EuropeanJournalofEndocrinology

ReviewK M Heppner and J Tong Glucose metabolism and ghrelin 171 :1 R21–R32

MECHANISMS IN ENDOCRINOLOGY

Regulation of glucosemetabolism by the ghrelin

system: multiple players and multiple actions

Kristy M Heppner and Jenny Tong1

Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health and

Science University, Beaverton, Oregon, USA and 1Division of Endocrinology, Diabetes and Metabolism, Department

of Medicine, University of Cincinnati, 260 Stetson Street, Suite 4200, Cincinnati, Ohio 45219-0547, USA

Invited Author’s profile

Dr J Tong is Associate Professor of Medicine, Division of Endocrinology, Diabetes and Metabolism,Cincinnati, USA. Her primary research interest is in the regulation of glucose homeostasis and abnolead to type 2 diabetes mellitus. Work in her lab is directed at understanding the role of gut hormoneregulation of glucose metabolism and food intake using a translational approach.

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Published by Bioscientifica Ltd.

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Abstract

Ghrelin is a 28-amino acid peptide secreted mainly from the X/A-like cells of the stomach. Ghrelin is found in circulation in

both des-acyl (dAG) and acyl forms (AG). Acylation is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). AG acts on

the GH secretagogue receptor (GHSR) in the CNS to promote feeding and adiposity and also acts on GHSR in the pancreas

to inhibit glucose-stimulated insulin secretion. These well-described actions of AG have made it a popular target for obesity

and type 2 diabetes mellitus pharmacotherapies. However, despite the lack of a cognate receptor, dAG appears to have

gluco-regulatory action, which adds an additional layer of complexity to ghrelin’s regulation of glucose metabolism.

This review discusses the current literature on the gluco-regulatory action of the ghrelin system (dAG, AG, GHSR, and GOAT)

with specific emphasis aimed toward distinguishing AG vs dAG action.

Urmgh

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European Journal of

Endocrinology

(2014) 171, R21–R32

Introduction

Ghrelin is a 28-amino acid peptide that was discovered as

the endogenous ligand for the growth hormone secreta-

gogue receptor 1a (GHSR) (1). Ghrelin possesses a unique

post-translational modification where an n-octanoic acid

is esterified to the serine3 residue of the peptide molecule.

The presence of a fatty acid (FA) side chain attached to

the ghrelin peptide is required for the full agonism of

GHSR (1). Acylation of ghrelin occurs before secretion

and is catalyzed by the enzyme, ghrelin O-acyltransferase

(GOAT) (2, 3). Ghrelin was initially noted for its

GH-releasing property and was later found to regulate

energy metabolism. Ghrelin has potent orexigenic and

adipogenic effects that are mediated through GHSR

located in the CNS (4, 5). These findings highlighted

ghrelin as a key component of the gut–brain axis in

regulating energy metabolism. In addition to being

expressed in areas that regulate energy homeostasis,

ghrelin and its receptor are both expressed in pancreatic

islet cells, suggesting that ghrelin may have paracrine or

autocrine action in the pancreas (6). Therefore, much

effort was dedicated to exploring the role of ghrelin in

regulating glucose homeostasis. The biological role of

des-acyl ghrelin (dAG) has been questioned due to the

lack of a known cognate receptor. However, increasing

niversity ofalities thatrelin in the

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EuropeanJournalofEndocrinology

Review K M Heppner and J Tong Glucose metabolism and ghrelin 171 :1 R22

evidence suggests that both dAG and AG have gluco-

regulatory action in different species (7, 8, 9). The recent

discovery of the ghrelin-acylating enzyme, GOAT, has

allowed for a more thorough dissection of AG vs dAG

action. This review focuses on the regulation of glucose

metabolism mediated by the ghrelin system, which

consists of dAG, AG, GHSR, and GOAT.

In vitro action of AG on pancreatic hormone secretion

Both ghrelin and GHSR1A are expressed in human, rat,

and mouse islets from early gestation to adulthood (10, 11,

12, 13, 14). Ghrelin is expressed in both a- and b-cells

(15, 16) as well as in a novel, developmentally regulated

endocrine islet cell type that shares lineage with glucagon-

secreting cells (17, 18). While the functional role of

ghrelin in the embryonic islet is not fully known, the

ghrelin-expressing epsilon lineage has a significant impact

on the final cell type composition of mature islets (19).

