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IAPP and Type 1 Diabetes: Implications For Immunity, Metabolism and Islet Transplants

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IAPP and Type 1 Diabetes: Implications For Immunity, Metabolism and Islet Transplants

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Journal of Molecular H C Denroche and C B IAPP and type 1 diabetes 60 :2 R57–R75

Endocrinology Verchere

REVIEW

IAPP and type 1 diabetes: implications for

immunity, metabolism and islet transplants

Heather C Denroche1 and C Bruce Verchere1,2

1Department of Surgery, BC Children’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada
2Department of Pathology and Laboratory Medicine, BC Children’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada

Correspondence should be addressed to C B Verchere: [email protected]

Abstract
Islet amyloid polypeptide (IAPP), the main component of islet amyloid in type 2 diabetes Key Words
and islet transplants, is now recognized as a contributor to beta cell dysfunction. ff amylin
Increasingly, evidence warrants its investigation in type 1 diabetes owing to both its ff islet amyloid polypeptide
immunomodulatory and metabolic actions. Autoreactive T cells to IAPP-derived epitopes ff autoimmune
have been described in humans, suggesting that IAPP is an islet autoantigen in type 1 ff inflammation
diabetes. In addition, although aggregates of IAPP have not been implicated in type 1 ff pancreatic beta cell
diabetes, they are potent pro-inflammatory stimuli to innate immune cells, and thus,
could influence autoimmunity. IAPP aggregates also occur rapidly in transplanted
islets and likely contribute to islet transplant failure in type 1 diabetes through sterile
inflammation. In addition, since type 1 diabetes is a disease of both insulin and IAPP
deficiency, clinical trials have examined the potential benefits of IAPP replacement
in type 1 diabetes with the injectable IAPP analogue, pramlintide. Pramlintide
limits postprandial hyperglycemia by delaying gastric emptying and suppressing
hyperglucagonemia, underlining the possible role of IAPP in postprandial glucose
metabolism. Here, we review IAPP in the context of type 1 diabetes: from its potential
involvement in type 1 diabetes pathogenesis, through its role in glucose metabolism
and use of IAPP analogues as therapeutics, to its potential role in clinical islet transplant
Journal of Molecular
failure and considerations in this regard for future beta cell replacement strategies. Endocrinology
(2018) 60, R57–R75

Introduction
Islet amyloid polypeptide (IAPP or amylin), the main persons with T2D and absent in most persons without
constituent of insoluble amyloid deposits in pancreatic T2D (Hull et al. 2004). Unlike human IAPP (hIAPP), rodent
islets of individuals with type 2 diabetes (T2D), is secreted IAPP (rIAPP) does not aggregate, due to the presence of
from pancreatic beta cells at a level of approximately 1% three proline residues within the amyloidogenic region
that of insulin (Kautzky-Willer et al. 1994, Dechenes et al. of the peptide; rodents expressing transgenic hIAPP in
1998, Kahn et al. 1998, Knowles et al. 2002). The unique beta cells develop extensive islet amyloid on high-fat diet,
property of IAPP to aggregate and form islet amyloid is accompanied by beta cell dysfunction and loss. Why IAPP
implicated in the pathology of T2D due to its toxic effects aggregates form in T2D, and their precise role in disease
on beta cells and, more recently, its pro-inflammatory pathogenesis remains unclear. In its monomeric form,
properties. Islet amyloid is present in the majority of IAPP may help regulate metabolism and satiety, though

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Journal of Molecular H C Denroche and C B IAPP and type 1 diabetes 60 :2 R58
Endocrinology Verchere

this biological role remains a matter of some debate. evidence for their role in disease progression. In contrast,
These properties of monomeric IAPP have been exploited autoreactive T cells are considered causal in beta cell killing
for the treatment of both type 1 diabetes (T1D) and T2D, and disease progression, and numerous T cell-targeted
as well as obesity. beta cell autoantigens have been identified in NOD mice
T1D, representing approximately 10% of diabetes and confirmed in humans (Panagiotopoulos et al. 2004).
cases and increasing in prevalence, results from the T cells autoreactive to insulin and its precursor forms are
autoimmune destruction of beta cells. While islet amyloid prevalent in both humans with T1D and NOD mice. Most
has long been studied for its role in T2D pathogenesis, autoreactive T cell targets are beta cell specific, including
little is known about its role, if any, in T1D. IAPP glucose-6-phosphatase catalytic subunit 2 (G6PC2, also
has been reported to be an autoantigen in both T1D known as IGRP) and solute carrier family 30 member 8
and the non-obese diabetic (NOD) mouse model of (SLC30A8 also known as ZNT8); others are not entirely
spontaneous autoimmune diabetes (Panagiotopoulos restricted to beta cells, including chromogranin A and
et al. 2003, Ouyang et al. 2006, Standifer et al. 2006, PTPRN. Studies in NOD mice have shed some light on the
Delong et al. 2011, 2016, Baker et al. 2013, Wiles et al. relative roles of individual autoantigens: deletion of either
2017). In addition, recent evidence has established IAPP proinsulin gene alters diabetes progression in NOD mice
aggregates as strong proinflammatory stimuli that elicit (Moriyama et al. 2003, Thébault-Baumont et al. 2003,
interleukin-1B (IL1B) secretion from innate immune cells Nakayama et al. 2007), whereas deletion of GAD or PTPRN
(Masters et al. 2010, Westwell-Roper et al. 2011, Sheedy does not alter disease progression (Yamamoto et al. 2004,
et al. 2013). Intriguingly, islet amyloid forms rapidly Kubosaki et al. 2005).
in islets transplanted into T1D recipients and likely Evidence suggesting IAPP is a prevalent autoantigen
plays a role in islet graft inflammation and dysfunction in diabetes has emerged. IAPP and its precursor forms
(Andersson et al. 2008, Udayasankar et al. 2009, Potter contain several epitopes that have been found to activate
et al. 2010, 2015, Westwell-Roper et al. 2011, Westermark either CD4 or CD8 T cells in NOD mice and T1D subjects
et al. 2012). In this review, we examine the underexplored (Panagiotopoulos et al. 2003, Ouyang et al. 2006, Standifer
yet plausible role for IAPP in T1D pathophysiology, the use et al. 2006, Delong et al. 2011, 2016, Baker et al. 2013,
of IAPP analogues for T1D treatment, and islet amyloid as Wiles et al. 2017). IAPP autoantibodies have also been
a potential contributor to clinical islet transplant failure. identified in humans, but do not associate specifically with
T1D, precluding a causal role in diabetes (Clark et al. 1991,
Gorus et al. 1992). Though IAPP-reactive T cells associate
IAPP as an autoantigen in type 1 diabetes
with T1D, much remains to be gleaned concerning their
Inappropriate targeting of self-peptides (autoantigens) by role in diabetes, particularly in light of the numerous beta
the adaptive immune system is central to autoimmune cell autoantigens identified to date and those yet to be
diseases. In T1D, autoimmune recognition of beta cell identified. Notably, as with GAD2 and PTPRN, genetic
antigens leads to the progressive destruction of beta deletion of IAPP does not alter diabetes progression
cells. A similar process occurs spontaneously in the NOD in NOD mice, indicating IAPP is not an essential islet
mouse, leading to extensive beta cell loss and diabetes, autoantigen in this model (Baker et al. 2013).
though on a shorter time scale than in human T1D; this To delineate the distinct autoimmune epitopes
model, sharing many similar features with human T1D, within IAPP and its precursor forms, a brief description of
has been used extensively to research the immunological proIAPP processing in beta cells is necessary. Like insulin,
processes underlying T1D (Thayer et al. 2010). Many beta IAPP is initially translated as an immature preprohormone
cell antigens, targeted by one or both of the humoral precursor (preproIAPP) (Fig. 1); removal of the signal
(autoantibodies) and cellular (autoreactive T cells) peptide yields proIAPP (in humans: hproIAPP1–67; in
branches of adaptive immunity, have been identified in mice: mproIAPP1–70). The proIAPP processing pathway
NOD mice and humans (Roep & Peakman 2012). Islet has been largely elucidated from studies in mice and
autoantibodies are strongly associated with T1D, with is assumed, but has not been shown, to be similar
insulin, glutamic acid decarboxylase 2 (GAD2, also known in humans. ProIAPP is first cleaved by prohormone
as GAD65) andprotein tyrosine phosphatase, receptor convertase (PC) 1/3 to release a C terminal fragment and,
type N (PTPRN, also known as IA2) autoantibodies often following carboxypeptidase E (CPE)-mediated removal of
appearing well before diabetes onset. Though circulating dibasic residues, an N-terminally extended intermediate
islet autoantibodies are predictive of T1D, there is little (in humans hproIAPP1–48; in mice mproIAPP1–50).

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A
hpreproIAPP
M G I L K L Q V F L I V L S V A L N H L K A T P I E S H Q V E K R K C N T A T C A T Q R L A N F L V H S S N N F G A I L S S T N V G S N T Y G K R N A V E V L K R E P L N Y L P L

hproIAPP1-67 T P I E S H Q V E K R K C N T A T C A T Q R L A N F L V H S S N N F G A I L S S T N V G S N T Y G K R N A V E V L K R E P L N Y L P L

PC1/3,CPE,PAM
hproIAPP1-48 T P I E S H Q V E K R K C N T A T C A T Q R L A N F L V H S S N N F G A I L S S T N V G S N T Y -NH2

PC2,CPE
hIAPP1-37 K C N T A T C A T Q R L A N F L V H S S N N F G A I L S S T N V G S N T Y -NH2

B
mpreproIAPP
M M C LI S K L P A V L L I L S V A L N H L R A T P V R S G T N P Q M D K R K C N T A T C A T Q R L A N F L V R S S N N L G P V L P P T N V G S N T Y G K R N A A R D P N R E S L D F L L V

mproIAPP1-70 T P V R S G T N P Q M D K R K C N T A T C A T Q R L A N F L V R S S N N L G P V L P P T N V G S N T Y G K R N A A R D P N R E S L D F L L V

PC1/3,CPE,PAM
mproIAPP1-51 T P V R S G T N P Q M D K R K C N T A T C A T Q R L A N F L V R S S N N L G P V L P P T N V G S N T Y -NH2

PC2,CPE
mproIAPP1-37 K C N T A T C A T Q R L A N F L V R S S N N L G P V L P P T N V G S N T Y -NH2

Figure 1
ProIAPP processing in humans and mice. Schematic of proIAPP processing in humans (A) and mice (B). The initially translated IAPP prepropeptide
contains a signal peptide (orange residues) linked to a proIAPP precursor containing the final IAPP peptide (green residues), flanked by N and C terminal
flanking regions (blue residues); the N and C terminal flanking regions are also termed IAPP1 and IAPP2, respectively, by some groups. Epitopes are
indicated in solid lines. Broken lines indicate residues within the peptide that form epitopes following additional modifications. The signal peptide is
cleaved from preproIAPP to produce the proIAPP peptide (hproIAPP1–67 in humans; mproIAPP1–70 in mice). The proIAPP precursor is subsequently cleaved
by PC1/3 to release the C-terminal-flanking region and an N-terminally extended proIAPP intermediate (hproIAPP1–48 in humans; mproIAPP1–51 in mice).
These are likely cleaved by PC2 to release the N-terminal-flanking region and mature IAPP (hIAPP1–37 in humans; mIAPP1–37 in mice). CPE removes the
basic residues (grey) after each PC cleavage. The glycine residue (dark grey) is removed and C-terminal tyrosine amidated by the enzyme peptidylglycine
alpha-amidating monooxygenase (PAM).

This proIAPP intermediate is then cleaved by PC2 to 6 near the Iapp locus. Subsequent analyses revealed
release an N-terminal fragment and the final 37-amino polymorphisms in the NOD Iapp sequence conferring two
acid hIAPP peptide (hIAPP1–37 or mIAPP1–37). Epitopes single amino acid substitutions in the proIAPP peptide
have been identified by ourselves and other groups in the (Fig. 2A). However, a number of synthetic peptides derived
signal peptide of preproIAPP, in the N- and C-terminal from NOD mproIAPP were unable to directly stimulate
regions of proIAPP, as well as in the mature form of IAPP. BDC 6.9 cells, and the precise epitope remained elusive
There is some variability in the nomenclature of these for two more decades. Through screening with a fusion
epitopes in the literature; in this review, we refer to them peptide library, the Haskins group recently discovered
based on their amino acid positions in their respective that the epitope recognized by the BDC 6.9 clone is in
IAPP precursor or mature forms. fact a hybrid peptide formed by the fusion of a previously
described proinsulin C-peptide cleavage product, LQTLAL
(Irminger et al. 1997), to a second peptide, NAARD (Delong
IAPP epitopes targeted by CD4 T cells
et al. 2016). The NAARD peptide sequence corresponds
The Haskins group originally described a CD4 T cell to amino acids 55–59 in the mproIAPP1–70 intermediate
clone isolated from NOD mice (BDC 6.9) that responded and is part of the C terminal fragment released following
to an autoantigen present in islets from NOD but not mproIAPP1–70 cleavage by PC2 (Fig. 1B). The LQTLAL-
BALB/c mice (Dallas-Pedretti et al. 1995). This unknown NAARD hybrid peptide is present in mouse islet fractions,
islet autoantigen was linked to a region on chromosome indicating that it is naturally formed by beta cells

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Figure 2
IAPP epitopes in type 1 diabetes. Primary structures of mouse and human proIAPP peptides are shown. Colours denote N- and C-terminal flanking
regions (blue), mature peptide (green), and residues removed by CPE and PAM during processing (grey). Epitopes are indicated in solid lines. Broken
lines indicate residues within the peptide that form autoantigens following additional modifications. (A) The primary structure of NOD and Balb/c
mproIAPP1–70: epitope mIAPP1–20, originally termed KS20, is present in the pro and mature peptide forms; an additional autoantigen is formed in NOD
mice by fusion between the mproIAPP55–59 sequence within the C-terminal-flanking region, and a C-peptide cleavage product (purple). Balb/c mice form
a non-antigenic hybrid peptide due to a single amino acid substitution in the C-terminal-flanking region of mproIAPP. (B) The primary structure of the
hpreproIAPP signal peptide (orange) and hproIAPP1–67: epitopes hpreproIAPP5–13 and hpreproIAPP9–17 are present in the signal peptide; two autoantigens
are formed by hybrid peptides derived from the N- and C-terminal flanking regions of hproIAPP1–67 fused with a C-peptide cleavage product (purple);
hproIAPP42–62 forms an additional epitope following citrullination of R51 and R59 (red asterisks). This epitope has also been termed IAPP65–84(73-Cit,81-
Cit) based on its position in the hpreproIAPP peptide.

