1 Department of Cell Pharmacology and 2 Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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ABSTRACT |
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Hyperglycemia associated
with obstructive jaundice seriously affects the prognosis of
patients with hepatobiliary diseases. We investigated secretory
properties of isolated islets from bile duct-ligated (BDL) rats.
Pancreatic islets from BDL rats lost their secretory responses to
glucagon-like peptide-1 (GLP-1), although their responses to glucose
were normal. Loss of potentiation of insulin release was also observed
in glucagon and glucose-dependent insulinotropic peptide (GIP), whereas
modulation of the release by forskolin, dibutyryl cAMP, or epinephrine
remained unaffected. cAMP production by BDL islets was not increased by
these insulinotropic hormones. Serum levels of glucagon, but not GIP,
were increased in BDL rats. GLP-1 levels were also elevated, although
they did not reach statistical significance. Immunoblotting of trimeric G protein subunits demonstrated that GsL and
Gs
S, but not Gi
1/2 and
Gi
3/o
, were less expressed in BDL islets. Therefore,
unresponsiveness of the
-cell to cAMP-raising hormones is involved
in glucose intolerance under cholestasis. It results from diminished
expression of
-subunits of the relevant G protein, Gs,
and desensitization of receptors of these hormones.
cholestasis; pancreatic -cell; glucagon-like peptide-1; trimeric
G protein; adenosine 3',5'-cyclic monophosphate
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INTRODUCTION |
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IMPAIRMENT OF LIVER FUNCTIONS causes abnormal carbohydrate metabolism both in patients with obstructive jaundice and in various experimental animals with bile duct ligation (18). Resultant hyperglycemia is one of the crucial factors in deciding prognosis of patients with liver diseases (15). The relevant mechanisms are not fully understood, although previous reports suggested a few possibilities to explain associated glucose intolerance.
Plasma insulin concentrations have been reported to be decreased in
bile duct-ligated (BDL) dogs (13, 17, 25). Some morphological changes of pancreatic islet cells in BDL dogs have been
demonstrated (17), and secretory response of the
pancreatic -cell to cholecystokinin showed deterioration in perfused
pancreas in situ in BDL dogs (13). Extrapancreatic effects
of cholestasis have also been shown: 1) specific binding
activities of insulin and glucagon to hepatic membranes were decreased
in BDL rats (10); 2) obstructive jaundice
decreased glucagon-induced synthesis of cAMP, a second messenger
responsible for multiple actions of glucagon, including cell
proliferation, bile acid uptake, and gluconeogenesis, in hepatocytes
from BDL hamsters (14).
In the present study, we examined secretory characteristics of isolated
islets from BDL rat pancreata, and we found that pancreatic islets from
BDL rats lost secretory responses to cAMP-increasing hormones, such as
glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent
insulinotropic peptide (GIP). Here, we suggest that this loss of
secretory responses results from selective decrease in expression of
-subunits of the trimeric G protein Gs and receptor downregulation for these hormones in the pancreatic
-cell.
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MATERIALS AND METHODS |
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Materials.
Collagenase (type V), leupeptin, IBMX, glucagon,
GLP-1-(7-36)amide, epinephrine, forskolin, dibutyryl
cAMP (DBcAMP), and bile acids (cholic acid, taurocholic acid,
deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid) were
purchased from Sigma (St. Louis, MO). Bovine serum albumin (fraction V)
was from Chemicon International (Temecula, CA). GIP was from the
Peptide Institute (Osaka, Japan). Bilirubin and phenylmethylsulfonyl
fluoride (PMSF) were from Wako (Osaka, Japan). The bilirubin assay kit
was from Azwell (Osaka, Japan). The insulin radioimmunoassay kit was
purchased from Eiken Chemical (Tokyo, Japan). The enzyme-linked
immunoassay (ELISA) kits for cAMP, insulin, "active" GLP-1 (which
recognizes the NH2 terminus of GLP-1), and GIP were from
Cayman (Ann Arbor, MI), Seikagaku Kogyo (Tokyo, Japan), Linco Research
(St. Charles, MO), and Peninsula Laboratories (Belmont, CA),
respectively. Anti-G protein antibodies Gs and
Gi
1/2 were from Gramsch (Schwabhausen, Germany), and
Gi
3/o
was from Biomol Research Laboratories (Plymouth Meeting, PA). Polyvinylidene difluoride (PVDF) membranes for Western blotting (Immobilon) were from Millipore (Bedford, MA).
