Distribution and kinetics of amylin in humans
M.
Clodi1,
K.
Thomaseth2,
G.
Pacini2,
K.
Hermann1,
A.
Kautzky-Willer1,
W.
Waldhäusl1,
R.
Prager1, and
B.
Ludvik1
1 Division of Endocrinology and
Metabolism, Department of Medicine III, University of Vienna, A-1097
Vienna, Austria; and 2 Institute
of Systems Science and Biomedical Engineering (LADSEB-Consiglio
Nazionale delle Ricerche), 35127 Padua, Italy
 |
ABSTRACT |
The aim of the study was to determine the
apparent volume of distribution
(VTOT), total body
clearance (CL), fractional clearance, and mean residence time (MRT) of
the
-cell hormone amylin. We therefore performed an intravenous
injection of 50 µg of human synthetic amylin (amlintide) in nine
healthy male subjects during suppression of endogenous amylin release
by intravenous somatostatin (0.06 µg · kg
1 · min
1). The plasma levels
of amylin concentrations over time were analyzed using
three-exponential curves. VTOT was
173 ± 16 ml/kg and was not different from that of insulin
reported in the literature (157 ml/kg). MRT was 27.7 ± 2.1 min and
thus two times the reported value for insulin (14.1 min) and C-peptide
(16.4 min). CL and fractional CL were 6.2 ± 0.2 ml · kg
1 · min
1
and 0.038 ± 0.003 min
1,
respectively. Fractional CL is therefore definitely lower than that
reported for insulin (0.12-0.2
min
1) but is, however, in
the range of that of C-peptide (0.05 min
1). In conclusion,
clearance of amylin is similar to that reported for C-peptide and much
slower than insulin, indicating that the commonly used molar
insulin-to-amylin ratio does not reflect the correct relationship of
the two peptides.
pharmakokinetics; noncompartmental analysis; compartmental
analysis; mathematical modeling
 |
INTRODUCTION |
IN 1987, pancreatic amyloid was shown
to be composed primarily of aggregates of amylin or islet amyloid
polypeptide, a peptide containing 37 amino acid residues (8, 34). The
chemical structure is nearly 50% homologous with that of calcitonin
gene-related peptide (CGRP), which has the same number of amino acid
residues and is a widespread neurotransmitter with many potent
biological actions (34). In in vitro and in animal experiments, amylin has been shown to cause dose-dependent increases in lactate and blood
glucose levels (38) and to impair glycogen synthesis through dose-dependent inhibition of insulin-stimulated incorporation of
glucose into glycogen in muscle (6, 19). Amylin, which increases
glycogenolysis (37) and stimulates hepatic gluconeogensis from lactate
(4), might act as a noncompetitive inhibitor of insulin (37). These
actions, however, have been obtained in vitro or in vivo in animals
only by administration of pharmacological doses. In human subjects,
however, only a high-dose infusion of amylin decreased insulin
secretion (3), whereas insulin action was not changed (35). These
findings did not suggest an effect of circulating amylin on glucose
metabolism in humans.
Amylin is secreted by pancreatic
-cells in response to nutrient
stimuli together with insulin (12). In obese subjects, amylin is
increased in parallel with insulin in the presence of insulin
resistance (22). In type 1 diabetes amylin secretion is absent (11),
whereas in type 2 diabetes its secretion is impaired before that of
insulin (22). Recently, it has been shown that administration of an
amylin antagonist led to an increase of insulin secretion (18),
suggesting that amylin might inhibit insulin secretion under
physiological conditions. Furthermore, the amylin agonist pramlintide (tri-pro amylin) is able to decrease postprandial glucagon secretion in type 1 diabetic subjects (27), thereby reducing continuing postprandial hepatic glucose output and
thus hyperglycemia. The administration of pramlintide has been shown to
restore accelerated gastric emptying in patients with diabetes (16) and
thus improve postprandial metabolic control (15, 26). Based on these
findings, amylin seems to act as a pancreatic hormone in controlling
glucose metabolism.
