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330

Current Protein and Peptide Science, 2013, 14, 330-337

Islet Amyloid Polypeptide and Diabetes

Gunilla T. Westermark1 and Per Westermark2,*
Departments of 1 Medical Cell Biology and 2Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Abstract: Islet amyloid polypeptide (IAPP, amylin) is a 37 amino acid residue hormone expressed mainly by pancreatic
islet beta cells and to less extent by some gastrointestinal endocrine cells and by certain regions in central nervous system.
In experimental systems a number of different effects have been ascribed to IAPP but the in vivo importance of many of
them is still unknown. At least effects on the central nervous system and on endocrine pancreatic cells are likely to be
physiologically relevant. In these tissues calcitonin receptors and receptor activity-modifying proteins (RAMPs) 1 and 3,
creating high affinity IAPP receptors have been identified. How expression of the components of these complexes are
regulated and how further signaling is conducted are more or less unknown. IAPP is most well-known for its ability to aggregate into amyloid fibrils in islets of Langerhans in association with type 2 diabetes leading to loss of beta cells. In addition, amyloid is deposited between endocrine cells and between such cells and capillaries and most likely disturbs important interactions between the cells. How IAPP receptor complexes are affected by the amyloid formation process or by
amyloid itself, or vice versa, are completely unknown.

Keywords: Amylin, amyloid, fibril, calcitonin receptor, islet amyloid polypeptide, receptor activity-modifying proteins, type 2
diabetes, IAPP, RAMP.
1. INTRODUCTION
The complexity of islets of Langerhans is increasingly
evident. Not only is an islet composed by a number of different cells producing specific polypeptide hormones but also a
single cell type may synthesize and release several biologically active products. The islet beta cell is a good example of
this since in addition to insulin the polypeptide hormone islet
amyloid polypeptide (IAPP, also called amylin) is expressed
by this cell. IAPP was discovered as late as 1986 [1] and was
fully characterized in 1987 [2, 3]. This discovery of the third
peptide belonging to the calcitonin gene related peptide
(CGRP) family as a major product of islet endocrine cells
was completely unexpected.
The pathological aggregation product of IAPP as amyloid
had been identified in the microscope already in 1901 [4, 5].
The nature of islet amyloid was long a complete puzzle [6]
but after the finding that amyloid fibrils in C-cell derived
medullary thyroid carcinoma is derived from calcitonin [7],
islet amyloid was suspected to be an aggregate of insulin,
proinsulin, or fragments thereof. An additional, indirect evidence for hormonal origin was that amyloid is more common
in insulin producing tumors than other pancreatic neoplasms
[8]. After initial difficulties due to the very low solubility of
the amyloid, overcome only by the use of concentrated formic acid [1, 9], the major peptide was purified from amyloid
deposits in an insulinoma [1] and its primary structure determined by Edman degradation. It is of some interest to note
that the two biochemically related peptides IAPP (characteristic of amyloid in Langerhans islets) and A
building up
*Address correspondence to this author at the Department of Immunology,
Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden;
Tel: +46 18 611 3849; Email: Per.Westermark@igp.uu.se
/13 $58.00+.00

fibrils in Alzheimers plaques [10], were originally identified

through a natures protein purification method, namely assembly into beta sheet fibrils.
The present report provides a short summary on IAPPs
physiology and its pathological behavior. Our own recent
studies have focused on how IAPP aggregates to fibrils and
which the consequences are of this aggregation. There is
strong evidence that IAPP has an important physiological
role in the pancreatic islets by its action as an autocrine or
paracrine agent. It is therefore surprising how little is known
regarding IAPP receptors and RAMPs in pancreatic islet
alpha, beta and delta cells. There are considerably more studies on the subject in the brain. Below follows a summary of
the present fragmented knowledge.
2. ISLET CELL ORGANIZATION
Islets of Langerhans consist of several endocrine cells. In
addition to insulin-producing beta cells there are A-cells
making glucagon, D-cells synthesizing somatostatin, PPcells making pancreatic polypeptide and rare cells producing
ghrelin. In some species including rat and mouse are beta
cells grouped together in the center while glucagon cells
appear in the periphery. In human are the cells more or less
mixed although there is a tendency for glucagon cells to occur in islet periphery. Since beta cells normally predominate
and constitute about 70% of the endocrine cells, each insulin
cell is in contact with another beta cell and many also with
glucagon cells. The other cell types constitute only less than
10% of the islets. In human, more than 70 % of the beta cells
are in contact with endocrine cells of other kind while in
rodent islets less than 30% of the beta cells are in contact
with a cell of different origin [11]. This means that results
from rodent islets cannot be completely translated into the
2013 Bentham Science Publishers

