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Department of Endocrinology and Chemical Biology, Merck Research Laboratories, Rahway, New Jersey 07065
Address all correspondence and requests for reprints to: Dr. Mathias Strowski, Merck Research Laboratories, Department of Endocrinology and Chemical Biology, RY80T-126, P.O. Box 2000, Rahway, New Jersey 07065. E-mail: mathias_strowski{at}merck.com
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Abstract |
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There was no difference in basal glucagon and insulin secretion between islets isolated from SSTR2KO and WT mice; however, potassium/arginine-stimulated glucagon secretion was approximately 2-fold higher in islets isolated from SSTR2KO mice. Neither SST nor any SSTR-selective agonist inhibited basal glucagon or insulin release. SST-14 potently inhibited stimulated glucagon secretion in islets from WT mice and much less effectively in islets from SSTR2KO mice. The SSTR2 selective analog L-779,976 inhibited glucagon secretion in islets from WT, but was inactive in islets from SSTR2KO mice. L-817,818, an SSTR5 selective analog, slightly reduced glucagon release in both animal groups, whereas SSTR1, -3, and -4 selective analogs were inactive. SST and L-817,818 inhibited glucose stimulated insulin release in islets from WT and SSTR2KO mice. L-779,976 much less potently reduced insulin secretion from WT islets.
In conclusion, our data demonstrate that SST inhibition of glucagon release in mouse islets is primarily mediated via SSTR2, whereas insulin secretion is regulated primarily via SSTR5.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There are two major physiological ligands for SSTRs: SST-14 and SST-28,
consisting of 14 and 28 amino acids, respectively. Radioligand binding
studies have shown that SST-14 and SST-28 interact with SSTR1–4 with
similar affinities, whereas SSTR5 preferentially binds SST-28 (13, 25).
Both forms of SST play an important role in the regulation of glucagon
and insulin release from the endocrine pancreas. SST-14 is considered
to be a more potent inhibitor of glucagon secretion from the 
-cells,
whereas SST-28 predominantly inhibits insulin secretion from the
ß-cells (26, 27, 28). Because of the different potencies of SST-14 and
SST-28 at the cloned receptors, it was suggested that the
inhibition of insulin and glucagon release is mediated by different
SSTRs (27).
As SST-14 and SST-28 bind with high affinity to all five SSTRs, it is not possible to distinguish between individual SSTRs using these peptides. Therefore, a number of SSTR selective agonists with distinct affinity profiles have been developed and used for pharmacological characterization of the individual SSTRs.
Our current understanding of the roles of SSTRs in the regulation of insulin and glucagon secretion derives from studies using SSTR selective peptide analogs. In vivo studies have demonstrated that SSTR5, but not SSTR2, selective SST analogs inhibit insulin secretion from rat endocrine islets (29). Recently, an in vitro study of mouse pancreatic islets showed that SSTR5, but not SSTR2, selective peptide analogs inhibit glucose-induced insulin release (30).
The development of SSTR-specific antibodies has allowed
investigation of the morphological distribution of SSTRs in the
endocrine pancreas (31). Thus, immunohistochemical studies of rat
endocrine islets have demonstrated that SSTR2 is expressed on
-cells, whereas ß-cells show only weak SSTR2 immunoreactivity
(32), providing the morphological correlate to the pharmacological
findings. Recently, a study of human pancreas demonstrated
immunostaining of ß- as well as -cells with SSTR2 antibody (33),
suggesting that species differences may exist.
Despite a number of pharmacological studies, the physiology of SSTRs in the endocrine islets of the pancreas has not been entirely defined, primarily due to the lack of the highly selective receptor ligands. An alternative approach for evaluation of the role of SSTRs is inactivation (knocking out) of a gene encoding a particular receptor subtype in an animal.
In the present study we used the SSTR2KO mice, developed in our laboratories (34), in combination with novel subtype-selective nonpeptidyl SST analogs (36) to evaluate the roles of SSTRs in regulation of insulin and glucagon secretion.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MEM, penicillin, and streptomycin
were obtained from Life Technologies, Inc. (Grand Island,
NY). RIA kits for insulin and glucagon were purchased from Linco Research, Inc. (St. Louis, MO). The SSTR selective compounds,
L-779,976, L-817,818, L-797,591, L-796,778, and L-803,087, were
provided by Dr. S. P. Rohrer (Merck, Rahway, NJ). The
identification and characterization of these compounds were previously
reported (35).