Relatively little, however, is known with regard to the metabolism of
amylin in humans. In a previous study, glucose, insulin, C-peptide, and
amylin serum levels have been measured in insulin-resistant subjects
and in healthy controls after a 75-g oral glucose tolerance test (OGTT;
see Ref. 14). Analysis of the concentration data of the three peptides
with a mathematical model clearly demonstrated that the time course of
endogenous amylin release could be predicted from the kinetics of
insulin and C-peptide. However, the kinetics of amylin appeared to be
slower than that of insulin and similar to that of C-peptide (32). The
importance of comparing the kinetics of the three peptides under
identical conditions is substantiated by the fact that the molar ratio
of amylin to insulin is often used as a marker of
-cell release in
pathological situations, even in dynamic conditions (1, 20, 22). If the
two substances exhibit different kinetics, however, the use of their
molar ratio is correct only during steady-state conditions. Amylin is
deficient in insulin-dependent diabetes mellitus (11) and late
non-insulin-dependent diabetes mellitus (22). Especially in the latter
case, the molar ratio of insulin to amylin has often been used as an
indicator of relative amylin deficiency. Identification of amylin
deficiency might thus be used to identify potential target populations
for substitution with amylin or its agonist pramlintide. The
possibility of different clearance parameters further warrants a more
robust study. In fact, amylin could be able to exert a more prolonged and sustained action than insulin in regulating carbohydrate metabolism by acting on glucose production, gastric emptying, and other yet unknown processes (36). In addition, knowledge of the volume of
distribution is a prerequisite to speculate about common sites of
action of amylin and insulin.
The purpose of the present study was therefore to elucidate amylin
pharmacokinetics, by injecting synthetic human amylin (amlintide) in
humans to analyze its disappearance curve, as well as its distribution volume, half-life, and plasma clearance rate.
 |
METHODS |
Subjects and Study Design
The study was performed in 9 male, healthy subjects [mean age = 26.0 ± 1.6 yr, body mass index (BMI) = 22.6 ± 0.4 kg/m2]
without family history of diabetes. The protocol was
reviewed and approved by the Ethics Committee of the University of
Vienna. The purpose, nature, and potential risks of the study were
explained in detail to the participants before obtaining their written
consent. After an overnight fast, subjects reported to the clinic in
the morning of the investigation day. One cannula was inserted into an
antecubital vein of the nondominant arm for infusion of somatostatin (SRIF; Curamed Pharma, Karlsruhe, Germany) and amylin. A dorsal hand
vein was cannulated to facilitate venous sampling of amylin concentrations.
SRIF was administered to suppress endogenous amylin release at a bolus
of 1.8 µg/kg at
30 min followed by constant infusion of 0.06 µg · kg
1 · min
1
throughout the study, as described previously (24). At
time 0 min, a rapid bolus of 50 µg
of amlintide (synthetic human amylin; provided by Amylin
Pharmaceuticals, San Diego, CA) was injected, and blood samples were
collected from the dorsal hand vein at 3, 5, 7, 10, 12.5, 15, 20, 25, 30, 40, 50, 60, 80, 120, and 180 min.
Assessment of amylin levels. Precisely
5 ml of blood were put into vacutainer tubes containing sodium-EDTA and
a lyophilized protease inhibitor. The samples were immediately placed
on ice, and the plasma was separated by centrifugation at 4°C,
2,000 rpm for 10 min within 20 min after collection. Plasma amylin
levels were measured using a monoclonal antibody-based sandwich assay (28) that was subsequently converted into a kit format. The changes
include the generation of both lyophilized standards and precoated
assay plates to increase kit (Amylin Pharmaceuticals) stability. All
plasma samples were diluted 1:1 with sample diluent to minimize
recovery differences between individual plasma samples.
In validation studies, the assay had a minimum detectable concentration
(mean ± 2 SD of the zero standard) of <2.0 pmol/l. Intra-assay
and interassay coefficients of variation were <15%. The accuracy of
the assay as judged by amlintide (synthetic amylin) spiked into human
plasma is 87.3 ± 10.4% (mean ± 1 SD) of the expected value.
Dilution of plasma samples with the zero standard provided results that
were 100.5 ± 9.2% (mean ± 1 SD) of the expected values.
The antibody (F024) does not cross-react with the glycosylated peptides
(amylin-like peptides) or with known homologous peptides (CGRP,
calcitonin). It does react with rat and human amylin as well as
pramlintide. Because the assay uses two specific antibodies, there is
added specificity because the epitope of the detection antibody
(F025-27) is at the far COOH-terminal end and requires the
amidation for binding.
Data Analysis
Noncompartmental analysis. Individual
amylin data were analyzed with the standard noncompartmental approach.