IAPP and Diabetes

human situation. Islets are highly vascularized and endothelium is fenestrated, making traffic to and from endocrine
cells efficient. To reach capillaries at exocytosis, released
hormones have to pass two basement membranes (at least in
human) and a short extracellular space in between.
3. ISLET AMYLOID POLYPEPTIDE
IAPP is a 37 amino acid residue (aa) molecule, Cterminally amidated and with a disulfide bridge between
residues 2 and 7. The peptide is expressed as a 89 aa prepromolecule from which a 22 aa leader peptide is removed to
yield the 67 aa proIAPP [12, 13] (Fig. 1). In this promolecule
IAPP is flanked by two short propeptides N- and Cterminally, in the human case 11 and 19 aa long, respectively. IAPP is a highly conserved molecule, particularly in
its N- and C-terminal parts while the flanking propeptides
have a higher degree of variability. While there is a high
degree of identity of IAPP with calcitonin gene-related peptide (CGRP), there are no aa sequence similarities between
proIAPP flanking peptides and other propeptides [14]. There
is a central segment of mature IAPP, however, in which
there also is a considerable sequence variation between species (Fig. 1). This area is of big interest since it is highly
determining the ability of the molecule to induce beta sheet
structure and assemble into amyloid fibrils. While IAPP has
been shown to be a polypeptide hormone, no possible function has so far been described for the flanking propeptides.
3.1. Expression of IAPP
Most of IAPP, circulating in plasma, is derived from islet
beta cells. In these cells, IAPP is stored together with insulin
and both hormones are released simultaneously at exocytosis. However, IAPP concentration is only ~1-2 % of that of
insulin in granules and in circulation. In mammals, IAPP is
also expressed in gastrointestinal tract [15] and in the brain
(M Oskarsson and GT Westermark, unpublished result) but
to a much lower degree.
Processing of proIAPP takes place in the golgi and secretory vesicles by the two endopeptidases proconvertase (PC)
1/3 and PC2 at double basic amino acid residues [16, 17].
PC1/3 and PC2 are also processing proinsulin at B-chain-Cpeptide junction and C-peptide-A-chain junction [18, 19]. A
second enzymatic processing of IAPP is performed by C-

Current Protein and Peptide Science, 2013, Vol. 14, No. 4

331

terminal amidation for which the proIAPP C-terminal glycine residue is a substrate. Although the enzymatic cleavages
are efficient there is normally some proinsulin and most
probably proIAPP left uncleaved or only partially processed.
These components are also delivered to the circulation at
exocytosis.
While insulin constitutes the electron dense core of beta
cell granules, IAPP is found in the outer halo region [20]
where also C-peptide and a number of other granule components including proIAPP flanking peptides are present.
3.2. IAPP as a Possible Auto- or Paracrine Molecule
IAPP has been suggested to have both peripheral effects
and to regulate islet cells. Experimentally, effects of IAPP on
insulin release have given contradictory results. Thus, a large
number of studies indicate that IAPP inhibits release of insulin from beta cells by an unknown mechanism but an opposite effect has been recorded in other studies (for references,
see [21]). However, an in vivo study in human, using hyperglycemic clamp in combination with a specific IAPP receptor antagonist, gave solid evidence that endogenous IAPP
restrains insulin secretion [22]. An IAPP knock-out mouse
had an almost normal phenotype but a careful analysis
showed a subtle but significant increased insulin secretion
upon glucose stimulation [23]. These two in vivo studies
very clearly indicate that IAPP may have an auto- or
paracrine effect on islet beta cells. This auto- and/or
paracrine action seems to be in concert with the central nervous system effects in smothering glucose excursions after a
meal. A possible paracrine effect on glucagon (A) cells,
which do not express IAPP is described below.
4. IAPP AND IAPP RECEPTORS
Soon after the discovery of IAPP there was a big excitement about the peptides peripheral effects on glucose, particularly in liver and skeletal muscle [24]. It was found that
IAPP inhibits effects of insulin and this was thought to be an
important cause of insulin resistance, typically seen in type 2
diabetes. However, the plasma concentration of IAPP is
normally around 10 pM and can increase slightly early in
type 2 diabetes but hardly much more than to 20 pM. On the
other hand, many studies have shown that the concentration
of IAPP, needed for induction of insulin resistance is much

