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Original Studies |
Department of Medicine, Lund University (K.F., B.A.), Malmö, Sweden; and the Department of Endocrinology and Metabolism, Panum Institute (K.T., J.H.), Copenhagen, Denmark
Address all correspondence and requests for reprints to: Dr. Karin Filipsson, Wallenberg Lab, Floor 2, Department of Medicine, Malmö University Hospital, S-205 02 Malmö, Sweden. E-mail: Karin.Filipsson{at}medforsk.mas.lu.se
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The physiological function of PACAP has not yet been established. In experimental animals, the peptide stimulates secretion from the pituitary, the adrenals, and pancreatic acini (for review, see 3 . In contrast, very little information on the effects of PACAP in humans exists. In one study, PACAP did not affect anterior pituitary hormone levels (7), whereas in another study, PACAP stimulated the release of arginine vasopressin (8). Moreover, in the human adrenal gland, PACAP enhanced aldosterone secretion indirectly, probably through local release of catecholamines (9). Other studies have shown that the peptide is a potent vasodilator in man (10, 11).
In conjunction with its localization to pancreatic islet nerves, PACAP has been shown to stimulate the secretion of insulin (5, 12, 13, 14, 15, 16, 17) and glucagon (4, 14, 15, 17) in experimental animals, both in vitro and in vivo, suggesting involvement of the neuropeptide in the regulation of islet function. However, whether PACAP exists in the human pancreas and whether the peptide affects insulin and glucagon secretion in humans are not known. Therefore, in this study, we determined the content of PACAP in extracts of human pancreas and then examined the effects of PACAP on insulin and glucagon secretion under baseline conditions and after a bolus glucose dose in humans. For the functional studies, both PACAP27 and PACAP38 could have been used. However, the PACAP receptor known to exist in human pancreas, the PACAP type 3 receptor (18), binds the two forms of PACAP with equal affinity, and in isolated islets as well as in perfused pancreas, PACAP27 and PACAP38 are equipotent (5, 14, 16). Therefore, it is sufficient to use only one of the PACAP forms to test its action on islet function in humans. We infused synthetic human PACAP27 and used a dose rate of 3 pmol/min·kg, in a homogeneous group of seven healthy postmenopausal women, all aged 57 yr. The dose of 3 pmol/min·kg was selected because a previous study has shown that the highest tolerable infusion rate of PACAP is 3.5 pmol/min·kg; higher doses cause intense flushing (7). To determine the circulating level of PACAP reached during peptide infusion, we also measured plasma PACAP27 immunoreactivity.
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Subjects and Methods |
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Fresh human pancreatic tissue was obtained from multi organ donors (n = 4) after approval of the ethics committee, Copenhagen University. The tissue was immediately frozen and subsequently extracted using an acid-ethanol technique (19).
The extracts were subjected to gel permeation chromatography on a G-50 (superfine grade) column (1000 x 16 mm), equilibrated, and eluted at 4 C with 0.5 mol/L CH3COOH at a flow rate of 19 mL/h. The sample size never exceeded 2% of the bed volume. Trace amounts of [125I]albumin and 22NaCl were added for internal calibration. Additional calibration was performed with synthetic PACAP27 and PACAP38 (Peninsula, Merseyside, UK). Elution positions are referred to by the coefficient of distribution Kd = (Ve - V0)/Vi, where Ve indicates the volume in which the peptide in question appeared, V0 indicates the distribution volume of molecules excluded from the gel-beads (the elution volume of [125I]albumin), and Vi indicates the available inner volume (defined as the difference between the elution volumes of [125I]albumin and 22NaCl). Fractions from the column effluent were collected, lyophilized, reconstituted in assay buffer (see below), and subjected to RIA for PACAP27 and PACAP38.
Infusion of PACAP27 in humans
Substance. Synthetic human PACAP27 was purchased from Saxon Biochemicals (Hannover, Germany). The peptide was dissolved in sterile distilled water and then diluted in 0.9% saline with the addition of 1% human serum albumin and filtered through 0.2-µm nitrocellulose filter (Millex-GV, Millipore Corp., Bedford, MA) and stored at -20 C before use. Net peptide content rather than gross weight was used for dose calculations.