The disappearance curve after bolus injection was described by a sum of
exponentials
|
(1)
|
where
c(t) is the plasma concentration
(pmol/l) at time t. Parameters
Ai
and
i are characteristic of
every single exponential and represent the zero intercept and the
elimination rate constant, respectively. The selection of the number of
exponentials (p) used in
Eq. 1 for fitting the measured plasma
disappearance curve of amylin is crucial for the precision of the
estimation of noncompartmental parameters. The measured plasma
disappearance curve of every single subject was fitted using two and
three exponentials, with the monoexponential description excluded
because it did not allow a comprehensive description of amylin
kinetics. Data fitting was performed by minimizing the sum of squared
residuals after log transformation of the data
|
(2)
|
where
c(tj),
j = 1, ... ,
N represents the amylin concentration
measured at N discrete time points
tj.
The logarithmic transformation of the data was motivated by the high
precision of the amylin assay at low concentrations (2-100 pmol/l;
see Ref. 28). To determine whether two or three is the most appropriate
number of exponential terms to describe amylin disappearance after
bolus injection, the F-test criterion
was used (31). Results were also empirically evaluated by their
physical plausibility, i.e., the solutions were not considered
acceptable if the parameters exhibited coefficients of variations that
were too elevated (e.g., coefficient of variation >100%)
and/or their estimated values were not physiologically
plausible.
Noncompartmental parameters were calculated according to standard
pharmacokinetic equations (10). In particular, the half-life (t1/2, min), of each
exponential component was calculated by
|
(3)
|
the
initial distribution volume (V1,
ml) was calculated as
|
(4)
|
where
Q0 is the known administered dose.
The conversion factor from grams to moles accounts for the fact that
the molecular mass is 3,905 daltons. The plasma clearance rate (CL,
ml/min) was calculated as
|
(5)
|
where
AUC is the total area under the concentration curve extrapolated to
infinity given by
|
(6)
|
The
total mean residence time of amylin in the system (MRT, min) was
calculated as
|
(7)
|
The
total distribution volume (VTOT,
ml) was then determined by
|
(8)
|
The
fractional clearance rate of amylin (k,
min
1) was defined as
|
(9)
|
and
will be used for comparing amylin clearance with that of C-peptide and
insulin.
Compartmental analysis. An equivalent
representation of multiexponential kinetics of amylin is the
compartmental structure that assumes distribution of amylin in
different pools. Under the hypothesis that elimination occurs from the
accessible compartment, i.e., where amylin is injected and measured,
the irreversible loss from the compartmental system is equivalent to
the clearance determined with the noncompartmental analysis. A support
to this hypothesis comes from a recent study that concluded that amylin disappearance seems to occur almost entirely in the kidneys (21, 33).
Moreover, the number of compartments is equal to the number of
exponentials used to fit the data. Among different possible compartmental structures, we adopted the catenary model shown in Fig.
1 for a three-exponential description of
disappearance data. Adaptation to a two-exponential description is
straightforward. The compartmental model of Fig. 1 is parameterized in
terms of the volumes of the compartments and by the intercompartmental flows, which determine the mass exchange between contiguous
compartments as a function of the concentration gradient. The
parameters of the compartmental model are related to the parameters of
the exponential model at different degrees of complexity. The
simplest relationships are the equivalences between the clearance rate
and distribution volume of the accessible compartment with parameters
CL and V1 of Eqs.
5 and 4, respectively.
The total "compartmental" volume given by the sum of the volumes
of the single compartments is equivalent to
VTOT of Eq. 8. The volumes of the nonaccessible compartments and
the intercompartment flows can be derived from the parameters
Ai
and
i of the exponential model
(see APPENDIX).

View larger version (12K):
[in this window]
[in a new window]
|
Fig. 1.
Compartmental model of amylin kinetics. Amylin injection and
measurements occur in the accessible compartment representing plasma.
Compartment volumes are initial volume of distribution
(V1), volume of
compartment 2 (V2), and volume of
compartment 3 (V3).