Fig. (1). Above. The amino acid sequence of human preproIAPP. Flanking peptides are cleaved off at double basic amino acid residues (arrows) by the same enzymes that cleave proinsulin. To become fully biologically active, IAPP is modified by an SS bridge between positions
2 and 7 and by C-terminal amidation of the tyrosine residue. Framed is a part of IAPP that is crucial for amyloidogenicity. Below. Amino
acid sequences of IAPP from three mammalian species of which the two upper are amyloidogenic. Islet amyloid does not develop in wild
type mice due to proline residues within the framed part.

332 Current Protein and Peptide Science, 2013, Vol. 14, No. 4

Westermark and Westermark

higher than is possible to reach physiologically and the induced insulin resistance was believed to be pharmacological
rather than physiological. Therefore, it seems unlikely that
IAPP is an important cause of diminished insulin effect on
skeletal muscle. However, subtle effects on peripheral insulin effects may be difficult to demonstrate and can hardly be
excluded [21].

later studies have shown expression of RAMPs as well. Different combinations of CTRs and RAMP 1 and 3 appear in
the specific IAPP binding brain areas (reviewed in [29, 30]).
IAPP has evident central nervous system effects when given
to experimental animals and to humans. It inhibits eating and
has been found to reduce meal duration [31] and can also
induce nausea. Effects of IAPP on gastric emptying is believed to depend on such CNS effects and experimentally in
rats, IAPP inhibits gastric emptying [32]. In type 1 diabetes,
where there may be an almost complete loss of islet beta
cells and therefore no pancreatic IAPP production, gastric
emptying is abnormally rapid [33] and this effect participates
in the glucose excursions in the disease. However, in a study
performed on adolescents with type 1 diabetes and IAPP
deficiency a delayed gastric empting was observed contrary
to an expected acceleration [34]. The cause of these diverging findings does not seem to have been clarified.

There was for a long time unsuccessful search for specific IAPP receptors although binding sites had been identified. Only when receptor activity-modifying proteins
(RAMPs) were discovered, it was found that combination of
calcitonin receptors (CTR) with RAMP1 or RAMP3 created
high-affinity IAPP receptors. However, in vitro studies point
to a significant difference in IAPP signaling through
CTR/RAMP 1 or CTR/RAMP 3 complexes depending on
used cell type, but the signal transduction mechanism downstream of the receptor still needs to be determined [25]. A
summary of available knowledge on expression of CTR and
RAMPs is given in Table 1.

In conclusion, there is still very sparse information on

expression of IAPP specific receptor complexes and surprisingly, almost nothing is known about IAPP signaling in islets
of Langerhans.

Experimentally, IAPP has effects on bone formation.

IAPP inhibits fusion of osteoclasts into multinuclear cells
and also migration of these cells in culture [26]. A second
phenotype identified in IAPP deficient mice was decreased
bone tissue due to increased bone resorption while bone formation remained unaffected [27]. In the same study it was
shown that mice made heterozygous for CTR exhibited increased bone formation. Interestingly, mice heterozygous for
CTR and IAPP kept the abnormalities thus suggesting that
IAPP does not signaling through the CTR in osteoclasts [27].
Laser capture micro dissection of multinuclear cells in bone
tissue followed by PCR showed that these cells express
CTR, calcitonin like receptor and RAPM 2, but not Ramp 1
and 3 [28]. IAPP binding with CTR and calcitonin like receptor in combination with RAMP2 is low and therefore
IAPP signaling in osteoclasts most likely is through a different receptor.

5. CALCITONIN RECEPTOR AND RAMPS IN ISLETS OF LANGERHANS

CTRs have been identified immunohistochemically in rat
islets with the aid of three antisera against synthetic peptides
[35]. According to this study, no binding of the antibodies
was observed with glucagon cells although the staining pattern with stronger immunoreactivity in the periphery of rat
islet in the published picture strongly resembles labeling of
glucagon cells. Two beta cell lines from mouse and hamster
showed expression of CTRs and the mouse line expressed
RAMP1 and RAMP2 while the hamster cells only were positive for RAMP3 [35]. Although CTRs or RAMPs do not
seem to have been directly studied in glucagon (A-) cells,
glucagon secretion is inhibited by IAPP. In one study, this
effect was found to be due to mechanisms outside the pancreas [36], but in experiments with isolated rat islets showed
a significant inhibitory effect on glucagon secretion by IAPP

High-affinity binding sites for IAPP were demonstrated

in certain areas of the brain, particularly nucleus accumbens
and area postrema. CTRs were localized to these regions and
Table 1.