Subjects. Seven healthy postmenopausal women participated in the study. They were all born in 1938, and they were 57 yr and 1 ± 8 months old at the time of the first infusion. The body mass index of the subjects was 24.9 ± 4.2 kg/m2 (range, 19.5–32.4), the fasting blood glucose was 4.6 ± 0.4 mmol/L, and the 2 h blood glucose after a 75-g oral glucose challenge was 6.5 ± 1.1 mmol/L (all values are the mean ± SD). All subjects were healthy and had normal liver and thyroid function tests, and none was taking any medication known to affect glucose tolerance, including estrogen replacement. All subjects received oral and written information concerning the aims and methods of the study and signed a consent declaration before start of the study. The study protocol was approved by the ethics committee of Lund University.
PACAP27 infusion. After an overnight fast, PACAP27 was infused iv at a dose rate of 3 pmol/kg·min for 75 min. After 15 min of infusion, an iv bolus glucose injection of 0.3 g/kg was given rapidly. Samples for determination of insulin, C peptide, glucagon, glucose, and PACAP27 were taken before and during PACAP27 infusion. They were immediately centrifuged at 4 C, and plasma or serum was stored at -20 C until analysis. Blood samples for analysis of plasma glucagon and plasma PACAP27 were obtained in prechilled test tubes containing 0.084 mL ethylenediaminotetraacetic acid (0.34 mol/L) and aprotinin (250 kallikrein inhibitor units/mL blood; Bayer, Leverkusen, Germany). Each individual underwent two examinations in random order, one with PACAP27 and one with saline instead of the peptide, with 2–4 weeks in between.
Analyses
PACAP. The concentration of PACAP27 in plasma was determined using a newly developed RIA. Before RIA analysis, PACAP27 was extracted from plasma using ethanol (0.7 mL plasma and 2.5 mL 96% ethanol). The samples, which were kept at 4 C during the whole procedure, were thoroughly mixed and centrifuged for 30 min at 3300 x g. The supernatant was blown dry by a stream of air overnight at room temperature. Before proceeding with the RIA, the samples were reconstituted in 0.7 mL assay buffer (see below), mixed thoroughly, left in a refrigerator for 30 min, and again mixed thoroughly. Antisera were raised in rabbits, using a previously described immunization procedure, against PACAP18–27 amide (20) and PACAP28–38 amide (21). The antisera used (code no. 91081–5 and 733C-5) were directed against the amidated C-terminus of PACAP27 and PACAP38, respectively (20), and showed no cross-reaction with any other peptide of the glucagon-secretin-vasoactive intestinal peptide (VIP)-PACAP family of peptides, except for the peptide against which they were raised. Synthetic human PACAP27 and PACAP38 (Peninsula) were used as the standard. Tracers were prepared using PACAP18–27 amide and PACAP28–38 amide (as described above) and labeled with 125I using the stoichiometric chloramine-T method followed by HPLC purification as previously described (19). The standard curves for assay of pancreas extracts were prepared in assay buffer, whereas for analysis of PACAP27 in plasma, the standard curve was prepared in human plasma with a low or immeasurable amount of PACAP27 and extracted with 75% ethanol as described above. Preparation of assay buffers, incubation conditions, and separation techniques (plasma-coated charcoal) followed previously described conventional principles (19). Using this procedure, the recovery of PACAP27 added to unknown plasma samples was approximately 95%. The PACAP27 assay prepared in plasma had a detection limit of approximately 5 pmol/L, 50% inhibition of binding at 72 pmol/L, and an intraassay coefficient of variation of 5% at 100 pmol/L. All samples were analyzed within the same assay.
Insulin. Serum insulin concentrations were analyzed with a double antibody RIA, using guinea pig antihuman insulin antibodies and human insulin standard and mono-[125I]Tyr-human insulin as tracer (Linco Research, St. Charles, MO).