(Delong et al. 2016). Moreover, LQTLAL-NAARD-reactive fragments fused with neuropeptide Y or chromogranin

CD4 T cells are present in NOD mouse pancreas prior to A fragments (Babon et al. 2016, Delong et al. 2016).
and following diabetes onset (Wiles et al. 2017). A second, Along with the GQVELGG-NAVEVLK hybrid peptide, an
independent pathogenic T cell clone, BDC 9.3, was also additional hproIAPP-derived hybrid autoantigen has been
found to react to this same hybrid peptide (Delong et al. identified in a T1D patient (Babon et al. 2016), consisting
2016). In BALB/c mice, an R58G substitution in mproIAPP of a fusion between C-peptide-derived LQTLAL and
renders the hybrid peptide only weakly immunogenic hproIAPP1–7 (Fig. 2B).
(Wiles et al. 2017), thus accounting for the original Additional epitopes derived from IAPP and its
findings that localized the NOD-specific autoantigen to preproIAPP precursor have been identified in human
the Iapp locus (Dallas-Pedretti et al. 1995). With respect T1D subjects and NOD mice. The NOD diabetogenic
to humans, the equivalent fusion peptide (GQVELGGG- T cell line BDC 5.2.9 was found to react to a 20 amino
NAVEVLK) is formed by parts of human C-peptide and the acid region, originally termed KS20 and referred to here
C-terminal fragment of hproIAPP (spanning hproIAPP52–58) as mIAPP1–20, corresponding to residues 1–20 of the
(Fig. 2B). When presented on major histocompatibility mature mIAPP1–37 peptide (Delong et al. 2011) (Fig. 2A).
complex class II (MHCII), encoded by the high-risk CD4 T cells reactive to mIAPP1–20 MHCII tetramers are
human leukocyte antigen (HLA) allele DQ8 (DQA1*03:01; present in the pancreases of ~40% of pre-diabetic NOD
DQB1*03:02), GQVELGGG-NAVEVLK activated two CD4 and >80% of diabetic NOD mice (Baker et al. 2013). Two
T cell clones expanded from a recent-onset T1D subject additional mIAPP1–20 reactive CD4 T cell lines (BDC-5/S34
(Delong et al. 2016), suggesting that hybrid peptide and BDC-9/S3.5) were also cloned from the original
epitopes containing IAPP regions may be of importance in BDC5 and BDC9 T cell lines, isolated from different NOD
human T1D. Other peptides fused to C-peptide fragments mice. Whether the equivalent region in hIAPP1–20 is also
also appear to form hybrids recognized by autoreactive an epitope in human T1D remains to be investigated.
T cells in NOD mice and/or humans, including C-peptide CD4 T cells derived from T1D islets recognize another

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IAPP-derived epitope in humans, corresponding to ProIAPP processing and IAPP epitopes

residues hproIAPP42–62, in which amino acids R51 and
The identification of multiple IAPP-derived autoepitopes
R59 have been post-translationally modified to citrulline
resulting from signal peptides, hybrid peptides and post-
residues (Babon et al. 2016) (Fig. 2B). This raises the further
translational modifications raises the possibility that IAPP
possibility that altered post-translational modification of
and its precursor forms may be processed differently in the
IAPP and its precursor forms could yield additional beta
presence of beta cell dysfunction in early autoimmunity.
cell autoantigens.
Indeed, we recently reported disproportionately
elevated levels of the proIAPP processing intermediate
IAPP epitopes targeted by CD8 T cells hproIAPP1–48 in T1D (Courtade et al. 2017a) suggesting
that, along with impaired proinsulin processing (Roder
We identified two regions derived from the signal
et al. 1994, Hartling et al. 1997, Truyen et al. 2005,
peptide of hpreproIAPP as epitopes, hpreproIAPP5–13 and
Mirmira et al. 2016, Sims et al. 2016, Watkins et al. 2016,
hpreproIAPP9–17 (Fig. 2B), which activate cytotoxic CD8
Rodriguez-Calvo et al. 2017), impaired proIAPP processing
T cells from T1D subjects (Panagiotopoulos et al. 2003,
may be a characteristic of beta cells in T1D. While IAPP
Ouyang et al. 2006, Standifer et al. 2006). These two
is normally secreted relative to insulin at a molar ratio
hpreproIAPP epitopes bind to HLA-A*0201, a common
of approximately 1:100 (Kautzky-Willer et al. 1994,
HLA Class I allele that confers additional T1D risk in
Dechenes et al. 1998, Kahn et al. 1998, Knowles et al. 2002,
patients carrying high-risk HLA Class II alleles (Fennessy
Hull et al. 2004), the ratio of IAPP:insulin secretion or
et al. 1994, Robles et al. 2002). Both of these epitopes
expression may increase in states of beta cell dysfunction
appear to associate with T1D; hpreproIAPP5–13 elicited a
(O’Brien et al. 1991, Pieber et al. 1993, Hiramatsu et al.
response in CD8 T cells from six of nine recent-onset T1D
1994, Mulder et al. 1995a, 1996, Ahrén & Gutniak 1997,
subjects carrying the HLA-A*0201 allele (Panagiotopoulos
Hull et al. 2004, Krizhanovskii et al. 2017). Interestingly,
et al. 2003), and hpreproIAPP5–13 autoreactive CD8 T cells
a small study from the Better Diabetes Diagnosis cohort
are increased in recent-onset HLA-A2-positive T1D
revealed that ~11% of children with T1D had markedly
subjects relative to non-diabetic HLA-A2 siblings (Velthuis
elevated plasma IAPP levels relative to C-peptide and
et al. 2010). hpreproIAPP9–17-reactive CD8 T cells were also
pro-insulin levels at diagnosis (Paulsson et al. 2014). An
elevated in T1D subjects and GAD2 autoantibody-positive
increase in the ratio of IAPP:insulin or aberrant IAPP and
first-degree relatives compared to autoantibody-negative
insulin processing in secretory granules during beta cell
subjects (Standifer et al. 2006). Autoreactive T cell
dysfunction may promote accumulation of antigenic IAPP
populations decline following diabetes onset (Trudeau
cleavage products and increase the probability of forming
et al. 2003, Coppieters et al. 2012), presumably due to lack
antigenic hybrid peptides. Collectively, the above findings
of antigen following substantive beta cell loss. Consistent
indicate that IAPP is likely a common autoantigen in T1D,
with this, hpreproIAPP5–13-reactive peripheral blood
but its importance in disease pathogenesis remains to
mononuclear cells (PBMCs) were diminished in HLA-
be determined.
A*0201-positive T1D subjects with long-standing diabetes
(>180 days) (Panagiotopoulos et al. 2003). The idea that
signal peptide-derived peptides could generate potential
IAPP aggregation and islet inflammation
epitopes in T1D has generated some interest, and indeed
an epitope derived from the signal peptide region of The propensity of IAPP to aggregate and form islet amyloid
preproinsulin has also been described (Skowera et al. renders it deleterious to beta cells. As IAPP aggregates, it
2008). Signal peptides are rich in hydrophobic amino acids first forms small soluble aggregate species, also termed
that could facilitate binding to the HLA-A*0201 cleft, and, oligomers, and subsequently proceeds to assemble into
because they are endoplasmic reticulum (ER) resident, can ordered beta-sheet-rich fibrils that amass into visible
also bypass transporter associated with antigen processing amyloid deposits. While fibrils are relatively inert, soluble
(TAP)-dependent processing (Henderson et al. 1992, Wei & pre-fibrillar aggregate species are cytotoxic to beta cells. In
Cresswell 1992, Panagiotopoulos et al. 2003). Ultimately, addition, recent evidence has established IAPP aggregates
studies in larger patient and at-risk (autoantibody as potent proinflammatory stimuli. In this section, we
positive) populations, including those early in disease discuss the role of IAPP aggregates in islet inflammation,
pathogenesis, will be necessary to determine the role of using the term pre-fibrillar aggregates to describe species
hpreproIAPP-derived epitopes in T1D. of soluble IAPP aggregates that populate the lag phase

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of IAPP fibrillation, from early formed, small oligomeric role in islet amyloid clearance and the ensuing deleterious
species to larger, soluble aggregates that have not yet inflammatory response. Though IL1B synthesis has been
formed fibrils. Through activation of pattern recognition demonstrated in most cell types, and reports suggest that
receptors, pre-fibrillar IAPP aggregates induce the release beta cells can produce IL1B under certain conditions
of a milieu of pro-inflammatory cytokines from innate (Ribaux et al. 2007, Böni-Schnetzler et al. 2008), we found
immune cells, including interleukin-1 beta (IL1B) and that clodronate-mediated depletion of islet macrophages
tumour necrosis factor alpha (TNF), both of which are in vivo virtually ablates islet Il1b and Tnf expression in
known to induce beta cell dysfunction and death. IAPP- hIAPP transgenic mice (Westwell-Roper et al. 2014b). These
induced islet inflammation seems increasingly likely to data indicate that macrophages are likely the major, if not
play a role in T2D pathogenesis (reviewed in Westwell- sole, source of inflammatory cytokines within the islet.
Roper et al. 2014a and Eguchi & Nagai 2017); little is Extracellular islet amyloid, localized in the perivascular
known about whether IAPP aggregates form and induce space between the beta cell basement membrane and islet
inflammation in T1D. capillaries, is ideally situated to interact with resident
islet macrophages residing next to intraislet blood
vessels (Hume et al. 1984, Calderon et al. 2008). Islet
IAPP aggregates induce islet inflammation
macrophages containing IAPP immunoreactive lysosome-
The inflammatory nature of IAPP aggregates appears to like structures were first described in human insulinomas,
be a major contributor to chronic sterile inflammation monkey pancreatic islets and hIAPP transgenic mouse
of pancreatic islets. Much of this evidence has been islets by de Koning and colleagues (1994). Similarly, we
garnered from hIAPP transgenic rodents, which express found macrophages within hIAPP transgenic mouse islets
the hIAPP sequence under control of the rat insulin frequently in close association with, and appearing to
promoter to drive hIAPP overexpression in beta cells. Beta phagocytose, amyloid deposits (Westwell-Roper et al. 2011,
cell dysfunction accompanied by secretory demand such 2014b). Depletion of macrophages in hIAPP transgenic
as that induced by high-fat diet or genetic obesity, leads mice improves glycemia while alleviating expression of
to hIAPP aggregation and islet amyloid formation (which inflammatory cytokines, pointing to an important role for
does not otherwise occur in wild-type rodents expressing macrophages in amyloid-induced beta cell dysfunction.
only rIAPP). Expression of inflammatory cytokines and Interestingly, macrophage depletion increased amyloid
chemokines is elevated in islets of hIAPP transgenic mice; severity (Westwell-Roper et al. 2014b), suggesting that islet
hIAPP transgenic islets express and secrete chemokines macrophages may play a role in islet amyloid clearance.
CXCL1 and CCL2 and have increased expression IAPP aggregates, due to their tendency to induce
of macrophage markers Itgam and Adgre1, as well as secretion of CCL2 and other chemokines from islets, likely
inflammatory genes Il1b and Nlrp3 (Westwell-Roper et al. recruit additional macrophages to islets. Indeed, we found
2011, 2014b, 2016). Moreover, hIAPP transgenic mice fed hIAPP treatment of human islets to have a concentration-
a high-fat diet for 12 months have dramatically elevated dependent chemotactic effect on THP-1 cells (Westwell-
proinflammatory gene expression in islets including Roper et al. 2011). Consistent with this, the number of
Ccl2, Cxcl1, Nlrp3, Pycard, Casp1, Il1b, Tnf, Il6, Adgre1 F4/80+ macrophages is increased in endogenous and
and Itgax (Meier et al. 2014), the expression of which is transplanted islets of hIAPP-expressing mice compared to
strikingly higher than the effect of high-fat diet alone, those of wild-type controls (Westwell-Roper et al. 2011,
supporting the idea that IAPP aggregates are a major – Meier et al. 2014). In contrast, de Koning and colleagues
and perhaps essential – trigger for islet inflammation. found that macrophage density was not different between
Consistent findings have recently been reported in islets with and without amyloid in diabetic humans and
cultured human islets, demonstrating that islet amyloid Macaca mulatta monkeys, nor between hIAPP transgenic
formation correlates with increased IL1B and decreased and control mice (de Koning et al. 1998). In a more
levels of endogenous IL1 receptor antagonist, IL1RN (Hui recent study, amyloid-positive islets in T2D were found
et al. 2017). Furthermore, inhibition of hIAPP expression to have significantly more macrophages (CD68+ cells)
or aggregation in human islets reduced IL1B levels accumulating within or near amyloid plaques and around
(Park et al. 2017). microvessels relative to matched T2D subjects without
Within islets, the primary source of inflammatory amyloid and to non-diabetic controls (Kamata et al. 2014).
cytokines in response to IAPP aggregates is islet The majority of CD68+ cells in this study co-expressed
macrophages, and these cells appear to play an integral nitric oxide synthase 2 (NOS2), whereas the number of