It has been proposed that the presence of higher number

of ghrelin-expressing epsilon cells in the embryonic islet

may modulate other islet hormone secretion (i.e. insulin)

to prevent hypoglycemia in the fetal period (17).

Moreover, the presence of GOAT expression in the

pancreas suggests that ghrelin acylation can occur within

pancreatic cells (2, 20). A large number of reports

demonstrate that AG acts on isolated islets and pancreatic

b-cells to inhibit glucose-stimulated insulin secretion

(GSIS) (11, 18, 21, 22). However, this effect seems to be

dependent on dose and experimental condition and a

stimulatory effect of AG on insulin secretion has also been

reported (13, 16, 21, 23). Application of a GHSR antagonist

to isolated rat islets or perfused pancreas enhances

glucose-induced insulin release (24), suggesting that the

constitutive activity of the receptor (25, 26, 27) alone may

regulate islet hormone secretion. However, other groups

have reported that a GHSR antagonist itself has no effect

on GSIS in isolated rat islets, but does act to block the

inhibitory action of exogenous AG on GSIS (28).

The inhibitory action of ghrelin on insulin secretion

initially seemed paradoxical because GHSR couples to a

Gaq/11 signaling pathway as first described in pituitary

cells (29). Activation of the Gaq/11 pathway stimulates

insulin secretion rather than inhibition (30, 31). In the

pancreas, AG attenuates cAMP and [Ca2C]i signaling in

b-cells through a non-canonical pathway (11). Further

investigation demonstrated that AG acts through a Gai2

signaling pathway leading to a reduction in cAMP

accumulation and subsequent inhibition of insulin

secretion (32). The underlying molecular mechanisms

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that explain why AG promotes GHSR coupling to a Gai/o as

apposed to a Gaq/11 signal transduction pathway in the

b-cell have recently been explored by Park et al. (33). These

investigators showed that GHSR heterodimerizes with the

somatostatin receptor 5 (SST5) and this heteromer

formation promotes GHSR coupling to Gai/o. Enhanced

GSIS is observed when AG is applied to INS-SJ cells that

overexpress GHSR but lack SST5 (SSTR5) expression. These

data support the requirement of SST5 for GHSR to couple

to a Gai/o pathway leading to AG inhibition of insulin

secretion. The GHSR:SST5 heteromer formation is influ-

enced by the relative abundance of ghrelin and SST (33); a

high (ghrelin):(SST) ratio promotes ghrelin suppression of

cAMP accumulation, whereas lowering the (ghrelin):(SST)

ratio attenuates ghrelin inhibition of cAMP accumulation.

Moreover, lowering the (ghrelin):(SST) ratio enhances

ghrelin-induced [Ca2C]i mobilization. These data indicate

that conditions that alter circulating ghrelin levels (such

as fasting and feeding) can modulate the effect of ghrelin

on insulin secretion (either inhibitory or stimulatory)

through the interaction of ghrelin and SST signaling.

Collectively, the in vitro data in the literature indicate

that AG action on insulin secretion is influenced by the

cell type used and the presence of other G-protein-coupled

receptors, as well as the concentration of ghrelin present.

Therefore, differences in these factors may account for

discrepancies in the literature, which demonstrate that AG

can have both stimulatory and inhibitory actions on GSIS.

In addition to regulating insulin secretion, AG acts on

isolated islet cells and cultured a-cells to regulate glucagon

secretion (34, 35). AG increases glucagon secretion from

both isolated islets and cultured a-cells (16, 34, 36). By

contrast, islets isolated fromGhsrK/K mice show no changes

in glucagon secretion in response to AG, indicating a GHSR-

mediated action (34). This effect is mediated, in part,

through an AG-induced rise in intracellular calcium as

well as AG-induced ERK-phosphorylation in a-cells (34).

Taken together, these data demonstrate that AG acts directly

on pancreatic islets to regulate insulin and glucagon release.

