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REVIEW
New insights into the architecture of the islet of Langerhans:
a focused cross-species assessment
Rafael Arrojo e Drigo
1
&Yusuf Ali
1
&Juan Diez
1
&Dinesh Kumar Srinivasan
1
&
Per-Olof Berggren
1,2,3
&Bernhard O. Boehm
1,2,4
Received: 8 March 2015 /Accepted: 26 June 2015/ Published online: 28 July 2015
#Springer-Verlag Berlin Heidelberg 2015
Abstract The human genome project and its search for
factors underlying human diseases has fostered a major
human research effort. Therefore, unsurprisingly, in recent
years we have observed an increasing number of studies on
human islet cells, including disease approaches focusing
on type 1 and type 2 diabetes. Yet, the field of islet and
diabetes research relies on the legacy of rodent-based
investigations, which have proven difficult to translate to
humans, particularly in type 1 diabetes. Whole islet phys-
iology and pathology may differ between rodents and
humans, and thus a comprehensive cross-species as well
as species-specific view on islet research is much needed.
In this review we summarise the current knowledge of
interspecies islet cytoarchitecture, and discuss its potential
impact on islet function and future perspectives in islet
pathophysiology research.
Keywords Cross-species assessment .Intra-islet signalling .
Islet cell architecture .Islets of Langerhans .Non-human
primates .Review
Abbreviations
ACE Anterior chamber of the eye
AMPA α-Amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid
[Ca
2+
]
i
Intracellular free calcium
CNS Central nervous system
GABA γ-Aminobutyric acid
GLP-1 Glucagon-like peptide-1
IR Insulin receptor
NHP Non-human primate
NMDA N-methyl-D-aspartate
VEGF-A Vascular endothelial growth factor-A
It is the pervading law of all things organic and inor-
ganic, of all things physical and metaphysical, of all
things human and all things superhuman, of all true
manifestations of the head, of the heart, of the soul, that
the life is recognizable in its expression, that form ever
follows function. This is the law.
Louis H. Sullivan (1896) [1]
Introduction
In his 1869 doctoral thesis, now a medical classic, the 22-year-
old German physician Paul Langerhans reported the
Rafael Arrojo e Drigo and Yusuf Ali contributed equally to this work.
*Per-Olof Berggren
Per-Olof.Berggren@ki.se
*Bernhard O. Boehm
Bernhard.boehm@ntu.edu.sg
1
Lee Kong Chian School of Medicine, Nanyang Technological
University, 50 Nanyang Drive, Research Techno Plaza, Level 4,
637 553 Singapore, Singapore
2
Imperial College London, London, UK
3
The Rolf Luft Research Center for Diabetes and Endocrinology,
Karolinska University Hospital L1, Karolinska Institutet,
SE-171 76 Stockholm, Sweden
4
Department of Internal Medicine 1, Ulm University Medical Centre,
Ulm, Germany
Diabetologia (2015) 58:2218–2228
DOI 10.1007/s00125-015-3699-0
microscopic appearance of scattered small groups of cells
among the acinar glandular cells in the pancreas of the rabbit
[2]. In 1893 Edouard Laguesse named these cell clusters the
‘islets of Langerhans’, and first postulated an endocrine role
for these clusters in the control of blood glucose levels [3].
Successful extractions of insulin and glucagon and the for-
mal experimental proof that these key hormones regulate glu-
cose levels firmly established the islets of Langerhans as key
mini-organs in the diabetes field. Research on the biology and
pathophysiology of islet cells burgeoned as a result of the
emergence of novel technologies and the application of vari-
ous diabetes animal models as a surrogate for studies on hu-
man islets from healthy and diabetic individuals [4–14].
Preclinical research on rodent models offers several logis-
tical, methodological and financial advantages. But this
approach may fall short in terms of reflecting critical aspects
of human islet pathophysiology [15,16]. Because islets of
non-human primate (NHP) or human origin are increasingly
becoming available (albeit in limited numbers), there is an
important and creeping increase in the number of studies on
primate islets. Although still in their infancy, such studies have
highlighted key structure–function differences between
rodents and NHP or human islets, with evidence pointing
towards a high degree of similarity between NHP and human
islets [8,14,17,18]. Moreover, mouse models may not reflect
the complexity of human pathophysiology [19], such as islet
amyloid deposition, underscoring the need for a better animal
model (i.e. NHP) that truly mirrors human islet biology in
health and disease [20].