Evidence of Expression of Calcitonin Receptor (CTR) and of RAMPs in Pancreas, Islets of Langerhans and Beta Cells.
CTR Combined with RAMP 1 or 3 Creates an IAPP Receptor

Tissue, cell, or cell line

CTR

RAMP 1

RAMP 2

RAMP 3

Species

Pancreas

+ [78, 79]

+ [78], [80],[81]

+ [78],[80],[81]

+ [78] [80] [81]

human

Islets

(+[82]) *

+*

+*

human

Pancreas

+ [79]

+ [83], [79]

+ [83]

+ 79] *

+ 79][83]*

+ 79][83]

mouse

+ [84]

+ [84]

mouse

+[35]

mouse

+[35]

hamster

Islets

+ 79]

Beta cells

+ [84]

+[84]

Beta cells CLR2055

+[35]

+[35]

Beta cells CLR1777

+) Evidence of presence by immunohistochemistry or mRNA analysis
(+[82]) Means evidence in a published figure, not commented upon
*) Fred R & Welsh N, Uppsala University, personal communication

mouse

IAPP and Diabetes

[37]. Obviously, much more direct studies of CTRs and

RAMPs in islets of Langerhans are warranted.
6. AMYLOID AND AMYLOIDOSIS
Amyloid is a specific type of aggregation in which misfolded protein molecules with a high degree of
-sheet conformation bind to each other particularly by hydrogen bonds
and form long fibrils. In these fibrils,
-strands are arranged
perpendicularly to the fibril axis. A limited number of human
proteins make amyloid fibrils in vivo, all associated with
specific diseases or locations [38]. Amyloid fibrils have certain characteristic properties including ultrastructural appearance, are insoluble, show relative resistance to enzymatic
degradation and possess specific staining characteristics, the
most well-known being affinity for Congo red and green
birefringence after such staining. Amyloid occurs as a number of relatively rare, usually life-threatening systemic diseases with protein aggregates found in many different tissues
but much more common are small deposits, localized to one
organ or tissue and associated with specific diseases. The
most well-known are Alzheimers disease where A
-peptide
constitutes the fibrils and type 2 diabetes, in which fibrillar
aggregates of IAPP are seen in islets of Langerhans. Amyloid is typically found as extracellular deposits although the
initial aggregation may take place intracellularly [21].
Amyloid deposits consist of a main protein, constituting
the amyloid fibril and some additional components, one of
which is serum amyloid P-component (SAP), bound to all
kinds of amyloid fibrils [39] and believed to be of importance for the stability of the fibril [40]. In addition there is
invariable presence of heparan sulfate proteoglycan [41]
which may promote
-sheet structure and amyloid formation.
There is a rapidly increasing understanding how and why
peptides or proteins assemble into characteristic amyloid
fibrils. Amyloid proteins are generally short and almost
never more than 300 amino acid residues long. The typical
amyloid fibril has a cross-
spine in which side chains from
two strands interdigitate tightly. This interaction model has
been named dry steric zipper [42, 43]. Amyloid fibrils
seem to assemble by short amino acid sequence-determined
segments and such parts can be identified in many proteins
[42].
Human IAPP is an unusually amyloidogenic peptide
which rapidly undergoes spontaneous fibril formation in
vitro. Although other residues also may participate in amyloidogenesis, the segment SNNFGAILSS (residues 20-29)
are particularly important [44]. Amyloidogenic sequences in
this region is present in human and non-human primates and
in different cat animals (Fig. 1) but not, for example, in rat
and mouse. Intriguingly, type 2 diabetes occurs in the first
animal group but not in rodents (reviewed in [21, 45]). An
important although as yet not resolved question is why IAPP
does not form amyloid fibril in the normal state. One possible explanation is presence of inhibitors in endoplasmic reticulum and secretory granules. Insulin and proinsulin both
strongly inhibit IAPP fibrillogenesis in vitro [20, 46-49] and
since IAPP and insulin normally are tightly co-regulated, it is
possible that a disturbed balance in molar ratio between these
components can lead to aggregation. Additional fibril formation inhibitors may also exist.

