1 Department of Internal Medicine, 2 Institute for Advanced Medical Research, and 3 Department of Pathology, Keio University School of Medicine, Tokyo 160-8582; and 4 Department of Internal Medicine, Hamamatsu Red Cross Hospital, Hamamatsu 430-0907, Japan
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ABSTRACT |
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Although peroxisome proliferator-activated
receptor (PPAR) agonists ameliorate insulin resistance, they
sometimes cause body weight gain, and the effect of PPAR agonists on
insulin secretion is unclear. We evaluated the effects of combination
therapy with a PPAR
agonist, pioglitazone, and a PPAR
agonist,
bezafibrate, and a dual agonist, KRP-297, for 4 wk in male C57BL/6J
mice and db/db mice, and we investigated glucose-stimulated
insulin secretion (GSIS) by in situ pancreatic perfusion. Body weight
gain in db/db mice was less with KRP-297 treatment than with
pioglitazone or pioglitazone + bezafibrate treatment. Plasma glucose,
insulin, triglyceride, and nonesterified fatty acid levels were
elevated in untreated db/db mice compared with untreated
C57BL/6J mice, and these parameters were significantly ameliorated in
the PPAR
agonist-treated groups. Also, PPAR
agonists ameliorated
the diminished GSIS and insulin content, and they preserved insulin and
GLUT2 staining in db/db mice. GSIS was further increased by
PPAR
and -
agonists. We conclude that combination therapy with
PPAR
and PPAR
agonists may be more useful with respect to body
weight and pancreatic GSIS in type 2 diabetes with obesity.
peroxisome proliferator-activated receptor; glucose-stimulated insulin secretion; glucolipotoxicity; insulin resistance; type 2 diabetes with obesity
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INTRODUCTION |
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PEROXISOME
PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) agonists have been used
for the treatment of type 2 diabetic patients, especially those with
obesity, all over the world. They ameliorate insulin resistance of
peripheral tissues, such as skeletal muscle, liver, and adipocytes, by
various suggested mechanisms. Although some literature has suggested
effects of PPAR
agonists on the pancreas (13, 32), only
a few studies have investigated this issue (23, 29, 30).
Because the expression of PPAR
is confirmed not only in rodent
(1) but also in human islets (5), an effect
of PPAR
agonists on the pancreas has been suggested.
On the other hand, fibrates are PPAR agonists and have been used for
patients with dyslipidemia. Some literature has reported that PPAR
agonists also ameliorated insulin resistance (6, 7, 14, 19, 24,
28, 36), but the effect on insulin secretion is unclear. Dual
agonists of PPAR
and -
, KRP-297 (12, 25, 26) and
JTT-501 (34), have been developed, and their utility for
diabetes and/or metabolic syndrome has been suggested. However, studies
of combination therapy with a PPAR
agonist and a PPAR
agonist are
rare (2, 21), and their effect on insulin secretion has
not been reported.
We hypothesized that combination therapy with PPAR and -
agonists
would be useful for reducing lipotoxicity (10, 20, 37) in
type 2 diabetes with obesity by augmenting the lipid-lowering effects.
We used the PPAR
agonist pioglitazone (PIO), combination therapy
with the PPAR
agonist PIO and the PPAR
agonist bezabibrate (P + B), and a dual agonist of PPAR
and -
, KRP-297, in male C57BL/6J
mice and male db/db mice as a model of type 2 diabetes with
obesity. We measured body weight, food and water intake, and metabolic
parameters, and we investigated the effects on the pancreas by
determining GSIS with in situ pancreatic perfusion and also by
histopathological examination.
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MATERIALS AND METHODS |
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Materials. Pioglitazone, bezafibrate, and KRP-297 were donated by Takeda (Osaka, Japan), Kissei (Matsumoto, Japan), and Kyorin Pharmaceuticals (Tokyo, Japan), respectively. Normal chow, CE-2, was purchased from Japan Clea (Tokyo, Japan). Pioglitazone, P + B, and KRP-297 were each blended with CE-2 by use of 0.1% carboxymethylcellulose.
Animals.