Q12 and
Q23 are intercompartmental
exchange fluxes from compartments 1 and 2 and from
compartments 2 and
3, respectively. CL is amylin
clearance rate assumed to occur only from the accessible compartment.
|
|
To determine an appropriate normalization of the kinetic parameters
with respect to anthropometric characteristics, three commonly adopted
criteria were considered [body weight (BW), BMI, and body surface
area (BSA)]. In particular, pairwise correlations of individual
parameters were calculated with respect to BW, BMI, and BSA.
 |
RESULTS |
Noncompartmental Analysis
The average disappearance curve of amylin in the nine subjects is shown
in Fig. 2. Regarding the choice of the
number of exponentials to describe in each individual amylin
disappearance curve, the F-test
criterion provided probability levels of
P < 0.05 in eight out of nine
subjects and a value of P = 0.45 in
one subject. These probabilities represent the risk that the increase
of the sum of squared residuals for two vs. three exponentials is due
to chance alone. Therefore, the use of three exponentials is suitable for all of the subjects and is the best representation of amylin disappearance. The kinetic parameters calculated in each subject from
the estimated model parameters
Ai
and
i of the three
exponentials are reported in Table 1. The
average distribution volume and clearance rate normalized to BW were
173 ± 16 ml/kg and 6.2 ± 0.2 ml · min
1 · kg
1,
respectively.

View larger version (10K):
[in this window]
[in a new window]
|
Fig. 2.
Average serum amylin concentration after a bolus injection of 50 µg
of synthetic human amylin (amlintide) in 9 normal subjects.
|
|
View this table:
[in this window]
[in a new window]
|
Table 1.
Kinetic parameters evaluated with noncompartmental analysis (3 exponentials) of amylin disappearance after an intravenous bolus
|
|
Compartmental Analysis
The compartmental model parameters obtained in each subject are
reported in Table 2 (only those not already
in Table 1 are shown). The analysis for determining the normalization
of the kinetic parameters indicated that, when a significant
correlation occurred, the correlation with BW was stronger than that
with BSA and BMI (data not shown). Thus we evaluated first the
correlation between the compartmental parameters and then the
correlation between every single parameter and BW (Table
3). It can be noted that a significant
correlation was found between each of four parameters, namely the BW,
the CL, the V1, and the
intercompartmental flow in compartments
2 and 3 (Q23). In addition, a
significant correlation was also found between the volume of
compartment 2 (V2) and the volume of
compartment 3 (V3). Normalization of all compartmental parameters with respect to individual BW markedly changed
the above situation. In particular, no correlation was found anymore
between any normalized parameters, except between V2/BW and
V3/BW (correlation coefficient = 0.78, P = 0.013). Normalized parameters were V1/BW = 58 ± 6 ml/kg, V2/BW = 67 ± 7 ml/kg,
V3/BW = 47 ± 8 ml/kg,
intercompartmental flow rate between compartments 1 and 2 (Q12)/BW = 8.4 ± 1.0 ml · min
1 · kg
1,
Q23/BW = 1.1 ± 0.2 ml · min
1 · kg
1.
View this table:
[in this window]
[in a new window]
|
Table 2.
Parameters evaluated with compartmental analysis (model of Fig. 1) of
amylin kinetics after an intravenous bolus
|
|
 |
DISCUSSION |
Most investigations on amylin and its effects on carbohydrate
metabolism have been performed in rats, both in vitro and in vivo (17,
25), whereas the present study directly assessed amylin kinetics in
humans by exogenously injecting synthetic human amylin (amlintide)
after prior blocking of its endogenous secretion with SRIF. In fact,
the potential use of amylin or its analog pramlintide in the therapy of
diabetes requires not only quantitative assessment of the dose/effect
but also the investigation of amylin kinetics. In addition, knowledge
of amylin distribution, metabolism, and excretion is important in view
of an individualized therapy.
