Contents
Introduction
Gene and protein information for GPR40
Ligands
Physiological role of GPR40 in mediating insulin
secretion
Emerging potential drugs targeting GPR40 for the
regulation of insulin secretion
Conclusion and perspectives
Introduction
Type 2 diabetes is one of the crucial health
problems worldwide, and its prevalence is rising dramatically
(1,2). In addition to insulin resistance,
pancreatic β-cell dysfunction typically characterized by
progressive decreases in glucose-stimulated insulin secretion
(GSIS), is another hallmark of type 2 diabetes. As is well known,
plasma glucose is a leading adaptor in mediating insulin secretion.
Elevated blood glucose levels cause glucose to diffuse into β-cells
through the non-insulin-dependent glucose transporter-2 (Glut2) and
then glucose metabolism results in the production of adenosine
triphosphate (ATP). Increased ATP levels, particularly a rise in
the ratio of ATP/adenosine diphosphate (ADP), lead to the closure
of K+-ATP channels and subsequent plasma membrane
depolarization. This opens voltage-dependent Ca2+
channels and causes subsequent Ca2+ influx, and
increased cytoplasmic free Ca2+ levels prompt insulin
granule exocytosis, thus triggering insulin secretion (3) (Fig.
1).
Additionally, free fatty acids (FFAs) are not only
essential dietary nutrients, but play a crucial role in the
modulation of insulin secretion (4–6).
It is believed that prolonged exposure to elevated FFAs results in
impaired insulin secretion involving lipotoxicity which exerts the
deleterious effects of lipid accumulation on β-cell secretory
function by inhibiting insulin biosynthesis (7,8),
promoting programmed cell death (9) and inducing reactive oxidant species
(ROS) generation and inflammatory reaction (10,11). However, recent evidence indicates
that not all FFAs inhibit insulin secretion. The long-term in
vitro treatment of INS-1 rat pancreatic β-cells by
polyunsaturated α-linolenic acid does not reduce insulin secretion
and saturated palmitic acid-induced suppression of basal insulin
secretion and GSIS is attenuated by α-linolenic acid (12). On the contrary, FFAs acutely
enhance basal insulin secretion and GSIS, and the molecular
mechanisms involve the surface receptors of pancreatic β-cells.
Over the past decades, a series of receptors have been identified
for FFAs, such as the nuclear receptors, peroxisome
proliferator-activated receptors (PPARs), fatty acid-binding
proteins (FABPs) and G-protein-coupled receptors (GPRs), a large
family of cell surface receptors (13,14). Moreover, cell surface receptors
have been proven to play a key role in FFA biological processes,
which suggests that FFAs do not need to enter into the cells to
elicit their effects. Recently, GPRs have been successfully
identified as multiple cell surface receptors for FFAs, also known
as FFA receptors (FFARs). Among these, GPR41 and GPR43, known as
FFAR3 and FFAR2, respectively, are activated by short-chain fatty
acids, such as formate, acetate, propionate and butyrate (15), while GPR40 and GPR120 by medium-
and long-chain ones, such as palmitate, palmitoleate and oleate
(16,17). GPR41 is expressed in adipose
tissue and the gastrointestinal tract, and short-chain FFAs induce
leptin secretion from adipocytes by stimulating GPR41, suggesting
that GPR41 regulates energy homeostasis (18). GPR43 has been detected in immune
cells, adipocytes and the gastrointestinal tract, and contributes
to inflammatory responses and metabolic homeostasis (19–21). GPR120, primarily expressed in the
intestine and macrophages, promotes glucagon-like peptide-1 (GLP-1)
secretion from the intestine and represses macrophage-induced
inflammation (22,23). GPR40, namely FFAR1, is executively
expressed in pancreatic β-cells and mediates insulin secretion upon
medium- and long-chain FFA stimulation (16,24). Type 2 diabetes islets have a lower
GPR40 expression with impaired insulin secretion (25) and GPR40 knockout leads to
decreases in both glucose- and arginine-stimulated insulin
secretion in vivo without changes in insulin sensitivity
(26). The overexpression of
GPR40 in pancreatic β-cells augments GSIS and improves glucose
tolerance in normal and diabetic mice (27), and the GPR40 agonist also displays
the same effects in rodents (28). Therefore, GPR40 has received
considerable attention as a potential therapeutic target for type 2
diabetes, and a series of novel agonists for GPR40 have been found,
leading to the development of new drugs for type 2 diabetes
(29,30).