Bile duct ligation.
Male Wistar rats (body wt 200-250 g) underwent laparotomy under
general anesthesia with diethyl ether. The common bile duct was
identified and ligated close to the liver to avoid any congestion of
pancreatic juice, because there is evidence that ligation of the
pancreatic ducts affects secretory activity of the rabbit pancreatic
-cell (8) and causes atrophy of rat islet cells (19). Evident jaundice appeared 3-7 days after
operation, and loss of body weight and dark-colored urine were also
observed. For sham operation, only laparotomy was performed. Total
bilirubin levels were 0.18 ± 0.023 (SE), 0.25 ± 0.08, and
6.37 ± 0.57 mg/dl for normal (nonoperated), sham-operated, and
BDL rats, respectively, significantly higher in the BDL group than in
the other two groups, P < 0.001, n = 5-7. Direct bilirubin levels were also raised in the BDL group
(4.51 ± 0.16 mg/dl, n = 5), whereas the levels
were undetectable in most of the samples in the normal and sham groups. These rats were killed for islet isolation within the following 4 wk
(1-5 wk after operation).
Blood sampling for intraperitoneal glucose tolerance test and hormone assay. After rats fasted overnight, an intraperitoneal glucose tolerance test was carried out. Glucose (2 g/kg body wt) dissolved in saline was injected intraperitoneally. Blood glucose levels were measured by a compact glucose analyzer (MediSafe, Terumo, Tokyo, Japan) at 0 (before), 30, 60, and 120 min after injection. Serum samples for glucagon, GLP-1, and GIP assay were taken by cardiac puncture. Glucagon and GIP were measured by RIA, and active GLP-1 was measured by ELISA.
Islet isolation and insulin release. Pancreatic islets were isolated using collagenase digestion from normal, sham-operated, and BDL rats fed ad libitum. Insulin contents of isolated islets were not affected by the BDL or sham operation [106 ± 8, 85.2 ± 10, and 93 ± 6 ng/islet for nonoperated, sham-operated, and BDL rats, respectively, n = 6, not significant (NS)]. Groups of five size-matched islets were preincubated at 37°C for 1 h in 1 ml of HEPES-buffered Krebs-Ringer solution containing (in mM): 119 NaCl, 4.75 KCl, 5 NaHCO3, 2.54 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, and 20 HEPES (pH 7.4 with NaOH), with 5 mg/ml BSA and 3 mM glucose. After preincubation, isolated islets were incubated for 1 h under various conditions. The amount of insulin released in the media was measured by RIA with bovine insulin as a standard.
cAMP assay.
After 1 h of the preincubation described above, 10 size-matched
islets were incubated for 1 h at 37°C with 0.5 ml HEPES-buffered Krebs-Ringer solution and 5 mg/ml BSA, 1 mM IBMX (an inhibitor of
phosphodiesterase), and various substances as indicated. At the end of
the incubation, islets were transferred into 500 µl of 5% TCA.
Extraction was performed by two freeze-and-thaw cycles in liquid
N2 and homogenization, followed by boiling for 5 min. Islet
extracts were spun at 13,000 g for 5 min, and the
supernatant was retained and stored at 20°C until assayed. cAMP
assay was carried out using an ELISA kit. Without IBMX, cAMP levels in
some batches were undetectable under nonstimulated conditions, and changes by the insulinotropic hormones were not detected.