In vitro action of dAG on pancreatic hormone secretion

The des-acyl form of ghrelin was initially characterized

as an inactive by-product of ghrelin secretion and

degradation because it does not act as a full GHSR agonist

(1). Despite this initial characterization, several studies

investigated GHSR-independent actions of dAG on islet

cell function. In INS-1E rat insulinoma cells, dAG

promotes insulin secretion in the presence or absence of

a GHSR antagonist (37). Furthermore, dAG promotes

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EuropeanJournalofEndocrinology

Review K M Heppner and J Tong Glucose metabolism and ghrelin 171 :1 R23

insulin secretion from HIT-T15 cells that lack the expre-

ssion of GHSR further supporting a GHSR-independent

mechanism of action (13). However, other groups have

found no effect of dAG on GSIS from isolated rat islets even

at high doses (1000 nM) (28). There is also evidence that

dAG alone does not regulate islet cell function, but rather

acts to antagonize the inhibitory action of AG on insulin

secretion (21). The receptor that mediates these actions of

dAG is still unknown, and although it is largely accepted

that dAG does not bind and activate GHSR (1), studies on

CHO-K1 cells transfected with human GHSR demonstrate

that dAG can act as a full agonist of GHSR in the high

nanomolar to micromolar range (38). Similarly, high

nanomolar concentrations of dAG activate GHSR in

HEK-293 cells transfected with the ghrelin receptor (9).

Collectively, dAG action on pancreatic islet cell function

is not fully understood, but most studies support a

GHSR-independent action. Few studies demonstrate that

dAG activates GHSR in cell types other than pancreatic

islets. Further investigation of both GHSR-dependent

and -independent actions of dAG is necessary to fully

understand the action of dAG on islet cell function.

Gluco-regulatory action of AG in rodents

Pharmacological treatment as well as genetic manipulation

of ghrelin in rodents indicates that AG regulates GSIS.

Although some data suggest that systemic administration

of AG enhances insulin secretion in rats (39), most rodent

data support that acute systemic administration of AG has

an inhibitory effect on insulin secretion. AG administered

i.v. to rats or mice attenuates GSIS (40, 41). This effect is

likely to be independent of AG-induced GH secretion,

as decreased GSIS and impaired glucose tolerance after

administration of AG are also observed in GH-deficient

mice (11). Pharmacological inhibition of AG synthesis

with a GOAT inhibitor (42) or antagonizing GHSR (28)

significantly increases GSIS and improves glucose toler-

ance. Together, these data indicate that antagonizing

AG or AG signaling enhances glucose-stimulated insulin

release and improves glucose tolerance in rodents.

Consistent with pharmacological studies, genetic

ablation of either ghrelin (Ghrl ) or Goat (Mboat4) leads to

improved glucose tolerance and increased GSIS in 16-h

fasted mice fed on a standard chow diet (43, 44). However,

other groups have found no differences in glucose

tolerance in GoatK/K or GhrlK/K mice when a shorter

fasting paradigm (6 h) was implemented (45, 46). The

different fasting durations used in these studies may

account for the differences in results. Fasting increases

circulating ghrelin levels (47, 48) and it has been recently

demonstrated that the (ghrelin):(SST) ratio determines

whether ghrelin will be stimulatory or inhibitory on

insulin secretion (33). Under fasting conditions, a high

(ghrelin):(SST) ratio promotes GHSR:SST5 heteromer

formation and GHSR then couples to Gai/o to inhibit

insulin secretion. However, when the (ghrelin):(SST) ratio

is low as seen in fed conditions, the GHSR:SST5 heteromer

destabilizes and GHSR no longer couples to Gai/o to inhibit

insulin secretion. This could explain why the glucose-

tolerant phenotype in GoatK/K and GhrlK/K mice is only

apparent under prolonged fasting conditions. However,

further investigation is required to test this hypothesis.

Mice lacking Ghsr have similar glucose tolerance

but decreased GSIS compared with WT mice suggesting

that GHSR ablation leads to improved insulin sensitivity

(49, 50). This is supported by studies that implement

hyperinsulinemic–euglycemic clamps in GhsrK/K mice.

When compared with WT controls, GhsrK/K mice have an

increased glucose infusion rate (GIR), increased glucose

disposal (Rd), and decreased endogenous glucose pro-

duction (EGP) indicating that peripheral and hepatic

insulin sensitivities are both enhanced in the absence

of GHSR signaling (50, 51). Similar to GhsrK/K mice,

improved hepatic and peripheral insulin sensitivities

measured by hyperinsulinemic–euglycemic clamps have

also been reported in ghrelin-deficient mice (43). Subject-

ing WT and Goat-deficient mice to an i.p. insulin tolerance

test led to a similar decrease in blood glucose levels in

both groups suggesting similar insulin sensitivity (52).

