Exploring inter-organ crosstalk to uncover mechanisms that regulate β-cell function and mass

Abstract

Impaired β-cell function and insufficient β-cell mass compensation are twin pathogenic features that underlie type 2 diabetes (T2D). Current therapeutic strategies continue to evolve to improve treatment outcomes in different ethnic populations and include approaches to counter insulin resistance and improve β-cell function. Although the effects of insulin secretion on metabolic organs such as liver, skeletal muscle and adipose is directly relevant for improving glucose uptake and reduce hyperglycemia, the ability of pancreatic β-cells to crosstalk with multiple non-metabolic tissues is providing novel insights into potential opportunities for improving β-cell function and/or mass that could have beneficial effects in patients with diabetes. For example, the role of the gastrointestinal system in the regulation of β-cell biology is well recognized and has been exploited clinically to develop incretin-related antidiabetic agents. The microbiome and the immune system are emerging as important players in regulating β-cell function and mass. The rich innervation of islet cells indicates it is a prime organ for regulation by the nervous system. In this review, we discuss the potential implications of signals from these organ systems as well as those from bone, placenta, kidney, thyroid, endothelial cells, reproductive organs and adrenal and pituitary glands that can directly impact β-cell biology. An added layer of complexity is the limited data regarding the relative relevance of one or more of these systems in different ethnic populations. It is evident that better understanding of this paradigm would provide clues to enhance β-cell function and/or mass in vivo in the long-term goal of treating or curing patients with diabetes.European Journal of Clinical Nutrition advance online publication, 15 March 2017; doi:10.1038/ejcn.2017.13.

Full text

REVIEW
Exploring inter-organ crosstalk to uncover mechanisms that
regulate β-cell function and mass
J Shirakawa
1,3
, DF De Jesus
1,2,3
and RN Kulkarni
1
Impaired β-cell function and insufficient β-cell mass compensation are twin pathogenic features that underlie type 2 diabetes (T2D).
Current therapeutic strategies continue to evolve to improve treatment outcomes in different ethnic populations and include
approaches to counter insulin resistance and improve β-cell function. Although the effects of insulin secretion on metabolic organs
such as liver, skeletal muscle and adipose is directly relevant for improving glucose uptake and reduce hyperglycemia, the ability of
pancreatic β-cells to crosstalk with multiple non-metabolic tissues is providing novel insights into potential opportunities for
improving β-cell function and/or mass that could have beneficial effects in patients with diabetes. For example, the role of the
gastrointestinal system in the regulation of β-cell biology is well recognized and has been exploited clinically to develop incretin-
related antidiabetic agents. The microbiome and the immune system are emerging as important players in regulating β-cell
function and mass. The rich innervation of islet cells indicates it is a prime organ for regulation by the nervous system. In this
review, we discuss the potential implications of signals from these organ systems as well as those from bone, placenta, kidney,
thyroid, endothelial cells, reproductive organs and adrenal and pituitary glands that can directly impact β-cell biology. An added
layer of complexity is the limited data regarding the relative relevance of one or more of these systems in different ethnic
populations. It is evident that better understanding of this paradigm would provide clues to enhance β-cell function and/or mass
in vivo in the long-term goal of treating or curing patients with diabetes.
European Journal of Clinical Nutrition (2017) 71, 896–903; doi:10.1038/ejcn.2017.13; published online 15 March 2017
INTRODUCTION
The prevalence of type 2 diabetes (T2D) is rapidly accelerating in
Asian countries and the large numbers are especially noticeable
given the large population density in these countries.
1
The
increased incidence is the result of an aging society, compounded
by lifestyle changes and epigenetic modifications, especially in
developing Asian countries. Furthermore, studies suggest that the
susceptibility to develop T2D is genetically higher in Asian
populations when compared to populations of European origin.
2
Notably, genetic variants associated with T2D from genome-wide
association studies are related to reduced pancreatic β-cell
function, rather than peripheral insulin resistance.
3
‘Diabetes’is
manifest when β-cells are unable to compensate for increasing
insulin demand to maintain normoglycemia by enhancing
their proliferation, mass and/or function. Most autopsy studies
have revealed a positive correlation between β-cell mass and
body-mass index in European, North American and Asian
populations.
4–6
Since Asian subjects generally show a lower
body-mass index than Caucasians, β-cell mass is expected to be
smaller in Asians. However, it is becoming evident that curiously
Asians easily develop insulin resistance and diabetes without
morbid obesity.
3
Thus, therapeutic strategies that protect and
enhance ‘functional β-cell mass’are essential to promote
appropriate glycemic control and to potentially cure diabetes in
Asian populations.
Considerable effort has been invested to progress our under-
standing of the complex intracellular signaling mechanisms and
pathways that regulate human β-cell function and mass including
those that modulate insulin secretion, islet cell replication,
apoptosis, dedifferentiation, autophagy, and endoplasmic reticu-
lum (ER) and oxidative stress. It is also evident that metabolites
(for example, glucose and free fatty acids) and hormones (for
example, glucagon-like peptide-1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP)) continue to be important
regulators of human islet function.
7–9
However, recent studies
have been steadily accumulating evidence to point to the concept
of in vivo regulation of islet cell function and mass secondary to
organ crosstalk. This relatively new area has become a focus to
explore novel targets to influence regeneration of ‘functional β-
cells’. This review focuses on the different metabolic tissues that
can crosstalk with β-cells to impact whole-body glucose
homeostasis.
MATERIALS AND METHODS
Search strategy and article selection
A systematic literature search was performed using the PubMed
database. The search terms used were ‘pancreatic beta cells’AND
(‘crosstalk’OR ‘inter-organ’OR ‘communication’). Studies were
restricted to those in the English language published between
1
Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women’s Hospital, Harvard Stem Cell Institute, Harvard Medical School,
Boston, MA, USA and
2
Graduate Program in Areas of Basic and Applied Biology (GABBA), Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.
Correspondence: Professor RN Kulkarni, Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women’s Hospital, Harvard Stem Cell
Institute, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
E-mail: rohit.kulkarni@joslin.harvard.edu
3
These two authors contributed equally to this work.
Received 19 January 2017; accepted 24 January 2017; published online 15 March 2017
European Journal of Clinical Nutrition (2017) 71, 896–903
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0954-3007/17
www.nature.com/ejcn

January 2000 and 31 December 2016. In all, 441 articles were
found in those search terms. First the journal name, the title and
then the abstract of each listed article was examined and only
those with the significant impact on this area of research were
retained. We selected 11 distinct publications that represent a
significant advance in the understanding of the regulation of
β-cell inter-organ crosstalk. Furthermore, reference lists of reviews,
original papers and our personal knowledge were reviewed, and
an additional 16 publications were selected.
CROSSTALK BETWEEN β-CELLS AND METABOLIC TISSUES
Liver
The existence of circulating β-cell growth factors was hypothe-
sized more than a decade ago, when Flier et al. demonstrated an
increase in β-cell mass in response to insulin resistance
independent of glucose or obesity.
10
The liver is an ideal
candidate for crosstalk with islet β-cells for several reasons. First,
the liver and the islets have a common embryonic origin and
teleologically it is conceivable that alterations in one or the other
organ would elicit signals to restore homeostasis. Second, multiple
metabolites and hormones regulate complex transcriptional
networks that modulate hepatic glucose metabolism that can
impact whole-body metabolism; and finally, being a major organ
of energy storage and in glucose and lipid metabolism the liver is
directly involved in development of insulin resistance and T2D.