In this review we will summarise the results on islet archi-
tecture and structure–function relationships between rodents,
NHPs and humans. In addition, we will briefly highlight the
plasticity of islet cell architecture observed under diabetic
conditions (reviewed in detail in [21]). As noted earlier,
assumptions on human islet function and regulation based
on rodent islets are not always true. Therefore, we would like
to propose, based on data on interspecies islet cytoarchitecture
and functional differences, a paradigm shift whereby investi-
gations of the NHP islet can serve as a successful diabetes
translational platform.
Cellular architecture and composition of islets
of Langerhans is heterogeneous
Islet morphology has been extensively studied using histolo-
gy, immunohistology and electron microscopy. In addition,
different in vivo and in vitro model systems have been used
to address islet cell function [22,23]. Islets contain a variety of
cell types, the most abundant being the insulin-producing
beta cells, the glucagon-producing alpha cells and the
somatostatin-producing delta cells [24](Fig.1). Furthermore,
ghrelin-producing epsilon cells and pancreatic polypeptide
(PP) cells have been described in the mammalian islet, albeit
in smaller numbers [25,26]. Besides hormone-producing
cells, the islet also houses immune cells, autonomic nerve
system endings (reviewed in detail in [27]) and is served by
an abundant vascular network [8,28,29].
Together, the different cells are architecturally arranged to
allow for a fine-tuned functional interrelationship between all
islet cells, possibly orchestrated by autocrine, paracrine and
endocrine signalling cascades, like a true mini-organ (Fig. 2).
With its unique cell organisation, mammalian islets success-
fully accomplish their ultimate physiological role, to adapt to
constant changes in metabolic demands and to maintain
optimal circulating glucose levels throughout life.
In the following section we will highlight the differences
that separate rodent from primate islet physiology.
Rodents Small animal research has been the cornerstone of
islet research for over a century, pioneered by Langerhans
himself in his description of the rabbit islet [2]. Today, mouse
and rat islets are widely studied, with consensus that these
islets are mainly comprised of an insulin-producing beta cell
core surrounded by a mantle of intermingled alpha and delta
cells (Fig. 1).
The islet vasculature is responsible for supplying the islet
cells not only with oxygen, but also with key metabolic cues
(i.e. glucose) and other nutrients, incretin hormones such as
glucagon-like peptide-1 (GLP-1) and cytokines [29,30]. This
vast vascular network develops early in islet embryogenesis,
providing essential developmental signals [31], and is driven
primarily by the secretion of vascular endothelial growth
factor-A (VEGF-A) from beta cells [32,33]. The islet vascular
bed consistsof both large and small fenestrated capillaries [11,
29]. The islet blood flow arrives from peripheral vascular net-
works, where the blood flow moves from the beta cell-rich
inner core to the outer alpha and delta cells [29,34]. The islet
blood flow pattern and speed has been suggested to be depen-
dent on blood glucose levels, with hyperglycaemia leading to
better islet perfusion with faster flow speeds compared with
states of hypoglycaemia [7]. Recent evidence suggests a
degree of heterogeneity of vascularisation within islets in a
single pancreas [35,36]. Such differences result in distinct
islet subpopulations with significant functional implications,
with highly perfused islets displaying an increased beta cell
proliferation rate and enhanced function [36]. Whether such a
phenotype is found in human islets remains unclear.
Furthermore, islet vasculature has been suggested to play a
crucial role in maintaining islet function in ageing [37].
The location of beta cells within the core of the rodent
islet also has important and direct functional consequences.
The biological activity between the majority of rodent beta cells
within any given islet, commonly measured by changes in
intracellular free calcium concentration ([Ca
2+
]
i
), is highly
synchronised, creating an integrated functional syncytium
Diabetologia (2015) 58:2218–2228 2219
[38]. This synchronisation is dependent on gap junctions made
of Connexin-36 channels between different beta cells [39].