However, a more sensitive measure, such as a hyperinsu-

linemic–euglycemic clamp, will be needed to more

accurately determine whether GoatK/K mice have altered

insulin sensitivity compared with WT animals. Together,

pharmacological inhibition or genetic ablation of AG or

AG signaling improves glucose metabolism by enhancing

insulin secretion and insulin sensitivity.

Gluco-regulatory action of dAG in rodents

Although the receptor-mediated actions of dAG have not

been established, dAG has been shown to regulate glucose

metabolism in vivo. During an intravenous glucose

tolerance test (ivGTT), dAG increased GSIS in rats (53).

This effect was blocked by co-administration of AG (53).

Chronic peripheral infusion of dAG does not alter glucose

metabolism in mice fed on a standard chow diet (9, 54).

However, chronic peripheral dAG treatment prevented

high-fat diet-induced glucose intolerance and insulin

resistance (54). Transgenic mice that express the

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EuropeanJournalofEndocrinology

Review K M Heppner and J Tong Glucose metabolism and ghrelin 171 :1 R24

preproghrelin gene under control of the mouse Fabp4

promoter have elevated levels of dAG and display improved

glucose tolerance and insulin sensitivity (55). These

findings suggest that dAG analogs might be a viable option

for the treatment of type 2 diabetes mellitus (T2DM).

However, a better understanding of dAG physiology,

pharmacology, and receptor-mediated actions is required

before a safe and effective therapy can be developed.

Gluco-regulatory action of AG in humans

The effect of AG on fasting plasma insulin and glucose levels

in humans is still a matter of debate. Some groups have

found no changes (56, 57, 58), whereas others have found

that AG increased fasting blood glucose and decreased

plasma insulin following administration of ghrelin

(59, 60, 61). Infusion of supraphysiological doses of AG

to healthy humans decreased insulin secretion during an

ivGTT, which led to an impairment in glucose tolerance

(56). Moreover, infusion of physiological concentration of

AG also attenuated GSIS without altering insulin sensitivity

(57). These findings highlight a pharmacological and

physiological role of AG in regulating GSIS in humans.

Under hyperinsulinemic–euglycemic clamp con-

ditions, ghrelin has also been reported to regulate insulin

action in peripheral tissues. AG infusion decreases GIR and

glucose disposal, while having no effect on EGP in healthy

subjects (62), GH-deficient patients (63), and those who

underwent gastrectomy (64). These data are consistent with

an acute effect of ghrelin to induce peripheral insulin

resistance while sparing insulin sensitivity in the liver

through a GH-independent mechanism. AG infusion into

the femoral artery of healthy subjects increased free FA (FFA)

levels suggesting that ghrelin can act directly on muscle to

increase lipolysis which in turn leads to the development of

insulin resistance (65). This concept was challenged by the

finding that AG infusion directly into the muscle resulted in

decreased interstitial blood glucose concentrations, which

indicates improved muscle insulin sensitivity (66). Further-

more, no alteration in classical insulin signaling pathways

was evident in muscle biopsy samples taken during ghrelin

infusion in another study (63). Further studies are needed

to understand the tissue-specific actions of AG in regulating

insulin sensitivity. As a whole, data in the literature

demonstrate that acute administration of physiological

and pharmacological doses of AG inhibit GSIS, whereas

supraphysiological doses are required to decrease peripheral

insulin sensitivity and glucose tolerance in humans.

The long-term effects of AG on glucose metabolism are

not well defined. In a healthy elderly population, an oral

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ghrelin mimetic taken daily for 1 year caused an increase

in fasting blood glucose levels and a decline in insulin

sensitivity as estimated by the Quicki Index (67). Although

ghrelin mimetics are currently being developed for the

treatment of cancer cachexia, heart failure, and conditions

related to GH deficiency, a better understanding of the

long-term effects of these ghrelin-related pharmaceutical

agents on glucose metabolism is necessary to avoid

unwanted side effects.

