (PVN) and
Central regulation of peripheral glucose metabolism
There is accumulating evidence that in addition to regulation of energy homeostasis, the CNS, specifically the ARC, also regulates normal glucose homeostasis. Glucose homeostasis is maintained via glucose output by the liver and glucose uptake by the tissues. Central administration of anorectic peptides (leptin, insulin, α-melanocortin stimulating hormone) and nutrients (glucose, lactate, long chain fatty acids) have all been found to alter glucose production by the liver while glucose uptake
Mechanisms of CNS GLP-1 signaling
While the data indicate the CNS GLP-1 plays a role in regulating glucose homeostasis, it remains unknown how this system is activated. Potential sources of peripheral GLP-1 that can activate CNS GLP-1r are via circulating blood after secretion from the GI tract, or via neural feedback to the hindbrain. Alternatively, it may be the case that other factors (e.g. cholecystokinin) released during meal absorption initiate central GLP-1 action [66]. There are several pieces of data illustrating that
The nervous system and peripheral GLP-1
Peripheral administration of GLP-1 and its agonists are very effective in reducing blood glucose levels in humans with type 2 diabetes [79]. Understanding the integration of specific functions of the peripheral and CNS GLP-1 systems will aid in our continued understanding of dysfunction in glucose homeostasis. Although at present there are many more questions than answers, that data is intriguing enough to generate an integrated model for peripheral and central GLP-1-induced regulation of
A detailed model for integration of peripheral and CNS GLP-1 systems in regulation of glucose homeostasis
Putting all of these data together, we see that regulation of glucose homeostasis should be added to the many distinct functions of CNS GLP-1 (regulation of stress responses, visceral illness, and food intake). It is important to note that this is in addition to the beneficial effects of peripheral GLP-1 on glucose homeostasis (Fig. 1). Specifically, we hypothesize that after a meal peripheral GLP-1 is secreted from the L-cells within the small intestine. GLP-1 acts directly on the β-cells to
References (98)
- et al.
New interpretation of oral glucose tolerance
Lancet
(1964) - et al.
Glucagon-like peptide-1 evokes action potentials and increases cytosolic Ca2+ in rat nodose ganglion neurons
Auton Neurosci
(2002) - et al.
Glucagon-like peptide 1: a potent glycogenic hormone
FEBS Lett
(1994) - et al.
Exendin-4 agonist and exendin(9-39)amide antagonist of the GLP-1(7-36)amide effects in liver and muscle
Arch Biochem Biophys
(1997) - et al.
Cell signalling of the GLP-1 action in rat liver
Mol Cell Endocrinol
(2003) - et al.
Characterization of brainstem preproglucagon projections to the paraventricular and dorsomedial hypothalamic nuclei
Brain Res
(2007) - et al.
Central infusion of glucagon-like peptide-1-(7-36) amide (GLP-1) receptor antagonist attenuates lithium chloride-induced c-Fos induction in rat brainstem
Brain Res
(1998) - et al.
Energy expenditure by intravenous administration of glucagon-like peptide-1 mediated by the lower brainstem and sympathoadrenal system
Peptides
(2005) - et al.
The inhibitory effects of peripheral administration of peptide YY(3-36) and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway
Brain Res
(2005) - et al.
Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men
Am J Clin Nutr
(1998)