Humans and NHPs Although human islets have been inten-
sively studied over the last decade, their cellular arrangement
is still a matter of debate, largely because of different experi-
mental methodologies. Earlier morphological analysis of
different regions of human and NHP pancreases showed that
the different islet cell types are intermingled, with beta and
alpha cells present in similar numbers with a higher degree of
heterotypic islet cell contacts [14,18]. Thus, human islets
have been perceived to be characterised by an intermingled
majority of beta cells, followed by alpha and delta cells [14,
18,24](Fig.1). However, other groups have provided
evidence of a non-random arrangement of human beta cells
within an islet. They have observed that despite the higher
percentages of alpha cells within the human islet, beta cells
still prefer to remain in contact with one another, in a similar
way to rodent beta cells [40–42]. With homotypic cell contacts
predominant, paracrine influences within human islets may be
limited. In a separate study in which three-dimensional recon-
structions of islets were created from serial human pancreatic
sections, the islets were reported to consist of a beta cell core
with a surrounding mantle of alpha cells and vessels that do
not penetrate the islet [43]. However, in the same paper, the
authors go on to suggest that, similar to rodents, human islet
cells are purposely arranged in a complex trilaminar epithelial
plate fold that favours heterologous contacts and paracrine
signalling between islet cells [43]. These varied concepts of
human beta cell distribution need to be resolved to allow a
thorough appreciation of the importance of paracrine interac-
tions within an intact human islet.
Regardless of heterotypic cell arrangements, human islet
cell composition is set early in human life, stemming from a
high proliferative phase (mainly beta cells) in the first 2 years
of life followed by a life-long low-proliferative state [44,45].
Strikingly, unlike rodents, not much is known about the
human (intra)islet vasculature anatomy and flow rate [37,
46], with the exception of early reports that the perfusion of
human and NHP islets is similar to that of rodent islets [47,
48]. We have shown that the vasculature of human islets
becomes inflamed and fibrotic with ageing, which is also
observed in islets from type 2 diabetic patients [37]. In addi-
tion, a unique double basement membrane between islet cells
and vascular cells has been observed in human islets [49], the
function of which is as yet unknown.
The functional consequences of the unique heterogeneous
cellular arrangement of the human islet are even less clear.
Some functional differences between rodent, NHP and human
islets can be attributed to differences in islet cytoarchitecture
Sympathetic
fibres
Blood
vessels
Parasympathetic
fibres
Primate
Rodent
~80%
~5%
~65%
~30%
~5%
Islet cell composition
Alpha cell
Beta cell
Delta cell
~15%
Fig. 1 The cytoarchitecture of islets of Langerhans of rodents and pri-
mates is different. In rodents, islets are composed of beta cells located in
the core of the islet, which are surrounded by a mantle of alpha and delta
cells. Sympathetic fibres surround the islet, while parasympathetic fibres
are distributed throughout the core of the islet, supplying acetylcholine to
beta cells. In contrast, NHP and human islets have a heterogeneous dis-
tribution of beta, alpha and delta cells. Here, sympathetic fibres target the
islet vasculature and parasympathetic fibres are rare, with alpha cells in
charge of the acetylcholine supply to beta and delta cells
2220 Diabetologia (2015) 58:2218–2228
[14]. By monitoring changes in islet [Ca
2+
]
i
, the authors dem-
onstrate that primate islet cells are activated by changes in low
glucose concentrations (from 3 mmol/l to 1 mmol/l), whereas
mouse islets are not [14]. Moreover, prolonged exposure
of whole mouse islets to 11 mmol/l glucose triggers a
synchronised oscillatory [Ca
2+
]
i
behaviour, an effect that is
absent in primate islets but has been seen in isolated primate
beta cells. [14]. However, such [Ca
2+
]
i
oscillatory behaviour
seen in isolated primate beta cells needs to be verified in an
in vivo setting.