Immunoblot analysis. Approximately 200-400 islets were isolated and homogenized in 20 mM MOPS (pH 7.4 with NaOH), supplemented with 1 mM PMSF and 10 µM leupeptin. The homogenates were centrifuged at 13,000 g for 2 min at 4°C to avoid nuclei and cell debris. The supernatants were denatured by SDS sample buffer and boiled for 5 min. Proteins in the sample were separated by SDS-PAGE and transferred to PVDF membranes in 25 mM Tris, 192 mM glycine, and 20% (vol/vol) methanol (pH 9.2) at 200 mA for 1 h. After blocking with PBS containing 1% BSA, immunodetection was performed by a chemiluminescence kit (Amersham ECL, Amersham Pharmacia Biotech, Chalfont, Bucks, UK). Highly sensitive films (X-OMAT, Kodak, Rochester, NY) were then exposed to the transferred membranes and developed. Quantification of each band was carried out densitometrically using a computer program, NIH Image (version 1.59).
Statistical analysis. Statistical analyses for insulin secretion and cAMP contents were carried out by ANOVA. A P value <0.05 was considered significant. For immunoblotting, significance between two groups was carried out by Student's t-test.
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RESULTS |
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Glucose tolerance and insulin levels in bile duct-ligated rats.
Figure 1 depicts changes in plasma
glucose levels in normal, sham-operated, and BDL rats after
intraperitoneal injection of glucose (2 g/kg body wt). Fasting plasma
glucose levels were similar among the three groups. However, plasma
glucose levels at 30 min after glucose injection, but not at 60 or 120 min, were significantly higher in the BDL group than in the other two
groups (P < 0.05). Under fasted conditions, the serum
insulin level was higher in BDL rats than in the sham-operated ones
(201 ± 44 pg/ml, n = 6, and 41 ± 20 pg/ml,
n = 4, for BDL and sham-operated mice, respectively, P < 0.05), whereas the blood glucose levels were
similar (86 ± 6 mg/dl, n = 6, and 86 ± 4 mg/dl, n = 5, for BDL and sham-operated mice,
respectively, NS), suggesting the presence of insulin resistance in the
BDL rats. Insulin levels at 30 min after glucose loading were higher in
the BDL rats than in the control rats (1,103 ± 248 ng/dl for BDL,
n = 6, and 569 ± 154 ng/dl for sham-operated mice, n = 5). However, when expressed as an
insulinogenic index (changes of insulin concentrations divided by those
in blood glucose concentrations during the 30-min duration), the values
were similar (4.05 ± 0.90, n = 6, and 3.68 ± 1.13, n = 5, for BDL and sham-operated mice,
respectively, NS). When insulin resistance is taken into consideration,
these findings suggest a secretory defect of insulin in the BDL rats.
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Serum levels of incretins. Serum glucagon levels in normal and sham-operated rats were 181 ± 13 pg/ml (n = 5) and 180 ± 8 pg/ml (n = 6), respectively. However, the levels were significantly higher in BDL rats (381 ± 43 pg/ml, n = 7, P < 0.01). Serum levels of GLP-1 were 9.3 ± 1.6 pM in normal animals (n = 5). GLP-1 levels in sham-operated rats were similar (12.1 ± 1.7 pM, n = 6). The levels in BDL rats were raised (21.5 ± 7.3 pM, n = 6), although they did not reach statistical significance. The serum GIP levels were similar among the three groups (924 ± 4, 898 ± 22, and 910 ± 13 pg/ml for normal, sham-operated, and BDL rats, respectively; n = 5-8, NS).
Insulin release by glucose and GLP-1 from pancreatic islets
isolated from normal, sham-operated, and BDL rats.
Insulin release from pancreatic islets derived from normal,
sham-operated, and BDL rats (1-3 wk after operation) is
demonstrated in Fig. 2. Insulin release
by glucose (3-40 mM) was unchanged among these groups (Fig.