The analysis of amylin data after a bolus injection was performed using
standard pharmacokinetic techniques to obtain physiological parameters
such as the VTOT and the clearance
rate. Because a suitable description of plasma disappearance of amylin
was obtained by multiexponential curve fitting, as also suggested for
kinetics in rats (17), the performance of the two competing models (2 and 3 exponentials) was rated according to statistical criteria to
determine the optimal model order. The three-exponential curves provided the best description of the data, which led to the three-pool compartmental representation of amylin kinetics (Fig. 1). This structure had the advantage, over the noncompartmental
(multiexponential) analysis, of providing a physiological model that
quantified the volumes of three pools of distribution and the exchange
fluxes between them. The correlation analysis for determining a
suitable normalization criterion showed that compartmental model
parameters were more correlated to BW than to other anthropometric
characteristics. In particular, it was found that BW allows correlation
between most kinetic parameters, which then disappears after
normalization, thus suggesting important effects of BW on amylin
kinetics. The normalized distribution
volumes of the three pools were similar (on average 58, 68, and 47 ml/kg), whereas Q12 was markedly
higher than Q23. This supports the
validity of the concept that compartments 1 and 2 are related to
rapid distribution phenomena between vascular and extravascular spaces,
whereas compartment 3 characterizes a
remote pool with a slower exchange rate. Another evidence for the
possible physiological meaning of the compartments derives from the
evaluation of the pool sizes. Assuming that plasma is 7.5% of the
total body water (TBW), which in liters is 60% of BW in kilograms
(23), plasma volume can be assumed to be roughly 45 ml/kg. This is
similar, although slightly lower (P = 0.03), to the estimated V1, which
was on average 58 ml/kg. Thus, with good approximation, amylin
distributes immediately in plasma and in other fluids with a fast
exchange rate. Assuming that plasma and interstitial fluids account for
25% of TBW (23), VTOT is ~150
ml/kg, which was not different (P = 0.19) from VTOT of amylin (173 ml/kg). This distribution space compares well to that of insulin (157 ml/kg; see Ref. 30), allowing the conclusion that amylin, as insulin,
distributes in the interstitial volume of muscle, adipose tissue, and
well-perfused organs in rapid equilibrium with plasma, such as heart,
kidneys, gut, and liver. With respect to this correspondence and
accepting that V1 is plasma
volume, we conclude that the distribution volumes
V2 and
V3 represent a partitioning of the
interstitial fluid volume. The correlation between
V2 and
V3, both with and without
normalization to BW, showed that this partitioning follows a linear
relationship. The lack of a statistical correlation between
V2,
V3, and BW may be due to the
limited number of subjects of our lean study group. Thus the three
compartments of the amylin model likely represent plasma
(V1) and the interstitial
fluids, partitioned in fast (V2) and slowly (V3) exchanging
pools.
Because amylin is cosecreted with insulin (12, 13) and therefore with
C-peptide, it is interesting to compare the kinetics of the three
peptides in a similar situation. The clearance rate of amylin (6.2 ml · min
1 · kg
1)
is lower than that of insulin (12.9 ml · kg
1 · min
1) calculated from a
total of 75 normal subjects in 5 different studies after a single
injection of insulin (9). The fractional clearance rate of amylin
(0.038 min
1) is
comparable, although slightly smaller, to that reported for C-peptide
(0.053-0.072 min
1; see
Ref. 29), whereas it is markedly lower than that of insulin (0.10-0.20 min
1; see
Ref. 5). This indicates that the commonly used insulin-to-amylin molar
ratio does not reflect the correct relationship of the two peptides in
non-steady-state conditions (32). These results also confirm the
clearance rate of endogenously produced amylin during an OGTT obtained
by mathematical modeling (14) and can be considered a validation of
that model (32). The MRT, which is strictly related to the clearance
rate when VTOT does not change, is
obtained as the ratio of VTOT over
the clearance. Thus the higher MRT of amylin (28 min) compared with
that of insulin (14.1 min; see Ref. 30) and C-peptide (16.4 min; see
Ref. 29) again supports the lower clearance of amylin. The similar
clearance rate of amylin and C-peptide supports our assumption from
previous studies that amylin might be cleared predominantly by the
kidneys (21, 33). Our data have been collected in lean, healthy
subjects with apparent normal kidney function. We have, however, no
data on the clearance of amylin in elderly, obese patients, who
represent a target population for the therapeutic administration of the amylin agonist pramlintide. Because glomerular filtration rate decreases in elderly people, one could speculate that amylin or pramlintide might exert a prolonged action in these subjects.
In this study, we had to administer SRIF in a dose that is able to
suppress pancreatic hormones. SRIF could change renal blood flow and
thus influence amylin kinetics. The similar clearance rate for amylin
(5.7 compared with 6.2 ml · kg
1 · min
1
in our study) in a paper by Bretherton-Watt and co-workers (2) during
high-dose infusion of amylin without SRIF administration, however,
suggests that the potential effects of SRIF do not profoundly affect
our calculations.
The similar distribution volumes of amylin and insulin found in our
study are a prerequisite for the suggested common sites of action as
postulated from animal experiments (7, 19, 37). The lower clearance and
fractional clearance rates as well as the higher MRT of amylin compared
with those of insulin might favor an extended mode of action after oral
glucose ingestion.