Five-week-old male C57BL/6J mice and male db/db mice were
purchased from Japan Clea. Our institution's guidelines for the care
and use of laboratory animals were followed. Both mouse strains were
fed CE-2 control chow and water ad libitum for 1 wk and each of the
following drug-blended chow and water ad libitum for the following 4 wk: PIO [C57BL/6J: 0.02% (wt/wt), 31.3 ± 0.3 mg · kg1 · day
1;
db/db: 0.02% (wt/wt), 34.2 ± 0.4 mg · kg
1 · day
1],
P + B [C57BL/6J: 0.02% (wt/wt), 29.2 ± 0.5 mg · kg
1 · day
1;
db/db: 0.02% (wt/wt), 33.3 ± 0.4 mg · kg
1 · day
1] + [C57BL/6J: 0.06% (wt/wt), 97.3 ± 1.5 mg · kg
1 · day
1;
db/db: 0.07% (wt/wt) 111.0 ± 1.5 mg · kg
1 · day
1],
and KRP-297 [C57BL/6J: 0.02% (wt/wt), 30.2 ± 0.3 mg · kg
1 · day
1;
db/db: 0.02% (wt/wt), 32.2 ± 0.4 mg · kg
1 · day
1].
Food intake, water intake, and body weight of all mice were measured in the morning 3 to 4 times/wk. Mice were fasted overnight and
underwent operation for in situ pancreatic perfusion.
Measurement of metabolic parameters in plasma. Blood from the retroorbital sinus of 10-wk-old mice in a nonfasting state was collected into hematocrit tubes coated with EDTA. Plasma glucose and triglycerides were determined with a Fuji Dry-Chem 5500 (Fuji Film, Tokyo, Japan). Plasma nonesterified fatty acid (NEFA) concentration was determined by the NEFA-C test (Wako Pure Chemical Industries, Osaka, Japan). Plasma insulin concentration was determined by enzyme immunoassay (EIA; Morinaga Institute of Biological Science, Yokohama, Japan).
Pancreatic insulin content. Each pancreatic specimen was homogenized in 1.8 ml of acid ethanol. The homogenates were stored at 4°C for 48 h and then centrifuged at 10,000 rpm for 10 min at 4°C. The supernatants were pooled, and the pellets were then resuspended in 0.2 ml of acid ethanol. After centrifugation, the supernatants were diluted 1:10,000 in 0.1 M PBS containing 0.25% BSA. Insulin concentration was determined by EIA.
In situ pancreatic perfusion.
The mice were anesthetized with 50 mg/kg pentobarbital sodium after an
overnight fast. The celiac artery and portal vein were cannulated after
other vessels had been ligated. Nonrecirculating perfusion was begun at
a constant flow rate of 0.5 ml/min. The perfusion medium consisted of
Krebs-Ringer bicarbonate buffer containing 3.0% (wt/vol) dextran T-40
(Pharmacia, Uppsala, Sweden), 1.0% (wt/vol) BSA (fraction V, RIA
grade; Sigma Chemical, St. Louis, MO), and 20 mM HEPES. A 95%
O2-5% CO2 gas mixture was bubbled through the
perfusate, and pH was maintained between 7.35 and 7.45. The pancreatic
venous effluent was collected into tubes via a catheter in the portal
vein at 2-min intervals, frozen immediately, and stored at 20°C for
subsequent EIA. To achieve postoperative equilibration, the pancreas
was perfused for 15 min with a buffer containing the glucose
concentration of the initial 10-min experimental period (5.6 mM).
Thereafter, insulin response to a high-glucose concentration (16.7 mM)
was examined for 20 min, and glucose concentration was then returned to
5.6 mM for another 20 min.
Histopathological examination. Pancreata from mice in all groups that were not operated on for in situ pancreatic perfusion were fixed in 35-38% Formalin for histopathological studies. The pancreata were embedded in paraffin, sectioned, and then stained with hematoxylin and eosin (H + E). Immunohistochemical studies were also performed using anti-human insulin guinea pig antibodies (Oriental Yeast, Osaka, Japan) and rabbit anti-GLUT2 polyclonal antibody (Chemicon International, Temecula, CA).
Statistical analyses. All results were expressed as means ± SE. Statistical analyses were performed with the Statview program (version 5.0-J, SAS Institute, Cary, NC). Analysis of variance (ANOVA), followed by a post hoc Bonferroni-Dunn multiple comparison test, was used to evaluate differences among groups. A P value <0.05 was considered statistically significant.