Gene and protein information for GPR40
In addition to being expressed in pancreatic β-cells
in a range of species including mice, rats and humans (6,31,32), GPR40 is expressed at very low
levels in all other tissues (16,33). The GPR40 gene is located on human
chromosome 19q13.1, and shares approximately 30–40% identity with
GPR41 and GPR43 (14). The mouse
gene is composed of a 24-bp non-coding exon, a 698-bp intron and a
4402-bp second exon, of which the intron is located between the 2
exons and is spliced out during RNA processing, and the second exon
contains the full coding sequence. Three evolutionarily conserved
sequences (HR1-HR3) are located upstream of the first exon. Among
these, HR2 is a potent β-cell-specific enhancer and binds
transcription factors, PDX1 and BETA2, and is thus responsible for
regulating the transcriptional levels of the gene in β-cells
(34,35). GPR40 belongs to class A GPRs,
showing a typical 7-transmembrane (TM) domain structure spanning
α-helices with 3 hydrophilic intracellular and 3 hydrophilic
extracellular loops. The N-terminus is located extracellularly
while the C-terminus resides in the cytosol (36). Although the full protein
information for GPR40 has not yet been revealed, its structure has
been analyzed by computational modeling, site-directed mutagenesis
and so on. GPR40 contains 2 sites (Thr215 and Ser298) bearing
potential protein kinase C (PKC) phosphorylation and 2 putative
N-glycosylation ones (Asn155 and Asn165) (37). Additionally, the anchored sites of
fatty acids are determined in amino residues Arg183, Asn244 and
Arg258 located close to the extracellular domains of TM5, 6 and 7
when GPR40 is stimulated. In the resting state, the Arg183 and
Arg258 residues consist of an ionic lock with 2 glutamate residues
(Glu145 and Glu172) located in TM2. In the presence of ligands,
however, the ionic lock is broken, and then Arg183 and Arg258 are
anchored by fatty ligands (37–40). A recent study revealed that His137
directly refers to ligand recognition through the NH-π interaction
with GW9508, while His86 does not interact with GW9508 in the NH-π
interaction (41). It has been
proven that the Arg211His and Gly180Ser polymorphisms in the GPR40
gene are strongly linked to receptor functionality and insulin
secretion (42,43).
Ligands
Three independent groups have reported that GPR40 is
activated by medium- and long-chain FFAs in the micromolar
concentration range (44–46), including saturated fatty acids and
unsaturated fatty acids. The agonistic activity of the former is
dependent on chain length from at least 10 carbon atoms (capric
acid) to as many as 23 (tricosanoic acid), of which pentadecanoic
acid (C15) and palmitic acid (C16) display the most potent
agonistic activity, while capric acid (C10) demonstrates either
weak or no activity. However, the latter, including a variety of
monounsaturated fatty acids such as 9Z-palmitoleic acid (C16:1) and
9Z-oleic acid (C18:1) and polyunsaturated fatty acids such as
9Z,12Z-linoleic acid (C18:2) and 5,8,11-eicosatrienoic acid
(C20:3), do not appear to be dependent on carbon chain length or
the degree of saturation (44).
Additionally, a series of synthetic agonists such as GW9508, AMG
837 and 3-substituted 3-(4-aryloxyaryl)-propanoic acids have been
recently reported (47–50). Several synthetic GPR40 antagonists
have also been well described, including DC260126 and GW1100
(51–54).
Physiological role of GPR40 in mediating
insulin secretion
Elevated plasma FFAs often co-exist with type 2
diabetes and obesity, and fatty acids play an important role in
insulin secre-tory function of β-cells. In the absence of fatty
acids, GSIS is impaired. On the contrary, an increase in blood FFA
concentration augments GSIS (55). Contrary to the acute effects of
FFAs, chronically elevated fatty acids have been strongly linked to
reduced insulin secretion (56).