In conclusion, we found evidence that amylin distributes equally to
insulin in plasma and interstitial fluids. The lower clearance rate of
amylin, which is close to that of C-peptide, as well as the higher MRT
compared with insulin, indicate that the commonly used
insulin-to-amylin ratio is not applicable under non-steady-state conditions.
 |
APPENDIX |
The most common mathematical representation of a catenary model, like
that of Fig. 1, describing the kinetics of a substance after bolus
injection is given by the following system of differential equations
|
(A1)
|
where x1 is
the mass of the accessible compartment, such that the measured
concentration is c(t) = x1/V1,
dose is the amount of substance administered by bolus injection, and
parameters kij represent the fractional exchange rates between the contiguous compartments i and
j. The complex relationships that
describe the equivalence between the
kij parameters
and those from the multiexponential model (Eq. 1) are reported in any pharmacokinetics textbook (10)
and have been used to calculate the equations that follow. In this
study, we adopted a compartmental representation that uses the
intercompartment flows Qij and
the volumes Vi instead of
kij as
physiological parameters. The relationships among
Qij,
Vi, and parameters kij of
Eq. A1 derive by the definition of
fractional clearance, i.e.
|
(A2)
|
which
yield the following relationship
|
(A3)
|
for intercompartment flows and compartment volumes of the
model of Fig. 1.
 |
ACKNOWLEDGEMENTS |
Part of this study has been supported by a grant to K. Thomaseth
from the Italian National Research Council (Progetto Bilaterale, Consiglio Nazionale delle Ricerche-Comitato 07). We are indebted to
Amylin (San Diego, CA) for kindly supplying the synthetic human amylin
(amlintide) used in this study and for running the amylin assays.
 |
FOOTNOTES |
Address for reprint requests: B. Ludvik, Division of Endocrinology and
Metabolism, Dept. of Medicine III, Univ. of Vienna, Waehringer Guertel
18-20, 1090 Vienna, Austria.
Received 23 July 1997; accepted in final form 5 February 1998.
 |
REFERENCES |
1.
Blackard, W. G.,
J. N. Clore,
and
J. M. Kellmun.
Amylin/insulin secretory ratios in morbidly obese man, inverse relationship with glucose disappearance rate.
J. Clin. Endocrinol. Metab.
78:
1257-1260,
1994[Abstract].
2.
Bretherton-Watt, D.,
S. G. Gilbey,
M. A. Ghatei,
J. Beacham,
and
S. R. Bloom.
Failure to establish islet amyloid polypeptide (amylin) as a circulating beta cell inhibiting hormone in man.
Diabetologia
333:
115-117,
1990.
3.
Bretherton-Watt, D.,
S. G. Gilbey,
M. A. Ghatei,
J. Beacham,
A. D. Macrae,
and
S. R. Bloom.
Very high concentrations of islet amyloid polypeptide are necessary to alter the insulin response to intravenous glucose in man.
J. Clin. Endocrinol. Metab.
74:
1032-1035,
1992[Abstract].
4.
Ciaraldi, T. P.,
M. Goldberg,
R. Odom,
and
M. Stolpe.
In vitro effects of amylin on carbohydrate metabolism in liver cells.
Diabetes
41:
975-981,
1992[Abstract].
5.
Cobelli, C.,
and
G. Pacini.
Insulin secretion and hepatic extraction in humans by minimal modelling of C-peptide and insulin kinetics.
Diabetes
37:
223-231,
1988[Abstract].
6.
Cooper, G. J.,
B. Leighton,
G. D. Dimitriades,
M. Parry-Billings,
J. M. Kowalchuk,
K. Howland,
J. B. Rothbard,
A. D. Willis,
and
K. B. M. Reid.
Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen metabolism in skeletal muscle.
Proc. Natl. Acad. Sci. USA
85:
7763-7766,
1988[Abstract].
7.
Cooper, G. J. S.
Amylin compared with calcitonin gene-related peptide: structure, biology, and relevance to metabolic disease.
Endocr. Rev.
15:
163-201,
1994[Medline].
8.
Cooper, G. J. S.,
A. Willis,
A. Clark,
R. C. Turner,
R. B. Sim,
and
K. B. M. Reid.
Purification and characterization of amyloid-rich pancreases of type 2 diabetic patients.
Proc. Natl. Acad. Sci. USA
84:
8628-8632,
1987[Abstract].
9.
Ferrannini, E.,
and
C. Cobelli.
The kinetics of insulin in man.
Diabetes Metab. Rev.
3:
365-397,
1987[Medline].
10.
Gibaldi, M.,
and
D. Perrier.
Pharmacokinetics (2nd ed.). New York: Dekker, 1982.
