The Brain as an Endocrine

OrganAlaa Wafa . MD

Associate Professor of Internal MedicineDiabetes & 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

• Historical perspective

• Brain control of glucose homeostasis

• Brain centered glucovregulatory system BCGS.

• Glucose effectiveness.

• Dysfunction in the 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 ofthe central nervous system (CNS) in glucosehomeostasis dates from the 19th century, whenClaude Bernand 1854 showed that when puncturing the flour of the fourth cerebral ventricle in dogs he induced hyperglycemia.

Historical perspective

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.

Historical perspective

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.

Historical perspective

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

• Historical perspective

• Brain control of glucose homeostasis

• Brain centerd glucoregulatory system BCGS.

• Glucose effectiveness.

• Dysfunction in the BCGS.

• Conclusion

.

The gut-brain-liver axis

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.

CNS control of glucose homeostasis

• 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.

CNS control of glucose homeostasis

• 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.

Insulin Signal Transduction

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.

Indirect control of hepatic glucose production

Indirect control of hepatic glucose production

Agenda

• Historical perspective

• Brain control of glucose homeostasis

• Brain centerd glucoregulatory system BCGS.

• Glucose effectiveness.

• Dysfunction in the BCGS.

• Conclusion

.

Schematic illustrations of brain- and islet-centred glucoregulatory systems

Agenda

• Historical perspective

• Brain control of glucose homeostasis

• Brain centerd glucoregulatory system BCGS.

• Glucose effectiveness.• Dysfunction in the BCGS.

• Conclusion

.

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 amygdalaHypothalamus (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 intake2. Appetite suppressing effects cannot be caused only by nausea or malaise3. Appetite suppressing effects must be observed at physiological doses4. Blockade of the signal must increase energy intake

, YES; ×, NO; ? Data unclear or not tested

GLP-1 is classified as a ‘true’ satiety signal

CriteriaHormone 1 2 3 4CCK 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

Agenda

• Historical perspective

• Brain control of glucose homeostasis

• Brain centerd glucoregulatory system BCGS.

• Glucose effectiveness.

• Dysfunction in the BCGS.

• Conclusion

.

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