However, it is not always true that all FFAs impair β-cell
function; prolonged exposure to unsaturated FFAs, such as
polyunsaturated α-linolenic acid but not saturated palmitic acid
protects β-cell function and augments GSIS (12). As a receptor of medium-and
long-chain FFAs, GPR40 has been well documented to contribute to
insulin secretion. GPR40 is highly expressed in human pancreatic
β-cells, islet cell tumors and various pancreatic-derived cell
lines, including INS-1E, MIN6, β-TC-3 and HIT-T15. Islets from type
2 diabetic patients chronically exposed to FFA have a lower GPR40
mRNA expression than those from non-diabetic multiorgan donors,
following impaired insulin secretion (25,57). Likewise, the deletion of GPR40
decreases GSIS in vivo in mice without affecting
intracellular fuel metabolism in islets and insulin sensitivity
(26,58), and the islets from GPR40 knockout
mice have a reduced capacity to release insulin in response to
fatty acids (26,59), which suggests that GPR40 is
required for normal insulin secretion. The overexpression of GPR40,
however, improves glucose tolerance with an increase in insulin
secretion in normal and diabetic mice. Moreover, mice have been
found to be resistant to high-fat diet-induced glucose intolerance,
and isolated islets from mice potentiate enhanced insulin secretion
in response to high glucose and resist the impairment of β-cells in
insulin secretion against prolonged palmitate exposure (27).
Upon stimulation by agonists, GPR40 couples to the
Ca2+-mobilizing G protein, Gaq (44). This results in phospholipase C
(PLC) activation which promotes plasma membrane
phosphatidylinositol-4,5-bisphosphate (PIP2) to generate
inositol-1,4,5-trisphosphate (IP3) and diacylglycerol
(DAG). Then, IP3 transfers into the endoplasmic
reticulum (ER), thus leading to the release of stored
Ca2+ from ER and subsequently increased cytoplasmic
Ca2+ levels, while DAG potentiates insulin secretion by
stimulating PKC (9,16). GPR40 knockout contributes to the
decrease in lyso-phosphatidylethanolamine species and absence in
intracellular inositol phosphate levels in response to fatty acids
and subsequent reduction in GSIS (26). The inhibition of PLC or L-type
Ca2+ channels attenuates rises in GPR40-dependent
Ca2+ levels and insulin secretion stimulated by fatty
acids; the same effects are observed in GPR40 knockout β-cells
(60–62). This process suggests that GPR40
mediates insulin secretion involving Ca2+ release from
ER and influx via L-type Ca2+ channels. Moreover,
linoleic acid reversibly reduces the voltage-gated K+
current in rat β-cells through GPR40, while GPR40-specific small
interfering RNA significantly reduce the decrease in K+
current induced by linoleic acid. Taken together, these data
indicate that activated GPR40 inhibits the opening of voltage-gated
K+ channels, resulting in increased Ca2+
influx via L-type Ca2+ channels, and therefore enhancing
the depolarization of the plasma membrane, thereby augmenting GSIS
(63) (Fig. 1).
Emerging potential drugs targeting GPR40 for
the regulation of insulin secretion
Due to tissue distribution, the pharmacological
activation of GPR40 provides a novel target for the treatment of
type 2 diabetes. Certain synthetic GPR40 agonists are very
promising to become the drug for mediating insulin secretion. For
example, GW9508, a small molecule agonist, activates GPR40 and
stimulates GSIS in MIN6 cells, implicating a potential
glucose-sensitive insulin secretagogue (64). A phenylpropanoic acid derivative
named
3-{2-fluoro-4-[({4′-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)
methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)amino]phenyl} propanoic
acid has been shown to exhibit a robust plasma glucose-lowering
effect and insulinotropic action during an oral glucose tolerance
test in rats with impaired glucose tolerance (65). AMG 837 is a potent GPR40 agonist
with a superior pharmacokinetic profile, improving glucose
intolerance and promoting GSIS in rodents (28,66). Although thiazolidinediones
including pioglitazone, the insulin sensitizers, are proven to
activate GPR40 and reverse palmitate-induced β-cell dysfunction
(67,68), the adverse effects such as heart
problems and bone fractures have already been reported (69,70). Recently, Zhou et al
(71) discovered a series of
thiazolidinediones (TZDs) as potent GPR40 agonists by systematic
structure-activity relationship studies of a screening. Among
these, compound C demonstrated an acute mechanism-based glucose
lowering in an intraperitoneal glucose tolerance test (IPGTT) in
lean mice, while no effects were observed in GPR40 knockout mice.