11.
Hartter, E.,
T. Svoboda,
B. Lell,
M. Schuller,
B. Ludvik,
W. Woloszczuk,
and
R. Prager.
Reduced islet amyloid polypeptide in insulin-dependent diabetes mellitus (Abstract).
Lancet
i:
854,
1990.
12.
Hartter, E.,
T. Svoboda,
B. Ludvik,
M. Schuller,
B. Lell,
E. Kuenburg,
M. Brunnbauer,
W. Woloszczuk,
and
R. Prager.
Basal and stimulated plasma levels of amylin indicate its cosecretion with insulin in humans.
Diabetologia
34:
52-54,
1991[Medline].
13.
Kahn, S.,
D. A. D'Alessio,
M. W. Schwartz,
W. Y. Fujimoto,
J. W. Ensinck,
G. J. Taborsky,
and
D. Porte.
Evidence of cosecretion of islet amyloid polypeptide and insulin by B cells.
Diabetes
39:
634-638,
1990[Abstract].
14.
Kautzky-Willer, A.,
K. Thomaseth,
G. Pacini,
M. Clodi,
B. Ludvik,
C. Streli,
W. Waldhäusl,
and
R. Prager.
Role of islet amyloid polypeptide secretion in insulin resistant humans.
Diabetologia
37:
188-194,
1994[Medline].
15.
Kolterman, O. G.,
S. Schwartz,
C. Corder,
B. Levy,
L. Klaff,
J. Peterson,
and
A. Gottlieb.
Effect of 14 days' subcutaneous administration of the human amylin analogue, pramlintide (AC137), on an intravenous insulin challenge and response to a standard liquid meal in patients with IDDM.
Diabetologia
39:
492-499,
1996[Medline].
16.
Kong, M.-F.,
P. King,
I. A. Macdonald,
T. A. Stubbs,
A. C. Perkins,
P. E. Blackshaw,
C. Moyses,
and
R. B. Tattersall.
Infusion of pramlintide, a human amylin analogue, delays gastric emptying in men with IDDM.
Diabetologia
40:
82-88,
1997[Medline].
17.
Koopmans, S. J.,
A. D. van Mansfeld,
H. S. Jansz,
H. M. Kraus,
J. K. Radder,
M. Frolich,
S. F. de Boer,
D. K. Kreutter,
G. C. Andrews,
and
J. A. Maassen.
Amylin-induced in vivo insulin resistance in conscious rats: the liver is more sensitive to amylin than peripheral tissues.
Diabetologia
34:
218-224,
1991[Medline].
18.
Leaming, R., A. Johnson, G. Hook, R. Hanley, and A. Baron.
Amylin modulates insulin secretion in humans. Studies with an
amylin antagonist. Diabetologia 38, Suppl. 1: A113, 437, 1995.
19.
Leighton, B.,
J. S. Garth,
and
G. J. S. Cooper.
Pancreatic amylin and calcitonin gene related peptide (CGRP) cause resistance to insulin in skeletal muscle in vitro.
Nature
335:
632-635,
1988[Medline].
20.
Ludvik, B.,
M. Clodi,
A. Kautzky-Willer,
M. Capek,
E. Hartter,
G. Pacini,
and
R. Prager.
Effect of dexamethasone on insulin sensitivity, islet amyloid polypeptide and insulin secretion in humans.
Diabetologia
36:
84-87,
1993[Medline].
21.
Ludvik, B.,
M. Clodi,
A. Kautzky-Willer,
M. Schuller,
H. Graf,
E. Hartter,
G. Pacini,
and
R. Prager.
Increased levels of circulating islet amyloid polypeptide in patients with chronic renal failure have no effect on insulin secretion.
J. Clin. Invest.
94:
2045-2050,
1994[Medline].
22.
Ludvik, B.,
B. Lell,
E. Hartter,
C. Schnack,
and
R. Prager.
Decrease of stimulated amylin precedes impairment of insulin secretion in type 2 diabetes.
Diabetes
40:
1615-1619,
1991[Abstract].
23.
Marsh, D. J.
Renal Physiology. New York: Raven, 1983.
24.
Mitsukawa, T.,
J. Takemura,
J. Asai,
M. Nakazato,
M. Kangawa,
H. Matsuo,
and
S. Matsukura.
Islet amyloid polypeptide response to glucose, insulin, and somatostatin analogue administration.