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RESULTS |
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Body weight change, total food intake, and total water intake.
The body weight of animals in PPAR agonist-treated groups
increased more than that of animals in the untreated group in both mouse strains (Table 1). Body weight gain
in the KRP-297-treated group was less than that in other
treated groups in db/db mice, but not in C57BL/6J mice.
Total food intake in the PPAR
agonist-treated groups was also
significantly greater than that in the untreated group in C57BL/6J
mice. On the contrary, total food intake of the KRP-297-treated group
was the smallest in db/db mice. The PPAR
agonist-treated
groups in C57BL/6J mice showed a mild increase in total water intake,
whereas the untreated group in db/db mice showed a marked
increase.
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Metabolic parameters in plasma.
Plasma glucose, insulin, triglyceride, and NEFA levels were elevated in
untreated db/db mice compared with untreated C57BL/6J mice,
and these parameters were significantly ameliorated in the PPAR
agonist-treated groups (Fig. 1).
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Pancreatic insulin content.
Pancreatic insulin content of untreated db/db mice was
almost completely diminished compared with untreated C57BL/6J mice (Fig. 2). Pancreatic insulin content of
the PIO- and P + B-treated db/db mice was
ameliorated compared with untreated db/db mice, although
these differences were not statistically significant (P = 0.051 by ANOVA). The pancreatic
insulin content of the KRP-297-treated db/db mice was almost
the same as that of untreated C57BL/6J mice.
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In situ pancreatic perfusion.
There was no difference in GSIS among the four groups of C57BL/6J mice
(Fig. 3A). In db/db
mice (Fig. 3B), whereas GSIS in the untreated group was
diminished compared with that in C57BL/6J mice, that in the PPAR
agonist-treated groups was preserved compared with that in the
untreated group. GSIS in the PIO-treated group showed no significant
difference from that in the untreated group in db/db mice,
whereas GSIS in both the P + B- and the KRP-297-treated groups was significantly increased (Table
2).
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Histopathological findings.
The islets of untreated db/db mice showed hyperplastic
changes (Fig. 4). Insulin in these islets
of untreated db/db mice was extremely reduced, and the
staining pattern was scattered. Islets in the PIO- and P + B-treated
db/db mice showed hyperplasia and almost normal staining of
insulin. In islets of the KRP-297-treated db/db mice, the
hyperplasia was improved, and the staining of insulin was almost
normal. The results of the insulin staining were consistent with those
of pancreatic insulin content. GLUT2 was expressed on the -cell
membrane of normal C57BL/6J mice. Although GLUT2 expression was not
detected in untreated db/db mice, it was preserved in
PPAR
agonist-treated db/db mice as well as in
C57BL/6J mice. However, there was no significant difference in
GLUT2 expression among the PIO-, P + B-, and KRP-297-treated groups of the db/db mice.
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DISCUSSION |
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PPAR agonists are well suited for the treatment of type 2 diabetic patients with obesity who have severe insulin resistance. However, because PPAR
is a master regulator of adipocytes
(22), its activation may induce increased fat mass and
obesity. The degree of body weight gain is dependent on different
PPAR
agonists (18). Also, body weight gain by PPAR
agonists is reported not only in rodents (11, 27) but also
in humans (16, 33), and it is speculated to be due to
adipogenesis by the drug effect (8, 31, 35) as well as
increased food intake (4, 40, 41). However, the effect of
PPAR agonists on insulin secretion is unclear.
In the present study, body weight in the PPAR agonist-treated groups
increased significantly with increased food intake in C57BL/6J mice.
However, weight gain in db/db mice was less with KRP-297
treatment compared with PIO or P + B treatment. We speculate that this
is due to the effects of a dual agonist that enhances lipid catabolism
and reduces fat mass by PPAR
activation, as previously suggested (2, 5a). We consider that KRP-297 ameliorated obesity most, so that
pancreatic insulin content of the KRP-297-treated group was almost the
same as that in normal mice (26), and the islets of the
KRP-297-treated group were not hyperplastic in contrast to those of the
PIO- or P + B-treated groups.