However, it is necessary to determine whether compound C has the
same adverse effects.
TAK-875, a GPR40-selective agonist (Fig. 2), enhances insulin secretion in a
glucose-dependent manner in both isolated rat and human islets,
which correlates with the elevation of intracellular inositol
monophosphate and Ca2+ concentration, similar to that
produced by GLP-1 (72,73), thus minimizing the risk of
hypoglycemia and representing a therapeutically useful feature. The
oral administration of TAK-875 significantly improves both fasting
hyperglycemia and glucose tolerance and augments GSIS in type 2
diabetic rats with no evidence of β-cell toxicity, showing
promising pharmacokinetic profiles (73,74). Further research has revealed that
TAK-875 is well tolerated in healthy volunteers and has
pharmacokinetic characteristics suitable for a once daily regimen,
and pharmacodynamic data have shown that TAK-875 has a low risk of
hypoglycemia (75). At present,
the agonist has been studied in clinical trials (76,77), including a phase II, multicentre,
randomized, double-blind, parallel group study. After treatment,
TAK-875 led to reductions in blood glucose levels and HbA1c and an
increase in insulin levels. Moreover, no episode of hypoglycemia
was observed despite the significant reduction in plasma glucose
levels. These findings indicate that the GPR40 agonist, TAK-875, is
a glucose-dependent insulinotropic reagent and a promising clinical
drug for the treatment of type 2 diabetes.
In China, a number of Chinese herbs have been shown
to possess antidiabetic activities with few adverse effects
(78), including Coptis
chinensis, Astragalus membranaceus and Lonicera
japonica (79,80); however, the mechanisms involved
remain unclear. Berberine, a botanical alkaloid (Fig. 3) extracted from Coptis
chinensis Franch., has been used to treat type 2 diabetes in
clinical practice. Although certain gastrointestinal complaints
from berberine treatment, including slight constipation appear to
be associated with the use of high doses, the tolerability is high
for low doses (81). Berberine
performs a series of pharmacological functions, including
anti-inflammation, ameliorating insulin resistance and has a
protective effect on β-cell lipoapoptosis (82,83). It is not only an insulin
sensitizer via enhancing glucose metabolism in insulin-sensitive
tissues, but also an insulinotropic reagent. Previous studies have
revealed that berberine stimulates glucose-dependent insulin
secretion from rat pancreatic β-cells and exhibits a dose-dependent
increase in calcium mobilization in a GPR40-overexpressed cell
line, similar to oleic acid, a GPR40 agonist (84,85). Therefore, it is possible that
berberine is a novel agonist of GPR40. Additionally, Rehmanniae
radix, Ginseng radix and Scutellariae radix have
also been shown to have the potential to improve GSIS (86,87).
Conclusion and perspectives
GPR40 is no doubt a novel therapeutic target for
type 2 diabetes involving mediating insulin secretion, and a series
of agonists for GPR40 have developed. However, further studies are
warranted to determined the safety, tolerability, pharmacokinetic
and pharmacodynamic properties. At present, a promising clinical
drug targeting GPR40 is TAK-875, which is currently undergoing
phase II, multicentre, randomized, double-blind, placebo-controlled
trials. However, adverse effects including long-term reaction are
not yet clear. GPR40 is also expressed in enteroendocrine and glial
cells, and the ligands display toxic activity (88–90). Therefore, it is necessary to
confirm whether TAK-875 affects these tissues. Additionally,
Chinese medicine has been used to treat diabetes for thousands of
years in clinical practice with few side-effects, and has become
popular complementary and alternative medicine. A number of Chinese
herbs have been proven to protect pancreatic β-cell function and to
regulate insulin secretion. It is worthwhile to screen
insulinotropic reagents from Chinese herbs and to develop GPR40
agonists. This may lead to a reduction in research funds and
time.
Acknowledgements
This study was supported by the
National Natural Science Foundation of China (no. 81202677) and
Guangxi Natural Science Foundation (no. 2012GXNSFBA053103).
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