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CD204+ CD163+ macrophages (indicative of an M2-like both the priming and activation stimulus for secretion
alternatively activated phenotype) was unaltered, of the pro-inflammatory cytokine IL1B.
suggesting that hIAPP specifically augments a population
of pro-inflammatory macrophages in islets. Thus, while
Mechanism of IAPP uptake and NLRP3
macrophage phenotype appears to be a major driver of
inflammasome activation
amyloid-induced islet inflammation, the importance of
macrophage number remains to be determined. hIAPP-induced IL1B release from BMDMs and BMDCs
The pro-inflammatory effects of hIAPP aggregates is dependent on phagocytosis of hIAPP aggregates and
on isolated innate immune cells can be clearly observed activation of NLRP3 and caspase 1 (CASP1). Deletion
in vitro. Some of the earliest evidence was provided by of either Nlrp3 or Casp1 abrogates hIAPP-induced IL1B
a study showing that hIAPP, but not rIAPP, augmented secretion in cells, regardless of whether they are first
ionophore-induced colony stimulating factor (CSF2) and primed with LPS or hIAPP aggregates (Masters et al.
leukotriene C4 release from human eosinophils, though 2010, Sheedy et al. 2013, Westwell-Roper et al. 2016).
it was unclear whether this was due to general toxicity Furthermore, pharmacological inhibition of NLRP3 with
of hIAPP aggregates (Hom et al. 1995). Subsequently, glyburide inhibited hIAPP-induced IL1B secretion (Masters
hIAPP was reported to induce the release of a number of et al. 2010, Westwell-Roper et al. 2011). Though the
cytokines, including IL1B, TNF, IL6 and IL8, in murine mechanism of NLRP3 activation by hIAPP has not been
microglia and human monocyte and astrocyte cell lines, fully elucidated, phagocytosis of hIAPP aggregates and
effects that were not exerted by rIAPP (Gitter et al. 2000, accumulation of hIAPP fibrils within the phagolysosome
Yates et al. 2000). Subsequent studies by our group and system appear to play a critical role. Accumulation of
others have more precisely defined the mechanisms by IAPP immunoreactivity in macrophages occurs through
which hIAPP aggregation induces inflammation. Masters a phagocytosis-dependent pathway (Badman et al. 1998),
and colleagues demonstrated that overnight incubation and IL1B release is attenuated by inhibition of phagocytosis
of lipopolysaccharide (LPS)-primed bone marrow-derived with cytochalasin D (Masters et al. 2010, Westwell-Roper
dendritic cells (BMDCs) with hIAPP induced processing et al. 2011, Sheedy et al. 2013). Extracellularly applied
and secretion of IL1B by activating the NLR family pyrin hIAPP appears intracellularly in cultured macrophages as
domain containing 3 (NLRP3) inflammasome (Masters early as 1 h following incubation and continues to increase
et al. 2010). We found that even in the absence of a priming up to 6 h, with IAPP co-localizing with macrosialin, a late
stimulus, hIAPP induced a broad pro-inflammatory endosome/lysosome marker (Badman et al. 1998). After
profile in bone marrow-derived macrophages (BMDMs), 6 h of incubation, IAPP immunoreactivity can be found
marked by increased expression and secretion of TNF, loosely packed in phagosome-like organelles, and from
IL1A, IL1B as well as numerous chemokines including 24 to 72 h, IAPP-reactive fibrils accumulate in dense
CCL2, CCL3, CXCL1, CXCL2 and CXCL10 (Westwell- lysosome-like organelles. This timeline is consistent with
Roper et al. 2011). The lack of any inflammatory that of IL1B release in hIAPP-treated cells: secretion of IL1B
action of rIAPP in these studies clearly shows that in unprimed or LPS-primed macrophages appears after
macrophage recruitment and activation is a property approximately 6 h of incubation and continues thereafter
of IAPP aggregates rather than a biological activity of (Masters et al. 2010, Sheedy et al. 2013, Westwell-Roper
IAPP monomers. Consistent with this, application of the et al. 2016). The requirement for longer incubation for
amyloid-binding dye Congo Red prevents hIAPP-induced maximal IL1B secretion indicates that the process of
inflammasome activation in BMDMs (Sheedy et al. NLRP3 activation by hIAPP aggregates is different from
2013), likely by either inhibiting hIAPP aggregation or that of ligands like ATP, which activate the inflammasome
possibly binding to and rendering aggregates non-toxic. more rapidly.
Likewise, Congo Red reduced IL1B levels in cultured Within phagolysosomes, hIAPP appears to form fibrils.
human islets (Park et al. 2017). Furthermore, inhibition This is evidenced by small fibrillar structures present
of the cognate receptor for monomeric IAPP with the in lysosome structures (Badman et al. 1998) and the
IAPP antagonist AC187 does not reduce hIAPP-induced accumulation of thioflavin S, which binds amyloid fibrils
IL1B secretion in primed cells (Masters et al. 2010). (Sheedy et al. 2013). Knockout of the scavenger receptor
Collectively, these data reveal that hIAPP aggregation CD36 abrogates the accumulation of the thioflavin
elicits a robust pro-inflammatory response in innate S signal in BMDMs and attenuates IL1B secretion,
immune cells, and further suggest that hIAPP can provide indicating its involvement in seeding aggregates within

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the phagolysosome system, and that the accumulation of 2 or a TLR 2/6 heterodimer and myeloid differentiation
fibrils is necessary for maximal NLRP3 activation (Sheedy primary response 88 (MYD88)-dependent signalling
et al. 2013). IAPP fibrils appear to persist in lysosomes even hIAPP induction of NFKB1 activity and pro-inflammatory
following a 72-h washout (Badman et al. 1998), suggesting cytokines is abrogated in Tlr2−/− and Myd88−/− BMDMs,
that macrophages are unable to break down and extrude and in a human TLR2-expressing reporter cell line treated
internalized fibrils. This may lead to phagolysosomal with TLR2- or TLR6-neutralizing antibodies (Westwell-
disruption, a known activation mechanism for the Roper et al. 2016). Furthermore, Tlr2 knockout islets
NLRP3 inflammasome. Thioflavin S accumulation in express less Il1b in response to hIAPP application, and
hIAPP-treated phagocytes is associated with leakage of immunoneutralization of TLR2 reduces Il1b expression
fluorescent dextran into the cytoplasm (Sheedy et al. in islets from hIAPP transgenic rodents (Westwell-Roper
2013). Furthermore, inhibition of cathepsin B, which is et al. 2016). Though hIAPP can act as a priming stimulus,
released during lysosomal disruption, attenuates hIAPP- it is notably less potent than LPS; LPS priming results in a
induced IL1B secretion in LPS-primed cells (Masters et al. 10-fold greater induction of TNF relative to hIAPP over 24 h
2010, Westwell-Roper et al. 2011, Sheedy et al. 2013) and (Westwell-Roper et al. 2011). Moreover, LPS-primed cells
inhibition of lysosomal acidification with bafilomycin A1 subsequently treated with hIAPP secrete approximately
attenuates hIAPP-induced IL1B secretion in LPS-primed 10-fold greater levels of IL1B than cells treated with hIAPP
BMDCs and BMDMs (Masters et al. 2010, Sheedy et al. only (Westwell-Roper et al. 2016); this may explain why
2013). Collectively, these data suggest that macrophages others have not observed robust IL1B secretion from cells
phagocytose hIAPP aggregates, and may not effectively stimulated with hIAPP alone compared to LPS-primed
extrude accumulating fibrils in lysosomes, resulting in the cells treated with hIAPP (Masters et al. 2010, Sheedy
activation of an inflammatory response (Fig. 2). et al. 2013). The relative contributions of hIAPP-induced
NFKB1 and NLRP3 activation in islet inflammation and
ensuing beta cell dysfunction in vivo remain to be tested,
IAPP priming of macrophages
though IL1 clearly plays a critical role, as IL1 antagonism
In addition to activating the NLRP3 inflammasome, ameliorates inflammation, and beta cell dysfunction and
hIAPP aggregates can also provide the priming signal death, in hIAPP transgenic mice and isolated human islets
leading to induction of nuclear factor kappa B subunit (Westwell-Roper et al. 2011, 2015, Hui et al. 2017, Jin et al.
1 (NFKB1) signalling and synthesis of pro-IL1B and 2017, Park et al. 2017). Furthermore, though occurring
other cytokines (Fig. 2). Application of aggregating through distinct mechanisms, both priming and NLPR3
concentrations of hIAPP to unprimed BMDMs induces activation by IAPP are likely to perpetuate a feed-forward
expression of pro-inflammatory cytokines including Il1b, inflammatory activation in macrophages; we found that
Il1a, Tnf and Il6. Furthermore, hIAPP-primed cells secrete IL1 signalling potentiates further IAPP-induced IL1B
numerous cytokines and chemokines, which do not secretion (Westwell-Roper et al. 2011), and IL1B has also
require inflammasome activation, including IL1A, TNF, been shown to enhance islet amyloid formation in both
IL6, IL-10, CCL2, CCL3, CCL4, CCL5, CXCL1, CXCL2 and human and hIAPP transgenic islets (Park et al. 2017).
CXCL10 (Westwell-Roper et al. 2011, 2016). Importantly,
this occurs under conditions and hIAPP concentrations
Inflammatory IAPP species
that do not induce cell death, nor is the effect of hIAPP
aggregates inhibited by polymyxin, indicating that it While both the priming and activating signals provided by
cannot be explained by contamination of hIAPP peptide IAPP are dependent on its ability to aggregate, the precise
preparations with LPS (Westwell-Roper et al. 2011). This aggregate species that induce maximal inflammatory
is consistent with the findings of Yates and colleagues responses have not been defined. Since aggregation of
who showed that application of hIAPP to unprimed hIAPP progresses in vitro from monomeric through to
THP-1 cells rapidly induced the expression of Il1b and Tnf pre-fibrillar aggregates and subsequently fibrillar forms
(Yates et al. 2000). Like activation of the inflammasome, over the course of minutes to hours (depending on the
hIAPP but not rIAPP induces cytokine expression and concentration and solvent used), application of freshly
NFKB1 signalling, indicating that priming is aggregation dissolved hIAPP to macrophages will expose these cells
dependent (Westwell-Roper et al. 2011, 2016). to a range of hIAPP aggregate species. Early, pre-fibrillar
We have reported that activation of NFKB1 and hIAPP species are the most pro-inflammatory (Masters
priming by hIAPP is dependent on toll-like receptor (TLR) et al. 2010, Westwell-Roper et al. 2011, 2016) and most

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toxic to INS1 cells (Abedini et al. 2016). It should be noted aggregation from monomers and through early pre-
that fibrillar hIAPP species can, however, activate the fibrillar aggregates to mature fibrils, exposes macrophages
inflammasome in LPS-primed macrophages, though to a to a series of cues that may maximize both inflammasome
lesser extent than freshly dissolved hIAPP (Westwell-Roper priming and activation; through binding of aggregates by
et al. 2016). Furthermore, through size fractionation, TLRs to disruption of phagolysosomes by accumulating
Masters and colleagues identified that smaller pre-fibrillar aggregates and/or fibrils (Fig. 3).
hIAPP aggregate species of <100 nm induced the highest
level of IL1B secretion from BMDCs after overnight
Could IAPP-induced inflammation play a role type
incubation (Masters et al. 2010). Though aggregation is
1 diabetes?
necessary for priming and activation of macrophages, it
should also be noted that monomeric forms of IAPP may Given the role of macrophages and islet inflammation
also influence macrophage function. Rodent IAPP as well in initiating T1D (Oschilewski et al. 1985, Charlton et al.
as the related peptide calcitonin related polypeptide alpha 1988, Lee et al. 1988a,b, Chung et al. 1997, Jun et al.
(CALCA) have both been shown to increase phagocytic 1999a,b, Calderon et al. 2006), it seems plausible that hIAPP
activity in murine peritoneal macrophages through a aggregates, via induction of islet inflammation, could be
cyclic AMP-dependent pathway (Ichinose & Sawada 1996). a trigger or accelerator of autoimmunity in T1D. Amyloid
We observed that both hIAPP and rIAPP enhance BMDM has not been thoroughly investigated in T1D pancreas,
viability, raising the possibility that both monomeric and and the deficiency of IAPP (along with insulin) associated
aggregate forms may provide survival signals to BMDMs with beta cell loss makes development of extensive
(Westwell-Roper et al. 2011). Thus, the process of hIAPP amyloid plaques in T1D seem unlikely. However, amyloid

TLR 2 or 2/6

CD36
NLRP3
1 inflammasome

NFkB 2 Figure 3
Macrophage activation by IAPP. Prefibrillar IAPP
aggregates may signal through toll-like receptor
(TLR) 2 or a TLR2/6 heterodimer to activate NFkB
signalling and provide signal 1 (indicated) for
proIL1B IL1B proIL1B synthesis. IAPP aggregates are also taken
up through phagocytosis and accumulate in the
phagolysosomal pathway where they may seed
inflammatory to form fibrils, possibly mediated via the
scavenger receptor CD36. Accumulation of IAPP
genes aggregates and/or fibrils results in lysosomal
disruption and the release of cathepsin B,
IL1A IAPP fibrils providing signal 2 (indicated) for NLRP3
activation and inflammasome assembly. The
TNF IAPP aggregates NLRP3 inflammasome processes proIL1B to
mature IL1B, which is subsequently secreted.
chemokines amyloid plaques Large extracellular deposits of mature IAPP fibrils
and/or amyloid plaques may also induce
frustrated phagocytosis resulting in further
inflammation.