Intra-islet signalling is important for human islet function
Rodent islet function relies on homotypic cellular communi-
cations between beta cells,configuring a functional syncytium
with coordinated islet activity [39,50]. On the other hand, the
cytoarchitecture of the human islet, rich in heterotypic islet
cell contacts, suggests that intra-islet paracrine signalling is
perhaps less straightforward [14,24,43](Fig.2). Although
reports indicate a rodent-like perfusion pattern of the human
islet [47], lending weight to the concept of limited intra-islet
paracrine signalling, the trilaminar-fold hypothesis coupled
with regulated (and directed) blood flow by vascular sphinc-
ters within the human islet suggest that paracrine signalling
may yet be important for islet function [8,51].
Intra-islet communication between different islet cells can
be established by the secretion of signalling molecules into
islet microvasculature or within the islet’s interstitial space.
Once these signalling molecules find their respective receptors
on target cells they trigger complex autocrine or paracrine
regulatory loops. In addition to hormones, islet cells secrete
an array of signalling molecules, including acetylcholine
[17,52], glutamate [53], ATP [54,55]andγ-aminobutyric
acid (GABA) [56–58], all of which are important for islet cell
function (Fig. 2).
Acetylcholine Acetylcholine, the first neurotransmitter to be
discovered, is an important modulator of beta cell activity and
insulin secretion in rodents [59]aswellasinhumans[17].
Although acetylcholine has a similar function in the islets of
Insulin
Insulin
ATP
Insulin gene
expression
Insulin
secretion
Glucagon gene
expression
Glucagon
secretion
Ach
Glutamate
Glucagon
Ach
Somatostatin
secretion
Somatostatin
secretion
llec atleDllec ahplA
Beta cell IR-A/-B
P2X/Y receptor
AMPA/NMDA
receptor
Muscarinic
receptors 1, 3, 5
Insulin
Glucagon/glutamate
Somatostatin
Acetylcholine
SSTR 1-5
Glucagon receptor
GABA
GABAA/B
receptor
Upregulation Downregulation
GABA
Fig. 2 Paracrine and autocrine signalling networks in mammalian islet of
Langerhans. In response to an increase in blood glucose levels, beta cells
secrete insulin. In turn, insulin binds to insulin receptors A and B (IR-A
and IR-B) in beta and alpha cells, regulating insulin gene expression and
insulin and glucagon exocytosis. ATP is secreted together with insulin
and acts on purinergic P2X/Y receptors in beta cells. Beta cells also
secrete GABA, which acts on beta cells in an autocrine manner through
GABA
A
and GABA
B
receptors. When blood glucose levels are low,
alpha cells secrete glucagon, glutamate and acetylcholine
a
. Glucagon
binds to glucagon receptors in beta and alpha cells, regulating insulin
secretion and glucagon gene expression. Similarly, glutamate binds to
AMPA and NMDA receptors in beta and alpha cells, regulating insulin
and glucagon exocytosis. Acetylcholine binds to muscarinic receptors in
beta and delta cells, regulating insulin and somatostatin secretion. At both
high and low blood glucose levels the delta cells secrete somatostatin,
which binds to somatostatin receptors (SSTRs) in beta and alpha cells,
inhibiting insulin and glucagon secretion.
a
In rodent islets, acetylcholine
is secreted by parasympathetic fibres that permeate the beta cell core
(see Fig. 1)
Diabetologia (2015) 58:2218–2228 2221
both, the source of acetylcholine is different [17,59]. In
rodents, acetylcholine isdelivered through autonomic nervous
system varicosities distributed throughout the islet [8], where-
as in humans islets it is secreted by alpha cells and influences
the activityof neighbouring beta and delta cells [8,17,52,60]
(Fig. 2).
Nonetheless, in both human and rodent islets acetylcholine
secretion is triggered by periods of low circulating levels of
glucose, and serves to sensitise beta cells to future rises in
blood glucose concentration. The shift from neural to intra-
islet acetylcholine delivery by alpha cells indicates that human
islets are better able to respond quickly to dynamic shifts in
blood glucose levels, bypassing neural networks. This may
explain why type 1 diabetic patients can show a reduced
dependency on exogenous insulin application as quickly as
20 days after islet transplantation [61], well before complete
islet innervation is established.
ATP ATP is one of the most important signalling molecules in
the body [62]. Besides its well-established role in glucose-
stimulated insulin secretion [63], ATP may also act as an
extracellular signalling molecule within islets. Although
ATP is found within insulin granules [9], its secretion seems
to precede insulin exocytosis [64,65].
