N E W S
A N D
V I EW S
Insulinotropic Actions of GLP-1: How Much in the Brain
and How Much in the Periphery?
Eva Tudurı́1,2 and Ruben Nogueiras1,2,3
1
G
lucagonlike peptide-1 (GLP-1) is a 30–amino acid
peptide hormone that upon food consumption is
produced and secreted by intestinal enteroendocrine
L-cells and certain neurons in the nucleus of the solitary
tract in the brainstem. GLP-1 is recognized mainly as an
incretin but is involved in a large variety of biological
actions because of the wide distribution of its receptor.
The GLP-1 receptor is highly expressed in the central
nervous system (CNS), including the lateral septum, the
subfornical organ, the thalamus, the hypothalamus, the
interpeduncular nucleus, the posterodorsal tegmental
nucleus, the area postrema, the inferior olive, and the
nucleus of the solitary tract (1).
The activation of CNS GLP-1 receptors is related to
some metabolic actions, such as food intake suppression,
activation of brown adipose tissue, nutrient partitioning,
and regulation of glucose homeostasis. The central injection of the GLP-1 agonist Ex-4 increased insulin secretion during hyperglycemia induced by intravenous
infusion of glucose (2). Along the same lines, acute central
administration of GLP-1 transiently lowered blood glucose levels (3) and increased insulin secretion in response
to a glucose load (3, 4), whereas a GLP-1 receptor antagonist impaired glucose tolerance (3, 4).
In the present issue, Jessen et al. (5) report that administration of the GLP-1 receptor antagonist Ex-9 in the
third ventricle impairs insulin response to hyperglycemia
and causes elevated postprandial glucose (5). Thus, these
results indicate that endogenous brain GLP-1 may have
an insulinotropic effect. However, the authors also found
that the central administration of GLP-1 reduced insulin
release and elevated glucagon secretion (Fig. 1), which
ultimately increased fasting glucose (5). These last results
were unexpected but are explainable by the effects of
CNS GLP-1 on the hypothalamic–pituitary–adrenal
(HPA) axis and the sympathetic nervous system (SNS),
both of which are known to produce hyperglycemia. In
the study by Jessen et al. (5), central GLP-1 increased
neuronal activity in brain regions (paraventricular nucleus and the nucleus of the solitary tract) mediating
autonomic nervous system and HPA activation and
stimulated circulating levels of corticosterone and epinephrine (5). These actions probably override and cofound the insulinotropic effect of endogenous CNS
GLP-1. Importantly, the effects of CNS Ex-9 on impaired insulin secretion did not affect the autonomic nervous system and the HPA, implying that the main
physiological role of brain GLP-1 involves the control of
glucose metabolism. If this is the case, testing lower doses of
GLP-1 might help clarify whether the insulinotropic action
occurs when the activation of SNS and HPA is absent.
Another important aspect of the current study is that
central Ex-9 infusions disrupted the tight regulation
of postprandial blood glucose found in rats freely
ingesting a test meal, which occurred independently of
changes in insulin secretion or gastric emptying (5). This
means that during meals, CNS GLP-1 uses alternative
mechanisms to control blood glucose, and according to
previous studies, this alternative seems to be the control
of hepatic metabolism. In line with this, under a
ISSN Print 0013-7227 ISSN Online 1945-7170
Printed in USA
Copyright © 2017 Endocrine Society
Received 28 April 2017. Accepted 5 May 2017.
Abbreviations: CNS, central nervous system; GLP-1, glucagonlike peptide-1; HPA,
hypothalamic–pituitary–adrenal; SNS, sympathetic nervous system.