was recently reported in two of six pancreas biopsies from Hassan & Heptulla 2009, Weinzimer et al. 2012).
recent onset T1D subjects (Westermark et al. 2017), and it Pramlintide and insulin co-administration was also shown
remains possible that early pre-fibrillar aggregates, which to be more effective relative to higher doses of insulin
are difficult to observe histologically (Zraika et al. 2012), alone, pointing to distinct metabolic actions of IAPP and
might be present early in disease. This is plausible given insulin (Heptulla et al. 2005). Improved postprandial
that beta cell dysfunction increase IAPP:insulin ratios glycemia with single-dose pramlintide supplementation
(O’Brien et al. 1991, Pieber et al. 1993, Hiramatsu et al. involves the inhibition of postprandial glucagon secretion
1994, Mulder et al. 1995a,b, 1996, Ahrén & Gutniak 1997) and delayed gastric emptying. Relative to insulin therapy
and impairs proIAPP processing (Courtade et al. 2017a), alone, single-dose pramlintide supplementation represses
and beta cell dysfunction is thought to occur early in T1D postprandial glucagon secretion in T1D subjects (Fineman
(Roder et al. 1994, Hartling et al. 1997, Keskinen et al. et al. 2002, Heptulla et al. 2005, Chase et al. 2009, Hassan &
2002, Truyen et al. 2005, Ferrannini et al. 2010, Rodriguez- Heptulla 2009). Furthermore, pramlintide administration
Calvo et al. 2017). As TLR signalling and the NLRP3 delays gastric emptying of both solids and liquids in T1D
inflammasome have been implicated in T1D pathogenesis subjects (Kong et al. 1997, 1998, Vella et al. 2002, Woerle
(Tai et al. 2016), it follows that, if pre-fibrillar hIAPP et al. 2008, Chase et al. 2009). In fact, IAPP deficiency may
aggregates form in T1D, the inflammatory properties of contribute to the accelerated gastric emptying observed in
hIAPP aggregates might also play a role in T1D pathology. uncomplicated T1D (Vinik et al. 2008, Woerle et al. 2008).
These findings indicate that IAPP limits postprandial
glycemic and glucagon excursions.
IAPP replacement in type 1 diabetes
In addition to its metabolic effects, preclinical
Beta cells are the major source of circulating IAPP, and studies have demonstrated that IAPP has anorectic effects
their loss in T1D results in deficiency of both circulating on food intake; these actions are dependent on IAPP-
insulin and IAPP. IAPP levels are reduced in T1D subjects responsive neurons in the brain, particularly within the
and negatively correlate with disease duration, as is the area postrema (Edwards et al. 1998, Lutz et al. 2010) and
case for T2D subjects requiring exogenous insulin therapy are not due to malaise or reduced water intake (Lutz et al.
(Hartter et al. 1990, Koda et al. 1992, Akimoto et al. 1993, 1995, Morley et al. 1996). In humans, pramlintide reduces
Heptulla et al. 2005, Huml et al. 2011). Thus, it has been food intake in both T1D and control subjects (Asmar et al.
postulated that IAPP deficiency may contribute to the 2010) and induces sustained weight loss in T1D subjects
metabolic dysregulation of established T1D. However, (Whitehouse et al. 2002, Ratner et al. 2005, Edelman et al.
Iapp knockout mice have a subtle metabolic phenotype 2006). However, given the modest phenotype of IAPP-
(Gebre-Medhin et al. 1998, Olsson et al. 2012), suggesting deficient animals, physiologically IAPP is likely a minor
only a modest role of IAPP in glucose homeostasis. contributor to overall satiety and may act to fine-tune the
Nevertheless, Iapp knockout mice with alloxan-induced more robust effects of other satiety signals.
diabetes have slightly more severe hyperglycemia than
wild-type controls (Mulder et al. 2000), indicating that,
Clinical use of pramlintide for type 1 diabetes
to some extent, IAPP loss may exacerbate metabolic
dysregulation in insulin-deficient states. In 2005, pramlintide (marketed as Symlin) became the first
Many studies have investigated the effects of IAPP injectable approved by the US FDA for the treatment of T1D
replacement in T1D using pramlintide, an analogue of since insulin and has been suggested for supplementation
IAPP that is similar to the non-aggregating rodent form of with meal-time insulin to improve postprandial
IAPP, containing three proline substitutions which prevent hyperglycemia in both T1D and T2D. In several clinical
aggregation. Pramlintide injection has no influence on trials conducted by Amylin Pharmaceuticals, meal-time
glycemia in the fasting state, nor during experimental pramlintide supplementation led to consistent and
hyperinsulinemic–euglycemic or hyperinsulinemic– lasting weight loss, reductions in insulin requirements, as
hypoglycemic challenge (Kolterman et al. 1996, Nyholm well as improved postprandial glycemia in T1D subjects
et al. 1996, Amiel et al. 2005). However, single-dose on insulin (Whitehouse et al. 2002, Ratner et al. 2005,
pramlintide injection in conjunction with insulin prior Edelman et al. 2006). The glycemic benefits of pramlintide
to a meal more effectively attenuates postprandial supplementation occur regardless of disease duration
glycemia than insulin alone in T1D subjects (Fineman (Herrmann et al. 2016), and pramlintide was also shown
et al. 2002, Heptulla et al. 2005, 2009, Chase et al. 2009, to improve glycemic control in T1D patients who are

approaching, but have not achieved, target glycemic 2012, Leõn Fradejas et al. 2015). Despite being absent at
control on insulin alone (Ratner et al. 2005). the time of transplantation, islet amyloid forms rapidly in
Given the potential indications of pramlintide hIAPP transgenic mouse islets and human islets engrafted
administration in T1D, one could reasonably question in diabetic mouse recipients, and its severity progresses
why its use as an adjunct therapeutic to insulin has not had over time (Westermark et al. 2003, Udayasankar et al.
more uptake clinically; most clinical studies of pramlintide 2009). Transplanted human islets in streptozotocin (STZ)-
in diabetes were reported over a decade ago. Side effects induced diabetic mice displayed amyloid as early as two
of pramlintide administration are a likely reason; nausea, weeks post-transplant (Westermark et al. 1995, 1999);
anorexia, vomiting and hypoglycemia are commonly likewise, hIAPP transgenic mouse islets transplanted into
reported adverse events (Whitehouse et al. 2002, Ratner syngeneic diabetic mice developed islet amyloid within
et al. 2004, Edelman et al. 2006) and appear to be worse one week post-transplant, which further progressed over
in T1D than in T2D or obese individuals. The anorexia 12 weeks (Udayasankar et al. 2009). In diabetic non-human
and nausea induced by pramlintide may also be factors primates transplanted with allogeneic islets, a minority
in sustained weight loss and long-term improvements of islet grafts were amyloid positive within four months,
in glycemia. The adverse side effects of pramlintide whereas islet amyloid was present in all grafts from
therapy occur early in the initiation of pramlintide recipients with longer-term graft survival (10–66 months)
therapy but reportedly lessen over time (Whitehouse et al. (Liu et al. 2012). To date, while only a small number of
2002, Ratner et al. 2004, Edelman et al. 2006). Insulin islet transplants in T1D recipients have been analyzed
dose titration, gradual pramlintide dose escalation and for islet amyloid, most have been found to someamyloid
changes to the mode of pramlintide administration, such deposition (Westermark et al. 2008, 2012). Thus, the
as administering pramlintide at a ratio with meal-time prevalence of amyloid may be widespread in clinical islet
insulin or as an infusion rather than injection, also appear transplants and warrants continued investigation.
to improve safety and tolerability (Edelman et al. 2006, Preclinical islet transplant models have revealed an
Rodriguez et al. 2007, Kovatchev et al. 2008, Micheletto association between islet amyloid formation and primary
et al. 2013, Riddle et al. 2015). A better understanding of islet graft dysfunction and failure. hIAPP transgenic
the biological actions of IAPP is clearly needed, along with mouse islet grafts fail more rapidly than control islet grafts
further clinical study and mitigation of adverse events, in diabetic syngeneic recipient mice, and amyloid severity
before the potential benefit of pramlintide as an adjunct within these islet grafts correlates with hyperglycemia and
therapeutic to insulin can be realized. Indeed, more than beta cell loss (Udayasankar et al. 2009, 2013). Similarly,
three decades after the discovery of IAPP, understanding of in diabetic non-human primates receiving allogeneic or
its receptor – thought to be a heteromer of the calcitonin autologous islet transplants, amyloid severity in grafts
receptor with receptor activity modifying proteins RAMP1 correlated positively with hyperglycemia recurrence, and
or RAMP3 (Christopoulos et al. 1999) – and its intracellular inversely with insulin positive area (Liu et al. 2012). This
signalling mechanism remains somewhat rudimentary. association is recapitulated in human islet transplants; we
found that amyloid severity is associated with reduced
beta cell area and graft failure following sub-optimal
IAPP aggregation and islet
transplantation of human islets into immune-deficient,
transplant dysfunction
diabetic recipient mice (Potter et al. 2010). Whether islet
IAPP aggregates may play an important role in islet amyloid contributes to clinical islet transplant failure
graft failure. Islet amyloid has been found in human requires further investigation. Westermark et al. reported
islets transplanted into diabetic immune-deficient mice varying degrees of amyloid severity in 33–44% of engrafted
(Westermark et al. 1995, 1999, Finzi et al. 2005, Bohman islets in three out of four T1D recipients of clinical islet
& Westermark 2012, Potter et al. 2015); hIAPP transgenic transplants (Westermark et al. 2012); intriguingly, the
mouse islets transplanted into syngeneic or immune- patient in which no amyloid was observed had the lowest
deficient diabetic mice (Udayasankar et al. 2009, 2013, glycated hemoglobin levels of the four patients in this
Westwell-Roper et al. 2011), and non-human primate islet study. Islet amyloid was also reported to be present in most
allografts (Liu et al. 2012). In addition, biopsies of whole islets in two T1D recipients of whole pancreas allografts
pancreas transplants and liver-engrafted islets obtained presenting with graft failure (Leõn Fradejas et al. 2015),
at autopsy from T1D subjects have demonstrated varying suggesting that amyloid may also contribute to failure of
degrees of islet amyloid formation (Westermark et al. 2008, pancreas transplants. Clear demonstration of a causal role

for amyloid in islet graft failure awaits inhibitors of IAPP macrophage accumulation and Il1b expression relative to
aggregation in preclinical models of islet transplantation. control grafts in diabetic, immune-compromised mouse
The reason for rapid amyloid accumulation in islet recipients (Westwell-Roper et al. 2011). Furthermore, when
grafts remains unclear. It appears to be independent of recipients of hIAPP transgenic islet grafts were treated
transplantation site, forming in islets engrafted under the with the endogenous IL1 receptor antagonist, IL1RN, graft
kidney capsule, liver, or spleen of nude mice (Westermark function and glycemic control were markedly improved
et al. 2003). It is possible that limited diffusion of secreted (Westwell-Roper et al. 2011), suggesting an important role
IAPP occurs prior to graft vascularization and perfusion, for amyloid-induced inflammation in graft dysfunction.
allowing time for IAPP accumulation and aggregation. In agreement with this, improved transplant outcomes
However, this possibility is countered by the presence were recently reported in immune-deficient mice that
of islet amyloid in whole pancreas transplants (Leõn received transplants of IL1RN-treated islets from non-
Fradejas et al. 2015). We previously pointed out the human primates (Jin et al. 2017).
similarities underlying islet dysfunction in T2D and Since inflammation may help trigger autoimmunity
following transplantation, and have proposed that the as well as allograft rejection, it is plausible that, in addition
beta cell dysfunction in islet grafts predisposes to amyloid to contributing to primary graft dysfunction, amyloid-
deposition, as in T2D (Potter et al. 2014). IAPP synthesis induced inflammation speeds immune-mediated loss of
and secretion is disproportionately elevated (relative islet grafts. Most studies of islet amyloid and primary graft
to insulin) in dysfunctional beta cells, including those dysfunction have used immune-deficient or syngeneic
following transplantation (Stadler et al. 2006, Rickels recipients, limiting insight into whether islet amyloid
et al. 2008). We recently found elevated levels of the might trigger islet allograft rejection. In one study of non-
intermediate hproIAPP1–48 in islet transplant recipients human primate islet allografts, Liu et al. found that when
(Courtade et al. 2017a), suggesting that impaired proIAPP islet allograft rejection occurred rapidly due to insufficient
processing may be a characteristic of transplanted islets, as immune suppression, islet amyloid was detected in only
we and others have suggested may be the case for proinsulin 1 of 6 recipients (Liu et al. 2012); however, it is plausible
(Davalli et al. 2008, Fiorina et al. 2008, Klimek et al. 2009). that early pre-fibrillar aggregates could have formed in
Because proinsulin:insulin ratios were higher in recipients islet grafts during this period. In addition, IAPP-derived
of fewer islets (Klimek et al. 2009), it is possible that the autoantigens described above could have important
secretory stress associated with sub-optimal mass islet implications for recurrent autoimmunity in clinical islet
transplantation exacerbates islet prohormone processing transplant recipients. Thus, the possibility that IAPP could
defects. Such a defect could contribute to amyloid accelerate immune-mediated graft loss via autoantigen
formation and further worsen beta cell dysfunction, a presentation or aggregate-induced inflammationwarrants
possibility that is supported by our recent findings: islets investigation.
from hIAPP transgenic mice lacking PC2 – and therefore
having markedly impaired processing of the hproIAPP1–48
Considerations for beta cell replacement strategies
intermediate – fail very rapidly following transplantation
(Courtade et al. 2017b). Consistent with this, treatments The importance of understanding the role of islet
that improve proIAPP processing and secretion of mature amyloid formation in islet graft failure has become more
IAPP are associated with decreased amyloid formation critical, as clinical islet transplantation and other beta
and improved beta cell function in cultured human islets cell replacement strategies show increasing promise as
(Park et al. 2013). These findings also raise the possibility potentially curative treatments for T1D. Approaches
that beta cell prohormones may have value as biomarkers to prevent or slow IAPP aggregation in transplanted
of graft function or impending graft failure. islets have the potential to enhance graft survival and
function. In fact, some therapeutic strategies intended
to improve transplant outcomes may actually exacerbate
Amyloid and islet transplant inflammation
IAPP aggregation and amyloid deposition. For example,
A putative mechanism of amyloid-induced primary islet immunosuppressive regimens currently used in clinical
graft dysfunction is islet inflammation and elevated islet transplantation have direct deleterious effects on beta
local concentrations of IL1B, owing to the potent cells (Johnson et al. 2009), some of which may promote
inflammatory action of IAPP aggregates discussed above. amyloid deposition. This is the case for glucocorticoids,
We found that hIAPP transgenic islet grafts have increased including dexamethasone, though these are no longer

