Brain as an endocrine organ

The Brain
as an Endocrine Organ
Alaa Wafa . MD
Associate Professor of Internal Medicine
Diabetes & Endocrine Unit.
Mansoura University

Agenda
• Historical perspective
• Brain control of glucose homeostasis
• Brain centerd glucoregulatory system (BCGS).
• Glucose effectiveness.
• Dysfunction in the BCGS.
• Conclusion

Agenda
• Brain centered glucovregulatory system BCGS.
• Conclusion
.

Claude Bernard
(1813-1878)
• Discovery of new
function of liver--
glucose secretion
into blood (1848)
• Previously thought
that only plants could
produce sugar
• Sugar must be taken
in by diet

Historical perspective
The first information regarding the role of
the central nervous system (CNS) in glucose
homeostasis dates from the 19th century, when
Claude Bernand 1854 showed that when
puncturing the flour of the fourth cerebral ventricle
in dogs he induced hyperglycemia.

In 1953 Jean Mayer mentioned the existence of two
types of cells:
 glucose excited (GE) neurons-activated by an
increase in glucose concentration
 glucose inhibited (GI) neurons activated by a decrease
in glucose concentration.

Twelve years later in 1965, ( during experiments on rabbits ),
Shimazu and his colleagues proved that electrical
stimulation of:
 VMH (containing mainly sympathetic nuclei) up
regulated plasma glucose level and decreased hepatic
glycogen
 LH (containing mainly parasympathetic nuclei) down
regulated plasma glucose and barely increased hepatic
glycogen.

Further studies underlined the importance of CNS in
glucose metabolism:
• An increase in glucose level and hyperglycemic
hormones was seen after intracerebroventricular
administration of 2-deoxyglucose (2-DG), a glucose
antagonist. These effects were altered by
hypothalamic deafferentation.
• At the same time counterregulatory response
following insulin administration in dogs was blocked
once sectioning the spinal cord or the vagus

It is the maintenance of
blood glucose level
within the normal range
What is glucose
homeostasis???

Glucose Homeostasis
• brain has high consumption of glucose
• during exercise, working muscle competes
with brain for glucose
• Many redundant systems for maintaining
glucose homeostasis
• hepatic glucose production (glycogen, lactate,
pyruvate, glycerol, alanine)
• pancreatic hormones (insulin, glucagon)
• sympathoadrenal stimulation (epinephrine)

Agenda
• Brain centerd glucoregulatory system BCGS.
• Conclusion
.

CNS control of glucose homeostasis
• A large literature documents glucoregulatory
effects of pharmacological or genetic
interventions targeting neurons in any of
several areas of the hypothalamus (arcuate,
ventromedial and paraventricular
hypothalamic nuclei) and brain stem.

• Injection of insulin or glucose into discrete
hypothalamic areas can lower blood glucose
levels and increase liver insulin sensitivity.
• A similar effects are achieved by restoring
functional leptin receptors to specific
hypothalamic nuclei of animals that otherwise
lack them.

• Conversely, deletion of receptors for either
insulin or leptin (or their downstream
signalling intermediates) from defined
hypothalamic neurons causes glucose
intolerance and systemic insulin resistance.
These highlight how the brain can influence
glucose homeostasis in response to afferent
input from peripheral signals
?

Control of hepatic glucose production
• Insulin regulates hepatic glucose
production (HGP) through a direct action
on hepatocytes, insulin has also been
proposed to regulate HGP via an indirect
mechanism involving insulin action at a
remote site.

Direct and indirect control of
HGP

Hormonal and nutrient pathways of
HGP regulation in hepatocytes

Direct control of hepatic glucose
production
• The direct action of insulin on hepatocytes
involves its binding to insulin receptors and
activation of signal transduction cascades ,of
particular relevance to glycaemic control is
the insulin receptor substrate
phosphatidylinositol-3-OH kinase (IRS–PI(3)K)
pathway , which mediates insulin inhibition of
both glycogenolysis and gluconeogenesis, the
two primary determinants of HGP.

Indirect control of hepatic glucose production

Indirect control of hepatic glucose
production
• The concept that HGP can also be controlled by insulin action at a
remote site was first proposed and received compelling support in
a recent study of ‘TLKO’ mice with hepatocytes unresponsive to
insulin owing to liver-specific deletion of key signal transduction
molecules (the two Akt isoforms as well as FOXO1).
• In these animals, insulin cannot directly regulate HGP via the Akt–
FOXO1 pathway. However, rather than exhibiting the expected loss
of regulation, both HGP and systemic glucose homeostasis are
controlled normally in these mice, even in response to exogenous
insulin.

These data point to the existence of an indirect pathway through
which insulin and nutrients can regulate HGP even when
hepatocytes themselves are insensitive to direct insulin action.
An intriguing question is what mechanism mediates the indirect
control of HGP by insulin ?
Although other explanations are possible, the BCGS is both
activated by insulin and capable of regulating HGP in humans as
well as rodent modeL.

Schematic illustrations of brain- and islet-
centred glucoregulatory systems

The term glucose effectiveness (GE) refers to the effect of an
increased concentration of glucose to promote its own disposal,
independent of insulin action‘insulin-independent glucose disposal’.
It is noteworthy that, by definition, GE increases in response to rising
blood glucose levels, and that glucose action on arcuate nucleus
neurons has a rapid glucose-lowering effect.