Current Protein and Peptide Science, 2013, Vol. 14, No. 4

333

7. ISLET AMYLOID AND DIABETES MELLITUS

Islet amyloid is a typical finding in type 2 but not type 1
diabetes. It is found in 95% of subjects with type 2 diabetes
and in about 50% of the cases at least 50% of islets are affected [50]. The amyloid is restricted to islets and is not
found in the exocrine part of the gland [51-54]. In a single
islet deposits are spread even when the total quantity of amyloid is small [55]. In pancreatic sections from patients with
type 2 diabetes, all amyloid is apparently extracellular and
appears between endocrine cells and capillaries [56] (Fig. 2).
There is a close topical connection between amyloid fibrils
and beta cells. Typically, parallel bundles of fibrils run perpendicularly into deep cytoplasmic membrane-bound pockets of such cells and seem to penetrate into the cytoplasm
[56, 57]. In spite of this, these beta cells are usually heavily
granulated but may contain a considerable amount of residual bodies [56]. Calcium oscillation triggers insulin release
from synchronized beta cells [58] and amyloid deposits between cells cause changes in islet cytostructure that most
likely affect cell-cell signaling and nutrient transport.
Earlier studies were based on autopsy material and islet
formation in such cases can be suspected to have gone on for
very long time, possibly a decade or more, a possibility underlined by common calcium deposits in this amyloid
(Westermark, unpublished observation). Initial islet amyloidogenesis has only later been possible to study when transgenic mice, overexpressing human IAPP and isolated islets
from human donors have become available. It has then become apparent that early IAPP aggregation into fibrils may
start intracellularly [59-61], probably in the endoplasmic
reticulum or in secretory vesicles [57, 62] (Fig. 3A-B). Assembly into amyloid fibrils includes misfolding of a protein
and is a nucleation-dependent phenomenon in which a limiting, and energetically unfavorable step is the formation of a
nucleus, consisting of a small number of misfolded molecules [63, 64]. As soon as a nucleus has been formed this
acts as seed and building up a fibril is rapid and goes on until
a steady state has been reached. Addition of new molecules
occurs at the ends of fibrils and the number of such ends
increases by fibril breakage. We have put forward the following theory on how islet amyloid develops: The very first
IAPP amyloid develops intracellularly. By mechanisms not
yet fully understood this leads to death of the affected beta
cell. Since IAPP amyloid is relatively stable and undegradable, amyloid will remain when the dead cell is degraded. The result will be an extracellular amyloid particle
which will seed further amyloid formation from IAPP delivered from remaining beta cells [21, 45, 57].
7.1. IAPP Amyloid and Beta Cell Death
It was earlier often stated that islets are morphologically
normal in type 2 diabetes. Occurrence of amyloid was then
obviously disregarded probably since this material is not
easily seen in hematoxylin-eosin stained sections. The number of beta cells is significantly reduced in type 2 diabetes
and this is at least partially depending on deposition of IAPP
amyloid [53, 54, 65, 66]. Many different studies have shown
that amyloid fibril proteins in a prefibrillar aggregated state,
often referred to as oligomers or protofibrils, have a general
capability to induce apoptosis, at least in vitro. This is also

334 Current Protein and Peptide Science, 2013, Vol. 14, No. 4

Westermark and Westermark

Fig. (2). Islets of Langerhans in a type 2 diabetic human. IAPP amyloid, stained with Congo red, occupy most of these islets. The section is
seen in ordinary light in A while the typical green-yellowish birefringence is apparent in polarization microscopy in B. Bar = 50
m.

true with IAPP and in a number of reports it has been shown

that oligomers, but not monomers and perhaps not mature
amyloid fibrils are toxic to beta cells, as well as other cells. It
has even been proposed that aggregation into amyloid fibrils
constitute a protective mechanism in which dangerous oligomers are avoided [67]. This could be a reasonable explanation as to why living beta cells can be seen in close contact
with heavy amyloid deposits [56]. The different possible
toxic pathways of aggregated IAPP have recently been reviewed [21].
7.2. Islet Amyloid, Receptors and RAMPs
Nothing seems to be known about effects of amyloid,
IAPP oligomers or the generation of amyloid on the function
of any islet cell receptor. However, it is very reasonable to
hypothesize that deposits of amyloid between endocrine cells
and between such cells and blood vessels severely affect
signaling particularly since molecular assembly to fibrils
likely takes place in contact with cell membranes. Ultrastructurally, beta cell membranes in contact with amyloid are not
intact [56, 57] (Fig. 3C). Deposition of considerable amount
of fibrillar protein between intra-islet capillaries and endocrine cells and in between beta cells most probably has a