11
Thus it is not surprising that several reports point to the liver as
a source of factors that can directly impact the islets and
contribute to organismal metabolism. For example, hepatic
growth factor (HGF), which is produced in the liver is known to
be involved in the regeneration capabilities in different tissues
12
and acts via the c-Met receptor, expressed on β-cells. Conditional
ablation of c-Met is not detrimental in normal conditions but is
crucial for adaptatin of β-cell mass in response to multiple low
doses of streptozotocin
12
and partial prancreatectomy.
13
El Ouaamari and colleagues used parabiosis and transplantation
experiments to specifically demonstrate the existence of
hepatocyte-derived factors that drive mouse and human β-cell
proliferation.
14
The leukocyte-neutrophil elastase inhibitor (Ser-
pinB1) was identified as a hepatocyte-derived secretory protease
inhibitor protein that regulates mouse, zebrafish and human β-cell
proliferation.
15
In a proof of concept, the authors shown that
Silvestat—a small-molecule compound that acts like SperbinB1-
inhibiting elastase activity, was able to increase β-cell proliferation
in in vitro cultured islets and in vivo transplanted islets.
15,16
The
conserved and defined activity of SerpinB1 among different
species argues for potential as a therapeutic to promote β-cell
regeneration in diabetes states.
The KISS-1 metastasis-supressor gene (KISS-1) known as
kisspeptin was first discovered to be enriched in non-metastatic
melanoma cells and found to have metastatic-suppressive
properties.
17
It is widely expressed in different tissues, particularly
in placenta and in the central nervous system.
17
Kisspeptin is
involved in several phases of puberty and reproduction. Estradiol
and testosterone regulate Kiss1 gene expression while kisspeptin
stimulates the release of gonadotropin releasing-hormone.
17
The
role of kisspeptin in glucose homeostasis is new and of great
interest. Kisspeptin is augmented in livers and sera of patients
with T2D and in rodent models of obesity and diabetes.
18
Glucagon acts on the liver by stimulating the cAMP-PKA-CREAB
signaling pathway and increasing the hepatic production of
kisspeptin.
18
Nutritional and genetic models of insulin resistance-
lacking Kiss1 gene present augmented glucose-stimulated insulin
secretion (GSIS) and improved glucose tolerance,
18
and provide
insights on the role of Kisspeptin on glucagon regulation of insulin
secretion.
Insulin-like growth factor binding proteins (IGFBPs) play a
central role in insulin signaling and are expressed in a widespread
variety of tissues, including the liver. Low concentrations of
circulating IGFBP1 are associated with T2D and increasing its
levels in mice has positive effects on insulin sensitivity.
19
Hepatic
IGFBP1 expression is positively regulated by fibroblast growth
factor 21 (FGF21) and causes bone loss by acting on integrin β1
receptors on osteoclasts.
20
Interestingly, IGFBP1 was shown to
promote β-cell regeneration by inducing α-to-β-cell transdiffer-
entiation in zebrafish, mouse and human islets.
21
In vitro
treatment of mouse and human islets with recombinant IGFBP1
increased the number of cells co-expressing insulin and
glucagon.
21
Liver has a central role in regulating metabolism and is
constituted by a complex and vast proteome. Further work is
necessary to identify additional novel hepatocyte-derived signal-
ing peptides that regulate β-cell function and/or mass.
Adipose tissue
Although adipose tissue was considered as a mere energy
reservoir for several decades, it has emerged as an active
endocrine organ that integrates multiple systemic signals and
secretes various adipokines.
22
Adiponectin is one of the major
secreted adipokines that is important for the overall regulation of
lipid homeostasis and metabolic flexibility. While, adiponectin
seems to be dispensable in normal physiological conditions,
recent work revealed its importance in β-cell regeneration.
23,24
Adiponectin promotes β-cell proliferation in response to experi-
mental β-cell ablation
23
and improves islet lipid metabolism to
enhance β-cell regeneration.
24
Leptin is a hormone produced by adipocytes in proportion to
the total fat mass and acts on multiple circuits, namely on central
nervous system controlling food-intake and energy expenditure.
Mice and humans lacking leptin exhibit hyperphagia and
consequently obesity and T2D.
25
Leptin acts on β-cells and
inhibits insulin secretion
26
in a K
+
ATP
-dependent manner.
27
The
effects of leptin on β-cells may be indirect and further studies are
needed to elucidate the mechanisms of its action.
22
Adipsin was among the adipokines identified early and
observed to be reduced in obesity and diabetes.
28
Mice
genetically manipulated to lack adipsin, present decreased insulin
secretion and glucose intolerance.
29
Adipsin generates the C3a
peptide, which acts on islets by increasing ATP and Ca
2+
levels
boosting insulin secretion.
29
Finally, recent work has shown that
brown adipose tissue, which is rich in mitochondria and regulates
thermogenesis by expressing high amounts of uncoupling
protein-1, also secretes factors able to influence overall glucose
and lipid metabolism. Some examples include FGF21, bone
morphogenetic protein, interleukin (IL)-6 and vascular endothelial
growth factor (VEGF; reviewed in Wang et al.
30
). Further work is
warranted to examine whether the brown adipose tissue
secretome can directly impact β-cell biology.
Skeletal and cardiac muscle
Physical activity reduces the risk of a myriad of health disorders
ranging from cancer to obesity. The concept of skeletal muscle as
an active signaling organ with the capacity to modulate the
function of other organs has gained relevance with the develop-
ment of high throughput methodologies.
31
IL-6 is one of the well
characterized myokines
22
and acts on α-cells to induce the
production of GLP-1 through increased expression of proglugacon
and prohormone convertase 1/3.
32
Consequently, exercise
increases the expression of IL-6 in skeletal muscle which crosstalks
to β-cells via GLP-1 and potentiating GSIS.
32
Exosome-mediated crosstalk is an attractive cell-to-cell com-
munication system and microRNAs are being recognized as key
regulators of β-cell function (reviewed in Guay and Regazzi
33
).
Recently, Jalabert et al. isolated skeletal muscle-derived exosomes
from mice fed chow or a palmitate-enriched diet for 16 weeks and
Inter-organ crosstalk regulating β-cell biology
J Shirakawa et al
897
© 2017 Macmillan Publishers Limited, part of Springer Nature. European Journal of Clinical Nutrition (2017) 896 –903

analyzed if pancreas could take up exosome cargoes.
34
The
authors showed that pancreas could not only take up these
muscle-derived exosome but also that these cargoes affected
MIN6B1 and isolated islet cell proliferation.
34
miR-16 was identified
as one of the principal mediators of this effects and MIN6B1 cells
transfected with miR-16 exhibited decreased Ptch1 gene expres-
sion—a gene involved in proliferation.
34
It would be of great
interest to validate these findings in human islets.
While peripheral tissues such as adipose, may increase the risk
of myocardial infarction as a consequence of obesity and an
altered adipokinome,
35
the role of heart itself as a metabolic
modulator has been neglected until recently.
35
Ischemic stress can
lead to infiltration and inflammation of the myocardium, affecting
a myriad of different inflammatory cytokines, known as
cardiokines.
35
Most of the known cardiokines act in a paracrine
manner and modulate cardiac metabolism, response to stress, and
angiogenesis. The discovery and understanding of new human
myokines constitute an interesting and active area of research that
can lead to the identification of novel therapeutical targets
including effects on β-cell function and/or mass.