To date, most of the data available on ATP function in islets
is from rodent models. ATP is reported to act via P2Y recep-
tors [66], either stimulating [67] or inhibiting [68] insulin
secretion (Fig. 2). Recent studies in human and NHP islets
show that ATP similarly may act as an autocrine signalling
molecule, taking part in an important positive-feedback loop
in active beta cells (Fig. 2). Although ATP is released at low
glucose concentrations [54], glucose-stimulated ATP has been
suggested to act via ionotropic purinergic P2X
3
receptors in
the membrane of active beta cells, resulting in P2X
3
-mediated
Na
+
–Ca
2+
influx and further depolarisation of beta cells and
enhanced insulin secretion [54]. However, another study pro-
duced contradictory data, with P2X isoforms observed to be
less relevant than P2Y
1
receptors in mediating the positive
autocrine role of ATP in human islets [69]. Based on these
intriguing findings, further investigations on the role of intra-
islet ATP signalling are warranted, especially given the
unknown sources of secreted ATP (besides the beta cell) and
the conservation of this autocrine mechanism among different
islet cells.
GABA Since its discovery in the 1950s [70], GABA has been
characterised as a key inhibitory neurotransmitter in the mam-
malian central nervous system (CNS), acting via ionotropic
GABA
A
and metabotropic GABA
B
receptors [71]. In neu-
rons, binding to the various receptor types leads to target cell
hyperpolarisation (i.e. electrical inhibition), either through the
opening of chloride (Cl
−
) channels and Cl
−
influx (GABA
A
),
or by the opening of K
+
channels via second-messenger
pathways (GABA
B
)[71]. Again, in islets the majority of data
on the function of GABA originates from rodent models.
Studies have shown that GABA molecules are found in the
cytoplasm of beta cells, both in insulin granules [9] and in
small core vesicles [72]. Acting via GABA
A
receptors,
GABA mediates the glucose-dependent inhibition of gluca-
gon secretion in alpha cells [73] and triggers beta cell prolife-
ration and survival in an autocrine loop [56,74].
Human islet cells contain high levels of the GABA-
synthesising enzyme glutamate decarboxylase 65 (GAD65,
also known as GAD2) [75]. Besides inducing beta cell prolif-
eration [56], GABA seems to work both as an inhibitory and
as an excitatory molecule. In the presence of physiological
glucose concentrations, GABA depolarises beta cells and
stimulates glucose-induced insulin secretion [76], whereas
the role of GABA in glucagon secretion by alpha cells is
controversial [57,76]. In addition, high levels of GABA can
depolarise delta cells, suggesting a role for GABA-mediated
regulation of somatostatin release [76].
As all three main islet endocrine cells contain GABA [76],
an exciting challenge will be to determine whether GABA
secretion from different islet cells is synchronised in vivo,
especially given the apparent antagonistic actions of GABA
on islet cell function.
Glutamate Glutamate is one of the key excitatory neurotrans-
mitters in the CNS. Glutamate acts via ionotropic kainite-type
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) or N-methyl-D-aspartate (NMDA) receptors [77].
Similar to acetylcholine, GABA, ATP and glutamate,
glutamate-synthesising enzymes and glutamate receptors are
found in the three main endocrine cells in rodent islets [78,
79]. According to one school of thought, in NHPs and humans
[53], intra-islet glutamate is provided by alpha cells, and gluta-
mate is compartmentalised inside glucagon-containing gran-
ules and secreted together with glucagon [80](Fig.2). Once
secreted, glutamate acts mainly in an autocrine fashion, driving
a positive-feedback loop that depolarises the active alpha cell
and upregulates glucagon release (Fig. 2). While this autocrine
function is conserved in rodents and humans, glutamate action
in rodents seems to be mediated by both AMPA and NMDA
receptors [78], while in humans only AMPA receptors are
involved [53]. This scheme has been challenged by the authors
of a recent study using mouse islets who propose a different
model [81], in which glutamate is neither secreted together with
glucagon nor does it modulate glucagon secretion. Rather,
inhibition of glutamate secretion increases cellular pools of
both glutamate and α-ketoglutarate, which are suggested to
enhance somatostatin secretion release from delta cells via a
new AMPA receptor variant [79]. These results highlight the
complexity of intra-islet signalling, and underline the need for
similar studies to be conducted with human islets.