Animals
Mice deficient in SSTR2 [homozygous (-/-) SSTR2KO] were
generated by gene targeting in mouse embryonic stem cells as previously
described (34). Corresponding wild-type adult C57BL/129 mice (20–35 g,
4–8 months of age) were used as controls. Mice were maintained under
controlled conditions at 25 C, with food and water available ad
libitum. All experimental protocols were approved by the Rahway
Institutional Animal Care and Use Committee.
In vitro insulin/glucagon secretion
Mice were euthanized with CO2, and blood
was collected via intracardiac puncture. Islets were isolated by
injection of 4 ml ice-cold collagenase solution (4 mg/ml GBSS
supplemented with 1% BSA) into the bile-pancreatic duct (36). The
distended pancreas was removed, trimmed from adjacent tissues, and
incubated under static conditions for 15 min at 37 C. The collagenase
action was stopped by the addition of 50 ml ice-cold GBSS. The digested
tissue was washed three times with GBSS to remove collagenase, and
islets were hand picked under a stereomicroscope. Islets were
maintained for 24 h in tissue culture medium RPMI 1640 containing
11 mM glucose, 10% FBS, penicillin (100 U/ml), and
streptomycin (0.1 mg/ml) at 37 C and 5% CO2.
Secretion experiments were carried out on islets that showed a round,
smooth surface and no attached exocrine or connective tissue. There was
no morphological difference between islets from WT and SSTR2KO mice as
judged by inspecting the islets under the stereomicroscope. Staining
with methylene blue indicated that approximately 95% of the isolated
islets survived the 24-h incubation period in RPMI 1640 medium and
GBSS. Approximately 80–160 islets/pancreas were isolated with no
obvious quantitative differences between islets isolated from SSTR2KO
and WT animals. Batch incubations were performed in GBSS (containing
5.5 mM glucose) supplemented with 0.2% BSA and
antibiotics. Islets were washed three times in GBSS and incubated in
GBSS at 37 C for a 45-min equilibration period. The 45-min
preincubation followed by repeated washing (37) was sufficient to
reverse the effects of the hyperglycemic RPMI 1640 on insulin secretion
as assessed by the low basal level and the fold increase in insulin
secretion during subsequent stimulation with 20 mM
D-glucose. In addition, there was no indication for the
presence of significant somatostatin levels in the serum-containing
RPMI 1640 based on the short half-life of somatostatin in serum (38, 39) and its potent inhibitory effects on insulin and glucagon
secretion. After the 45-min preincubation, islets were washed once with
GBSS and transferred into a dish containing 4 ml GBSS. Islets in
batches of 40 were then preincubated with somatostatin or analogs for
45 min. Islets were divided by size into three groups: small, medium,
and large. Three islets from each group were combined into individual
wells. Nine islets per 1 ml GBSS were divided into quadruplicates and
incubated for an additional 2 h with 20 mM
L-arginine plus 20 mM KCl or 20 mM
D-glucose in the continued presence of SST or analogs.
Basal glucagon and insulin secretions were determined from supernatants
of islets incubated for 2 h without stimulators and SST or
analogs. The incubation was terminated by brief centrifugation at 1000
x g. Supernatants were collected and assayed immediately
for insulin and glucagon content by double antibody RIA.
Determination of glucagon and insulin contents in endocrine
islets
Animals were fasted overnight, with water available ad
libitum before experiments. Isolated islets in batches of 40 were
cultivated for 24 h in RPMI 1640. Islets were washed three times
in GBSS and preincubated for 45 min at 37 C, followed by an additional
wash in GBSS and subsequent incubation for an additional 45 min at 37
C. Islets were divided into quadruplicates (9 islets/1 ml GBSS) and
incubated for an additional 2 h at 37 C. Incubation medium was
carefully removed, and islets were extracted overnight at -20 C in 1ml
acid-ethanol (0.2 N HCl in 70% ethanol) (40).
The extract was centrifuged 12,000 x g at 4 C, and the
hormone content of the supernatant was measured by RIA.