36
THE β-CELL AND INTRA-ISLET ENDOTHELIAL CELL
INTERACTION
Pancreas is constituted by an endocrine component that secrete
hormones directly into the bloodstream, and an exocrine
component that secretes enzymes through a duct network into
the gastrointestinal tract, likely favored by evolution to improve
homeostatic responses via endocrine and paracrine
communication.
37
Although the total islet mass represents
between 1 and 2% of the total pancreatic mass, islets receive a
significant part of the pancreatic blood flow.
38
Indeed, islets are
intensely vascularized and endothelial cells play a role in β-cell
glucose sensing and insulin secretion.
38
VEGF-A is a major
modulator of islet vascularization. Islets secrete large amounts of
VEGF-A that acts on endothelial cells to stimulate cell migration
and proliferation.
38
Mice genetically modified to have reduced
levels of β-cell VEGF-A present normal β-cell mass but decreased
GSIS.
39
It is also notable that endothelial cells secrete multiple
factors that regulate β-cell function and survival (reviewed in Peiris
et al.
38
). Among them, thrombospondin-1 (TSP-1) regulates β-cell
function partially via transforming growth factor-1 (TGF-β1)
signaling.
40
Recently, TSP-1 was reported to induce a protective
antioxidant response against palmitate in β-cells via the PERK-
NRF2 pathway.
41
Other factors secreted by endothelial cells
include endothelin-1 and hepatic growth factor acting on β-cells
to stimulate insulin secretion and proliferation respectively.
38
In
T2D, endothelial cells are exposed to diverse stress factors that
induce inflammatory responses which ultimately leads to fibrosis,
destruction of islet microvasculature and consequent β-cell
dysfunction. Thus, islet microvasculature is important for main-
tenance of islet function and alterations in islet blood supply
appear to be related to the development of T2D.
GASTROINTESTINAL SYSTEM-MEDIATED REGULATION OF
β-CELLS
Incretins and decretins
The term incretin was coined from observations in which oral
administration of glucose leads to a greater amount of secreted
insulin in comparison to an intravenous administration of
glucose.
42
GLP-1 and GIP are among the most famous
incretins.
22
GIP and GLP-1 are released from intestinal K and L
cells, respectively, in response to glucose and lipids and improve
GSIS.
42
GLP-1 stimulates insulin secretion in response to glucose
and also acts on α-cells through glucagon like peptide 1 receptor
(GLP-1R) to inhibit glucagon secretion.
22,42
Interestingly, ablation
of GLP-1R in β-cells does not disrupt GLP-1 effects on insulin
secretion, suggesting that GLP-1 acts on β-cells through a
neuronal mechanism.
22,43
Variants in the GIP receptor gene locus
have been associated with higher susceptibility for T2D
42
but its
mechanism of action in β-cells are complex.
22
Transgenic mice
lacking glucose-dependent insulinotropic polypeptide receptor
selectively on β-cells present with decreased GSIS in response to
meals but preserve their insulin sensitivity.
44
Nonetheless, β-cells
lacking glucose-dependent insulinotropic polypeptide receptor
are more susceptible to apoptosis and exhibit lower expression of
T-cell specific transcription factor-1 (from Tcf7 gene).
44
Tcf7 has
been relatively recently reported to be decreased in diabetic
rodent islets and in T2D islets and suggested to be important for
the anti-apoptotic effects of GIP.
44
Although incretins stimulate
insulin secretion in response to nutrients, decretins act by
inhibiting insulin secretion in fasting conditions. Using the same
conceptual experiment for incretins, decretins were discovered by
their inability to reduce insulin secretion after an intravenous
injection of glucose in the fasting state.
22
Neuromedin U, ghrelin
and galanin are among the most studied decretins secreted by the
gastrointestinal tract. The mechanism by which they reduce β-cell
GSIS is largely unknown and this topic has been reviewed
recently.
22
Microbiome
The human gut is colonized by thousands of different anaerobic
bacterial genomes that play an important physiological role in
modulating digestion and playing a role in the synthesis of
vitamins and other metabolites
45
(reviewed in Baothman et al.
45
).
Alterations in the gut microbiota are known to be associated with
obesity, T2D and other diseases. Transfer of microbiota from lean
humans to individuals with metabolic syndrome improves insulin
sensitivity after only 6 weeks.
46
Short-chain fatty acids are
produced in the distal gut by bacterial fermentation of different
substrates that escape digestion in the upper part of the
gastrointerstinal tract and is considered to be an important
mediator of the microbiome effects on metabolism.
47
Receptors
for short-chain fatty acids are widely expressed and include two
G-protein coupled proteins: free fatty acid receptor 2 (also known
as GPR43) and FFAR3 (also known as GPR41).
47
β-cells express free
fatty acid receptor 2 and mice genetically lacking free fatty acid
receptor 2 present glucose intolerance, impaired insulin secretion
and decreased β-cell mass when challenged with a high-fat diet.
48
Indeed, in vitro treatment of mouse and human islets with a free
fatty acid receptor 2 agonist potentiates insulin secretion
48
constituting a promising therapeutic intervention strategy.
NEURAL CONTROL OF β-CELLS
It is well established that the brain regulates global metabolic and
energy homeostasis by integrating multiple signals, such as
hormones and nutrients from different metabolic organs and
exerts a continuous and coordinated control of most metabolic
organs. The β-cell is one of the major targets of neurons. Indeed,
β-cells are highly innervated by sympathetic and parasympathetic
neurons, and expresses multiple neurotransmitters and neuropep-
tide receptors.
49
Parasympathetic nerve activation provokes
increased GSIS and β-cell proliferation probably through muscari-
nic acethylcholine receptor-3 (m3AChR).
50,51
In mice, genetic
ablation of sympathetic innervation by tyrosine hydroxylase
promoter-driven cre-induced TrkA receptor conditional knockout
or pharmacological ablation by administration with the neuro-
toxin 6-hydroxydopamine has been reported to result in
disorganized islet architecture, impaired insulin secretion and
glucose intolerance during development.
52
Intriguingly, leptin
negatively regulates parasympathetic innervation of pancreatic
islets and causes impaired glucose tolerance.
53
Interestingly, the
Inter-organ crosstalk regulating β-cell biology
J Shirakawa et al
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European Journal of Clinical Nutrition (2017) 896 –903 © 2017 Macmillan Publishers Limited, part of Springer Nature.

innervation patterns of human islets and mouse islets are
different.
54
Mouse islets being densely innervated with para-
sympathetic neurons in the core, and with sympathetic neuron in
the periphery, compared to the exocrine tissues. In contrast,
human islets show minimal penetration by parasympathetic
neurons while sympathetic nerves mainly project to blood vessels
within islets.
54
Instead, human α-cells release acetylcholine and
provide cholinergic input on surrounding β-cells in human islets.
55
Thus, neural regulation of β-cell function and mass likely differ
between mouse and man.
An interesting observation links the brain and the liver in the
inter-organ regulation of β-cell function and mass. Imai et al.
injected the liver with an adenovirus that expresses constitutively
active MEK-1 in mice
56
and observed that the animals exhibited
enhanced GSIS and β-cell proliferation. Furthermore, ablation of
efferent vagal signals by pancreatic vagotomy, the selective
blockade of afferent splanchnic nerve with capsaicin, or bilateral
mid brain transection markedly blunted the effects of ERK on
β-cell function and proliferation.