2222 Diabetologia (2015) 58:2218–2228
Insulin Since the first description of insulin [82], its action
and anti-diabetic potential have been studied for almost a
century. Insulin is critical for proper control of blood glucose
levels and acts in almost all tissues, such as brain, liver, muscle,
adipose tissue and pancreatic islets. Insulin action is mediated
by two different isoforms of the insulin receptor (namely IR-A
and IR-B; Fig. 2). Spatial differences between IR-A and IR-B
on cell membranes may explain their differences in intracellular
signalling networks [83]. Mice lacking IR expression specifi-
cally in beta cells (the βIRKO mouse model) develop a
hyperinsulinaemic state and unlike wild-type mice do not show
acute glucose-induced insulin secretion [84]. Moreover, insulin
released in response to glucose is important for forkhead box
protein O1 (FOXO1) transcriptional activity and K
ATP
channel
opening in beta cells [85,86]. In addition, deletion of IR in
alpha cells (the αIRKO mouse model) leads to hyperglycaemia,
glucose intolerance and hyperglucagonaemia, indicating that
insulin acts also at the alpha cell level to suppress glucagon
secretion [87].
In humans, the results available on intra-islet insulin action
are conflicting. Insulin has been described both as a positive
and a negative regulator of islet cell function. Wu et al [88]
reported that insulin acts via the phosphoinositide 3-kinase
pathway, upregulates pancreatic and duodenal homeobox pro-
tein 1 (PDX-1) transcriptional activity and induces insulin
gene expression. In contrast, Persaud et al noted a negative
effect of insulin on beta cell insulin secretion [89]. Similarly,
human pancreases perfused with low glucose and anti-insulin
antibodies have impaired glucagon secretion [90]. Given the
inconsistency of the experimental data, further studies are
necessary to determine the effects of intra-islet insulin.
Glucagon Glucagon is the key hormone in mammals that
maintains glucose availability during fasting periods. Acting
primarily on the liver, glucagon stimulates hepatic glucose
production and excursion [91]. The systemic role of glucagon
is clearly demonstrated in rodents, where deletion of the glu-
cagon receptor leads to low blood glucose levels,
hyperglucagonaemia and improved glucose tolerance [92].
Glucagon signalling within the islet is not well understood,
mainly due to a potential crosstalk with the pre-proglucagon–
incretin pathway [30,93]. Glucagon receptors are found in
both rodent and human islets and in all three major islet cell
types [94,95]. There is consensus that glucagon causes intra-
cellular cAMP levels to rise, which stimulates beta cell
glucose-induced insulin secretion in both rodents and humans
[92,94,96]. This insulinotropic effect of glucagon is also
observed in isolated rodent islets, where deletion or inhibition
of the glucagon receptor blocks insulin secretion and impairs
glucose oxidation [94,97]. In perfused human pancreas, anti-
body neutralisation of glucagon under both low and high
glucose conditions increases insulin secretion [90], contradic-
ting the above data from isolated human islets [94](Fig.2).
Furthermore, glucagon also plays a positive autocrine role by
binding to glucagon receptors on alpha cells to enhance its
own expression [98].
Somatostatin The peptide hormone somatostatin is secreted by
nerve cells in different regions of the brain, by cells in the diges-
tive system and by pancreatic islet delta cells [99](Fig.2).
Somatostatin secreted by gastrointestinal cells is the main source
of circulating somatostatin [99], whereas delta cell-derived
somatostatin plays a key role in intra-islet cell signalling [100]
(Fig. 2). In both rodents and humans, somatostatin inhibits alpha
and beta cell activity, repressing glucagon and insulin secretion
[90,100]. The actions of somatostatin are mediated by five
different isoforms of the somatostatin receptor (SSTR), found
throughout the islet [101,102]. Deletion of the gene encoding
somatostatin in mice leads to a hyperinsulinaemic and
hyperglucagonaemic state, but, surprisingly, without major
whole body metabolic aberrations [100]. Accordingly, somato-
statin neutralisation in perfused human pancreas leads to higher
glucagon and insulin secretion [90].