C Peptide. Plasma C peptide concentrations were analyzed with a double antibody RIA, using guinea pig anti human C peptide antibodies, [125I]human C peptide, and human C peptide standard (Linco). According to the manufacturer, the antibodies show very low (<4%) cross-reactivity with human proinsulin.
Glucagon. Analysis of plasma glucagon was performed with double antibody RIA using guinea pig antihuman glucagon antibodies specific for pancreatic glucagon, [125I]glucagon as tracer, and glucagon standard (Linco). The antibodies showed no cross-reactivity with PACAP27.
Glucose. Plasma glucose concentrations were determined using the glucose oxidase method. Concentrations of PACAP27, insulin, C peptide, and glucose were determined as the means of duplicate samples.
Calculations and statistics
MCR of PACAP27, expressed as milliliters per min/kg, was calculated as the PACAP27 infusion rate divided by the steady state concentration of PACAP27 above the basal level. Glucose elimination rate after the glucose injection (K value) was calculated using the t1/2 after logarithmic transformation of the individual plasma glucose values. All statistical analyses were performed with the SPSS for Windows system. The mean ± SEM are shown unless otherwise stated. Statistical evaluation was performed by Wilcoxon paired rank-sum test. For estimation of linear relationships between variables, Pearson’s product-moment correlation was used. In all statistical tests, a P < 0.05 was considered significant.
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Results |
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Both PACAP27 and PACAP38 eluted as two immunoreactive peaks upon
chromatographic analysis of extracts of human pancreata subjected to
gel filtration (Fig. 1
, a and b). The
major fraction of immunoreactive PACAP27 and PACAP38 eluted as
homogeneous peaks corresponding to the elution positions of synthetic
PACAP27 and PACAP38, respectively. The concentrations of the peptides,
calculated as the sum of immunoreactive material eluted at the position
of synthetic peptide, amounted to 0.44 ± 0.04 pmol/g tissue for
PACAP27 (Fig. 1a) and 29.6 ± 6.4 pmol/g tissue for PACAP38 (Fig. 1b). Variable amounts of both PACAP27 and PACAP38 immunoreactivity
eluted at the void volume, probably due to interference by plasma
proteins.
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Clinics and PACAP27 levels. The PACAP27 infusion was well tolerated in all women, although all experienced flushing of the facial skin and a peripheral paleness of various intensity. The flush occurred immediately at the start of the infusion and was visible or was felt as heating of the face for 4–24 h after the end of the infusion. The peripheral paleness was mainly observed in the distal parts of the extremities. It occurred immediately at the start of the peptide infusion, but vanished after disconnection of PACAP administration.
Blood pressure was measured every 2.5 min. Immediately after the start
of the peptide infusion, both diastolic and systolic blood pressures
decreased. After approximately 35 min of PACAP27 infusion, the blood
pressures had stabilized at approximately 15 mm Hg below basal (Fig. 2). Simultaneously, heart rate was
increased during PACAP27 infusion. Thus, by 5 min, PACAP27 had
increased the heart rate to 89 ± 5.7 beats/min compared to
74 ± 2.9 beats/min during the infusion of saline
(P = 0.018). This difference in heart rates between
PACAP27 and control experiments persisted until the end of the
infusions.
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Insulin and C peptide.
At 14 min after the start of the
PACAP27 infusion, the serum insulin concentration had increased to
75 ± 11 pmol/L compared to 49 ± 8 pmol/L in the control
study (P = 0.018; Fig. 3a); the plasma C peptide level was
0.64 ± 0.10 nmol/L during the peptide infusion vs.
0.41 ± 0.10 nmol/L during saline (P = 0.028; Fig. 3b). The glucose-induced peak of serum insulin in the control study
occurred 4 min after glucose injection and was 559 ± 164 pmol/L.
In the presence of PACAP27, the insulin peak occurred by 2 min and was
797 ± 232 pmol/L, which is higher than that during the infusion
of saline (P = 0.018; Fig. 3a). The concentration of
plasma C peptide after glucose increased more rapidly and was
potentiated by PACAP27 (P = 0.018; Fig. 3b).