Glucose Effectiveness
• Collectively, these observations support a model in
which, by increasing plasma concentrations of insulin,
leptin, GLP-1, FGF19 and glucose, consuming a meal
generates diverse signals that activate the BCGS.
• This BCGS activation then contributes to glucose
disposal via stimulation of both insulin-dependent and
-independent mechanisms that, together with islet
responses, are essential for proper glucose handling
by the body

Hormonal action in the hypothalamic arcuate nucleus regulates hepatic glucose fluxes A:
insulin, binding to its receptor, activates IRS and PI3K.
Carol K. L. Lam et al. Physiology 2009;24:159-170
©2009 by American Physiological Society

Model of the hypothalamic regulation of hepatic glucose production.
Gregory J. Morton, and Michael W. Schwartz Physiol Rev 2011;91:389-411

CNS neurocircuits regulating energy and
glucose homeostasis.
Gregory J. Morton, and Michael W. Schwartz Physiol Rev 2011;91:389-411

GLP-1 activates brain areas in humans
that regulate food intake
Pannacciulli et al. Neuroimage 2007;35:511–7
PET scan of the hypothalamus
GLP-1, glucagon-like peptide-1; PET, positron emission tomography

For internal use Liraglutide is not approved for weight management
GLP-1 induces neuron activation in
multiple sites in the rat brain
Vehicle
Liraglutide
AP
NTS
Brain stem (receiving input from the intestine)
• Increased cFos in area postrema (AP) and nucleus
tractus solitarus (NTS)
Amygdala (associated with eating patterns)
• Increased cFos in the central amygdala
Hypothalamus (main appetite center in the brain)
• Increased cFos in the paraventricular nucleus
• Decreased cFos in the arcuate nucleus
Raun, Vrang, Jelsing, Tang-Christensen and Bjerre Knudsen.
Poster 584 at ADA 2010. Diabetes 2010;59(S1):A159.
.

Four criteria define what is considered a physiologically relevant satiety signal:
1. Levels must be rapidly and transiently increased by energy intake
2. Appetite suppressing effects cannot be caused only by nausea or malaise
3. Appetite suppressing effects must be observed at physiological doses
4. Blockade of the signal must increase energy intake
, YES; ×, NO; ? Data unclear or not tested
GLP-1 is classified as a ‘true’ satiety
signal
Criteria
Hormone 1 2 3 4
CCK    
GLP-1    
OXM   ? (?)
PYY (?)   ×
PP (?)  ? ?
Amylin   ? (?)
Leptin ×  ? ×(?)
Woods. Physiol Behav 2005;86:709–16
CCK, cholecystokinin; GLP-1, glucagon-like peptide-1; OXM, oxyntomodulin; PP, pancreatic polypeptide; PYY, peptide YY

• The effects of GLP-1 on appetite and
energy intake are mediated via:
1. GLP-1 secreted from the gut that
signals the brain through GLP-1R
activation on vagal afferents; or
2. GLP-1 secreted and released in brain
that activates the GLP-1R in specific
appetite centres
GLP-1 effects on appetite and energy intake
may be mediated via the brain–gut axis
Simpson et al. Expert Rev Endocrinol Metab 2008;3:577–92; Cooke & Bloom. Nature Reviews Drug Discovery 2006;5:919–31
Vagus nerve
GLP-1
GLP-1
GLP-1R, glucagon-like peptide-1 receptor

OMINOUS OCTET:A New Paradigm for the
Treatment of Type 2 Diabetes Mellitus

Two–system control of glucose
homeostasis

Is diabetes a failure of two
systems?

Is diabetes a failure of two systems?

Prospects for diabetes
remission

The mechanism underlying metabolic benefit conferred by bariatric procedures is
incompletely understood but may involve improvements of both islet- and brain-
centred glucoregulatory systems.
A study in a model of bariatric surgery (‘duodenal exclusion’) showed that blood
glucose levels could be normalized in diabetic rats via insulin-independent activation
of a neural circuit that inhibits HGP.
Although mechanisms underlying BCGS activation by bariatric surgery await further
study, recent evidence offers a link between enhanced secretion of FGF19, the
nervous system and the gastrointestinal tract.

Conclusions
• Normal glucose homeostasis depends on cooperation
between the brain-centered glucoregulatory system (BCGS) and
the islet-centered system. Damage to either side of the system
initiates secondary damage to both sides. Glucose
intolerance develops after both systems are compromised.
• l BCGS model : Increasing postprandial levels of GLP-1, FGF19,
insulin, and glucose activate the BCGS, which, in turn, stimulates
both insulin-dependent and insulin-independent mechanisms that
coordinate with islet cell functioning to maintain homeostasis.
• Islet-centered model: Increased postprandial blood glucose
levels stimulate islet cells to release insulin, which acts on the
liver to decrease hepatic glucose production and on adipose and
muscle tissues to increase glucose uptake.

Conclusion
Looking to the future, there are several important fundamental
questions to address before the broader scientific community
can (or should) be expected to embrace a role for the brain
comparable to that of the islet in the day-to-day control of
blood glucose levels.
 Studies are needed to determine whether the maintenance of
normal GE, which is known to be required for normal glucose
tolerance, is dependent on a properly functioning BCGS ?
 A related and equally important question is whether the link
between reduced GE and the development of T2D is explained
by BCGS dysfunction ?
Such findings would offer direct evidence that failure of
both the BCGS and the islet is integral to diabetes
pathogenesis.

Thank
you
dralaawafa@hotmail.com

Brain as an endocrine organ

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