Diabetes
39:
639-642,
1990[Abstract].
25.
Nagamatsu, S.,
R. J. Caroll,
G. M. Grodsky,
and
D. F. Steiner.
Lack of islet amyloid polypeptide regulation of insulin secretion in normal rat islets.
Diabetes
39:
871-874,
1990[Abstract].
26.
Nyholm, B.,
N. Moller,
C. H. Gravholt,
L. Orskov,
A. Mengel,
G. Bryan,
C. Moyses,
K. G. M. M. Alberti,
and
O. Schmitz.
Acute effects of the human amylin analog AC137 on basal and insulin-stimulated euglycemic and hypoglycemic fuel metabolism in patients with insulin-dependent diabetes mellitus.
J. Clin. Endocrinol. Metab.
81:
1083-1089,
1996[Abstract].
27.
Nyholm, B., L. Orskov, K. Hove, C. Gravholt, N. Moller, K. Alberti, and O. Schmitz. The amylin analogue pramlintide decreases
post-prandial plasma glucose and glucagon in IDDM.
Diabetes 56, Suppl. 1: 33A, 128, 1997.
28.
Percy, A. J.,
D. A. Trainor,
J. Rittenhouse,
J. Phelps,
and
J. E. Koda.
Development of sensitive immunoassays to detect amylin and amylin-like peptides in unextracted plasma.
Clin. Chem.
42:
576-585,
1996[Abstract/Free Full Text].
29.
Polonsky, K.,
J. Licinio-Paixao,
B. D. Given,
W. Pugh,
P. Rue,
J. Galloway,
T. Karrison,
and
B. Frank.
Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients.
J. Clin. Invest.
77:
98-105,
1986[Medline].
30.
Sherwin, R. S.,
K. Kramer,
J. D. Tobin,
P. A. Insel,
J. E. Liljenquist,
M. Berman,
and
R. Andres.
A model of the kinetics of insulin in man.
J. Clin. Invest.
53:
1481-1492,
1974[Medline].
31.
Söderström, T.,
and
P. Stoica.
System Identification. New York: Prentice Hall, 1989.
32.
Thomaseth, K.,
A. Kautzky-Willer,
B. Ludvik,
R. Prager,
and
G. Pacini.
An integrated mathematical model to assess B-cell activity during the oral glucose test.
Am. J. Physiol.
270 (Endocrinol. Metab. 33):
E522-E531,
1996[Abstract/Free Full Text].
33.
Thomaseth, K.,
G. Pacini,
M. Clodi,
A. Kautzky-Willer,
J. J. Nolan,
R. Prager,
J. M. Olefsky,
and
B. Ludvik.
Amylin release during oral glucose tolerance test.
Diabet. Med.
14:
S29-S34,
1997[Medline].
34.
Westermark, P.,
C. Wernstedt,
E. Wilander,
and
K. Sletten.
A novel peptide in the calcitonin gene related peptide family as an amyloid fibril protein in the endocrine pancreas.
Biochem. Biophys. Res. Commun.
140:
826-831,
1986.
35.
Wildling, J. P. H.,
N. Khandan-Nia,
W. M. Bennet,
S. J. Glibey,
J. Beacham,
M. A. Ghatei,
and
S. R. Bloom.
Lack of acute effects of amylin (islet associated polypeptide) on insulin sensitivity during hyperinsulinemic euglycemic clamp in humans.
Diabetologia
37:
166-169,
1994[Medline].
36.
Young, A. A.,
B. Gedulin,
W. Vine,
A. Percy,
and
T. J. Rink.
Gastric emptying is accelerated in diabetic BB rats and is slowed by subcutaneous injections of amylin.
Diabetologia
38:
642-648,
1995[Medline].
37.
Young, A. A.,
B. Gedulin,
D. Wolfe-Lopez,
H. E. Green,
T. J. Rink,
and
G. J. S. Cooper.
Amylin and insulin in rat soleus muscle, dose response for cosecreted noncompetitive antagonists.
Am. J. Physiol.
263 (Endocrinol. Metab. 26):
E274-E281,
1992[Abstract/Free Full Text].
38.
Young, A. A.,
M. W. Wang,
and
G. J. S. Cooper.
Amylin injection causes elevated plasma lactate and glucose in the rat.
FEBS Lett.
343:
237-241,
1991.
AJP Endocrinol Metab 274(5):E903-E908
0193-1849/98 $5.00
Copyright © 1998 the American Physiological Society