Recent data indicate that human delta cells are influenced
by alpha and beta cells, thus being an intricate part of a com-
plex paracrine islet cell signalling network [52].
Islet structure–function and diabetes
Structural changes in pancreatic islets have been observed in
both type 1 and type 2 diabetes (summarised in Table1). Most
of the studies show that besides the loss in beta cell mass in
type 1 diabetes, both rodent and human/NHP islets display an
increase in alpha and delta cell mass and alpha cell prolifera-
tion [6,103–105]. Surprisingly, studies have suggested the
presence of glucose-responsive beta cells in patients with long
standing type 1 diabetes [106,107].
In rodent modelsof type 2 diabetes, a large increase in islet
volume/mass is commonly observed, largely as a result of
increased beta cell proliferation and vascular density
[108–113]. This massive increase in beta cell mass is attribut-
ed to an intra-islet, rather than systemic, insulin resistance [84,
114]. In type 2 diabetic humans and NHP models, a more
heterogeneous scenario is observed. Studies have described
a loss in beta cell mass coupled to an increase in amyloid
(IAPP) deposition and alpha cell proliferation (Table 1). We
refer to a recent review article describing beta cell pathophys-
iology in type 2 diabetes [115], describing beta cell failure as a
central mechanism in both type 1 and type 2 diabetes.
Interestingly, in non-diabetic humans, insulin resistance has
been reported to contribute to increased beta cell number
and islet size [116]. Recently, in a mouse model, beta cell
dedifferentiation rather than accelerated death has been sug-
gested as a key driver of beta cell failure [117,118]. However,
at this stage, no direct histopathological evidence has been
Diabetologia (2015) 58:2218–2228 2223
found in human type 2 diabetes to support this observation
besides the well-known imbalance observed in the peripheral
blood between alpha and beta cell hormone levels [12].
Nevertheless,todatewearelimitedtocross-sectional
studies on highly selected patient cohorts (Table 1). In
view of the fact that the data from the UKPDS indicated
a constant loss of beta cell function over time [119], it is
imperative to investigate, longitudinally, the natural history
of human islet dysfunction from pathological onset to pro-
gressive mini-organ failure. Only this approach will allow
the dissection the molecular mechanisms responsible for
the morphological changes of pancreatic islets in the
different metabolic phenotypes [119].
Conclusion
In this review we have summarised key interspecies differ-
ences in the islet cytoarchitecture of rodents, NHPs and
humans (Fig. 1). Such differences might explain disparities
observed in the intra-islet networks regulating islet physiology
and pathophysiology between mice and humans (Fig. 2). In
Tabl e 1 Islet cell phenotype in type 1 and type 2 diabetes in rodents, NHPs and humans
Environment Islet cell changes Species Reference
T1DM ↓Islet endothelial cell density Mouse [122,123]
T1DM ↑Alpha and delta cell mass Mouse [103,104]
T1DM ↓Beta cell mass
↔Alpha and delta cell mass
Mouse [124]
T1DM ↑Islet alpha cell mass NHP [105]
T1DM ↑Alpha, beta cell proliferation Human [6]
T2DM ↓Beta cell area Mouse [125]
T2DM Pericyte hypertrophy and capillary hypertension db/db mouse [110]
T2DM ↑Total islet blood flow
↓When normalised to islet content
ob/ob mouse [108]
T2DM ↑Intra-islet vessel diameter
↓With leptin treatment
ob/ob mouse [109]
T2DM ↑Beta cell mass
↓Islet organisation with alpha cells in the core
IGF-II TG mouse [126]
T2DM ↓1st phase insulin secretion,
↓Alpha:beta cell ratio
Glut2 KO mouse [127]
T2DM ↑Beta cell mass Mouse [113]
T2DM ↑Blood vessel diameter Mouse [111]
T2DM ↑High MW IGF-II
↑Starfish-shaped islets
GK rat [128]
DIO ↑Beta cell mass Rat [112]
DIO↑Islet vascularisation Mouse [129]
T2DM ↑Islet amyloid, ↓beta cell mass NHP [5]
T2DM ↑Islet amyloid deposition NHP [130]
T2DM ↑Alpha cell volume NHP [131]
T2DM ↑Large islet alpha:beta cell ratio NHP [13]
T2DM ↑Amyloid deposition Human [132]
T2DM ↓Beta cell mass Human [133]
T2DM ↑Large islet alpha:beta cell ratio