commonly used in islet transplants (Couce et al. 1996, and thus whether amyloid occurs in hESC-derived cell
Mulder et al. 1996). Another practice that may exacerbate transplants needs to be examined.
islet amyloid formation in islet grafts is the use of heparin
to prevent clotting during islet infusion. We found that
Conclusions
the pre-treatment of islets with heparin enhances islet
amyloid formation by promoting fibrillation of IAPP Though our current understanding of IAPP’s role in T1D is
(Potter et al. 2015). Consequently, heparin pre-treatment limited, the evidence reviewed here suggests that IAPP could
was associated with poorer function of human islet grafts potentially play an immunomodulatory role in diabetes
in immune-deficient mice. Encapsulation, a strategy progression, while the lack of IAPP in established diabetes
being pursued to protect islet grafts from the recipient may have glucoregulatory consequences. Opportunities
immune system, may further exacerbate islet amyloid for intervention of T1D exist at multiple disease stages:
formation and impair transplant outcomes (Bohman prevention of autoimmunity; slowing or reversing of beta
& Westermark 2012). In addition, putative adjunct cell loss prior to clinical onset of diabetes; and improving
therapies may influence islet amyloid formation in grafts. glycemic control after diabetes onset via injectable or cell-
For example, the glucagon-like peptide 1 (GLP1) agonist based therapies. IAPP could be a putative target at each
exenatide was shown to increase plasma IAPP levels in of these intervention stages. Targeting IAPP to prevent
T1D subjects with islet allograft dysfunction (Froud et al. or slow T1D progression prior to clinical onset is an
2008). While GLP-1 agonism increases secretion of IAPP avenue that warrants further evaluation, as IAPP-derived
and potentiates amyloid formation, it also alleviates the autoantigens or IAPP aggregate-induced inflammation
toxic effects of IAPP on beta cells (Aston-Mourney et al. may accelerate beta cell autoimmunity and beta cell loss.
2011). In cultured human islets, exenatide was shown to In individuals with established T1D, IAPP replacement
improve islet function and survival, improving proIAPP has been investigated as an adjunct to insulin to improve
processing thereby restoring mature IAPP secretion, and glycemic control, but with limited success. On the other
reduce IAPP aggregation (Park et al. 2013). Additional hand, while beta cell replacement strategies continue to
factors such as recipient diet and sex could have significant show great promise as a potentially curative treatment for
influences on islet amyloid formation in transplants; high T1D, IAPP aggregation likely limits transplanted beta cell
fat diet was shown to augment amyloid formation in survival and function; thus, efforts to elucidate the factors
human islet grafts in immune-deficient mice (Dai et al. that influence aggregate formation in this setting (as in
2016), and in both preclinical animal models and human T2D), and strategies to circumvent this, are warranted.
T2D, males tend to have more extensive pancreatic islet Finally, as the pathogenesis of T1D is still poorly defined
amyloid formation than females (Verchere et al. 1996, but involving both beta cell dysfunction and breakdown
Zhao et al. 2008). of immune tolerance, exploring the potential utility
Alternative sources of beta cells are being pursued of proIAPP intermediates as biomarkers for beta cell
as more cost-effective and unlimited sources for dysfunction could be important to inform other possible
transplantation, and these cells also need to be therapeutic strategies and to better understand this
investigated for their propensity to form amyloid complex and increasingly prevalent disease.
following transplantation. One potential source of islets
for transplantation is pigs. We have previously shown
that porcine IAPP differs from hIAPP by 10 amino acids, Declaration of interest
and as such, is non-amyloidogenic and non-toxic (Potter H C D is a scientific advisor and owns shares in Integrated Nanotherapeutics.
C B V is a co-founder and own shares in Integrated Nanotherapeutics.
et al. 2010). Our finding that pig islet transplants lack
These activities do not pertain to the content covered in this review.
any detectable amyloid may be one reason why porcine
islets survive and function well following transplant. As
another alternative beta cell source, glucose-responsive
insulin producing cells can now be fully differentiated Funding
H C D is supported by a Juvenile Diabetes Research Foundation Postdoctoral
in vitro from human embryonic stem cells (hESCs) and Fellowship and Canadian Diabetes Association Postdoctoral Fellowship.
show great promise for transplantation (Pagliuca et al. C B V was supported by an investigator award from BC Children’s Hospital
2014, Rezania et al. 2014). As observed by Rezania and the Irving K. Barber Chair in Diabetes Research, and research is supported
by the Canadian Institutes of Health Research (MOP-123338; MOP-130518;
et al. differentiated insulin-producing cells express MOP-14682), Canadian Diabetes Association (OG-3-11-3413-CV), Stem Cell
IAPP, albeit at lower levels than adult human islets, Network, and Juvenile Diabetes Research Foundation (3-SRA-2014-39-Q-R).

Calderon B, Suri A & Unanue ER 2006 In CD4+ T-cell-induced diabetes,

Author contribution statement macrophages are the final effector cells that mediate islet β-cell
H C D and C B V wrote and edited the manuscript. killing. American Journal of Pathology 169 2137–2147. (https://doi.
org/10.2353/ajpath.2006.060539)
Calderon B, Suri A, Miller MJ & Unanue ER 2008 Dendritic cells in islets
References of Langerhans constitutively present cell-derived peptides bound to
their class II MHC molecules. PNAS 105 6121–6126. (https://doi.
Abedini A, Plesner A, Cao P, Ridgway Z, Zhang J, Tu L-H, Middleton CT, org/10.1073/pnas.0801973105)
Chao B, Sartori DJ, Meng F, et al. 2016 Time-resolved studies define Charlton B, Bacelj A & Mandel TE 1988 Administration of silica particles
the nature of toxic IAPP intermediates, providing insight for anti- or anti-Lyt2 antibody prevents beta-cell destruction in NOD mice
amyloidosis therapeutics. eLife 5 1–28. (https://doi.org/10.7554/ given cyclophosphamide. Diabetes 37 930–935. (https://doi.
eLife.12977) org/10.2337/diab.37.7.930)
Ahrén B & Gutniak M 1997 No correlation between insulin and islet Chase HP, Lutz K, Pencek R, Zhang B & Porter L 2009 Pramlintide
amyloid polypeptide after stimulation with glucagon-like peptide-1 lowered glucose excursions and was well-tolerated in adolescents
in type 2 diabetes. European Journal of Endocrinology 137 643–649. with type 1 diabetes: results from a randomized, single-blind,
(https://doi.org/10.1530/eje.0.1370643) placebo-controlled, crossover study. Journal of Pediatrics 155
Akimoto K, Nakazato M & Hayakawa K 1993 Plasma concentration of 369–373. (https://doi.org/10.1016/j.jpeds.2009.03.012)
islet amyloid polypeptide in healthy children and patients with Christopoulos G, Perry KJ, Morfis M, Tilakaratne N, Gao Y, Fraser NJ,
insulin-dependent diabetes mellitus. Acta Paediatrica 15 5–6. Main MJ, Foord SM & Sexton PM 1999 Multiple amylin receptors
(https://doi.org/10.1111/j.1651-2227.1993.tb12669.x) arise from receptor activity-modifying protein interaction with the
Amiel SA, Heller SR, Macdonald IA, Schwartz SL, Klaff LJ, Ruggles JA, calcitonin receptor gene product. Molecular Pharmacology 56
Weyer C, Kolterman OG & Maggs DG 2005 The effect of pramlintide 235–242. (https://doi.org/10.1124/mol.56.1.235)
on hormonal, metabolic or symptomatic responses to insulin- Chung YH, Jun HS, Kang Y, Hirasawa K, Lee BR, Van Rooijen N &
induced hypoglycaemia in patients with type 1 diabetes. Diabetes, Yoon JW 1997 Role of macrophages and macrophage-derived
Obesity and Metabolism 7 504–516. (https://doi. cytokines in the pathogenesis of Kilham rat virus-induced
org/10.1111/j.1463-1326.2004.00417.x) autoimmune diabetes in diabetes-resistant BioBreeding rats. Journal
Andersson A, Bohman S, Borg LAH, Paulsson JF, Schultz SW, of Immunology 159 466–471.
Westermark GT & Westermark P 2008 Amyloid deposition in Clark A, Yon SM, de Koning EJ & Holman RR 1991 Autoantibodies to
transplanted human pancreatic islets: a conceivable cause of their islet amyloid polypeptide in diabetes. Diabetic Medicine 8 668–673.
long-term failure. Experimental Diabetes Research 2008 1–8. (https://doi.org/10.1111/j.1464-5491.1991.tb01675.x)
(https://doi.org/10.1155/2008/562985) Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay TWH,
Asmar M, Bache M, Knop FK, Madsbad S & Holst JJ 2010 Do the actions Atkinson MA, Roep BO & von Herrath MG 2012 Demonstration of
of glucagon-like peptide-1 on gastric emptying, appetite, and food islet-autoreactive CD8 T cells in insulitic lesions from recent onset
intake involve release of amylin in humans? Journal of Clinical and long-term type 1 diabetes patients. Journal of Experimental
Endocrinology and Metabolism 95 2367–2375. (https://doi. Medicine 209 51–60. (https://doi.org/10.1084/jem.20111187)
org/10.1210/jc.2009-2133) Couce M, Kane LA, O’Brien TD, Charlesworth J, Soeller W, McNeish J,
Aston-Mourney K, Hull RL, Zraika S, Udayasankar J, Subramanian SL & Kreutter D, Roche P & Butler PC 1996 Treatment with growth
Kahn SE 2011 Exendin-4 increases islet amyloid deposition but hormone and dexamethasone in mice transgenic for human islet
offsets the resultant beta cell toxicity in human islet amyloid amyloid polypeptide causes islet amyloidosis and beta-cell
polypeptide transgenic mouse islets. Diabetologia 54 1756–1765. dysfunction. Diabetes 45 1094–1101. (https://doi.org/10.2337/
(https://doi.org/10.1007/s00125-011-2143-3) diab.45.8.1094)
Babon JAB, DeNicola ME, Blodgett DM, Crèvecoeur I, Buttrick TS, Courtade JA, Klimek-Abercrombie AM, Chen Y-C, Patel N, Lu PYT,
Maehr R, Bottino R, Naji A, Kaddis J, Elyaman W, et al. 2016 Speake C, Orban PC, Najafian B, Meneilly G, Greenbaum CJ, et al.
Analysis of self-antigen specificity of islet-infiltrating T cells from 2017a Measurement of pro-islet amyloid polypeptide (1–48) in
human donors with type 1 diabetes. Nature Medicine 22 1482–1487. diabetes and islet transplants. Journal of Clinical Endocrinology and
(https://doi.org/10.1038/nm0217-264a) Metabolism 102 2595–2603. (https://doi.org/10.1210/jc.2016-2773)
Badman MK, Pryce RA, Chargé SBP, Morris JF & Clark A 1998 Fibrillar Courtade JA, Wang EY, Yen P, Dai DL, Soukhatcheva G, Orban PC &
islet amyloid polypeptide (amylin) is internalised by macrophages Verchere CB 2017b Loss of prohormone convertase 2 promotes beta
but resists proteolytic degradation. Cell and Tissue Research 291 cell dysfunction in a rodent transplant model expressing human
285–294. (https://doi.org/10.1007/s004410050998) pro-islet amyloid polypeptide. Diabetologia 60 453–463. (https://doi.
Baker RL, Delong T, Barbour G, Bradley B, Nakayama M & Haskins K org/10.1007/s00125-016-4174-2)
2013 Cutting edge: CD4 T Cells reactive to an islet amyloid Dai C, Kayton NS, Shostak A, Poffenberger G, Holly A, Aramandla R,
polypeptide peptide accumulate in the pancreas and contribute to Thompson C, Papagiannis IG, Emfinger C, Shiota M, et al. 2016
disease pathogenesis in nonobese diabetic mice. Journal of Stress-impaired transcription factor expression and insulin secretion
Immunology 191 3990–3994. (https://doi.org/10.4049/ in human islets. Journal of Clinical Investigation 126 1–14.
jimmunol.1301480) (https://doi.org/10.1172/JCI83657)
Bohman S & Westermark GT 2012 Extensive amyloid formation in Dallas-Pedretti A, McDuffie M & Haskins K 1995 A diabetes-associated
transplanted microencapsulated mouse and human islets. Amyloid T-cell autoantigen maps to a telomeric locus on mouse chromosome
19 87–93. (https://doi.org/10.3109/13506129.2012.679988) 6. PNAS 92 1386–1390. (https://doi.org/10.1073/pnas.92.5.1386)
Böni-Schnetzler M, Thorne J, Parnaud G, Marselli L, Ehses JA, Davalli AM, Perego L, Bertuzzi F, Finzi G, La Rosa S, Blau A, Placidi C,
Kerr-Conte J, Pattou F, Halban PA, Weir GC & Donath MY 2008 Nano R, Gregorini L, Perego C, et al. 2008 Disproportionate
Increased interleukin (IL)-1β messenger ribonucleic acid expression hyperproinsulinemia, beta-cell restricted prohormone convertase 2
in β-cells of individuals with type 2 diabetes and regulation of IL-1β deficiency, and cell cycle inhibitors Expression by human islets
in human islets by glucose and autostimulation. Journal of Clinical transplanted into athymic nude mice: insights into nonimmune-
Endocrinology and Metabolism 93 4065–4074. (https://doi. mediated mechanisms of delayed islet graft fai. Cell Transplantation
org/10.1210/jc.2008-0396) 17 1323–1336. (https://doi.org/10.3727/096368908787648137)

