1 Department of Surgery, Islet amyloid polypeptide (IAPP, or amylin) is produced in
pancreatic
amylin; somatostatin; insulin; glucagon
ISLET AMYLOID POLYPEPTIDE (IAPP, or amylin) is a
37-amino acid peptide sharing ~50% amino acid homology with
calcitonin gene-related peptide (CGRP) (8, 28). IAPP is synthesized in
pancreatic
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
-cells. The intraislet significance of IAPP is still uncertain. In the present study, paracrine effects of endogenous IAPP
and somatostatin were investigated in isolated rat pancreatic islets.
The intraislet IAPP activity was inhibited with an IAPP antiserum or a
specific antagonist [IAPP-(8
37)]. Somatostatin activity
was inhibited by immunoneutralization. Basal insulin and glucagon
secretion were not affected by the somatostatin and/or IAPP
blockade. Arginine-stimulated insulin and glucagon secretion were dose
dependently increased by IAPP antiserum, IAPP-(8
37), and somatostatin
antiserum, respectively. Arginine-stimulated somatostatin secretion was
dose dependently potentiated by IAPP antiserum. Insulin secretion
induced by 16.7 mM glucose was enhanced by IAPP antiserum and
IAPP-(8
37), respectively. A combination of somatostatin antiserum
with IAPP antiserum or IAPP-(8
37) further enhanced the
arginine-stimulated insulin and glucagon secretion compared with
effects when the blocking reagents were used individually. These results indicate that endogenously produced IAPP tonally inhibits
stimulated insulin, glucagon, and somatostatin secretion. Furthermore,
the paracrine effects of IAPP and somatostatin are additive.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
-cells (8, 28) and normally cosecreted with insulin (7). As shown in Table 1, the physiological function of IAPP
in pancreatic islets is uncertain and highly controversial (2-6,
9-12, 14-17, 24).
Table 1.
Regulatory effects of exogenous IAPP on -,
-, and
-cell secretion
The paracrine effects of IAPP have also been investigated with specific
antagonists such as IAPP-(837), CGRP-(8
37), and salmon
calcitonin-(8
32). IAPP-(8
37) and CGRP-(8
37) increase arginine-stimulated insulin secretion in anesthetized rats (4, 29). In
perifused rat pancreatic islets, IAPP-(8
37) increases insulin
secretion stimulated by glucose and carbamylcholine (26). In perfused
rat pancreas, salmon calcitonin-(8
32) enhances glucose-induced insulin secretion (22). The effects of these IAPP antagonists are
assumed to result from a competitive displacement of IAPP from its
receptor in islet cells (22). In addition, IAPP antagonists are known
to inhibit binding of IAPP to CGRP receptor (19). Although there is
considerable evidence in favor of a distinct IAPP receptor (19), the
IAPP receptor has not been identified to date.
Unlike IAPP antagonist, IAPP antibody can deplete endogenous IAPP from
intercellular space before the peptide binds to its putative receptor.
In the present study, isolated rat pancreatic islets were incubated
with IAPP antiserum, IAPP-(837), and somatostatin antiserum to
investigate the effects of IAPP and somatostatin on hormone secretion
of the islets.
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MATERIALS AND METHODS |
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Chemicals. Rabbit antiserum against
synthetic human somatostatin was purchased from Dakopatts (Glostrup,
Denmark). The somatostatin antiserum (code no. A0566, lot no. 015A)
showed a selective reactivity with somatostatin in a large number of
mammalian species. The rabbit antiserum against rat IAPP has been
described elsewhere (27). The IAPP antiserum showed no cross-reactivity
with insulin, glucagon, somatostatin and pancreatic polypeptide and
<1% cross-reactivity with CGRP. Rat IAPP-(837) [rat
IAPP-(8
37)amide] was purchased from Chiron Mimotopes (Clayton,
Australia), culture medium (RPMI 1640) from Life Technologies (Paisley,
UK), and L-arginine from Sigma
(St. Louis, MO).
Islet preparation. Male Sprague-Dawley rats (250-300 g) were purchased from B & K Universal (Stockholm, Sweden) and kept in a 12:12-h light-dark cycle with free access to water and pelleted rat chow. Rat pancreatic islets were isolated as described elsewhere (25). The study was approved by the local animal ethical committee. Islets in each experiment came from two to three pancreata. The isolated islets were preincubated overnight with RPMI 1640 medium (10% fetal calf serum) at 37°C in 95% humidified air and 5% CO2.