Data analysis
All data represent the mean ± SEM and were
obtained from four to six independent experiments unless otherwise
stated. Data are presented as the percentage of maximal hormone release
induced with 20 mM L-arginine plus 20
mM KCl or 20 mM D-glucose unless
otherwise stated. Statistical comparisons between means within a group
were made using Student’s paired t test. Comparisons
between means of different groups were analyzed by one-way ANOVA with a
Neuman-Keuls multiple comparison posttest. Statistical comparisons and
nonlinear regression analysis were performed with Prism 2.01
(GraphPad Software, Inc., San Diego, CA). Statistical
significance was defined as P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The estimated secretion rate was 0.8
± 0.07 pg/h·islet from WT mice and 0.63 ± 0.06 pg/h·islet
from SSTR2KO mice. Neither SST nor nonpeptidyl agonists altered the
basal glucagon secretion (data not shown). Potassium/arginine (P/A) at
a concentration of 20 mM stimulated glucagon secretion from
islets isolated from either WT or SSTR2KO mice (Fig. 1). As shown in
Fig. 1, 20 mM P/A-stimulated glucagon secretion in islets
isolated from SSTR2KO animals after 2 h of incubation was 326
± 32 pg (18.1 ± 1.8 pg/h·islet), approximately 2-fold higher
than that in islets from WT animals (169 ± 17 pg; 9.39 ±
0.9 pg/h·islet). Islets isolated from SSTR2KO mice showed an
increased glucagon content; however, intracellular glucagon content was
not statistically different compared with that in WT islets (SSTR2KO,
1.87 ± 0.42 ng/islet; WT, 1.27 ± 0.15 ng/islet;
P > 0.05).
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). SST-14 inhibited glucagon release in
islets isolated from SSTR2KO mice by only 27 ± 4% (Fig. 2).
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). Compared with SST-14,
SST-28 appeared less effective in reducing stimulated glucagon release;
however, the difference was not statistically significant
(IC50 =1.2 nM; P >
0.05 vs. SST-14). As shown in Fig. 2, the inhibitory potency
of SST-28 on glucagon secretion from SSTR2KO islets was markedly
reduced (100 nM SST-28, 36 ± 9%
inhibition) compared with its effects on WT islets (100
nM SST-28, 73 ± 4% inhibition). The
reduction of SST-14 and SST-28 effects on glucagon release in SSTR2KO
islets indicates that these endogenous peptides act predominantly via
SSTR2. To confirm that the inhibition of glucagon release is mediated by SSTR2, we investigated effects of a novel nonpeptidyl SSTR2 selective compound, L-779,976 (35). A previous study demonstrated that L-779,976 displays over 10,000-fold selectivity to the human SSTR2 over SSTR1, -3, -4, and -5 (35). L-779,976 potently inhibits rat GH release in vivo and mouse glucagon secretion in vitro (35).
In our study, L-779,976 mimicked the inhibitory action of SST on
P/A-stimulated glucagon release from WT islets in a
concentration-dependent manner, with an IC50
value of 1.2 nM (Fig. 3A). The
maximal inhibitory effect (72 ± 4%) was observed at the highest
dose of 100 nM (Fig. 3A). L-779,976 did not inhibit
P/A-stimulated glucagon secretion from SSTR2KO islets (Fig. 3A). This
finding provides convincing evidence that SST inhibits glucagon
secretion in mouse pancreatic islets via SSTR2.
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L-817,818 displays highest selectivity for the human SSTR5 (35). In radioligand binding assays, L-817,818 was at least 100-fold selective for human SSTR5 compared with human SSTR2, -3, and -4, and 10-fold selective compared with human SSTR1 (35).
In the present study, L-817,818 was markedly less potent than SST-14,
SST-28, or L-779,976 at reducing P/A-stimulated glucagon release (Fig. 3B). L-817,818 reduced glucagon secretion in islets from WT animals by
26 ± 5% at 100 nM, but was inactive at lower
concentrations (Fig. 3B). Similar effects were observed in SSTR2KO
islets (Fig. 3B).
Thus, it appears that SSTR5 may play a role in regulating glucagon release from the murine pancreas, an idea reinforced by our results with WT and SSTR2KO islets and the SSTR5 selective compound L-817,818.
To determine whether other SSTRs are involved in the regulation of glucagon secretion, we studied the effects of the SSTR1, -3, and -4 selective SST analogs, L-797,591, L-796,778, and L-803,087 (35). None of the nonpeptidyl SST agonists showed any effect on P/A-stimulated glucagon secretion in islets isolated from WT or SSTR2KO animals (data not shown), suggesting that murine glucagon secretion is predominantly controlled by SSTR2.
Effects of SST and analogs on insulin secretion
We next investigated which SSTR regulates insulin secretion in the
mouse pancreas. Islets isolated from WT mice showed insulin content
comparable to that in islets from SSTR2KO animals (WT, 76 ± 5.1
ng/islet; SSTR2KO, 87 ± 5.3 ng/islet; P > 0.05).
Basal insulin secretion from WT and SSTR2KO islets was similar after
2 h of incubation (WT, 29 ± 11 pg/h·islet; SSTR2KO,
42 ± 13 pg/h·islet; P > 0.05).