Gluco-regulatory action of dAG in humans

The effects of dAG on glucose metabolism have not been

extensively studied in humans (summarized in Table 1) and

the findings have been inconsistent. During i.v. infusion

in humans, AG is deacylated to dAG and therefore it is

important to understand the possible actions of dAG. It is

also important to note that dAG has a slower rate of

clearance when compared with AG (68). An acute i.v. bolus

of dAG in healthy subjects did not alter fasting GH, insulin,

or glucose levels (59), whereas co-administration of dAG

with AG acted to abolish AG’s inhibitory action on fasting

insulin in a similar study population (61). Similarly, dAG

given for 4 days as an i.v. bolus once daily to obese non-

diabetic patients had no effect on fasting or postprandial

serum insulin, glucose, or FFA levels (69). We have recently

shown that a 210-min continuous infusion of AG or

co-infusion of AG and dAG to healthy subjects yielded a

decreased acute insulin response to glucose and i.v. glucose

tolerance, whereas dAG infusion alone did not alter these

parameters (70). However, the lack of effect of dAG on

glucose metabolism is not universally observed. An over-

night infusion of dAG to healthy humans decreased overall

glucose and FFA levels but did not have a significant impact

on overall insulin concentration during the 16-h infusion

period when compared with saline (71). In obese patients

with T2DM, the same duration of dAG infusion decreases

postprandial glucose levels as well as fasting and post-

prandial AG levels without altering postprandial insulin.

Insulin sensitivity, as estimated by the M-index during a

hyperinsulinemic–euglycemic clamp, was improved when

compared with saline infusion (72). Taken as a whole, the

literature on dAG action in humans is very inconsistent

and may be a result of different doses, subject populations,

and length of infusion. Furthermore, the method employed

to stabilize AG (and, therefore, dAG) in blood samples

varies from study to study and this may also account for the

discrepancies between studies. The long-term effects of

dAG and how it interacts with AG to regulate glucose

metabolism still warrant further investigation.

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Table 1 Effects of dAG on glucose homeostasis in humans.

Reference Sample size Dose of dAG Measurements Results

Tong et al. (2014)(69)

17 healthysubjects

210 min of continuousinfusion at(4 mg/kg per h)

Fasting glucose and insulin 5 Fasting insulinFSIGT: AIRg, insulin sensitivity

index (SI), disposition index(DI), and kg

5 Fasting glucose5 AIRg or SI

5 DI5 kg

Ozcan et al. (2013)(71)

Eight overweightT2DM patients

Overnight (16 h) infusion(3 or 10 mg/kg per h)

Glucose and insulin response toa standardized meal. Insulinsensitivity (M-Indexcalculated from H–E clamp)

Y Postprandial glucose5 Postprandial insulin[ Insulin sensitivity during

H–E clampBenso et al. (2012)

(70)Eight healthy

subjectsOvernight (16 h) infusion

(1 mg/kg per h)Meal-related (dinner and

breakfast) and inter-mealglucose, insulin, and FFA

Y Overall glucose AUC5 Overall insulin AUC[ 1 h post-meal insulin AUCY Overall FFA AUC

Kiewiet et al. (2009)(68)

Eight morbidlyobesenon-diabeticpatients

Once daily i.v. bolus(200 mg/day) for 4consecutive days

Fasting and postprandialinsulin, glucose, and FFA

5 Fasting or postprandialinsulin

5 Fasting or postprandialglucose

5 Fasting or postprandialFFA

Gauna et al. (2004)(113)

Eight adult-onsetGH-deficientpatients

i.v. bolus (1 mg/kg) Fasting and postprandialglucose, insulin, and FFA

[ Fasting and postprandialglucose

5 Fasting or postprandialinsulin

5 Fasting or postprandialFFA

Broglio et al. (2004)(60)

Six healthysubjects

i.v. bolus (1 mg/kg) Fasting plasma glucoseand insulin

5 Fasting glucose5 Fasting insulin

Broglio et al. (2003)(58)

Seven healthysubjects

i.v. bolus (1 mg/kg) Fasting plasma glucoseand insulin

5 Fasting glucose5 Fasting insulin

Summary of the current literature of dAG action on glucose metabolism in humans. [, increase; Y, decrease; 5, no change; T2DM, type 2 diabetes mellitus;dAG, des-acyl ghrelin; H–E clamp, hyperinsulinemic–euglycemic clamp; FSIGT, frequently sampled i.v. glucose tolerance test; kg, i.v. glucose tolerance; AIRg,acute insulin response to glucose; FFA, free fatty acid; AUC, area under the curve.