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Glucagon.
Plasma glucagon increased to 70 ± 10 pg/mL
after 14 min of PACAP27 administration compared to 50 ± 5 pg/mL
in the control experiment at the same time point (P =
0.018; Fig. 3c
). Injection of glucose reduced the plasma glucagon level
to 60 ± 7 pg/mL with PACAP27 vs. 47 ± 5 pg/mL
with saline (at 17 min; P = 0.035). This difference of
approximately 10 pg/mL persisted during the entire experiment [50
± 4 vs. 39 ± 3 pg/mL (P = 0.018) at
75 min during PACAP27 and saline infusions, respectively; Fig. 3c].
Glucose.
Infusion of PACAP27 did not alter plasma glucose
levels significantly under basal conditions, as the increases (delta)
in plasma glucose between preinfusion samples and 14 min after the
start of the infusion were 0.3 ± 0.1 and 0.0 ± 0.2 mmol/L
during PACAP27 and saline infusions, respectively (P =
NS; Fig. 3d). At 4 min after the glucose injection, the plasma glucose
concentration was 14.8 ± 0.7 mmol/L during PACAP27 infusion and
13.0 ± 0.9 mmol/L during saline infusion (P =
0.018). This slight difference persisted throughout the experiment
(P = 0.028 at 75 min; Fig. 3d). The glucose elimination
rate during the 30 min after the glucose injection was not altered by
PACAP27. Thus, during the peptide infusion, the K value was 0.87
± 0.06%/min, whereas it was 1.14 ± 0.12%/min during saline
infusion (P = NS).
C Peptide/insulin molar ratio.
Figure 4 shows the C peptide/insulin molar ratio
before the infusion of saline or PACAP27 and at 14 and 19 min after the
start of the infusion as well as the ratio of the peak increases in C
peptide and insulin induced by glucose. As shown, infusion of PACAP27
did not alter the C peptide/insulin molar ratio at any of these time
points, and the reduction of the ratio induced by glucose
(P = 0.04) was not altered by PACAP27.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Three types of receptors for PACAP have been cloned, the PACAP type 1, 2, and 3 receptors (3, 24). All receptors, except for one subtype of the type 1 receptor, have approximately the same affinity for PACAP27 and PACAP38. In the human pancreas, only messenger ribonucleic acid for the type 3 receptor has been found (18). Hence, the human pancreas seems to contain a PACAP receptor showing equal affinity for PACAP27 and PACAP38.
In experimental animals such as rats, mice, and dogs, PACAP27 and PACAP38 have previously been shown to stimulate insulin and glucagon secretion, both in vitro and in vivo (4, 5, 14, 15, 16, 17). The two forms of the peptide show similar potency in this respect (5, 14, 16). To study the potential influence of PACAP on insulin and glucagon secretion in humans, we infused PACAP27 at a dose rate of 3 pmol/kg·min in seven healthy postmenopausal women. The plasma concentration of PACAP27 during peptide infusion was approximately 40 pmol/L vs. less than 5 pmol/L during saline infusion. The physiological significance of the achieved plasma concentration is difficult to ascertain, as PACAP27 mainly acts as a neuropeptide (3), and its local concentration is not known. Moreover, the MCR of the infused PACAP reached 69 ± 18 mL/kg·min, which is a high value, approaching cardiac output, suggesting that PACAP is rapidly degraded. This enforces the idea that PACAP functions as a neurotransmitter.
Our study shows that basal insulin and C peptide concentrations were increased during the infusion of PACAP27. The increases in serum insulin and plasma C peptide concentrations induced by a glucose challenge were exaggerated by PACAP27, and the slope of the linear regression between insulin and glucose after glucose injection was potentiated by the peptide. This indicates that both basal and glucose-stimulated insulin secretion are potentiated by PACAP in humans.