Basal insulin secretion was unaffected by either SST or the nonpeptidyl agonists after 2-h incubation (data not shown). We therefore investigated the effects of SST and analogs on D-glucose (20 mM)-stimulated insulin secretion. A 2-h incubation with 20 mM D-glucose led to an approximately 5-fold increase in insulin secretion from WT and SSTR2KO islets (WT, 150 ± 39 pg/h·islet; SSTR2KO, 210 ± 57 pg/h·islet; P > 0.05).
As shown in Fig. 4A, SST-28 inhibited
glucose-stimulated insulin secretion from both WT and SSTR2KO islets.
Maximal inhibition (55 ± 5%) of insulin release was observed at
the highest tested concentration of 100 nM SST-28 (Fig. 4A). SST-14 inhibited glucose-induced insulin secretion with a similar
potency as SST-28 in islets from WT and SSTR2KO mice (Fig. 4B). SST-14
and SST-28 also displayed similar effects on P/A (20
mM)-stimulated insulin secretion (data not shown).
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). However, L-779,976 did not statistically
significant inhibit insulin secretion from SSTR2KO islets (Fig. 5A).
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), an effect that was similar to that observed
in SSTR2KO islets (Fig. 5B). Thus, our insulin secretion data suggest
that SSTR5 is primarily responsible for SST inhibition of insulin
release in mouse endocrine islets.
Taken together our data support the current hypothesis that SST
regulates insulin secretion from ß-cells via a different SSTR than
the subtype that controls glucagon secretion from -cells. Our
results with SSTR2KO mice and receptor subtype selective SST agonists
show that SSTR2 primarily mediates SST inhibition of glucagon, whereas
SSTR5 is the principal subtype involved in the SST inhibition of
insulin secretion.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-cells, whereas it is barely detectable on ß-cells (32),
suggesting a selective role for this receptor in regulating glucagon
release. An in vivo study of the rat using SSTR2 selective
peptidergic analogs implicated a role for SSTR2 in inhibition of
glucagon release from pancreatic islets (29). Our in vitro study, using a combination of islets from SSTR2 knockout animals and subtype selective SST analogs, demonstrates that SSTR2 mediates the inhibitory action of SST-14 on glucagon release in murine pancreatic islets. These findings are in concordance with previous pharmacological and morphological findings in rodents; however, earlier studies have relied on peptidyl analogs of SST-14, which may lack the desired specificity at a given receptor subtype (25, 44).
Several lines of evidence in our study support the idea that SSTR2 controls glucagon secretion in mouse endocrine islets. First, SST-14 potently inhibited glucagon release in islets isolated from WT animals up to 85%, whereas the effect was reduced to 27% in islets lacking SSTR2. Similarly, SST-28 decreased glucagon release in islets isolated from WT mice, but was much less potent in islets from SSTR2KO animals. The inhibitory role of SSTR2 on glucagon release in rodents is based merely on an in vivo study (29). It was demonstrated in rat pancreas that infusion of the SSTR2 selective peptide analog NC8–12 inhibited glucagon release (29). However, the inhibition of glucagon release did not correlate with the predicted potency that was observed in studies with cells heterologously expressing SSTR2. Moreover, NC8–12, although with reduced potency, also inhibited insulin release (29). In the same study another peptidyl analog, DC25–100, with approximately 10-fold higher affinity for SSTR5 than SSTR2, showed more potent inhibition of glucagon release than NC8–12 (29). Thus, it was not entirely clear from this study which receptor subtype plays a major role in the regulation of glucagon and insulin release.
In our study, however, SST potently inhibited glucagon release in islets isolated from WT animals, but its potency on glucagon secretion from SSTR2KO islets was dramatically reduced, indicating that SSTR2 plays the major role in this process. In addition, our data for SSTR2KO animals provide the first evidence that SSTR2 expressed on glucagon-producing cells mediates inhibition of glucagon release by the endogenous peptides SST-14 and SST-28.
An additional finding in our study was that P/A-stimulated glucagon
secretion in SSTR2KO islets was higher than that in WT islets. As
endocrine islets of the pancreas contain SST-14-producing 
-cells, we
believe that this difference could be explained by the inhibitory
action of intrapancreatic secreted SST (45) via SSTR2 in WT islets. In
SSTR2KO islets, however, the inhibitory effect of intrapancreatic SST
on stimulated glucagon secretion is abolished.