Dechenes CJ, Verchere CB, Andrikopoulos S & Kahn SE 1998 Human amyloid deposition in islets. The Belgian Diabetes Registry.
aging is associated with parallel reductions in insulin and amylin Diabetologia 35 1080–1086. (https://doi.org/10.1007/BF02221685)
release. American Journal of Physiology-Endocrinology and Metabolism Hartling SG, Knip M, Røder ME, Dinesen B, Akerblom HK & Binder C
275 E785–E791. (https://doi.org/10.1152/ajpendo.1998.275.5.E785) 1997 Longitudinal study of fasting proinsulin in 148 siblings of
Delong T, Baker RL, Reisdorph N, Reisdorph R, Powell RL, Armstrong M, patients with insulin-dependent diabetes mellitus. Study Group on
Barbour G, Bradley B & Haskins K 2011 Islet amyloid polypeptide is Childhood Diabetes in Finland. European Journal of Endocrinology 137
a target antigen for diabetogenic CD4 + T cells. Diabetes 60 490–494. (https://doi.org/10.1530/eje.0.1370490)
2325–2330. (https://doi.org/10.2337/db11-0288) Hartter E, Lell B, Ludvik B, Svoboda T, Schuller M, Woloszczuk W &
Delong T, Wiles TA, Baker RL, Bradley B, Barbour G, Reisdorph R, Prager R 1990 Reduced islet-amyloid polypeptide in insulin-
Armstrong M, Powell RL, Reisdorph N, Kumar N, et al. 2016 dependent diabetes mellitus. Lancet 335 854. (https://doi.
Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed org/10.1016/0140-6736(90)90966-9)
by peptide fusion. Science 351 711–714. (https://doi.org/10.1126/ Hassan K & Heptulla RA 2009 Reducing postprandial hyperglycemia
science.aad2791) with adjuvant premeal pramlintide and postmeal insulin in children
Edelman S, Garg S, Frias J, Maggs D, Wang Y, Zhang B, Strobel S, Lutz K with type 1 diabetes mellitus. Pediatric Diabetes 10 264–268.
& Kolterman O 2006 A double-blind, placebo-controlled trial (https://doi.org/10.1111/j.1399-5448.2008.00490.x)
assessing pramlintide treatment in the setting of intensive insulin Henderson RA, Michel H, Sakaguchi K, Shabanowitz J, Appella E,
therapy in type 1 diabetes. Diabetes Care 29 2189–2195. (https://doi. Hunt DF & Engelhard VH 1992 HLA-A2.1-associated peptides from a
org/10.2337/dc06-0042) mutant cell line: a second pathway of antigen presentation. Science
Edwards GL, Gedulin BR, Jodka C, Dilts RP, Miller CC & Young A 1998 255 1264–1266. (https://doi.org/10.1126/science.1546329)
Area postrema (AP)- lesions block the regulation of gastric emptying Heptulla RA, Rodriguez LM, Bomgaars L & Raymond MW 2005 The role
by amylin (Abstract). Gastroenterology 114 A748. (https://doi. of amylin and glucagon in the dampening of glycemic excursions in
org/10.1016/S0016-5085(98)83064-3) children with type 1 diabetes. Diabetes 54 1100–1107. (https://doi.
Eguchi K & Nagai R 2017 Islet inflammation in type 2 diabetes and org/10.2337/diabetes.54.4.1100)
physiology. Journal of Clinical Investigation 127 14–23. (https://doi. Heptulla RA, Rodriguez LM, Mason KJ & Haymond MW 2009 Twenty-
org/10.1172/JCI88877) four-hour simultaneous subcutaneous basal-bolus administration of
Fennessy M, Metcalfe K, Hitman GA, Niven M, Biro PA, Tuomilehto J & insulin and amylin in adolescents with type 1 diabetes decreases
Tuomilehto-Wolf E 1994 A gene in the HLA class I region postprandial hyperglycemia. Journal of Clinical Endocrinology and
contributes to susceptibility to IDDM in the Finnish population. Metabolism 94 1608–1611. (https://doi.org/10.1210/jc.2008-2580)
Diabetologia 37 937–944. (https://doi.org/10.1007/BF00400951) Herrmann K, Brunell SC, Li Y, Zhou M & Maggs DG 2016 Impact of
Ferrannini E, Mari A, Nofrate V, Sosenko JM & Skyler JS 2010 disease duration on the effects of pramlintide in type 1 diabetes: a
Progression to diabetes in relatives of type 1 diabetic patients: post hoc analysis of three clinical trials. Advances in Therapy 33
mechanisms and mode of onset. Diabetes 59 679–685. (https://doi. 848–861. (https://doi.org/10.1007/s12325-016-0326-5)
org/10.2337/db09-1378) Hiramatsu S, Inoue K, Sako Y, Umeda F & Nawata H 1994 Insulin
Fineman M, Weyer C, Maggs DG, Strobel S & Kolterman OG 2002 The treatment improves relative hypersecretion of amylin to insulin in
human amylin analog, pramlintide, reduces postprandial rats with non-insulin-dependent diabetes mellitus induced by
hyperglucagonemia in patients with type 2 diabetes mellitus. neonatal streptozocin injection. Metabolism 43 766–770. (https://doi.
Hormone and Metabolic Research 34 504–508. (https://doi. org/10.1016/0026-0495(94)90128-7)
org/10.1055/s-2002-34790) Hom T, Estridge T, Pechous P & Hyslop PA 1995 The amyloidogenic
Finzi G, Davalli A, Placidi C, Usellini L, La Rosa S, Folli F & Capella C peptide human amylin augments the inflammatory activites of
2005 Morphological and ultrastructural features of human islet grafts eosinophils. Journal of Leukocyte Biology 58 526–532.
performed in diabetic nude mice. Ultrastructural Pathology 29 Hui Q, Asadi A, Park YJ, Kieffer TJ, Ao Z & Warnock GL 2017 Amyloid
525–533. (https://doi.org/10.1080/01913120500323563) formation disrupts the balance between interleukin-1β and
Fiorina P, Vergani A, Petrelli A, D’Addio F, Monti L, Abdi R, Bosi E, interleukin-1 receptor antagonist in human islets. Molecular
Maffi P & Secchi A 2008 Metabolic and immunological features of Metabolism 6 833–844. (https://doi.org/10.1016/j.
the failing islet-transplanted patient. Diabetes Care 31 436–438. molmet.2017.05.016)
(https://doi.org/10.2337/dc07-1831) Hull RL, Westermark GT, Westermark P & Kahn SE 2004 Islet amyloid: a
Froud T, Faradji RN, Pileggi A, Messinger S, Baidal DA, Ponte GM, critical entity in the pathogenesis of type 2 diabetes. Journal of
Cure PE, Monroy K, Mendez A, Selvaggi G, et al. 2008 The use of Clinical Endocrinology and Metabolism 89 3629–3643. (https://doi.
exenatide in islet transplant recipients with chronic allograft org/10.1210/jc.2004-0405)
dysfunction: safety, efficacy and metabolic effects. Transplantation 86 Hume DA, Halpin D, Charlton H & Gordon S 1984 The mononuclear
36–45. (https://doi.org/10.1097/TP.0b013e31817c4ab3) phagocyte system of the mouse defined by immunohistochemical
Gebre-Medhin S, Mulder H, Pekny M, Westermark G, Törnell J, localization of antigen F4/80: macrophages of endocrine organs.
Westermark P, Sundler F, Ahrén B, Betsholtz C 1998 Increased insulin PNAS 81 4174–4177. (https://doi.org/10.1073/pnas.81.13.4174)
secretion and glucose tolerance in mice lacking islet amyloid Huml M, Kobr J, Siala K, Varvařovská J, Pomahačová R, Karlíková M &
polypeptide (amylin). Biochemical and Biophysical Research Sýkora J 2011 Gut peptide hormones and pediatric type 1 diabetes
Communications 250 271–277. (https://doi.org/10.1006/ mellitus. Physiological Research/Academia Scientiarum Bohemoslovaca
bbrc.1998.9308) 60 647–658.
Gitter BD, Cox LM, Carlson CD & May PC 2000 Human amylin Ichinose M & Sawada M 1996 Enhancement of phagocytosis by
stimulates inflammatory cytokine secretion from human glioma calcitonin gene-related peptide (CGRP) in cultured mouse peritoneal
cells. Neuroimmunomodulation 7 147–152. (https://doi. macrophages. Peptides 17 1405–1414. (https://doi.org/10.1016/S0196-
org/10.1159/000026432) 9781(96)00198-2)
Gorus FK, Sodoyez JC, Pipeleers DG, Keymeulen B, Foriers A & Van Irminger JC, Verchere CB, Meyer K & Halban PA 1997 Proinsulin targeting
Schravendijk CF 1992 Detection of autoantibodies against islet to the regulated pathway is not impaired in carboxypeptidase
amyloid polypeptide in human serum. Lack of association with type E-deficient Cpe(fat)/Cpe(fat) mice. Journal of Biological Chemistry 272
1 (insulin-dependent) diabetes mellitus, or with conditions favouring 27532–27534. (https://doi.org/10.1074/jbc.272.44.27532)

Jin SM, Shim W, Oh BJ, Oh SH, Yu SJ, Choi JM, Park HJ, Park JB & mice and humans. Diabetes 43 640–644. (https://doi.org/10.2337/
Kim JH 2017 Anakinra protects against serum deprivation-induced diab.43.5.640)
inflammation and functional derangement in islets isolated from de Koning EJ, van den Brand JJG, Mott VL, Chargé SBP, Hansen BC,
nonhuman primates. American Journal of Transplantation 17 365–376. Bodkin NL, Morris JF & Clark A 1998 Macrophages and pancreatic
(https://doi.org/10.1111/ajt.13953) islet amyloidosis. Amyloid: The International Journal of Experimental
Johnson JD, Ao Z, Ao P, Li H, Dai LJ, He Z, Tee M, Potter KJ, Klimek AM, and Clinical Investigation 5 247–254. (https://doi.
Meloche RM, et al. 2009 Different effects of FK506, rapamycin, and org/10.3109/13506129809007297)
mycophenolate mofetil on glucose-stimulated insulin release and Kovatchev BP, Crean J & Mccall A 2008 Pramlintide reduces the risks
apoptosis in human islets. Cell Transplantation 18 833–845. associated with glucose variability in type 1 diabetes. Diabetes
(https://doi.org/10.3727/096368909X471198) Technology and Therapeutics 10 391–396. (https://doi.org/10.1089/
Jun HS, Yoon CS, Zbytnuik L, van Rooijen N & Yoon JW 1999a The role dia.2007.0295)
of macrophages in T cell-mediated autoimmune diabetes in Krizhanovskii C, Fred RG, Oskarsson ME, Westermark GT & Welsh N
nonobese diabetic mice. Journal of Experimental Medicine 189 2017 Addition of exogenous sodium palmitate increases the IAPP/
347–358. (https://doi.org/10.1084/jem.189.2.347) insulin mRNA ratio via GPR40 in human EndoC-βH1 cells. Upsala
Jun HS, Santamaria P, Lim HW, Zhang ML & Yoon JW 1999b Absolute Journal of Medical Sciences 122 149–159. (https://doi.org/10.1080/030
requirement of macrophages for the development and activation of 09734.2017.1368745)
beta-cell cytotoxic CD8+ T-cells in T-cell receptor transgenic NOD Kubosaki A, Nakamura S & Notkins AL 2005 Dense core vesicle proteins
mice. Diabetes 48 34–42. (https://doi.org/10.2337/diabetes.48.1.34) IA-2 and IA-2beta: metabolic alterations in double knockout mice.
Kahn SE, Verchere CB, Andrikopoulos S, Asberry PJ, Leonetti DL, Diabetes 54 (Supplement 2) S46–S51. (https://doi.org/10.2337/
Wahl PW, Boyko EJ, Schwartz RS, Newell-Morris L & Fujimoto WY diabetes.54.suppl_2.S46)
1998 Reduced amylin release is a characteristic of impaired glucose Lee K, Amano K & Yoon J 1988a Evidence for initial involvement of
tolerance and type 2 diabetes in Japanese Americans. Diabetes 47 macrophage in development of insulitis in NOD mice. Diabetes 37
640–645. (https://doi.org/10.2337/diabetes.47.4.640) 989–991. (https://doi.org/10.2337/diab.37.7.989)
Kamata K, Mizukami H, Inaba W, Tsuboi K, Tateishi Y, Yoshida T & Lee KU, Pak CY, Armano K & Yoon JW 1988b Prevention of lymphocytic
Yagihashi S 2014 Islet amyloid with macrophage migration correlates thyroiditis and insulitis in diabetes-prone BB rats by the depletion of
with augmented β-cell deficits in type 2 diabetic patients. Amyloid 21 macrophages. Diabetologia 31 400–402. (https://doi.org/10.1007/
191–201. (https://doi.org/10.3109/13506129.2014.937857) BF02341511)
Kautzky-Willer A, Thomaseth K, Pacini G, Clodi M, Ludvik B, Streli C, Leõn Fradejas M, Kandil D, Papadimitriou JC, Del Pino Flõrez Rial M,
Waldhäusl W & Prager R 1994 Role of islet amyloid polypeptide Prieto Sánchez E & Drachenberg CB 2015 Islet amyloid in whole
secretion in insulin-resistant humans. Diabetologia 37 188–194. pancreas transplants for type 1 Diabetes Mellitus (DM): possible role
(https://doi.org/10.1007/s001250050092) of type 2 DM for graft failure. American Journal of Transplantation 15
Keskinen P, Korhonen S, Kupila A, Veijola R, Erkkilä S, Savolainen H, 2495–2500. (https://doi.org/10.1111/ajt.13269)
Arvilommi P, Simell T, Ilonen J, Knip M, et al. 2002 First-phase Liu C, Koeberlein B, Feldman MD, Mueller R, Wang Z, Li Y, Lane K,
insulin response in young healthy children at genetic and Hoyt CC, Tomaszewski JE, Naji A, et al. 2012 Accumulation of
immunological risk for Type I diabetes. Diabetologia 45 1639–1648. intrahepatic islet amyloid in a nonhuman primate transplant
(https://doi.org/10.1007/s00125-002-0981-8) model. Endocrinology 153 1673–1683. (https://doi.org/10.1210/
Klimek AM, Soukhatcheva G, Thompson DM, Warnock GL, Salehi M, en.2011-1560)
Rilo H, D’Alessio D, Meneilly GS, Panagiotopoulos C & Verchere CB Lutz TA, Geary N, Szabady MM, Del Prete E & Scharrer E 1995 Amylin
2009 Impaired proinsulin processing is a characteristic of decreases meal size in rats. Physiology and Behavior 58 1197–1202.
transplanted islets. American Journal of Transplantation 9 2119–2125. (https://doi.org/10.1016/0031-9384(95)02067-5)
(https://doi.org/10.1111/j.1600-6143.2009.02740.x) Lutz TA, Mollet A, Rushing PA, Riediger T & Scharrer E 2010 The
Knowles NG, Landchild MA, Fujimoto WY & Kahn SE 2002 Insulin and anorectic effect of a chronic peripheral infusion of amylin is
amylin release are both diminished in first-degree relatives of abolished in area postrema nucleus of the solitary tract (AP/NTS)
subjects with type 2 diabetes. Diabetes Care 25 292–297. (https://doi. lesioned rats. International Journal of Obesity 25 1005–1011.
org/10.2337/diacare.25.2.292) (https://doi.org/10.1038/sj.ijo.0801664)
Koda JE, Fineman M, Rink TJ, Dailey GE, Muchmore DB & Linarelli LG Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM,
1992 Amylin concentrations and glucose control. Lancet 339 Sharp FA, Becker C, Franchi L, Yoshihara E, Chen Z, et al. 2010
1179–1180. (https://doi.org/10.1016/0140-6736(92)90785-2) Activation of the NLRP3 inflammasome by islet amyloid polypeptide
Kolterman O, Schwartz S, Corder C, Levy B, Klaff L, Peterson J & provides a mechanism for enhanced IL-1β in type 2 diabetes. Nature
Gottlieb A 1996 Effect of 14 days’ subcutaneous administration of Immunology 11 897–904. (https://doi.org/10.1038/ni.1935)
the human amylin analogue, pramlintide (AC137), on an Meier DT, Morcos M, Samarasekera T, Zraika S, Hull RL & Kahn SE 2014
intravenous insulin challenge adn response to a standard liquid meal Islet amyloid formation is an important determinant for inducing
in patients with IDDM. Diabetologia 39 492–499. (https://doi. islet inflammation in high-fat-fed human IAPP transgenic mice.
org/10.1007/BF00400683) Diabetologia 57 1884–1888. (https://doi.org/10.1007/s00125-014-
Kong MF, King P, Macdonald IA, Stubbs TA, Perkins AC, Blackshaw PE, 3304-y)
Moyses C & Tattersall RB 1997 Infusion of pramlintide, a human Micheletto F, Dalla ManC, Kolterman O, Chiquette E, Herrmann K,
amylin analogue, delays gastric emptying in men with IDDM. Schirra J, Kovatchev B & Cobelli C 2013 In silico design of optimal
Diabetologia 40 82–88. (https://doi.org/10.1007/s001250050646) ratio for co-administration of pramlintide and insulin in type 1
Kong MF, Stubbs TA, King P, Macdonald IA, Lambourne JE, diabetes. Diabetes Technology and Therapeutics 15 802–809.
Blackshaw PE, Perkins AC & Tattersall RB 1998 The effect of single (https://doi.org/10.1089/dia.2013.0054)
doses of pramlintide on gastric emptying of two meals in men with Mirmira RG, Sims EK, Syed F & Evans-Molina C 2016 Biomarkers of
IDDM. Diabetologia 41 577–583. (https://doi.org/10.1007/ β-Cell stress and death in type 1 diabetes. Current Diabetes Reports 16
s001250050949) 95. (https://doi.org/10.1007/s11892-016-0783-x)
de Koning EJP, Hoppener JWM, Verbeek SJ, Oosterwijk C, van Hulst KL, Moriyama H, Abiru N, Paronen J, Sikora K, Liu E, Miao D, Devendra D,
Baker CA, Lips CJM, Morris JF & Clark A 1994 Human islet amyloid Beilke J, Gianani R, Gill RG, et al. 2003 Evidence for a primary islet
polypeptide (IAPP) accumulates at similar sites in islets of transgenic autoantigen (preproinsulin 1) for insulitis and diabetes in the