EuropeanJournalofEndocrinology

Review K M Heppner and J Tong Glucose metabolism and ghrelin 171 :1 R25

Ghrelin regulation of glucose homeostasis during

calorie restriction

Endogenous ghrelin levels rise during fasting or calorie

restriction (CR) (4, 47, 48). Furthermore, exogenous

ghrelin stimulates the secretion of all four counter-

regulatory hormones (GH, cortisol, epinephrine, and

glucagon), and therefore it has been implicated in

maintaining blood glucose in states of negative energy

balance. GhrlK/K and GhsrK/K mice placed on a 50%

calorie-restricted diet have significantly lower blood

glucose levels when compared with WT controls (73).

Placing animals on a 60% calorie-restricted diet depletes

fat mass stores, which then leads to severe hypoglycemia

in both GhrlK/K and GoatK/K mice (44, 74). Hypoglycemia

in these animals is attributed to the lack of AG-induced

GH secretion as AG or GH treatment rescues the

hypoglycemic phenotype in calorie-restricted GoatK/K

mice (44). However, the hypoglycemic and the relative

GH-deficient phenotypes were not universally observed

(75, 76). Adult-onset isolated GH-deficient (AOiGHD)

mice placed on a 60% calorie-restricted diet lose

significantly less fat mass, but maintain similar blood

glucose levels as controls, (75) indicating that GH may

regulate adiposity during CR, but is not essential to

maintain glycemia. Furthermore, mice lacking Ghrl,

Ghsr, or Goat expression maintain similar blood glucose

levels as WT controls when placed on a 60% calorie-

restricted diet even when fat mass stores were completely

depleted (76). The reason for the discrepancies among

these data is unclear, but differences in the age of the mice

could be one of the contributing factors. Zhao et al. (44)

and Li et al. (74) used young 8-week-old male mice that are

still in the growing phase, whereas Yi et al. (76) and Gahete

et al. (75) used mature (7–13 months) adult mice. In

rodents, pancreatic ghrelin expression is highest before

birth and slowly declines after birth (16), while gastric

ghrelin gene expression increases rapidly after birth and

then slowly declines with age (77). These data may suggest

that ghrelin in the pancreas plays a more predominant

role in regulating glucose metabolism at early stages of life.

The role of ghrelin in glucose counter-regulation during

acute or chronic CR needs to be more clearly defined.

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Review K M Heppner and J Tong Glucose metabolism and ghrelin 171 :1 R26

CNS regulation of glucose metabolism

A large body of literature provides clear evidence that

the CNS is involved in regulating peripheral glucose

metabolism (78, 79). Islet cell function is influenced by

the CNS through the autonomic nervous system (80).

Both parasympathetic and sympathetic neurons synapse

on b- and a-cells (81) to activate or inhibit insulin

secretion (82). GHSR is found in parasympathetic pregan-

glionic neurons (83) and the brainstem, where ghrelin

activates pathways controlling sympathetic and parasym-

pathetic nerve activity (84, 85, 86). These data raise the

possibility that in addition to direct effects, AG may

suppress insulin secretion indirectly via neural signaling.

For example, AG inhibited GSIS when infused into the

portal but not the femoral vein, and hepatic vagotomy or

intraportal atropine diminished this inhibitory effect

(41, 87). In humans, administration of AG increased

plasma epinephrine (88) and decreased heart rate varia-

bility (89), suggesting that AG mediates a sympathetic

response that could affect islet secretion. An intact vagus

nerve is required for many of the physiological effects of

AG in mice and humans (10, 89, 90), but no studies have

directly tested the hypothesis that AG controls insulin via

the autonomic nervous system. I.c.v. administration of

AG to rodents has shown a stimulatory rather than an

inhibitory action on plasma insulin levels. Chronic i.c.v.

administration of AG to rats increases fasting insulin levels

that are independent of the hyperphagia induced by

AG (91). Similarly, chronic i.c.v. administration of AG

increases GSIS in mice (9). However, the central

mechanisms that mediate the stimulatory action of AG

on GSIS have not been identified. Furthermore, it is

unclear as to why AG has an inhibitory action on GSIS in

the periphery, whereas it appears to be stimulatory when

administered centrally.

Limited data are available on the central effects of

dAG on glucose homeostasis. One study demonstrated

that i.c.v. administration of dAG to mice increases GSIS

through a GHSR-dependent mechanism (9). Whether this

is a pharmacological effect or a physiological action of

dAG requires further investigation.