56
These results suggest that the
nerve-mediated liver–brain–pancreas axis is an attractive pathway
to replenish functional β-cell in addition to hepatic humoral
factors such as SerpinB1. However, the precise mechanism
by which hepatic ERK activation affects neural control of
β-cells warrants selective activation of liver-mediated afferent
splanchnic nerve.
Brain is a physiological sensor for glucose particularly in
response to hypoglycemia. The neuronal counter-regulatory
response to hypoglycemia suppresses insulin release and induces
glucagon and catecholamine release to restore normoglycemia. In
mouse β-cells, glucose uptake and sensing are mediated by
glucose transporter 2 (Glut2), the major glucose transporter, and
glucokinase, a low affinity hexokinase, whereas human β-cells
predominantly express GLUT1 rather than GLUT2.
57
The β-cell
glucokinase is a rate-limiting enzyme in the induction of glycolysis,
glucose oxidation, ATP production, calcium influx and GSIS
through ATP-gated potassium (K
ATP
) channel. The brain also
expresses Glut2, glucokinase and K
ATP
channel, and those three
molecules in the brain play crucial roles in the regulation of
glucagon secretion in response to glucose.
58–61
Tarussio et al.
generated neuron-specific Glut2 knockout (NG2KO)
62
and demon-
strated they exhibit glucose intolerance due to impaired insulin
secretion in response to aging and high-fat diet-induced obesity.
β-cell mass and proliferation were also reduced in NG2KO mice in
the postnatal period.
62
Thus, in mice glut2-mediated glucose
sensing in neurons regulates β-cell function and mass mainly
through modulating parasympathetic activity.
Acetylcholine is a major neurotransmitter for the parasympa-
thetic action on β-cells. Interestingly, Rodriguez-Diaz et al.
demonstrated that pancreatic α-cells secrete acetylcholine in
response to kinate stimulation or a decline in ambient glucose,
and have a cholinergic effect on neighboring β-cells in human
islets.
55
These studies indicate that paracrine signals from islet
endocrine cells contribute to neuroendocrine regulation of β-cells.
In addition to autonomic nerves, islets reportedly receive sensory
innervation
63
and functional modulation of β-cells by neuropep-
tides such as encephalin, neuropeptide Y, cholecystokinin,
substance P or PACAP have also been reported. Further
investigation of neuron/neurotransmitter-mediated regulation of
β-cells would contribute to a better understanding of how one
could potentially replenish β-cells through activation of proteins in
the central nervous system.
CROSSTALK BETWEEN β-CELLS AND OTHER TISSUES
In addition to the aforementioned tissues, the β-cell has been
reported to interact with multiple other tissues including the
bone, placenta, reproductive glands, kidney, the immune system,
thyroid, endothelial cells, adrenal and pituitary glands. We will
discuss recent research only on some of these tissues due to space
limitations.
Bone
Bone, now recognized as an endocrine tissue, is known to secrete
humoral factors that are involved in systemic metabolism. Lee
et al. generated a mouse with a osteoblast-specific knockout of a
receptor-like protein phosphatase,
64
and observed that the
animals showed an increase in β-cell proliferation and insulin
secretion.
64
Osteocalcin is an osteoblast-specific secreting protein
and osteocalcin knockout mice exhibit a reduction in β-cell
proliferation and insulin secretion.
64
Osteocalcin haploinsuffi-
ciency reversed both metabolic and β-cell phenotypes of
osteoblast-specific knockout of a receptor-like protein phospha-
tase knockout mice.
64
They also showed that the receptor-like
protein phosphatase regulates osteocalcin activity by modulating
γ-carboxylation.
64
A recent study revealed that effects of
osteocalcin on β-cells is mediated by Gprc6a, an osteocalcin
receptor.
65
These studies have positioned osteoblast-derived
osteocalcin as a prominent regulator of β-cell function and mass.
Conversely, β-cell-derived insulin stimulates osteocalcin produc-
tion through insulin receptor mediated suppression of Twist2, a
Runx2 inhibitor, in osteoblasts.
66
Osteoblast-specific insulin
receptor knockout mice showed low circulating osteocalcin levels
and decreased β-cell mass and function.
66,67
Interestingly, this
osteocalcin activity is also regulated by sympathetic nerves and is
modulated by adipose tissue-derived leptin.
68
Since leptin and
sympathetic nerves directly regulate
β-cell function,
49,69
this interplay between the adipocyte, brain,
sympathetic nerve, osteoblast and β-cells represents a complex
inter-organ network in the regulation of whole-body homeostasis.
Pregnancy and sex hormones
In rodents, an increase in β-cell mass during pregnancy occurs
primarily as a result of enhanced cell replication. Since the
prolactin receptor is required for β-cell adaptation during
pregnancy, prolactin secreted from the pituitary and placental
lactogen have been reported to contribute to the expansion of
β-cell mass during pregnancy.
70
Prolactin and lactogen mediate
their actions on β-cell proliferation through hepatic growth factor,
menin, serotonin and/or osteoprotegerin pathways.
71–75
However,
the factors that promote β-cell adaptation that potentially occurs
during pregnancy in humans are still unclear and is a timely area
for additional studies. Women after menopause are more
susceptible to diabetes compared to men and postmenopausal
diabetes has been associated with β-cell dysfunction in addition
to insulin resistance.
76
Hormone replacement therapy in post-
menopausal women improves glycemic control.
77
Meanwhile,
men with testosterone deficiency exhibit impaired insulin secre-
tion and T2D. These observations indicate significant effects of
reproductive hormones in the maintenance of β-cell function. The
receptors for estrogen, ERα,ERβand G-protein coupled ER, are all
expressed on β-cells and contribute to β-cell function and mass.
ERαcontributes to reduction in apoptosis, allevaites ER stress, and
decrease in fatty acid synthesis, and enhances proliferation and
survival in β-cells.
78,79
ERαis required for the generation of
Neurogenin-3-mediated β-cell regeneration during development
and pregnancy, and following partial duct ligation.
80
ERβand
G-protein coupled ER play roles in GSIS and β-cell
proliferation.
79,81
An involvement of estrogen in prevention of
T1D by modulating iNKT cell function has also been reported.
82
The activation of androgen receptors in β-cell potentiates glucose-
stimulated insulin secretion in co-operation with GLP-1 receptor
activation and altering cAMP levels.
83
Progesterone reportedly
facilitates insulin secretion and β-cell proliferation; however,
progesterone receptor knockout mice also show enhanced β-cell
proliferation.
84,85
These examples of communication between
Inter-organ crosstalk regulating β-cell biology
J Shirakawa et al
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β-cells and reproductive organs indicate the potential for gender-
specific approaches for replenishment of functional β-cell mass
and is discussed in a recent review.
81
Thyroid
Hyperthyroidism due to Graves’Disease, or due other causes of
thyrotoxicosis, is known to cause hyperinsulinemia associated
with various metabolic changes. Thyroid hormone has been
linked to altered GSIS in people with prediabetes, suggesting that
thyroid hormones are involved in the regulation of insulin
secretion from β-cells.
86
Aguayo-Mazzucato et al. demonstrated
that β-cells express thyroid hormone receptors and that thyroid
hormone enhances β-cell maturation by enhancing expression
of MAFA.
87
Recently, Bruin et al. investigated the impact of
thyroid dysregulation on the development of encapsulated
human embryonic stem cell-derived progenitor cells in mice.