nonobese diabetic mouse. PNAS 100 10376–10381. (https://doi. implications in type 2 diabetes and islet transplantation. Diabetologia
org/10.1073/pnas.1834450100) 56 508–519. (https://doi.org/10.1007/s00125-012-2802-z)
Morley JE, Suarez MD, Mattamal M & Flood JF 1996 Amylin and food Park YJ, Warnock GL, Ao Z, Safikhan N, Meloche M, Asadi A, Kieffer TJ
intake in mice: effects on motivation to eat and mechanism of & Marzban L 2017 Dual role of interleukin-1β in islet amyloid
action. Pharmacology Biochemistry and Behavior 56 123–129. formation and its β-cell toxicity: implications for type 2 diabetes and
(https://doi.org/10.1016/S0091-3057(96)00168-2) islet transplantation. Diabetes, Obesity and Metabolism 19 682–694.
Mulder H, Ahrén B, Stridsberg M & Sundler F 1995a Non-parallelism of (https://doi.org/10.1111/dom.12873)
islet amyloid polypeptide (amylin) and insulin gene expression in Paulsson JF, Ludvigsson J, Carlsson A, Casas R, Forsander G, Ivarsson SA,
rat islets following dexamethasone treatment. Diabetologia 38 Kockum I, Lernmark Å, Marcus C, Lindblad B, et al. 2014 High
395–402. (https://doi.org/10.1007/BF00410276) plasma levels of islet amyloid polypeptide in young with new-onset
Mulder H, Ahrén B & Sundler F 1995b Differential expression of islet of type 1 diabetes mellitus. PLoS ONE 9 1–5. (https://doi.
amyloid polypeptide (amylin) and insulin in experimental diabetes org/10.1371/journal.pone.0093053)
in rodents. Molecular and Cellular Endocrinology 114 101–109. Pieber TR, Stein DT, Ogawa A, Alam T, Ohneda M, McCorkle K, Chen L,
(https://doi.org/10.1016/0303-7207(95)03646-O) McGarry JD & Unger RH 1993 Amylin-insulin relationships in
Mulder H, Ahrén B & Sundler F 1996 Islet amyloid polypeptide (amylin) insulin resistance with and without diabetic hyperglycemia.
and insulin are differentially expressed in chronic diabetes induced American Journal of Physiology 265 E446–E453. (https://doi.
by streptozotocin in rats. Diabetologia 39 649–657. (https://doi. org/10.1152/ajpendo.1993.265.3.E446)
org/10.1007/s001250050492) Potter KJ, Abedini A, Marek P, Klimek AM, Butterworth S, Driscoll M,
Mulder H, Gebre-Medhin S, Betsholtz C, Sundler F & Ahrén B 2000 Islet Baker R, Nilsson MR, Warnock GL, Oberholzer J, et al. 2010 Islet
amyloid polypeptide (amylin)-deficient mice develop a more severe amyloid deposition limits the viability of human islet grafts but not
form of alloxan-induced diabetes. American Journal of Physiology: porcine islet grafts. PNAS 107 4305–4310. (https://doi.org/10.1073/
Endocrinology and Metabolism 278 E684–E691. (https://doi. pnas.0909024107)
org/10.1152/ajpendo.2000.278.4.E684) Potter KJ, Westwell-Roper CY, Klimek-Abercrombie AM, Warnock GL &
Nakayama M, Beilke JN, Jasinski JM, Kobayashi M, Miao D, Li M, Verchere CB 2014 Death and dysfunction of transplanted β-cells:
Coulombe MG, Liu E, Elliott JF, Gill RG, et al. 2007 Priming and lessons learned from type 2 diabetes? Diabetes 63 12–19. (https://doi.
effector dependence on insulin B:9-23 peptide in NOD islet org/10.2337/db12-0364)
autoimmunity. Journal of Clinical Investigation 117 1835–1843. Potter KJ, Werner I, Denroche HC, Montane J, Plesner A, Chen Y, Lei D,
(https://doi.org/10.1172/JCI31368) Soukhatcheva G, Warnock GL, Oberholzer J, et al. 2015 Amyloid
Nyholm B, Moller N, Gravholt CH, Orskov L, Mengel A, Bryan G, formation in human islets is enhanced by heparin and inhibited by
Moyses C, Alberti KGMM & Schmitz O 1996 Acute effects of the heparinase. American Journal of Transplantation 15 1519–1530.
human amylin analog AC137 on basal and insulin-stimulated (https://doi.org/10.1111/ajt.13134)
euglycemic and hypoglycemic fuel metabolism in patients with Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel SA,
insulin-dependent diabetes mellitus. Journal of Clinical Endocrinology Weyer C & Kolterman OG 2004 Amylin replacement with
and Metabolism 81 1083–1089. (https://doi.org/10.1210/ pramlintide as an adjunct to insulin therapy improves long-term
jcem.81.3.8772580) glycaemic and weight control in Type 1 daibetes mellitus: a 1-year,
O’Brien TD, Westermark P & Johnson KH 1991 Islet amyloid randomized controlled trial. Diabetic Medicine 21 1204–1212.
polypeptide and insulin secretion from isolated perfused pancreas of (https://doi.org/10.1111/j.1464-5491.2004.01319.x)
fed, fasted, glucose-treated, and dexamethasone-treated rats. Diabetes Ratner R, Whitehouse F, Fineman MS, Strobel S, Shen L, Maggs DG,
40 1701–1706. (https://doi.org/10.2337/diab.40.12.1701) Kolterman OG & Weyer C 2005 Adjunctive therapy with pramlintide
Olsson M, Herrington MK, Reidelberger RD, Permert J, Gebre-Medhin S, lowers HbA1c without concomitant weight gain and increased risk
Arnelo U 2012 Food intake and meal pattern in IAPP knockout mice of severe hypoglycemia in patients with type 1 diabetes approaching
with and without infusion of exogenous IAPP Scandinavian. Journal glycemic targets. Experimental and Clinical Endocrinology and Diabetes
of Gastroenterology 47 191–196. (https://doi.org/10.3109/00365521.20 113 199–204. (https://doi.org/10.1055/s-2005-837662)
11.638392) Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I, Asadi A,
Oschilewski U, Kiesel U & Kolb H 1985 Administration of silica prevents O’Dwyer S, Quiskamp N, Mojibian M, Albrecht T, et al. 2014
diabetes in BB-rats. Diabetes 34 197–199. (https://doi.org/10.2337/ Reversal of diabetes with insulin-producing cells derived in vitro
diab.34.2.197) from human pluripotent stem cells. Nature Biotechnology 32
Ouyang Q, Standifer NE, Qin H, Gottlieb P, Verchere CB, Nepom GT, 1121–1133. (https://doi.org/10.1038/nbt.3033)
Tan R & Panagiotopoulos C 2006 Recognition of HLA class Ribaux P, Ehses JA, Lin-Marq N, Carrozzino F, Böni-Schnetzler M,
I-restricted -cell epitopes in type 1 diabetes. Diabetes 55 3068–3074. Hammar E, Irminger JC, Donath MY & Halban PA 2007 Induction of
(https://doi.org/10.2337/db06-0065) CXCL1 by extracellular matrix and autocrine enhancement by
Pagliuca FW, Millman JR, Gürtler M, Segel M, Van Dervort A, Ryu JH, interleukin-1 in rat pancreatic beta-cells. Endocrinology 148
Peterson QP, Greiner D & Melton DA 2014 Generation of functional 5582–5590. (https://doi.org/10.1210/en.2007-0325)
human pancreatic β cells in vitro. Cell 159 428–439. (https://doi. Rickels MR, Collins HW & Naji A 2008 Amyloid and transplanted islets.
org/10.1016/j.cell.2014.09.040) New England Journal of Medicine 359 2729–2731. (https://doi.
Panagiotopoulos C, Qin H, Tan R & Verchere CB 2003 Identification of a org/10.1056/NEJMc082011)
β-cell–specific HLA class I restricted epitope in type 1 diabetes. Riddle MC, Yuen KCJ, de Bruin TW, Herrmann K, Xu J, Öhman P &
Diabetes 52 2647–2651. (https://doi.org/10.2337/diabetes.52.11.2647) Kolterman OG 2015 Fixed ratio dosing of pramlintide with regular
Panagiotopoulos C, Trudeau JD & Tan R 2004 T-cell epitopes in type 1 insulin before a standard meal in patients with type 1 diabetes.
diabetes. Current Diabetes Reports 4 87–94. (https://doi.org/10.1007/ Diabetes, Obesity and Metabolism 17 904–907. (https://doi.
s11892-004-0062-0) org/10.1111/dom.12504)
Park YJ, Ao Z, Kieffer TJ, Chen H, Safikhan N, Thompson DM, Robles DT, Eisenbarth GS, Wang T, Erlich HA, Bugawan TL, Babu SR,
Meloche M, Warnock GL & Marzban L 2013 The glucagon-like Barriga K, Norris JM, Hoffman M, Klingensmith G, et al. 2002
peptide-1 receptor agonist exenatide restores impaired pro-islet Millennium award recipient contribution. Identification of children
amyloid polypeptide processing in cultured human islets: with early onset and high incidence of anti-islet autoantibodies.