2A). Figure 2B shows dose dependency for GLP-1 to
potentiate insulin release induced by 10 mM glucose. In normal and
sham-operated groups, significant enhancement by GLP-1 was seen within
a nanomolar range. In contrast to glucose response, potentiation of
insulin release by GLP-1 disappeared in isolated islets from the BDL
rats.
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Hormonal regulation and pharmacological modification of insulin
release.
Figure 3 demonstrates glucose-induced
insulin release enhanced by glucagon, GLP-1, and GIP at 100 nM (Fig.
3A) and by forskolin (5 µM) and DBcAMP (2 mM) (Fig.
3B) and inhibited by epinephrine (1 µM) (Fig.
3A). Because such cAMP-raising agents require the copresence
of insulin secretagogues to enhance insulin release, we examined the
effects of those incretins and pharmacological substances with glucose
at 10 mM (180 mg/dl), the half-maximal concentration for insulin
release. Insulin release by 10 mM glucose was enhanced by these
insulinotropic hormones by 60-70% in the normal and sham groups,
but such effects disappeared in the BDL group. In contrast,
potentiation of insulin release by forskolin and DBcAMP was retained in
islets from the BDL rats. Epinephrine was equally effective in
inhibiting glucose-induced insulin release among these three groups. To
identify relevant component(s) in the bile, we examined effects of
cholic acid, taurocholic acid, deoxycholic acid, ursodeoxycholic acid,
and chenodeoxycholic acid and bilirubin on insulin release. None of
these bile acids at 100 µM affected insulin release by 10 mM glucose
with or without 100 nM GLP-1 (data not shown). Bilirubin, up to 10 mg/dl, also failed to inhibit insulin release by glucose with or
without GLP-1 (Fig. 4).
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cAMP production by pancreatic islets.
Increases of cAMP contents in pancreatic islets after 1 h of
incubation with glucagon, GLP-1, and GIP are demonstrated in Fig.
5. These three hormones stimulated cAMP
production in normal islets. Glucagon and GIP were also effective in
increasing cAMP contents in the sham-operated group, whereas GLP-1
failed to cause a statistically significant increase. None of these
hormones raised the islet cAMP contents in the BDL group.
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Immunoblotting of G protein subunits.
Figure 6 shows Western blotting of islet
extracts from sham-operated and BDL rats with specific antibodies
against trimeric G protein subunits. Immunoblotting with an antibody
against Gs demonstrated two specific bands,
Gs
L with an apparent molecular mass of 50 kDa and
Gs
S with 45 kDa (Fig. 6, left). Although not shown in Fig. 6, contents of the two Gs
subunits in
normal islet extracts were almost similar to those of sham-operated
rats (the mean values for sham-operated islets from 4 independent
experiments: 93.0 ± 4.9 and 90.7 ± 8.3% of those for the
normal group for Gs
L and Gs
S,
respectively). In BDL islets, however, both of the two subunits were
less well expressed (Gs
L: 63.4 ± 5.1%,
P < 0.005, and Gs
S: 62.7 ± 5.3%,
P < 0.05, respectively). Neither the
Gi
1/2-specific band nor the
Gi
3/o
-specific band was affected by the BDL operation (Fig. 6, middle and right).
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DISCUSSION |
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Trimeric G proteins are distributed in the pancreatic -cells
and are involved in the regulation of insulin release by the action of
various hormones and neurotransmitters (6). Insulinotropic hormones such as glucagon, GLP-1, and GIP potentiate insulin release via activation of Gs and resultant cAMP production. In the
present study, we found that potentiation of insulin release and
stimulation of cAMP production by these hormones were attenuated in the
BDL rats.
Impairment of cAMP production has been reported in neonatal streptozotocin-diabetic rats (4), but the underlying mechanism in our cholestatic model seems to be distinct from that in the diabetic model, because insulin release and cAMP production by glucose were not affected in the present study. Moreover, sensitivities to cAMP-producing hormones were retained in the streptozotocin-treated rats. In the present study, the defect is not due to impairment of adenylate cyclase or any part of secretory machinery distal to cAMP production, because insulin secretion by the adenylate cyclase activator forskolin or the membrane-permeable cAMP analog DBcAMP was not deteriorated in the BDL islets.