Preparation of test media. Modified
Krebs-Ringer bicarbonate (KRB) buffer was prepared for islet
incubation. The KRB buffer consisted of (in mM) 114 NaCl, 4.4 KCl, 1 MgSO4, 29.5 NaHCO3, 1.28 CaCl2, 10 HEPES, and 0.1% bovine
serum albumin (BSA). The buffer (pH 7.4) was supplemented with (in mM)
5.6 glucose, 16.7 glucose, or 5.6 glucose + 15 L-arginine. When individual
effects of IAPP antiserum, IAPP-(837), or somatostatin antiserum were investigated, the three reagents were used separately in different KRB
buffers. IAPP or somatostatin antiserum was added to the test buffers
at final concentrations of 0.02, 0.1, and 0.5%. The incubation buffers
with <0.5% antiserum had additional amounts of nonimmunized rabbit
serum added to bring the final serum concentration to 0.5%. IAPP-(8
37) was used at final concentrations of 0.5, 5, or 50 µM,
together with 0.5% nonimmunized rabbit serum. The control buffers
contained 0.5% nonimmunized rabbit serum only.
In a subset of experiments, 0.5% somatostatin antiserum was combined
with 0.5% IAPP antiserum or 50 µM IAPP-(837) in KRB buffers
containing 5.6 mM glucose or 5.6 mM glucose + 15 mM
L-arginine. Control buffers
contained 1% nonimmunized rabbit serum only. Buffers containing 0.5%
IAPP antiserum, 50 µM IAPP-(8
37), or 0.5% somatostatin antiserum
were also prepared in the arginine-containing buffer. Nonimmunized
rabbit serum was added, if necessary, to bring the final serum
concentration to 1% in all of the groups.
Islet incubation in test media. Islet
incubation was performed in a similar manner in different subsets of
experiments. Preincubated pancreatic islets were rinsed with KRB buffer
containing 5.6 mM glucose. In 96-well plates, batches of three islets
(150-250 µm in diameter) were incubated with 300 µl of
different test media. The islets were matched so that the total islet
volumes were comparable among the different wells. In each experiment,
the islet incubation was performed in triplicate for each group. After
a 90-min incubation, 200-µl aliquots were collected into chilled
tubes containing 50 µl of benzamidine (300 mM)-EDTA (30 mM) solution.
The samples were stored at 20°C for subsequent radioimmunoassay.
Efficiency of immunoneutralization. Immunoneutralization of IAPP and somatostatin by respective antisera was assessed after islet incubation. An aliquot of incubation buffer (100 µl) from each culture well was mixed with 10 µl (1.5 nCi) of monoiodinated IAPP or somatostatin. The bound fraction was precipitated with 100 µl of 1% gamma globulin and 1.25 ml of 25% polyethylene glycol. The tubes were mixed and centrifuged at 1,700 g for 20 min. The free fraction (supernatant) was discarded and bound fraction (pellet) was counted in an automated gamma counter (LKB WALLAC, model 1277, Turku, Finland). The binding ability of each dilution of antisera was calculated as the percentage of the total binding seen with antisera in excess.
Radioimmunoassay. Insulin and glucagon concentrations in the incubation buffers were measured with radioimmunoassay kits for rat insulin and glucagon (Linco Research, St. Charles, MO). For the somatostatin assay, the antiserum against somatostatin was used at a final concentration of 1:25,000 (1). Synthetic somatostatin was used as standard and 125I-labeled somatostatin (Amersham, Arlington Heights, IL) as tracer. The assay buffer (pH 7.4) consisted of (in mM) 10 KH2PO4, 60 Na2HPO4, 10 EDTA, 7.6 sodium azide, and 0.3% BSA. The assays were incubated for 7 days at 4°C, and bound radioactivity was separated and counted as described in the previous paragraph.
Statistics. The analyses were carried out by the Instat computer program (version 1.12, Graph Pad, San Diego, CA) with analysis of variance (ANOVA) with the Bonferroni post test for multiple comparisons. The islet incubations presented in each figure were performed simultaneously. The data are presented as means ± SE with n representing the number of experiments performed. A P value of <0.05 was considered significant.
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RESULTS |
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Efficiency of immunoneutralization.
Table 2 shows the specific binding
abilities of IAPP and somatostatin antisera left in the test media
after islet incubation. More than 90% of radioactive IAPP and
somatostatin was bound by 0.1 and 0.5% IAPP antiserum or by 0.5%
somatostatin antiserum, respectively. The lower concentrations of
antisera were only able to partially bind their respective tracers.