For article see page 2124
doi: 10.1210/en.2017-00410
Endocrinology, July 2017, 158(7):2071–2073
https://academic.oup.com/endo
2071
Downloaded from https://academic.oup.com/endo/article/158/7/2071/3920680 by guest on 15 February 2024
Instituto de Investigaciones Sanitarias, Centro de Investigaciones Médicas de la Universidad de Santiago
(CIMUS), University of Santiago de Compostela, Santiago de Compostela 15782, Spain; 2Centro de
Investigación Biomédica en Red (CIBER) Fisiopatologı́a de la Obesidad y Nutrición, Santiago de Compostela
15706, Spain; and 3Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de
Compostela 15782, Spain
2072
Tudurı́ and Nogueiras
Insulinotropic Actions of GLP-1
Endocrinology, July 2017, 158(7):2071–2073
Downloaded from https://academic.oup.com/endo/article/158/7/2071/3920680 by guest on 15 February 2024
central mechanisms responding to
changes in glucose and nutrient availability might also regulate the expression of GLP-1. Clearly, more studies
are needed to assess these issues. On
the other hand, given the complexity
of the numerous neuronal pathways
controlling glucose metabolism, it
will be also important to identify the
neuronal populations by which CNS
GLP-1 regulates insulin secretion
from islets and insulin sensitivity in
other peripheral tissues such as liver,
muscle, and adipose tissue. The hypothalamus and the brainstem, where
Figure 1. Effects of activation (GLP-1) and blockade (GLP-1 antagonist) of central GLP-1
GLP-1 receptor is located, have been
receptors on pancreatic hormone release. The central administration of the GLP-1 receptor
studied largely as key centers for the
antagonist Ex-9 in the third ventricle impairs insulin response to hyperglycemia and causes
elevated postprandial glucose. However, the central administration of GLP-1 also reduced
regulation of glucose metabolism.
insulin release and elevated glucagon secretion. The effects of GLP-1 seem to be mediated by
Therefore, it might be possible that
the activation of the HPA axis and the SNS.
different brain areas control different
peripheral tissues affecting insulin secretion and sensitivity and glucose production and uptake.
hyperinsulinemic–euglycemic clamp, activation of CNS
Supporting this idea, the activation of GLP-1 receptors in
GLP-1 receptor stimulates hepatic glycogen stores and
the arcuate nucleus, but not in the paraventricular nucleus,
decreases muscle insulin-stimulated glucose utilization
reduces hepatic glucose production (4). This specificity
(2). Moreover, the administration of GLP-1 directly into
might also be important to dissect the different actions of
the hypothalamic arcuate nucleus reduced hepatic gluCNS GLP-1, because the manipulation of GLP-1 receptor
cose production (4).
in some areas probably affects one function (i.e., insulin
Despite compelling evidence indicating that brain
secretion) but not others (e.g., stress, food intake).
GLP-1 is a physiological modulator of glucose homeoAnother intriguing topic of the study by Jessen et al. (5)
stasis, there is an ongoing debate on why GLP-1 would
is the possibility that during meals, unlike in fasting
need to reach the brain to control glucose metabolism if
conditions, central GLP-1 action on blood glucose is not
the entire machinery for exerting its antidiabetic actions is
insulin dependent. Why and how CNS GLP-1 exerts its
available in the periphery. An elegant article showed that
effects depending on the nutrient status raises relevant
pancreatic GLP-1 receptor activation is sufficient for the
questions about the physiology of GLP-1. Importantly,
effects of GLP-1 on glucose metabolism and that this
most of the studies assessing the role of brain GLP-1 have
effect does not require neural pathways (6), and a sepbeen done in animals fed a chow diet. If nutrient availability
arate study reported that the lack of neuronal GLP-1
causes a switch in CNS GLP-1–dependent mechanisms, it
receptor does not affect glucose metabolism (7). One
seems plausible to hypothesize that these pathways might
possibility is that disruption of CNS GLP-1 receptor in
be different in lean and obese conditions. So far, in mice
adulthood (achieved with pharmacological tools) and not
fed a high-fat diet, central activation of GLP-1 receptor
in embryonic stages (as it occurs in genetic models) is
increased basal insulin levels and did not modify glucosenecessary to detect the importance of CNS GLP-1 in
stimulated insulin secretion, whereas its blockade deglucose homeostasis. Thus, the use of more sophisticated
creased hyperinsulinemia and reversed insulin resistance.
tools such as pharmacogenetics, optogenetics, and inFinally, the most relevant question is perhaps how imducible knockouts would probably help clarify this issue.