Also, we have shown in this study that PPAR agonists normalized the
elevated plasma glucose, insulin, triglyceride, and NEFA levels in
db/db mice. However, we did not find an additional effect of
a PPAR
agonist on these parameters. Plasma glucose level in the
KRP-297-treated group was the lowest in db/db mice, probably because of the lowest food consumption in addition to the drug effect.
GSIS in C57BL/6J mice showed a good response and was not changed by
4-wk treatment with PPAR and/or PPAR
agonists. In untreated db/db mice, on the other hand, there was no GSIS response,
due to insulin shortage resulting from severe insulin resistance, glucotoxicity, and lipotoxicity. Plasma insulin level in untreated db/db mice at this age, however, was higher than that in any
other group; the islets of untreated db/db mice secreted
insulin against an extremely high plasma glucose level. The stimulatory
glucose level of the perfusate was 16.7 mM in our experiments, which
was lower than the plasma level of untreated db/db mice.
Therefore, we speculate that the islets of untreated db/db
mice might be desensitized to glucose and thus did not show a GSIS
response at 16.7 mM. However, we have shown reduced insulin staining
with hyperplasia of islets, and pancreatic insulin content was barely detectable in untreated db/db mice, both suggesting insulin shortage.
In the present study, GSIS in db/db mice was preserved by
PPAR agonist treatment. There was amelioration of plasma glucose, insulin, triglycerides, and NEFA levels in these groups. We also observed preserved insulin staining in the islets of the PPAR
agonist-treated groups, and we concluded that the insulin-saving effects of PPAR
agonists were mediated by ameliorating insulin resistance. De Souza et al. (3) also suggested
amelioration of insulin resistance in Zucker diabetic fatty (ZDF) rats.
These authors showed that there was no direct effect of pioglitazone on
the pancreas in perifusion experiments. Although P + B and KRP-297 treatments in our study significantly increased GSIS in db/db mice, it is unclear why GSIS was increased by
the addition of a PPAR
agonist. Because there was no difference in
plasma glucose, insulin, triglyceride, and NEFA levels among the
PIO-, P + B-, and KRP-297-treated groups, increased insulin
secretion in the P + B- and KRP-297-treated groups might not be
through amelioration of glucolipotoxicity but through increased
glucose sensitivity in pancreatic
-cells.
Lipotoxicity may cause -cell abnormalities, loss of GSIS and GLUT2,
and triglyceride accumulation (37, 38). Higa et al. (9), using ZDF rats, reported that troglitazone prevented
these features of lipotoxicity. Because the peroxisome proliferator response element (PPRE) was identified in the rat GLUT2 gene (promoter) (17), PPAR
and/or PPAR
agonists may affect PPRE in
the GLUT2 gene in pancreatic
-cells. Wang et al. (39)
suggested that PPAR
might be one of the transcription factors
involved in the direct upregulation of GLUT2 in normal rat islets.
Furthermore, Zhou et al. (42) reported that expression of
PPAR
was suppressed in ZDF rat islets. In the present study, GSIS
was increased by addition of a PPAR
agonist, and we evaluated the
staining of GLUT2, which is associated with glucose sensing and GSIS.
We showed that treatment with PPAR
agonist preserved GLUT2 in
db/db mice. However, it was difficult to identify
differences in GLUT2 staining among the PIO-, P + B-, and
KRP-297-treated groups. It is possible that a PPAR
agonist reduced
the islet triglyceride content in db/db mice, although we
were not able to examine this. Further studies will be needed to
clarify the direct effect of PPAR
on islet function.
To summarize, body weight in PPAR agonist-treated groups increased
significantly with increased food intake in C57BL/6J mice. In contrast,
weight gain in db/db mice was less with KRP-297 treatment compared with PIO- or P + B treatment. PPAR
agonists ameliorated the
diminished GSIS by improving insulin sensitivity in db/db mice, and GSIS was further increased by the combined PPAR
and PPAR
agonists. We conclude that combination therapy with PPAR
and
PPAR
agonists may be more useful than PPAR
alone with
respect to body weight gain and pancreatic GSIS in type 2 diabetes with obesity.
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FOOTNOTES |
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Address for reprint requests and other correspondence: K. Yajima, Dept. of Internal Medicine, Keio Univ. School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan (E-mail: n62383{at}sc.itc.keio.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.
10.1152/ajpendo.00149.2002
Received 8 April 2002; accepted in final form 10 December 2002.
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