↓IAPP-positive cells
Human [134]
T2DM ↑Beta cell neogenesis Human [135]
T2DM ↓Beta cell mass Human [4]
T2DM ↓Large islet beta cell mass in head-region of pancreas Human [26]
T2DM ↓Beta cell mass in body and tail region of pancreas Human [136]
T2DM Marginal ↓in beta cells Human [137]
T2DM ↑Intra-islet CD45
+
leucocytes Human [138]
T2DM ↑Intra-islet macrophages and vessel fibrosis Human [37]
DIO, Diet-induced obesity; IAPP, islet amyloid polypeptide; IGF-II, insulin-like growth factor II; MW, molecular weight; T1DM, type 1 diabetes
mellitus; T2DM, type 2 diabetes mellitus
2224 Diabetologia (2015) 58:2218–2228
view of the evidence provided, we believe that islet and
diabetes research should consider differences in islet
cytoarchitecture when conducting and interpreting results
from one given species, especially rodents. Since human islet
composition is heterogeneous and significantly different from
that of rodents but similar to that of NHPs, the NHP may serve
as a more appropriate animal model for studying human islet
pathophysiology from a translational perspective.
The future of islet research to address existing knowledge
gaps in islet physiology and pathophysiology
Besides understanding the main differences in microanatomy
betweentherodentandthehumanislet,itisessentialtostudy
islet physiology and pathophysiology in an in vivo setting.
Only by using an in vivo platform can researchers truly appre-
ciate an integrated view of islet biology. The islet micro-
environment is highly dynamic, and cross-sectional studies
are limited to snapshots of changes in islet cytoarchitecture
andfunction(Fig.1and Table 1), ignoring the longitudinal
dimension that takes into account the natural history of such
changes. Moreover, isolated islets lack functionally important
nerve fibres and blood vessels, and are thus not under the
influence of crucial peripheral and central regulatory factors.
Therefore, as long as the majority of islet research is conducted
ex vivo, whether in isolated islets or pancreatic slices, our
knowledge of islet pathophysiology will remain incomplete
and lacking the translation from bench to bedside. Over the
years islet researchers have developed various in vivo islet
imaging techniques to provide a glimpse of islet morphology,
function, innervation and vascularisation (reviewed in [22,23]).
The next step in the evolution of these techniques would
involve in vivo islet imaging in the NHP, as these islets rep-
resent a close surrogate of human islet physiology. An increas-
ing number of publications suggest that islets transplanted into
the mouse anterior chamber of the eye (ACE) mirror those of
the endogenous pancreas, both structurally and functionally
[11,37,109,120,121]. Whether or not this holds true during
diabetes pathogenesis (e.g. in states of glucolipotoxicity and
of an immune attack) remains to be elucidated. It is notewor-
thy that studies on the autologous transplantation of NHP
islets following partial pancreatectomy into the ACE are
already under way. If successful, these studies may offer a
quantum leap in understanding human-like islet plasticity,
thus improving translational islet research.
Acknowledgements This work was supported by grants from the Sin-
gapore Ministry of Education, Academic Research Fund Tier 1(2014-T1-
001-149toY.A.)andbyLeeKongChianSchoolofMedicine,Nanyang
Technological University, Singapore (NTU) start-up grants (separately for
Y.A., P.O.B. and B.O.B.). The Lee Kong Chian School of Medicine is a
partnership between Nanyang Technological University, Singapore (NTU)
and Imperial College London. Due to space constraints we have not been
able to provide a comprehensive presentation of the theme and have there-
by disregarded many important contributions to the field of our colleagues.
Duality of interest POB is co-founder and CEO of Biocrine AB, a
diabetes-related biotech company.
Contribution statement All authors were responsible for drafting the
article and revising it critically. All authors approved the version to be
published.
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