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Insulin secretion. Basal insulin
secretion from the isolated islets was unchanged in the presence of
IAPP antiserum, IAPP-(837), or somatostatin antiserum at the
concentrations investigated (Fig. 1,
A-C).
Arginine-stimulated insulin secretion was significantly increased by
0.1-0.5% IAPP antiserum (P < 0.05; Fig. 1A) or by 5-50
µM IAPP-(8
37) (P < 0.01; Fig.
1B) compared with control. Arginine-stimulated insulin secretion was also enhanced by 0.5% somatostatin antiserum compared with control
(P < 0.01) or with the group
containing 0.02% somatostatin antiserum
(P < 0.05; Fig. 1C). The combination of somatostatin
antiserum (0.5%) with either IAPP antiserum (0.5%) or IAPP-(8
37)
(50 µM) had no significant effect on basal insulin secretion (5.6 mM
glucose) (data not shown) but significantly increased the
arginine-stimulated insulin secretion compared with control
(P < 0.001) or with the groups where
the blocking reagents were used separately
(P < 0.05; Fig.
2). Insulin secretion induced by 16.7 mM
glucose was significantly enhanced by 0.1% IAPP antiserum and 50 µM
IAPP-(8
37), respectively (Fig. 3).
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Glucagon secretion. Basal glucagon
secretion from the isolated islets was unchanged in the presence of
IAPP antiserum, IAPP-(837), or somatostatin antiserum at the
concentrations investigated (Fig. 4,
A-C).
Arginine-stimulated glucagon secretion was significantly increased by
0.1-0.5% IAPP antiserum (P < 0.01; Fig. 4A), by 5 and 50 µM
IAPP-(8
37) (P < 0.05 and
P < 0.01, respectively; Fig. 4B), or by 0.1-0.5%
somatostatin antiserum (P < 0.05;
Fig. 4C) compared with control. The
combination of somatostatin antiserum (0.5%) with either IAPP
antiserum (0.5%) or IAPP-(8
37) (50 µM) had no significant effect
on basal glucagon secretion (5.6 mM glucose) (data not shown) but
significantly increased the arginine-stimulated glucagon secretion
compared with control (P < 0.001) or
with the groups where the blocking reagents were used separately
(P < 0.05; Fig.
5).
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Somatostatin secretion. Arginine-stimulated somatostatin secretion was significantly enhanced by 0.1 and 0.5% IAPP antiserum compared with control (P < 0.05 and P < 0.01, respectively; Fig. 6). The somatostatin secretion at 0.5% IAPP antiserum was also increased compared with that at 0.02% antiserum (P < 0.01; Fig. 6).
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DISCUSSION |
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Immunoneutralization of one islet hormone can lead to alterations in secretion of other pancreatic hormones (13, 20, 21, 23). The alterations in islet secretion are believed to reflect the paracrine potential of the neutralized hormone. Immunoneutralization has been used both in perfused pancreas (20) and in batch incubation of isolated islets (13, 21, 23). In the present study, inhibition of intraislet IAPP with either IAPP antiserum or IAPP antagonist potentiated arginine-stimulated insulin and glucagon secretion from isolated rat pancreatic islets. Insulin secretion induced by 16.7 mM glucose was enhanced by the IAPP blockers as well. In addition, arginine-stimulated somatostatin secretion from the islets was also enhanced by IAPP immunoneutralization. To our knowledge, this is the first report on the paracrine effects of IAPP with immunoneutralization.
The enhancement of stimulated insulin secretion by IAPP blockade is consistent with previous studies with IAPP antagonists (4, 22, 26, 29). These results indicate that the depletion of endogenous IAPP activity increases insulin secretion. In previous studies, exogenous IAPP inhibited insulin secretion at concentrations that were much higher (11, 14, 24, 26) than the IAPP levels seen in the systemic circulation (7, 18). Because the extracellular IAPP concentrations in pancreatic islets are uncertain, the demonstration that endogenous IAPP regulates insulin secretion is of considerable importance.