We found that lowered expression of G protein subunits occurs in the
BDL group; immunoblotting of subunits of the trimeric G proteins
demonstrated that the -subunits of Gs,
Gs
L and Gs
S, were less detected in the
BDL islets. It is interesting that loss of Gs-mediated
response has been reported in hepatocytes from cholestatic models.
Decreased cAMP production by glucagon and reduction of
Gs
S expression have also been demonstrated in
hepatocytes from BDL hamsters, although the other Gs
subunit was unchanged (3). In contrast, functional loss of
Gs
in rat hepatocytes has been reported during
cholestasis without changes in Gs
expression levels
(20). In that report, expression of Gi
subunits was decreased in BDL hepatocytes, whereas these subunits were
not influenced in the present study. Unaffected Gi
expression in BDL islets is compatible with results from the present
secretion experiments showing that inhibition of insulin release by
epinephrine, which suppresses insulin release via Gi and
Go (11), remained in BDL islets.
Obstructive jaundice has been reported to cause changes in plasma
concentrations of incretins; plasma glucagon levels are increased in
both patients and animals with bile duct obstruction (9,
12). Indeed, circulating glucagon levels were raised in the BDL
rats in the present study. Such was not the case for GLP-1 and GIP,
although some stimulation may be required, as suggested for elevated
levels of fat-induced GIP in cholestatic human subjects (24). It has been reported that glucagon injection into
cholestatic animals resulted in abnormal responses (9).
Because the incretin receptors are known to cause downregulation in
pancreatic -cells and other types of cells (7, 16, 22,
23), it is possible that impairment of insulin release under
cholestasis is, at least in part, due to desensitization of these
receptors. Heterozygous disruption of the GLP-1 receptor gene resulted
in a pattern of plasma glucose profiles similar to that for the BDL
animals: 1) no difference was observed in fasting glucose
levels, and 2) significant increases in the glucose levels
appeared only 30 min after glucose loading (21), although
the administration route was different, intraperitoneally for BDL rats
in the present study vs. orally for the GLP-1 receptor knockout mice.
Several bile acids are known to be increased under cholestasis (14), and some of them are suggested to impair cAMP formation in hamster hepatocytes, human fibroblasts, and endothelial cells (1, 2). We therefore examined effects of various bile acids and bilirubin on insulin secretion by glucose and GLP-1. However, we could not find any effects of bile acids in our attempt. Bilirubin at a high concentration (10 mg/dl) did influence insulin secretion, but inhibition of GLP-1 potentiation did not take place. Biliary component(s) relevant to such alteration in islet functions still remain(s) unidentified, although we cannot eliminate a possibility that these components may exhibit some effects after prolonged exposure.
Impairment of glucose tolerance associated with obstructive jaundice is a serious complication and a decisive factor for prognosis of the patients. Previous publications and the present study demonstrate that attenuated secretory response to Gs-mediated hormones occurs under cholestasis in two major organs for glucose homeostasis, the liver and the pancreatic islets. We also suggest that a variety of systematic disorders may result from disturbance of G protein-mediated signal transduction in patients with obstructive jaundice.
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ACKNOWLEDGEMENTS |
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We thank Drs. M. Komatsu (Shinshu University), M. Ikeda, and M. Miyao (Nagoya University School of Medicine) for their helpful comments.
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FOOTNOTES |
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This work was supported in part by Grants-in-Aid for Research from the Ministry of Education, Science, Sports and Culture, Japan.
Address for reprint requests and other correspondence: I. Niki, Dept. of Pharmacology, Nagoya Univ. School of Medicine, 65 Tsuruma-cho, Nagoya 466-8550, Japan (E-mail: iniki{at}med.nagoya-u.ac.jp).
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. Section 1734 solely to indicate this fact.
Received 29 March 2000; accepted in final form 14 September 2000.
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