88
Hypothyroidism showed a negative effect on human embryonic
stem cell-derived β-cell development and induced higher
numbers of human embryonic stem cell-derived glucagon-
positive α- and ghrelin-positive ε-cells.
88
Thus, thyroid hormone
contributes to the maintenance of βcell function as well as
the differentiation and maturation steps during development of
βcells.
Immune system
The innate immune system and inflammatory pathways have
been recognized to play important roles during the onset and
development of T2D. Chronic inflammation has been observed in
adipose tissue, liver, vascular endothelial cells, circulating leuko-
cytes as well as in pancreatic islets in obese and/or diabetic
subjects. Islet inflammation has been suggested to be a factor in
the decline of β-cell mass in both T1D and T2D.
89
Currently, islet
macrophages are recognized as important and emerging reg-
ulators of islet inflammation, and saturated fatty acid and TLR4/
Myd88 signaling are considered to be involved in crosstalk
between macrophages and islets in the development of β-cell
dysfunction.
90
Increased islet macrophages in human T2D have
been reported in pathological studies
91
and accumulating
evidence suggests that islet-infiltrated macrophages exhibit a
wide range of functional heterogeneity in the interaction with
β-cells in terms of cytokine expression. In addition to β-cell failure
or death, islet macrophages reportedly contribute to β-cell
Brain
Immune
System Skeletal Muscle
Cardiac Muscle
Epithelium
Liver Adipose Tissue
Bone
Sex Hormones
Gut
Thyroid
SerpinB1
KISS-1
IGFBP1
Adiponectin
Leptin
Adipsin
TSP-1
Endothelin-1
TNF-α
IL-1β
IFN-γ
Acetylcholine
Enkephalin
Neuropeptide Y IL-6
miR-16
ANP
Osteocalcin
Prolactin
Lactogen
Estrogen
GLP-1, GIP
Ghrelin
SCFAs
T3, T4
Islets
Figure 1. Inter-organ crosstalk impacting β-cell function and/or mass. The figure represents different factors that are secreted by diverse
metabolic organs and tissues with the potential to regulate glucose-stimulated insulin secretion and β-cell proliferation. Each of the pathways
denoted are discussed briefly in the text. ANP, atrial natriuretic peptide; IGFBP1, insulin-like growth factor-binding protein 1 IFN-γ, interferon γ;
miR-16, microRNA 16; SCF, short-chain fatty acids; SerpinB1, leukocyte elastase inhibitor; T3, triiodothyronine; T4, thyroxine; TNF-α, tumor
necrosis factor α.
Inter-organ crosstalk regulating β-cell biology
J Shirakawa et al
900
European Journal of Clinical Nutrition (2017) 896 –903 © 2017 Macmillan Publishers Limited, part of Springer Nature.

differentiation, regeneration and proliferation.
92
For example,
Brissova et al. showed that inducible vascular endothelial growth
factor-A (VEGF-A) expression in β-cells led to islet endothelial cell
expansion, β-cell loss and bone marrow-derived macrophage
recruitment into the injured islets.
93
Interestingly, the macrophage
infiltration was essential for the β-cell proliferation after this VEGF-
A-induced β-cell loss.
93
Thus, crosstalk between β-cells and
macrophages is complex and contribute to different roles in the
patho-physiology underlying β-cell dysfunction in diabetes.
Further studies are necessary to clarify the origin and subtypes
of macrophages in pathological and physiological situations to
define whether islet macrophages can serve as appropriate targets
for diabetes therapy.
It is well-known that adaptive immune system components
including cytotoxic, helper, and regulatory T-cells, B-cells, and
dendritic cells play roles in autoimmunity leading to β-cell
destruction in T1D. However, cytokines or chemokines released
from CD4
+
and CD8
+
T cells have also been shown to enhance
β-cell proliferation in mouse islets.
94
Furthermore, stimulation with
a combination of TNF-a, IL-1b and IFN-g led to an induction of
Neurogenin-3 expression in pancreatic ductal cells to promote
differentiation to endocrine cells in NOD mice.
95
These observa-
tions point to inflammatory cells as potential therapeutic targets
for the prevention of β-cell failure as well as for expanding β-cell
mass. Butcher et al. investigated immune cells within human islets
from non-diabetes or T2D donors.
96
The islets from T2D donors
showed increased infiltration of CD45
+
leukocytes and an elevated
ratio of B cells in those leukocytes, suggesting an involvement of
adaptive immune response in T2D.
96
Jaeckle Santos et al.
demonstrated that intrauterine growth restriction causes T2D in
rat by inducing inflammation by recruitment of T-helper 2 (Th)
lymphocytes and macrophages in fetal islets.
97
Neutralizing Th2
response with IL-4 antibody during the neonatal period restored
inflammation and β-cell function in intrauterine growth restricted
rats. The adaptive Th2 response might be involved in epigenetic
control of β-cell function in T2D. Thus, both innate and adaptive
immune systems closely interact with β-cells in both T1D and T2D.
The unifying models that account for mechanistic integration of
the innate and adaptive immune responses in β-cells in T1D and
T2D would greatly benefit in dissecting their respective
pathogenesis.
DISCUSSION
In this review, we highlight crosstalk between β-cells and multiple
tissues (Figure 1). An issue that requires urgent attention in this
field of research relates to the significance of inter-organ
communication in regulating human β-cells in vivo. This is
especially significant given that human β-cells exhibit features
that are distinct from rodents in regard to structure, function and
gene expression.
98,99
Furthermore, an understanding of the
crosstalk between β-cells and other tissues in the context of
altered glycemia and overt diabetes is particularly necessary as
β-cells are exposed to variable ‘diabetes niches’such as
hyperglycemia (glucotoxicity), hyperlipidemia (lipotoxicity),
inflammatory cytokines and other factors for prolonged periods
in patients susceptible to diabetes or the metabolic syndrome.
Each of these conditions potentially trigger epigenetic changes in
islet cells and other organs
75
and warrant investigations focused
on examining the impact of epigenetics in the context of inter-
organ crosstalk. A related topic that is not fully explored is the
ability of antidiabetic drugs or factors that can differentially
influence organ-crosstalk and treatment outcomes in diverse
ethnic backgrounds. Investigations in these and associated areas
over the next several years are likely to provide therapeutic
opportunities that can be targeted to improve glycemia and/or
prevent the onset of diabetes in susceptible populations.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
This review was supported by R01 DK67536 and R01 DK103215 (to RNK). JS is
supported by a Post-doctoral Fellowship for Research Abroad, the Japan Society for
the Promotion of Science (JSPS) and the Uehara Memorial Foundation.
REFERENCES
1 Nanditha A, Ma RC, Ramachandran A, Snehalatha C, Chan JC, Chia KS et al. Dia-
betes in Asia and the Pacific: implications for the Global Epidemic. Diabetes Care
2016; 39:472–485.
2 Chan JC, Malik V, Jia W, Kadowaki T, Yajnik CS, Yoon KH et al. Diabetes in Asia:
epidemiology, risk factors, and pathophysiology. JAMA 2009; 301: 2129–2140.
3 Ramachandran A, Ma RC, Snehalatha C. Diabetes in Asia. Lancet 2010; 375:
408–418.
4 Saisho Y, Butler AE, Manesso E, Elashoff D, Rizza RA, Butler PC. Beta-cell mass and
turnover in humans: effects of obesity and aging. Diabetes Care 2013; 36:
111–117.