Ghrelin interaction with glucagon-like peptide 1

The postprandial release of glucagon-like peptide 1 (GLP1)

stimulates GSIS by enhancing cAMP signaling and increas-

ing [Ca2C]i in pancreatic b-cells (92). AG inhibits insulin

secretion by suppressing glucose stimulated [Ca2C]i in

b-cells (11), and therefore, it was hypothesized that AG can

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counteract the stimulatory action of GLP1 on insulin

secretion (93). Indeed, the effect of GLP1 on [Ca2C]i levels

in isolated b-cells was attenuated by administration of

AG (93). Isolated rat pancreatic islets treated with both

GLP1 and a GHSR antagonist had increased insulin release

when compared with treatment with GLP1 alone (93).

The clinical relevance of these findings was tested in a

study of Prader–Willi syndrome (PWS), a congenital

disease that is associated with hyperphagia, T2DM, and

elevated ghrelin levels. A patient with PWS treated with

liraglutide, a GLP1 analog, for 12 months (94) lost 5.7 kg of

weight, and had improved glycemic control and lower

plasma ghrelin levels. The metabolic benefits observed

with liraglutide treatment may be in part due to GLP1

suppression of ghrelin secretion, but the mechanisms

involved require further clarification. However, a recent

study using GLP1 infusion at a rate of 1 pmol/kg per min

failed to observe any changes in ghrelin levels in either

obese T2DM patients or healthy lean subjects (95).

Conversely, administration of ghrelin has been reported

to accelerate gastric emptying and increase GLP1 secretion

following a test meal in healthy subjects (96). Collectively,

these data indicate that GLP1 and ghrelin interact with

each other at the level of the pancreas to regulate islet

cell function. Further studies are needed to address the

interaction of ghrelin and GLP1 in other tissues that

regulate glucose metabolism such as the brain.

Metabolic benefits of bariatric surgery: is ghrelin

a key player?

Bariatric surgery is the most effective way to reduce body

weight and improve glucose metabolism in obese subjects

(97). Studies comparing the effects of the two most

common bariatric procedures, Roux-en-Y gastric bypass

(RYGB) and vertical sleeve gastrectomy (VSG), in obese

T2DM patients demonstrate that body weight reduction

and remission of T2DM are comparable in patients who

undergo one vs the other operation (98). Furthermore,

patients receiving either RYGB or VSG had similar

improvements in oral glucose tolerance 6 months after

surgery (99) as well as improved insulin sensitivity as

measured by the homeostasis model assessment index

(100). Studies in rodents and humans have demonstrated

that both surgical procedures result in the development

of improved glycemic control, which interestingly occurs

before a significant reduction in body weight and

adiposity suggesting that other factors besides weight

loss are involved (101, 102, 103, 104). RYGB and VSG

produce similar metabolic benefits through a very

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EuropeanJournalofEndocrinology

Review K M Heppner and J Tong Glucose metabolism and ghrelin 171 :1 R27

different rearrangement of the gastrointestinal anatomy

(reviewed in (105)). A common characteristic of the two

types of surgeries is that they both prevent nutrients

from contacting ghrelin-producing cells in the stomach.

A number of studies indicate that AG has detrimental effects

on glucose metabolism, and therefore, many groups aimed

to determine whether circulating ghrelin levels are lower

following bariatric surgery. Indeed, ghrelin levels are lower

in subjects who underwent RYGB when compared with

normal weight controls as well as subjects who experienced

diet-induced weight loss (106). However, these results have

been inconsistent and some groups have found no changes

in fasting or postprandial ghrelin levels after RYGB, whereas

other groups found decreased fasting and postprandial

ghrelin levels (reviewed in (107)). Ghrelin measurements

following VSG have been more consistent, and most groups

find reduced fasting and postprandial ghrelin levels in VSG-

operated patients (108, 109, 110, 111). Most studies find

that VSG causes a 20–30% reduction in fasting ghrelin levels

α-cell

Low (AG)(obesity/insulin resistance,

GOAT inhibition, andgastrectomy/gastric sleeve

surgery)

Pancreatic

Glucose

GHSRGlucagon

AG

Figure 1

AG regulation of islet cell function. Similar to the schematic

depicted by Park et al. (33), high AG concentrations activate GHSR

on a-cells to promote glucagon secretion and activate GHSR on

b-cells to inhibit insulin secretion. GHSR signaling in b-cells may

be regulated by heterodimerization with other GPCRs. These

combined actions will lead to an overall increase in circulating

glucose levels. High AG concentrations occur during CR, weight

loss, in PWS, and after pharmacological administration of AG

(108, 109, 110, 112), while some show w60% reduction

from presurgical levels 6 months following surgery (111).