50 nm

1 m

negative effect on signaling. Insulin secretion occurs in a

pulsatile fashion and beta cells are acting synchronically [68]
and therefore need to communicate. Aggregated IAPP in the
form of oligomers have been reported to impair cell coupling
[69]. Whether this effect involves any receptors is unknown.
7.3. Islet Transplantation: type 2 Pathology in Type 1
Diabetes
Normal human islets, when cultured in vitro or when
transplanted into mice rapidly (within days or weeks) develop IAPP amyloid [70, 61] and this is also true for isolated
mouse islets expressing human IAPP [71- 73]. The reason
for this rapid IAPP aggregation is not completely clear but
an impaired clearance of synthesized IAPP may be an important factor since encapsulation of islets in alginate enhances
amyloid formation [74]. Other factors, such as aberrant processing of proIAPP may also play a role (reviewed in [21]).
A strategy in treatment of certain groups of patients with
type 1 diabetes is transplantation of islets. Islets are recovered from healthy organ donors and are infused usually via
the portal vein into the liver. A general finding has been that
most patients become free from insulin treatment for a period

1 m

Fig. (3). A. Beta cell granules in an islet with early amyloid development. Amyloid formation seems to start at the periphery of the granules.
Arrowheads point to fibrillar material present in the halo region of the granules. Islet from a transgenic mouse overexpressing hIAPP. B.
IAPP amyloid deposited within membrane structured most likely ER, golgi and secretory granules of a beta cell. Arrow heads point at membrane structures. Human islet transplanted into nude mouse. C. Extracellular IAPP amyloid in contact with a beta cell. The cytoplasm membrane is almost invisible. IAPP -amyloid is immunolabelled with antibodies against IAPP and visualized with 10 nm gold particles. Human
islet transplanted into nude mouse.

IAPP and Diabetes

of time but that there is usually a gradual decline in beta cell

function. Against the background described above there was
a suspicion that aggregation of IAPP into a toxic material
and subsequent loss of functional beta cells could be a reason
for the declining effect of transplantation [75]. This suspicion was confirmed by autopsy studies of type 1 diabetic
subjects who died several years after islet transplantation.
Many islets had appearance as in type 2 diabetes and IAPP
amyloid deposits were seen in 3 out of 4 transplants [76, 77].
These findings make further studies of IAPP aggregation as
an important cause of loss of transplanted islet cells important.

Current Protein and Peptide Science, 2013, Vol. 14, No. 4

[5]

[6]
[7]

[8]
[9]
[10]

8. CONCLUDING REMARK
IAPP plays an important role in the development of type
2 diabetes by its pathological aggregation into amyloid. Less
is known about the physiological function of the polypeptide. It is particularly evident that the knowledge about
IAPPs receptors and signaling pathways is still very fragmentary. Much more studies on IAPPs autocrine and
paracrine signaling in the islets of Langerhans are warranted.
For this, studies on the expression of CTRs and RAMPS in
the specific endocrine cells are necessary, both in the normal
state and in pathological conditions, particularly type 2 diabetes, but also in type 1 diabetes and in islets in culture or
after transplantation.
CONFLICT OF INTEREST

[11]

[12]

[13]

[14]

The author(s) confirm that this article content has no conflicts of interest.
[15]

ACKNOWLEDGEMENTS
Own work supported by the Swedish Research Council,
the Research Fund of the Swedish Diabetes Association and
Family Ernfors Fund.
ABBREVIATIONS
IAPP

= Islet amyloid polypeptide

CGRP

= Calcitonin gene-related peptide

CNS

= Central nervous system

CTR

= Calcitonin receptor

RAMP

= Receptor activity-modifying protein

[16]

[17]

[18]

[19]

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Received: October 17, 2012

Revised: Jan 05, 2013

Accepted: Jan 05, 2013

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