5 Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, Song KH et al. Selective beta-cell loss
and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin
Endocrinol Metab 2003; 88: 2300–2308.
6 Rahier J, Guiot Y, Goebbels RM, Sempoux C, Henquin JC. Pancreatic beta-cell
mass in European subjects with type 2 diabetes. Diabetes Obes Metab 2008; 10:
32–42.
7 Kulkarni RN, Mizrachi EB, Ocana AG, Stewart AF. Human beta-cell proliferation and
intracellular signaling: driving in the dark without a road map. Diabetes 2012; 61:
2205–2213.
8 Bernal-Mizrachi E, Kulkarni RN, Scott DK, Mauvais-Ja rvis F, Stewart AF, Garcia-
Ocana A. Human beta-cell proliferation and intracellular signaling part 2: still
driving in the dark without a road map. Diabetes 2014; 63:819–831.
9 Stewart AF, Hussain MA, Garcia-Ocana A, Vasavada RC, Bhushan A, Bernal-
Mizrachi E et al. Human beta-cell proliferation and intracellular signaling: part 3.
Diabetes 2015; 64: 1872–1885.
10 Flier SN, Kulkarni RN, Kahn CR. Evidence for a circulating islet cell growth factor in
insulin-resistant states. Proc Natl Acad Sci USA 2001; 98:7475–7480.
11 Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol
Hepatol 2016; 14:32
–42.
12 Mellado-Gil J, Rosa TC, Demirci C, Gonzalez-Pertusa JA, Velazquez-Garcia S, Ernst S
et al. Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic
β-cell death and accelerates the onset of diabetes. Diabetes 2011; 60: 525–536.
13 Alvarez-Perez JC, Ernst S, Demirci C, Casinelli GP, Mellado-Gil JMD, Rausell-
Palamos F et al. Hepatocyte growth factor/c-Met signaling is required for β-cell
regeneration. Diabetes 2014; 63: 216–223.
14 El Ouaamari A, Kawamori D, Dirice E, Liew Chong W, Shadrach Jennifer L, Hu J
et al. Liver-derived systemic factors drive beta cell hyperplasia in insulin-
resistant states. Cell Rep 2013; 3:401–410.
15 El Ouaamari A, Dirice E, Gedeon N, Hu J, Zhou J-Y, Shirakawa J et al. SerpinB1
promotes pancreatic beta cell proliferation. Cell Metab 2016; 23:194–205.
16 Shirakawa J, Kulkarni RN. Novel factors modulating human beta-cell proliferation.
Diabetes Obes Metab 2016; 18:71–77.
17 Hussain MA, Song W-J, Wolfe A. There is kisspeptin—and then there is kisspeptin.
Trends Endocrinol Metab 2015; 26: 564–572.
18 Song W-J, Mondal P, Wolfe A, Alonso Laura C, Stamateris R, Ong Benny WT et al.
Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab 2014;
19:667–681.
19 Rajwani A, Ezzat V, Smith J, Yuldasheva NY, Duncan ER, Gage M et al. Increasing
circulating IGFBP1 levels improves insulin sensitivity, promotes nitric oxide pro-
duction, lowers blood pressure, and protects against atherosclerosis. Diabetes
2012; 61:915–924.
20 Wang X, Wei W, Krzeszinski Jing Y, Wang Y, Wan Y. A liver-bone endocrine relay
by IGFBP1 promotes osteoclastogenesis and mediates FGF21-induced bone
resorption. Cell Metab 2015; 22:811–824.
21 Lu J, Liu K-C, Schulz N, Karampelias C, Charbord J, Hilding A et al. IGFBP1 increases
β-cell regeneration by promoting α-toβ-cell transdifferentiation. EMBO J 2016;
35: 2026–2044.
22 Hussain MA, Akalestou E, Song W-j. Inter-organ communication and regulation of
beta cell function. Diabetologia 2016; 59: 659–667.
23 Ye R, Holland WL, Gordillo R, Wang M, Wang QA, Shao M et al. Adiponectin is
essential for lipid homeostasis and survival under insulin deficiency and promotes
β-cell regeneration. eLife 2014; 3: e03851.
Inter-organ crosstalk regulating β-cell biology
J Shirakawa et al
901
© 2017 Macmillan Publishers Limited, part of Springer Nature. European Journal of Clinical Nutrition (2017) 896 –903

24 Ye R, Wang M, Wang QA, Scherer PE. Adiponectin-mediated antilipotoxic effects
in regenerating pancreatic islets. Endocrinology 2015; 156: 2019–2028.
25 Amitani M, Asakawa A, Amitani H, Inui A. The role of leptin in the control of
insulin-glucose axis. Front Neurosci 2013; 7:51.
26 Kulkarni RN, Wang ZL, Wang RM, Hurley JD, Smith DM, Ghatei MA et al. Leptin
rapidly suppresses insulin release from insulinoma cells, rat and human islets and,
in vivo, in mice. J Clin Invest 1997; 100: 2729–2736.
27 Chen P-C, Kryukova YN, Shyng S-L. Leptin regulates KATP channel trafficking in
pancreatic β-cells by a signaling mechanism involving amp-activated protein
kinase (AMPK) and cAMP-dependent protein kinase (PKA). J Biol Chem 2013; 288:
34098–34109.
28 Polyzos SA, Kountouras J, Mantzoros CS. Adipokines in nonalcoholic fatty liver
disease. Metabolism 2016; 65: 1062–1079.
29 Lo James C, Ljubicic S, Leibiger B, Kern M, Leibiger Ingo B, Moede T et al. Adipsin
is an adipokine that improves βcell function in diabetes. Cell 2014; 158:41–53.
30 Wang G-X, Zhao X-Y, Lin JD. The brown fat secretome: metabolic functions
beyond thermogenesis. Trends Endocrinol Metab 2015; 26: 231–237.
31 Whitham M, Febbraio MA. The ever-expanding myokinome: discovery challenges
and therapeutic implications. Nat Rev Drug Discov 2016; 15: 719–729.
32 Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT et al.
Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-
1 secretion from L cells and alpha cells. Nat Med 2011; 17: 1481–1489.
33 Guay C, Regazzi R. New emerging tasks for microRNAs in the control of β-cell
activities. Biochim Biophys Acta 2016; 1861: 2121–2129.
34 Jalabert A, Vial G, Guay C, Wiklander OPB, Nordin JZ, Aswad H et al. Exosome-like
vesicles released from lipid-induced insulin-resistant muscles modulate gene
expression and proliferation of beta recipient cells in mice. Diabetologia 2016; 59:
1049–1058.
35 Jahng JWS, Song E, Sweeney G. Crosstalk between the heart and peripheral
organs in heart failure. Exp Mol Med 2016; 48: e217.
36 Baskin Kedryn K, Winders Benjamin R, Olson Eric N. Muscle as a ‘mediator’of
systemic metabolism. Cell Metab 2015; 21:237–248.
37 Hayden MR, Patel K, Habibi J, Gupta D, Tekwani SS, Whaley-Connell A et al.
Attenuation of endocrine-exocrine pancreatic communication in type 2 diabetes:
pancreatic extracellular matrix ultrastructural abnormalities. J Cardiometab Syndr
2008; 3: 234–243.
38 Peiris H, Bonder CS, Coates PTH, Keating DJ, Jessup CF. The β-cell/EC axis: how do
islet cells talk to each other? Diabetes 2014; 63:3–11.