Plasma glucagon levels were increased by PACAP27 under basal conditions, indicating that glucagon secretion is also stimulated by PACAP in humans. The bolus glucose injection reduced plasma glucagon levels during both saline and peptide infusions. However, after the increase in blood glucose, plasma glucagon levels were higher during the infusion of PACAP27 than during saline infusion. This confirms previous experimental studies in which PACAP has been demonstrated to stimulate glucagon secretion (4, 14, 15, 17).
During the 15-min infusion of PACAP27 before glucose was given, the plasma glucose concentration was not altered, yet insulin, C peptide, and glucagon levels were increased. This shows that the islet action of PACAP27 under basal conditions is not mediated by an altered level of glucose. In contrast, the plasma glucose level following the peak after glucose administration was slightly higher during PACAP27 infusion than during saline infusion, although the glucose elimination rate was not significantly different. However, elevation of the plasma glucose concentration is an unlikely main mechanism for the potentiated rapid glucose-induced insulin response by PACAP27, as it was not evident until 4 min after glucose injection compared to that in the control, whereas the increases in serum insulin and plasma C peptide were evident by 2 min after the introduction of the sugar. Nevertheless, we cannot exclude that the slightly elevated plasma glucose level during PACAP27 infusion contributes to the increase in serum insulin at later time points. In contrast, the increased glucagon levels might have contributed to the increased serum insulin levels, as elevation of glucagon induced by PACAP27 preceded the increase in insulin, and glucagon is a well known stimulator of insulin secretion (25).
During the infusion of PACAP27, catecholamine levels might have been elevated, as PACAP is known to stimulate catecholamine secretion in humans (9), and reduced blood pressure increases circulating catecholamine levels. This would have underestimated the direct insulinotropic effect of PACAP27, as catecholamines inhibit insulin secretion (26). This is inferred by a study in anesthetized dogs, in which plasma glucagon and glucose levels increased after the injection of PACAP38, yet serum insulin levels did not change, whereas after adrenalectomy, PACAP38 no longer increased plasma glucagon, but elevated serum insulin (17). This suggests that catecholamines mediated the glucagon elevation and concealed the direct effect on insulin secretion by PACAP38 in dogs.
The glucose elimination rate was not altered by PACAP27 despite the fact that insulin levels were significantly elevated. Possibly the stimulated secretion of glucagon explains this, although PACAP has also been demonstrated to increase the secretion of GH (1), cortisol, and catecholamines (3, 9, 16), which all exhibit insulin antagonistic properties.
The C peptide/insulin molar ratio may be used to roughly estimate hepatic extraction of insulin, if calculated before the time point where the short half-life of serum insulin influences the ratio (27). The C peptide/insulin ratio was decreased by glucose injection, as described previously (28). In contrast, PACAP27 did not alter either the C peptide/insulin molar ratio at any time point or the ratio of the delta values. These results indicate that the hepatic extraction of insulin was not altered by PACAP27. Similarly, as judged from the serum decay of insulin, the elimination of circulating insulin does not seem to be affected by PACAP27. Thus, the peripheral changes in serum insulin concentrations are mainly the result of changing insulin secretion.
In its action to stimulate both insulin and glucagon secretion, PACAP resembles some other neuropeptides, such as VIP and gastrin-releasing peptide, as well as parasympathetic nerve activation and muscarinic receptor agonism (26). The physiological implication of simultaneous stimulation of insulin and glucagon secretion is difficult to envisage. As previously discussed (26), increases in the circulating levels of both hormones will increase glucose turnover without an accompanying hyperglycemia, which might be of importance during, for example, exercise. Whether PACAP is involved in such a regulation of carbohydrate metabolism, however, remains to be established.
In conclusion, this study has shown that human pancreas contains PACAP27 and PACAP38, the latter in a concentration as high as that of VIP. Furthermore, infusion of PACAP27 stimulates insulin and glucagon secretion in healthy postmenopausal women, without altering insulin elimination or hepatic insulin extraction. Based on these results, we suggest that PACAP might be involved in the local regulation of islet function in man.
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Acknowledgments |
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Footnotes |
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Received March 20, 1997.
Revised May 28, 1997.
Accepted June 3, 1997.
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References |
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