Clinical Immunology 102 217–224. (https://doi.org/10.1006/ Truyen I, De Pauw P, Jørgensen PN, Van Schravendijk C, Ubani O,
clim.2001.5171) Decochez K, Vandemeulebroucke E, Weets I, Mao R, Pipeleers DG,
Roder ME, Knip M, Hartling SG, Karjalainen J, Akerblom HK, Binder C, et al. 2005 Proinsulin levels and the proinsulin:C-peptide ratio
Akerblom HK, Tuomilehto J, Lounamaa R, Toivanen L, et al. 1994 complement autoantibody measurement for predicting type 1
Disproportionately elevated proinsulin levels precede the onset of diabetes. Diabetologia 48 2322–2329. (https://doi.org/10.1007/
insulin-dependent diabetes mellitus in siblings with low first phase s00125-005-1959-0)
insulin responses. The Childhood Diabetes in Finland Study Group. Udayasankar J, Kodama K, Hull RL, Zraika S, Aston-Mourney K,
Journal of Clinical Endocrinology and Metabolism 79 1570–1575. Subramanian SL, Tong J, Faulenbach MV, Vidal J & Kahn SE 2009
(https://doi.org/10.1210/jcem.79.6.7989457) Amyloid formation results in recurrence of hyperglycaemia following
Rodriguez LM, Mason KJ, Haymond MW & Heptulla RA 2007 The role transplantation of human IAPP transgenic mouse islets. Diabetologia
of prandial pramlintide in the treatment of adolescents with type 1 52 145–153. (https://doi.org/10.1007/s00125-008-1185-7)
diabetes. Pediatric Research 62 746–749. (https://doi.org/10.1203/ Udayasankar J, Zraika S, Aston-Mourney K, Subramanian SL, Brooks-
PDR.0b013e318159af8c) Worrell BM, Taborsky GJ & Hull RL 2013 Rosiglitazone treatment
Rodriguez-Calvo T, Zapardiel-Gonzalo J, Amirian N, Castillo E, does not decrease amyloid deposition in transplanted islets from
Lajevardi Y, Krogvold L, Dahl-Jørgensen K & von Herrath MG 2017 transgenic mice expressing human islet amyloid polypeptide.
Increase in pancreatic proinsulin and preservation of beta cell mass Transplantation Proceedings 45 574–579. (https://doi.org/10.1016/j.
in autoantibody positive donors prior to type 1 diabetes onset teresa. transproceed.2012.05.079)
Diabetes 66 1334–1345. (https://doi.org/10.2337/db16-1343) Vella A, Lee JS, Camilleri M, Szarka LA, Burton DD, Zinsmeister AR,
Roep B & Peakman M 2012 Antigen targets of type 1 diabetes Rizza RA & Klein PD 2002 Effects of pramlintide, an amylin
autoimmunity. Cold Spring Harbor Perspectives in Medicine 2 1–14. analogue, on gastric emptying in type 1 and 2 diabetes mellitus.
(https://doi.org/10.1101/cshperspect.a007781) Neurogastroenterology and Motility 14 123–131. (https://doi.
Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Carpenter SB, Becker CE, org/10.1046/j.1365-2982.2002.00311.x)
Ediriweera HN, Adam E, Golenbock DT, Stuart LM, et al. 2013 CD36 Velthuis JH, Unger WW, Abreu JRF, Duinkerken G, Franken K,
coordinates NLRP3 inflammasome activation by facilitating the Peakman M, Bakker AH, Reker-hadrup S, Keymeulen B, Drijfhout JW,
intracellular nucleation from soluble to particulate ligands in sterile et al. 2010 Simultaneous detection of circulating autoreactive CD8+
inflammation. Nature Immunology 14 812–820. (https://doi. T-cells specific for different islet cell-associated epitopes using
org/10.1038/ni.2639) combinatorial MHC multimers. Blood 59 1721–1730. (https://doi.
Sims EK, Chaudhry Z, Watkins R, Syed F, Blum J, Ouyang F, Perkins SM, org/10.2337/db09-1486)
Mirmira RG, Sosenko J, DiMeglio LA, et al. 2016 Elevations in the Verchere CB, D’Alessio DA, Palmiter RD, Weir GC, Bonner-Weir S,
fasting serum Proinsulin-to-C-peptide ratio precede the onset of type Baskin DG & Kahn SE 1996 Islet amyloid formation associated with
1 diabetes. Diabetes Care 39 1519–1526. (https://doi.org/10.2337/ hyperglycemia in transgenic mice with pancreatic beta cell
dc15-2849) expression of human islet amyloid polypeptide. PNAS 93 3492–3496.
Skowera A, Ellis RJ, Varela-Calviño R, Arif S, Huang GC, Van-Krinks C, (https://doi.org/10.1073/pnas.93.8.3492)
Zaremba A, Rackham C, Allen JS, Tree TIM, et al. 2008 CTLs are Vinik A, Nakave A & Chuecos MDPS 2008 A break in the brake
targeted to kill β cells in patients with type 1 diabetes through mechanism in diabetes a cause of postprandial hyperglycemia.
recognition of a glucose-regulated preproinsulin epitope. Journal of Diabetes Care 31 2410–2413. (https://doi.org/10.2337/dc08-1694)
Clinical Investigation 118 3390–3402. (https://doi.org/10.1172/ Watkins RA, Evans-Molina C, Terrell JK, Day KH, Guindon L,
JCI35449) Restrepo IA, Mirmira RG, Blum JS & DiMeglio LA 2016 Proinsulin
Stadler M, Anderwald C, Karer T, Tura A, Kästenbauer T, Auinger M, and heat shock protein 90 as biomarkers of beta-cell stress in the
Bieglmayer C, Wagner O, Kronenberg F, Nowotny P, et al. 2006 early period after onset of type 1 diabetes. Translational Research 168
Increased plasma amylin in type 1 diabetic patients after kidney and 96.e1–106.e1. (https://doi.org/10.1016/j.trsl.2015.08.010)
pancreas transplantation: a sign of impaired beta-cell function? Wei ML & Cresswell P 1992 HLA-A2 molecules in an antigen-processing
Diabetes Care 29 1031–1038. (https://doi.org/10.2337/dc05-1247) mutant cell contain signal sequence-derived peptides. Nature 356
Standifer NE, Ouyang Q, Panagiotopoulos C, Verchere CB, Tan R, 443–446. (https://doi.org/10.1038/356443a0)
Greenbaum CJ, Pihoker C & Nepom GT 2006 Identification of novel Weinzimer SA, Sherr JL, Cengiz E, Kim G, Ruiz JL, Carria L,
HLA-A*0201-restricted epitopes in recent-onset type 1 diabetic Voskanyan G, Roy A & Tamborlane WV 2012 Effect of pramlintide
subjects and antibody-positive relatives. Diabetes 55 3061–3067. on prandial glycemic excursions during closed-loop control in
(https://doi.org/10.2337/db06-0066) adolescents and young adults with type 1 diabetes. Diabetes Care 35
Tai N, Wong FS & Wen L 2016 The role of the innate immune system in 1994–1999. (https://doi.org/10.2337/dc12-0330)
destruction of pancreatic beta cells in NOD mice and humans with Westermark P, Eizirik DL, Pipeleers DG, Hellerström C & Andersson A
type I diabetes. Journal of Autoimmunity 71 26–34. (https://doi. 1995 Rapid deposition of amyloid in human islets transplanted into
org/10.1016/j.jaut.2016.03.006) nude mice. Diabetologia 38 543–549. (https://doi.org/10.1007/
Thayer TC, Wilson SB & Mathews CE 2010 Use of nonobese diabetic BF00400722)
mice to understand human type 1 diabetes. Endocrinology and Westermark G, Westermark P, Eizirik DL, Hellerstrom C, Fox N,
Metabolism Clinics of North America 39 541–561. (https://doi. Steiner DF & Andersson A 1999 Differences in amyloid deposition in
org/10.1016/j.ecl.2010.05.001) islets of transgenic mice expressing human islet amyloid polypeptide
Thébault-Baumont K, Dubois-Laforgue D, Krief P, Briand JP, Halbout P, versus human islets implanted into nude mice. Metabolism 48
Vallon-Geoffroy K, Morin J, Laloux V, Lehuen A, Carel JC, et al. 2003 448–454. (https://doi.org/10.1016/S0026-0495(99)90102-6)
Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient Westermark GT, Westermark P, Nordin A, Törnelius E & Andersson A
NOD mice. Journal of Clinical Investigation 111 851–857. (https://doi. 2003 Formation of amyloid in human pancreatic islets transplanted
org/10.1172/JCI200316584) to the liver and spleen of nude mice. Upsala Journal of Medical
Trudeau JD, Kelly-Smith C, Verchere CB, Elliott JF, Dutz JP, Finegood DT, Sciences 108 193–203. (https://doi.org/10.3109/2000-1967-113)
Santamaria P & Tan R 2003 Prediction of spontaneous autoimmune Westermark GT, Westermark P, Berne C & Korsgren O 2008 Widespread
diabetes in NOD mice by quantification of autoreactive T cells in amyloid deposition in transplanted human pancreatic islets. New
peripheral blood. Journal of Clinical Investigation 111 217–223. England Journal of Medicine 359 977–979. (https://doi.org/10.1056/
(https://doi.org/10.1172/JCI16409) NEJMc0802893)

Westermark GT, Davalli AM, Secchi A, Folli F, Kin T, Toso C, Shapiro AMJ, extension evaluating long-term efficacy of pramlintide as an adjunct
Korsgren O, Tufveson G, Andersson A, et al. 2012 Further evidence for to insulin therapy in type 1 diabetes. Diabetes Care 25 724–730.
amyloid deposition in clinical pancreatic islet grafts. Transplantation (https://doi.org/10.2337/diacare.25.4.724)
93 219–223. (https://doi.org/10.1097/TP.0b013e31823e46ef) Wiles TA, Delong T, Baker RL, Bradley B, Barbour G, Powell RL,
Westermark GT, Krogvold L, Dahl-Jørgensen K & Ludvigsson J 2017 Islet Reisdorph N & Haskins K 2017 An insulin-IAPP hybrid peptide is an
amyloid in recent-onset type 1 diabetes-the DiViD study. Upsala endogenous antigen for CD4 T cells in the non-obese diabetic
Journal of Medical Sciences 122 201–203. (https://doi.org/10.1080/030 mouse. Journal of Autoimmunity 78 11–18. (https://doi.org/10.1016/j.
09734.2017.1359219) jaut.2016.10.007)
Westwell-Roper C, Dai DL, Soukhatcheva G, Potter KJ, van Rooijen N, Woerle HJ, Albrecht M, Linke R, Zschau S, Neumann C, Nicolaus M,
Ehses JA & Verchere CB 2011 IL-1 blockade attenuates islet amyloid Gerich JE, Göke B & Schirra J 2008 Impaired hyperglycemia-induced
polypeptide-induced proinflammatory cytokine release and delay in gastric emptying in patients with type 1 diabetes deficient
pancreatic islet graft dysfunction. Journal of Immunology 187 for islet amyloid polypeptide. Diabetes Care 31 2325–2331.
2755–2765. (https://doi.org/10.4049/jimmunol.1002854) (https://doi.org/10.2337/dc07-2446)
Westwell-Roper C, Nackiewicz D, Dan M & Ehses JA 2014a Toll-like Yamamoto T, Yamato E, Tashiro F, Sato T, Noso S, Ikegami H, Tamura S,
receptors and NLRP3 as central regulators of pancreatic islet Yanagawa Y & Miyazaki JI 2004 Development of autoimmune
inflammation in type 2 diabetes. Immunology and Cell Biology 92 diabetes in glutamic acid decarboxylase 65 (GAD65) knockout NOD
314–323. (https://doi.org/10.1038/icb.2014.4) mice. Diabetologia 47 221–224. (https://doi.org/10.1007/s00125-003-
Westwell-Roper CY, Ehses JA & Verchere CB 2014b Resident 1296-0)
macrophages mediate islet amyloid polypeptide-induced islet IL-1β Yates SL, Burgess LH, Kocsis-Angle J, Antal JM, Dority MD, Embury PB,
production and β-cell dysfunction. Diabetes 63 1698–1711. Piotrkowski AM & Brunden KR 2000 Amyloid B and amylin fibrils
(https://doi.org/10.2337/db13-0863) induce increases in proinflammatory cytokine and chemokine
Westwell-Roper CY, Chehroudi CA, Denroche HC, Courtade JA, Ehses JA production by THP-1 cells and murine microglia. Journal of
& Verchere CB 2015 IL-1 mediates amyloid-associated islet Neurochemistry 74 1017–1025. (https://doi.
dysfunction and inflammation in human islet amyloid polypeptide org/10.1046/j.1471-4159.2000.0741017.x)
transgenic mice. Diabetologia 58 575–585. (https://doi.org/10.1007/ Zhao H-L, Sui Y, Guan J, He L, Lai FMM, Zhong D-R, Yang D, Baum L,
s00125-014-3447-x) Tong PCY, Tomlinson B, et al. 2008 Higher islet amyloid load in men
Westwell-Roper C, Denroche HC, Ehses JA & Verchere CB 2016 than in women with type 2 diabetes mellitus. Pancreas 37 e68–e73.
Differential activation of innate immune pathways by distinct islet (https://doi.org/10.1097/MPA.0b013e3181788e18)
amyloid polypeptide (IAPP) aggregates. Journal of Biological Chemistry Zraika S, Hull RL, Verchere CB, Clark A, Potter KJ, Fraser PE, Raleigh DP
291 8908–8917. (https://doi.org/10.1074/jbc.M115.712455) & Kahn SE 2012 Toxic oligomers and islet beta cell death: guilty by
Whitehouse F, Kruger DF, Fineman M, Shen L, Ruggles JA, Maggs DG, association or convicted by circumstantial evidence? Diabetologia 29
Weyer C & Kolterman OG 2002 A randomized study and open-label 997–1003. (https://doi.org/10.1007/s00125-010-1671-6)

Received in final form 30 November 2017

Accepted 6 December 2017

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IAPP and Type 1 Diabetes: Implications For Immunity, Metabolism and Islet Transplants

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IAPP and Type 1 Diabetes: Implications For Immunity, Metabolism and Islet Transplants

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Journal of Molecular H C Denroche and C B IAPP and type 1 diabetes 60 :2 R57–R75

IAPP and type 1 diabetes: implications for

Heather C Denroche1 and C Bruce Verchere1,2

Correspondence should be addressed to C B Verchere: [email protected]

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(Delong et al. 2016). Moreover, LQTLAL-NAARD-reactive fragments fused with neuropeptide Y or chromogranin

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IAPP-derived epitope in humans, corresponding to ProIAPP processing and IAPP epitopes

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Calderon B, Suri A & Unanue ER 2006 In CD4+ T-cell-induced diabetes,

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Received in final form 30 November 2017

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