39 Brissova M, Shostak A, Shiota M, Wiebe PO, Poffenberger G, Kantz J et al.
Pancreatic islet production of vascular endothelial growth factor-a is essential
for islet vascularization, revascularization, and function. Diabetes 2006; 55:
2974–2985.
40 Olerud J, Mokhtari D, Johansson M, Christoffersson G, Lawler J, Welsh N et al.
Thrombospondin-1: an islet endothelial cell signal of importance for β-cell
function. Diabetes 2011; 60: 1946–1954.
41 Cunha DA, Cito M, Carlsson P-O, Vanderwinden J-M, Molkentin JD, Bugliani M
et al. Thrombospondin 1 protects pancreatic [beta]-cells from lipotoxicity via the
PERK-NRF2 pathway. Cell Death Differ 2016; 23:1995–2006.
42 Kulkarni RN. GIP: no longer the neglected incretin twin? Sci Transl Med 2010; 2:
49ps7.
43 Smith Eric P, An Z, Wagner C, Lewis Alfor G, Cohen Eric B, Li B et al. The role of β
cell glucagon-like peptide-1 signaling in glucose regulation and response to
diabetes drugs. Cell Metab 2014; 19: 1050–1057.
44 Campbell JE, Ussher JR, Mulvihill EE, Kolic J, Baggio LL, Cao X et al. TCF1 links GIPR
signaling to the control of beta cell function and survival. Nat Med 2016; 22:
84–90.
45 Baothman OA, Zamzami MA, Taher I, Abubaker J, Abu-Farha M. The role of Gut
Microbiota in the development of obesity and Diabetes. Lipids Health Dis 2016;
15: 108.
46 Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, Bartelsman JFWM et al.
Transfer of intestinal microbiota from lean donors increases insulin sensitivity in
individuals with metabolic syndrome. Gastroenterology 2012; 143:913–6.e7.
47 Puddu A, Sanguineti R, Montecucco F, Viviani GL. Evidence for the gut microbiota
short-chain fatty acids as key pathophysiological molecules improving diabetes.
Mediators Inflamm 2014; 2014:9.
48 McNelis JC, Lee YS, Mayoral R, van der Kant R, Johnson AM, Wollam J et al. GPR43
potentiates beta-cell function in obesity. Diabetes 2015; 64: 3203–3217.
49 Thorens B. Neural regulation of pancreatic islet cell mass and function. Diabetes
Obes Metab 2014; 16:87–95.
50 Lausier J, Diaz WC, Roskens V, LaRock K, Herzer K, Fong CG et al. Vagal control of
pancreatic β-cell proliferation. Am J Physiol Endocrinol Metab 2010; 299:
E786–E793.
51 Gautam D, Han SJ, Duttaroy A, Mears D, Hamdan FF, Li JH et al. Role of the M3
muscarinic acetylcholine receptor in beta-cell function and glucose homeostasis.
Diabetes Obes Metab 2007; 9: 158–169.
52 Borden P, Houtz J, Leach SD, Kuruvilla R. Sympathetic innervation during devel-
opment is necessary for pancreatic islet architecture and functional maturation.
Cell Rep 2013; 4:287–301.
53 Croizier S, Prevot V, Bouret SG. Leptin controls parasympathetic wiring of the
pancreas during embryonic life. Cell Rep 2016; 15:36–44.
54 Rodriguez-Diaz R, Abdulreda MH, Formoso AL, Gans I, Ricordi C, Berggren PO et al.
Innervation patterns of autonomic axons in the human endocrine pancreas. Cell
Metab 2011; 14:45–54.
55 Rodriguez-Diaz R, Dando R, Jacques-Silva MC, Fachado A, Molina J, Abdulreda MH
et al. Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming
beta cell function in humans. Nat Med 2011; 17: 888–892.
56 Imai J, Katagiri H, Yamada T, Ishigaki Y, Suzuki T, Kudo H et al. Regulation of
pancreatic beta cell mass by neuronal signals from the liver. Science 2008; 322:
1250–1254.
57 De Vos A, Heimberg H, Quartier E, Huypens P, Bouwens L, Pipeleers D et al.
Human and rat beta cells differ in glucose transporter but not in glucokinase gene
expression. J Clin Invest 1995; 96: 2489–2495.
58 McCrimmon RJ, Evans ML, Fan X, McNay EC, Chan O, Ding Y et al. Activation of
ATP-sensitive K+ channels in the ventromedial hypothalamus amplifies counter-
regulatory hormone responses to hypoglycemia in normal and recurrently
hypoglycemic rats. Diabetes 2005; 54: 3169–3174.
59 Thorens B, Guillam MT, Beermann F, Burcelin R, Jaquet M. Transgenic reexpression
of GLUT1 or GLUT2 in pancreatic beta cells rescues GLUT2-null mice from early
death and restores normal glucose-stimulated insulin secretion. J Biol Chem 2000;
275: 23751–23758.
60 Marty N, Dallaporta M, Foretz M, Emery M, Tarussio D, Bady I et al. Regulation of
glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-
dependent glucose sensors. J Clin Invest 2005; 115: 3545–3553.
61 Ogunnowo-Bada EO, Heeley N, Brochard L, Evans ML. Brain glucose sensing,
glucokinase and neural control of metabolism and islet function. Diabetes Obes
Metab 2014; 16(Suppl 1): 26–32.
62 Tarussio D, Metref S, Seyer P, Mounien L, Vallois D, Magnan C et al. Nervous
glucose sensing regulates postnatal beta cell proliferation and glucose home-
ostasis. J Clin Invest 2014; 124:413–424.
63 Razavi R, Chan Y, Afifiyan FN, Liu XJ, Wan X, Yantha J et al. TRPV1+ sensory
neurons control beta cell stress and islet inflammation in autoimmune diabetes.
Cell 2006; 127: 1123–1135.
64 JUN regulation of energy metabolism by the skeleton. Cell 2007; 130:456–469.
65 Wei J, Hanna T, Suda N, Karsenty G, Ducy P. Osteocalcin promotes beta-cell
proliferation during development and adulthood through Gprc6a. Diabetes 2014;
63: 1021–1031.
66 Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D et al. Insulin receptor
signaling in osteoblasts regulates postnatal bone acquisition and body compo-
sition. Cell 2010; 142:309–319.
67 Wei J, Ferron M, Clarke CJ, Hannun YA, Jiang H, Blaner WS et al. Bone -specific
insulin resistance disrupts whole-body glucose homeostasis via decreased
osteocalcin activation. J Clin Invest 2014; 124:1–13.
68 Hinoi E, Gao N, Jung DY, Yadav V, Yoshizawa T, Myers MG Jr. et al. The sympa-
thetic tone mediates leptin's inhibition of insulin secretion by modulating
osteocalcin bioactivity. J Cell Biol 2008; 183: 1235–1242.
69 Morioka T, Asilmaz E, Hu J, Dishinger JF, Kurpad AJ, Elias CF et al. Disruption of
leptin receptor expression in the pancreas directly affects beta cell growth and
function in mice. J Clin Invest 2007; 117: 2860–2868.
70 Huang C, Snider F, Cross JC. Prolactin receptor is required for normal glucose
homeostasis and modulation of beta-cell mass during pregnancy. Endocrinology
2009; 150:1618–1626.