In the present study, the secretion of insulin, glucagon, and
somatostatin was measured simultaneously in the presence of IAPP
antiserum. The effects of IAPP or IAPP antagonist on -,
-, and
-cell secretion have been investigated in perfused rat pancreas (10,
22). IAPP stimulates insulin secretion but inhibits glucagon and
somatostatin secretion (10). Salmon calcitonin-(8-32) increases
insulin secretion but has no effects on glucagon or somatostatin
secretion (22). Therefore, different conclusions have been drawn from
these studies (10, 22). In the perfused pancreas, intraislet regulation
takes place in both the vascular and interstitial compartments in the
-cell order (20). Thus hormone secretions from
the perfused pancreas reflect an integrated response of the different
islet cells. In the present study, the effects of endogenous IAPP on
insulin, glucagon, and somatostatin secretion were studied in isolated
islets. In these islets, the IAPP blockers reached
-,
-, and
-cells via the interstitial space of the islets. Under these
conditions, the islet cell types are more likely to react directly to
the IAPP blockade. Thus the results from the present study may help us to understand the direct reaction of islet cells to IAPP depletion.
In the present study, arginine-stimulated insulin and glucagon secretion was also enhanced by somatostatin antiserum. These results are in agreement with previous reports about the effect of intraislet somatostatin on stimulated insulin and glucagon secretion (13, 21).
From the binding studies, it is evident that a nearly complete
immunoneutralization was achieved by the two highest concentrations of
IAPP antiserum and by the highest concentration of somatostatin antiserum. However, IAPP and somatostatin blockade, either separately or in combination, had no effects on basal secretion of - and
-cells. Schatz and Kullek (21) have found that the blockade of
intraislet somatostatin does not affect insulin secretion from unstimulated isolated rat pancreatic islets. Similarly, IAPP-(8
37) has no significant effects on basal insulin levels in rat plasma (4).
As unstimulated pancreatic islets have a slow rate of hormone release
(21), it is not inconceivable that the extracellular concentrations of
pancreatic hormones are also low in these islets. Thus the lack of
effect of the intraislet blockade on basal insulin and glucagon
secretion may be caused by the downregulated intercellular communication in unstimulated islets.
In the present study, combined blockade of somatostatin and IAPP caused
a greater increase in arginine-stimulated insulin and glucagon
secretion, compared with the separate use of somatostatin and IAPP
blockers. These findings suggest that in the stimulated pancreatic
islets, IAPP and somatostatin interact to downregulate hormone
secretion from - and
-cells. These results are also consistent
with our previous observation that exogenous IAPP enhanced the
inhibitory effect of somatostatin on arginine-stimulated insulin secretion from isolated rat pancreatic islets (25). The mechanism underlying this IAPP-somatostatin interaction is unknown.
The results from this study also support the hypothesis that the effect
of endogenous IAPP on insulin secretion may mask the effects of
exogenous IAPP on -cells and be at least partially responsible for
the divergent insulin response to IAPP administration (26). This
hypothesis is based on the observation that islet
-cells show
distinct IAPP sensitivity in different experimental models. For
instance, insulin secretion is inhibited by 75 pM IAPP in the perfused
rat pancreas (9), but 10 µM IAPP is required to achieve the same
inhibitory effect in incubated isolated islets (2, 14). The relatively
high sensitivity to IAPP in the perfused pancreas is believed to be
caused by the continuous washout of endogenous IAPP from the islets
(26). This concept is in line with the observation that the IAPP
sensitivity of
-cells in isolated islets is improved substantially
in a nonrecirculating perifusion system (26). As islet
- and
-cells are also exposed to the local release of endogenous IAPP,
intraislet IAPP may influence the effects of exogenous IAPP on glucagon
and somatostatin secretion as well.
In summary, this study demonstrates that intraislet IAPP is a local
inhibitor of stimulated -,
-, and
-cell secretion in isolated
rat pancreatic islets. Induction of the same effects by exogenous IAPP
usually requires pharmacological doses of the peptide. Thus the
intraislet effect of endogenous IAPP through short-loop feedback
control may be of more physiological importance than the possible
effect of circulating IAPP through an endocrine mechanism. The
downregulation of stimulated
-,
-, and
-cell secretion by
endogenous IAPP may serve as an intraislet feedback control to
prevent oversecretion of hormonal products from islet cells.
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ACKNOWLEDGEMENTS |
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We express our sincere gratitude to Dr. P. Westermark for constructive comments on the present study.
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FOOTNOTES |
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This work was supported by grants from the Swedish Medical Research Council (PROD no. 5941), the Swedish Diabetes Association, the Swedish Cancer Society (2870-B95-05XBB and 2870-B96-06XAC), Novo Nordisk Insulin Fund, and the State of Nebraska Cancer and Smoking-Related Disease Program (LB595).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: F. Wang, Arvid Wretlind Laboratory, Clinical Research Center, Novum, Karolinska Institute at Huddinge Univ. Hospital, Huddinge 14186, Sweden.
Received 16 June 1998; accepted in final form 1 September 1998.
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