The relevance that these changes in circulating ghrelin

levels have to the metabolic benefits of bariatric surgery

has recently been challenged by a study in which DIO

GhrlK/K mice were subjected to VSG. Interestingly,

VSG-operated GhrlK/K mice achieved a similar improve-

ment in oral glucose tolerance when compared with their

VSG-operated WT controls (113). In addition to improve-

ments in glucose metabolism, a reduction in body weight

and adiposity is also seen in the VSG GhrlK/K animals

indicating that ghrelin is not the critical hormone that

determines the metabolic benefits of VSG (113). However,

these genetically modified animals may undergo compen-

sation by other metabolic signaling systems during

development, which is a factor that cannot be ignored

using this gene deletion approach. Therefore, the relevance

of postoperative ghrelin changes to the overall metabolic

benefits of bariatric surgery remains to be elucidated.

High (AG)(CR, weight loss, PWS,

and pharmacological AG administration)

Islets

β-cell

GHSR

GHSR

OtherGPCRs?

SST5

AGInsulin

analogs. When AG levels are low, AG does not act to regulate

blood glucose through modulation of islet cell function. Low AG

concentrations occur in obese and insulin-resistant subjects,

following pharmacological inhibition of GOAT, and following

gastrectomy or gastric sleeve surgery. AG, acyl ghrelin; GOAT,

ghrelin O-acyltransferase; CR, calorie restriction; GHSR, growth

hormone secretagogue receptor; SST5, somatostatin receptor

subtype 5; GPCR, G-protein-coupled receptor.

www.eje-online.org

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EuropeanJournalofEndocrinology

Review K M Heppner and J Tong Glucose metabolism and ghrelin 171 :1 R28

Summary

The gastrointestinal hormone ghrelin has received much

attention for its ability to regulate glucose metabolism.

The two major ghrelin isoforms found in circulation, AG

and dAG, appear to have distinct actions. From in vitro

studies to clinical studies in humans, the majority of

reports demonstrate that AG has an inhibitory effect on

GSIS and tissue glucose uptake when administered

peripherally. Conversely, blocking AG synthesis improves

glucose tolerance and enhances insulin secretion in

rodents (42). Therefore, pharmaceutical agents that aim

to antagonize AG or AG signaling could be potential

therapeutics for treating T2DM. A summary of AG action

in pancreatic islets is provided in Fig. 1. The effects of dAG

on b-cell function and insulin action are less clear. Some

studies suggest that dAG has no effect, whereas others

indicate that dAG can stimulate insulin secretion and

improve glucose tolerance, and still others show that dAG

acts to antagonize AG action. Before dAG analogs can be

used for therapeutic purposes, it is essential to clearly

define the physiological function of dAG and to uncover

possible dAG receptor-mediated actions. The rise and fall

of AG and dAG correspond to the duration of fasting (47).

It is likely that the ghrelin action on the pancreas and/or

the CNS is linked to the metabolic states of the species in

order to maintain glucose homeostasis.

Collectively, the major effects of ghrelin are linked

as a protective mechanism against starvation: orexigenic

actions to promote food intake, stimulation of GH

secretion to promote lipolysis and restrict peripheral

glucose uptake, and restraint of insulin secretion to

prevent hypoglycemia. Much research is still needed to

learn about the contribution of each of the components of

the ghrelin system (dAG, AG, GOAT, and GHSR) to the

regulation of these functions. Lastly, identifying the

tissue-specific actions of each of these components

through the use of advanced genetic technology and

pharmacology will help to pinpoint the underlying

mechanisms involved in ghrelin system’s regulation of

glucose and energy homeostasis.

Declaration of interest

The authors declare that there is no conflict of interest that could be

perceived as prejudicing the impartiality of the review.

Funding

This review did not receive any specific grant from any funding agency in

the public, commercial or not-for-profit sector.

www.eje-online.org

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Received 4 March 2014

Revised version received 3 April 2014

Accepted 7 April 2014

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