71 Karnik SK, Chen H, McLean GW, Heit JJ, Gu X, Zhang AY et al. Menin controls
growth of pancreatic beta-cells in pregnant mice and promotes gestational dia-
betes mellitus. Science 2007; 318: 806–809.
72 Kim H, Toyofuku Y, Lynn FC, Chak E, Uchida T, Mizukami H et al. Serotonin
regulates pancreatic beta cell mass during pregnancy. Nat Med 2010; 16:
804–808.
73 Demirci C, Ernst S, Alvarez-Perez JC, Rosa T, Valle S, Shridhar V et al. Loss of
HGF/c-Met signaling in pancreatic beta-cells leads to incomplete maternal
beta-cell adaptation and gestational diabetes mellitus. Diabetes 2012; 61:
1143–1152.
74 Kondegowda NG, Fenutria R, Pollack IR, Orthofer M, Garcia-Ocana A, Penninger
JM et al. Osteoprotegerin and denosumab stimulate human beta cell proliferation
through inhibition of the receptor activator of NF-kappaB ligand pathway. Cell
Metab 2015; 22:77–85.
75 De Jesus DF, Kulkarni RN. Epigenetic modifiers of islet function and mass. Trends
Endocrinol Metab 2014; 25:628–636.
76 Ahren B. Beta- and alpha-cell dysfunction in subjects developing impaired glu-
cose tolerance: outcome of a 12-year prospective study in postmenopausal
Caucasian women. Diabetes 2009; 58: 726–731.
Inter-organ crosstalk regulating β-cell biology
J Shirakawa et al
902
European Journal of Clinical Nutrition (2017) 896 –903 © 2017 Macmillan Publishers Limited, part of Springer Nature.

77 Ferrara A, Karter AJ, Ackerson LM, Liu JY, Selby JV. Hormone replacement therapy is
associated with better glycemic control in women with type 2 diabetes: The Northern
California Kaiser Permanente Diabetes Registry. Diabetes Care 2001; 24:1144–1150.
78 Tiano JP, Delghingaro-Augusto V, Le May C, Liu S, Kaw MK, Khuder SS et al. Estrogen
receptor activation reduces lipid synthesis in pancreatic islets and prevents beta cell
failure in rodent models of type 2 diabetes. J Clin Invest 2011; 121:3331–3342.
79 Tiano JP, Mauvais-Jarvis F. Importance of oestrogen receptors to preserve func-
tional beta-cell mass in diabetes. Nat Rev Endocrinol 2012; 8:342–351.
80 Yuchi Y, Cai Y, Legein B, De Groef S, Leuckx G, Coppens V et al. Estrogen receptor
alpha regulates beta-cell formation during pancreas development and
following injury. Diabetes 2015; 64: 3218–3228.
81 Mauvais-Jarvis F. Role of sex steroids in beta cell function, growth, and survival.
Trends Endocrinol Metab 2016; 27:844–855.
82 Gourdy P, Bourgeois EA, Levescot A, Pham L, Riant E, Ahui ML et al. Estrogen
therapy delays autoimmune diabetes and promotes the protective efficiency of nat-
ural killer T-cell activation in female nonobese diabetic mice. Endocrinology 2016; 157:
258–267.
83 Navarro G, Xu W, Jacobson DA, Wicksteed B, Allard C, Zhang G et al. Extranuclear
actions of the androgen receptor enhance glucose-stimulated insulin secretion in
the male. Cell Metab 2016; 23:837–851.
84 Costrini NV, Kalkhoff RK. Relative effects of pregnancy, estradiol, and progesterone
on plasma insulin and pancreatic islet insulin secretion. JClinInvest1971; 50:
992–999.
85 Picard F, Wanatabe M, Schoonjans K, Lydon J, O'Malley BW, Auwerx J. Proges-
terone receptor knockout mice have an improved glucose homeostasis secondary
to beta -cell proliferation. Proc Natl Acad Sci USA 2002; 99: 15644–15648.
86 Oda T, Taneichi H, Takahashi K, Togashi H, Hangai M, Nakagawa R et al. Positive
association of free triiodothyronine with pancreatic beta-cell function in people
with prediabetes. Diabet Med 2015; 32:213–219.
87 Aguayo-Mazzucato C, Zavacki AM, Marinelarena A, Hollister-Lock J, El Khattabi I,
Marsili A et al. Thyroid hormone promotes postnatal rat pancreatic beta-cell
development and glucose-responsive insulin secretion through MAFA. Diabetes
2013; 62: 1569–1580.
88 Bruin JE, Saber N, O'Dwyer S, Fox JK, Mojibian M, Arora P et al. Hypothyroidism
impairs human stem cell-derived pancreatic progenitor cell maturation in mice.
Diabetes 2016; 65: 1297–1309.
89 Donath MY, Halban PA. Decreased beta-cell mass in diabetes: significance,
mechanisms and therapeutic implications. Diabetologia 2004; 47: 581–589.
90 Eguchi K, Manabe I, Oishi-Tanaka Y, Ohsugi M, Kono N, Ogata F et al. Saturated
fatty acid and TLR signaling link beta cell dysfunction and islet inflammation. Cell
Metab 2012; 15: 518–533.
91 Ehses JA, Perren A, Eppler E, Ribaux P, Pospisilik JA, Maor-Cahn R et al. Increased
number of islet-associated macrophages in type 2 diabetes. Diabetes 2007; 56:
2356–2370.
92 Morris DL. Minireview: emerging concepts in islet macrophage biology in type 2
diabetes. Mol Endocrinol 2015; 29: 946–962.
93 Brissova M, Aamodt K, Brahmachary P, Prasad N, Hong JY, Dai C et al. Islet
microenvironment, modulated by vascular endothelial growth factor-A signaling,
promotes beta cell regeneration. Cell Metab 2014; 19:498–511.
94 Dirice E, Kahraman S, Jiang W, El Ouaamari A, De Jesus DF, Teo AK et al. Soluble
factors secreted by T cells promote beta-cell proliferation. Diabetes 2014; 63:
188–202.
95 Valdez IA, Dirice E, Gupta MK, Shirakawa J, Teo AK, Kulkarni RN. Proinflammatory
cytokines induce endocrine differentiation in pancreatic ductal cells via STAT3-
dependent NGN3 activation. Cell Rep 2016; 15:460–470.
96 Butcher MJ, Hallinger D, Garcia E, Machida Y, Chakrabarti S, Nadler J et al.
Association of proinflammatory cytokines and islet resident leucocytes with islet
dysfunction in type 2 diabetes. Diabetologia 2014; 57:491–501.
97 Jaeckle Santos LJ, Li C, Doulias PT, Ischiropoulos H, Worthen GS, Simmons RA.
Neutralizing Th2 inflammation in neonatal islets prevents beta-cell failure in adult
IUGR rats. Diabetes 2014; 63: 1672–1684.
98 Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A. The
unique cytoarchitecture of human pancreatic islets has implications for islet cell
function. Proc Natl Acad Sci USA 2006; 103:2334–2339.
99 Fiaschi-Tae sch NM, Kleinberger JW, Salim FG, Troxell R, Wills R, Tanwir M et al.
Human pancreatic beta-cell G1/S molecule cell cycle atlas. Diabetes 2013; 62:
2450–2459.
Inter-organ crosstalk regulating β-cell biology
J Shirakawa et al
903
© 2017 Macmillan Publishers Limited, part of Springer Nature. European Journal of Clinical Nutrition (2017) 896 –903