portant the CNS GLP-1 system is in controlling glucose
Assuming that the CNS plays a relevant role in glucose
metabolism in the clinical situation. GLP-1 receptor is indeed
homeostasis, important aspects remain to be elucidated.
expressed in the human brain. Functional studies in the
One important caveat is the scarce knowledge on what
human brain have obvious limitations, and to our knowledge
regulates GLP-1 in the CNS. It has been reported that
there is no clear evidence of an association between brain
leptin and cholecystokinin modulate the activity of GLPGLP-1 and insulin sensitivity in humans. However, one study
1–expressing neurons, suggesting that central GLP-1 exindicated that intranasal GLP-1 administration had benefipression might be regulated by peripheral signals involved
cial metabolic effects in patients with type 2 diabetes (8), and
in energy homeostasis or glucose metabolism. Obviously,
doi: 10.1210/en.2017-00410
these actions might be, at least partially, due to absorption of
GLP-1 directly into the brain as it occurs with insulin.
While endocrinologists wait for more answers, studies
like the one from Jessen et al. (5) are helping to build on
our understanding of the complex puzzle constituted by
multiple organs and mechanisms of the GLP-1 biology.
Acknowledgments
References
1. Göke R, Larsen PJ, Mikkelsen JD, Sheikh SP. Distribution of GLP-1
binding sites in the rat brain: evidence that exendin-4 is a ligand of
brain GLP-1 binding sites. Eur J Neurosci. 1995;7(11):2294–2300.
2073
2. Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E,
Benhamed F, Grémeaux T, Drucker DJ, Kahn CR, Girard J, Tanti JF,
Delzenne NM, Postic C, Burcelin R. Brain glucagon-like peptide-1
increases insulin secretion and muscle insulin resistance to favor
hepatic glycogen storage. J Clin Invest. 2005;115(12):3554–3563.
3. Tudurı́ E, Beiroa D, Porteiro B, López M, Diéguez C, Nogueiras R.
Acute but not chronic activation of brain glucagon-like peptide-1
receptors enhances glucose-stimulated insulin secretion in mice.
Diabetes Obes Metab. 2015;17(8):789–799.
4. Sandoval DA, Bagnol D, Woods SC, D’Alessio DA, Seeley RJ. Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis
but not food intake. Diabetes. 2008;57(8):2046–2054.
5. Jessen L, Smith EP, Ulrich-Lai Y, Herman JP, Seeley RJ, Sandoval D,
D’Alessio D. Central nervous system GLP-1 receptors regulate islet
hormone secretion and glucose homeostasis in male rats. Endocrinology. 2017;158(7):2124–2133.
6. Lamont BJ, Li Y, Kwan E, Brown TJ, Gaisano H, Drucker DJ.
Pancreatic GLP-1 receptor activation is sufficient for incretin
control of glucose metabolism in mice. J Clin Invest. 2012;122(1):
388–402.
7. Sisley S, Gutierrez-Aguilar R, Scott M, D’Alessio DA, Sandoval DA,
Seeley RJ. Neuronal GLP1R mediates liraglutide’s anorectic but not
glucose-lowering effect. J Clin Invest. 2014;124(6):2456–2463.
8. Ueno H, Mizuta M, Shiiya T, Tsuchimochi W, Noma K, Nakashima
N, Fujihara M, Nakazato M. Exploratory trial of intranasal administration of glucagon-like peptide-1 in Japanese patients with
type 2 diabetes. Diabetes Care. 2014;37(7):2024–2027.
Downloaded from https://academic.oup.com/endo/article/158/7/2071/3920680 by guest on 15 February 2024
Address all correspondence and requests for reprints to: Ruben
Nogueiras, PhD, Department of Physiology, Centro de Investigaciones Médicas de la Universidad de Santiago, University of
Santiago de Compostela, and Centro de Investigación Biomédica en Red (CIBER) Fisiopatologı́a de la Obesidad y
Nutrición, Avda de Barcelona s/n, 15782 Santiago de Compostela (A Coru~
na), Spain. E-mail: ruben.nogueiras@usc.es.
Disclosure Summary: The authors have nothing to disclose.
https://academic.oup.com/endo