The structural organization of the rat pancreatic islets with
glucagon-producing -cells in proximity to somatostatin-producing
-cells (46, 47, 48) makes a paracrine inhibitory action of SST via SSTR2
likely. However, as static incubation leads to accumulation of all
secreted hormones in the incubation medium, more detailed studies,
e.g. perfusion or perifusion of endocrine islets, would
provide additional support for the hypothesis of paracrine action of
SST on -cells via SSTR2.
Recently, nonpeptidyl SST agonists with potent selectivity for all five human SSTRs have been developed (35, 49). However, their selectivity for rodent SSTRs has not yet been demonstrated. Recent studies on cells stably transfected with mouse SSTR2 show similar selectivity of SSTR2 and SSTR5 agonists as reported for human SSTRs (Strowski, M. Z., A. D. Blake, and J. M. Schaeffer, unpublished results). Whether this selectivity is retained for the mouse SSTR5 is currently under investigation (Strowski, M. Z., A. D. Blake, H. A. Wilkinson, M. P. Dashkevicz, M. Kohler, and J. M. Schaeffer, unpublished results).
In the present study the SSTR2 selective nonpeptidyl analog L-779,976 provides additional evidence that SSTR2 regulates glucagon release. L-779,976 inhibited glucagon secretion in WT islets, but was ineffective in SSTR2KO islets. The fact that L-779,976, as a potent and selective human SSTR2 agonist, was inactive in SSTR2KO islets suggests that L-779,976 has much higher selectivity for SSTR2 compared with other currently known peptidyl analogs.
Third, the SSTR1, SSTR3, and SSTR4 selective analogs did not show inhibitory effects on glucagon release despite potent activity in heterologous expression studies (35). This finding supports the hypothesis that SSTR1, SSTR3, and SSTR4 do not mediate the inhibitory action of SST on stimulated glucagon release in mouse endocrine islets, confirming data from an earlier in vivo study (29).
The inhibitory effect of L-817,818 suggests a minor role for this
receptor in controlling glucagon secretion from -cells. L-817,818
reduced stimulated glucagon release in mouse pancreatic islets, but the
effect was substantially lower than that observed with L-779,976.
However, the present study does not rule out that SSTR5 might be
expressed on rodent -cells at low levels, but cannot be detected by
conventional immunocytochemistry techniques (41) or in previous
pharmacological studies (30). L-817,818 at the highest concentration of
100 nM may interact in vivo with SSTR2. However,
as L-817,818 inhibited glucagon secretion in islets from WT and SSTR2KO
mice at comparable potencies, it appears less likely that L-817,818
interacts with SSTR2. The possibility of interaction of L-817,818 with
SSTR1 (L-817,818 displays only a 10-fold selectivity for hSSTR5 over
hSSTR1) (35) was also ruled out, as we did not detect inhibition of the
SSTR1 selective analog L-797,591 on glucagon secretion. However, as
endocrine islets of the pancreas contain at least four distinct
hormonal active cell types, we cannot rule out indirect effects of
L-817,818 to reduce glucagon secretion.
Inhibition of insulin secretion by SST is believed to be mediated by SSTR5 (30, 50). SSTR5 mRNA was found in the whole pancreas (15), and a recent immunohistochemical study on rat endocrine islets detected presence of SSTR5 on ß-cells (41). A pharmacological in vitrostudy of murine pancreatic islets demonstrated that an SSTR5 selective analog, DC32–92 (BIM23052), significantly reduced glucose-stimulated insulin release, whereas an SSTR2 selective analog, NC8–12, did not (30). An in vivo study in the rat demonstrated that a SSTR5 selective analog, DC 23–99, decreased insulin secretion, whereas a SSTR2 selective analog, NC8–12, did not (50). In our study, L-817,818, a SSTR5 selective SST analog, inhibited glucose-stimulated insulin secretion in islets from WT and SSTR2KO mice. These results support the role of SSTR5 in inhibiting rodent insulin release.
The present study shows that SSTR2 does not play a major role in inhibiting insulin release from mouse pancreatic islets despite a slight inhibitory effect of L-779,976 in WT islets. Our functional data are supported by immunological studies showing barely detectable SSTR2 expression on ß-cells in the pancreatic islets in rodents (32). Both SST-14 and SST-28 inhibited insulin secretion from WT and SSTR2KO islets with comparable potencies in our study, providing additional support that SSTR2 does not play a crucial role in insulin secretion. However, data from human pancreatic islets suggest that species differences for SSTR expression may exist (33). Thus, further studies are necessary to clarify the role of the individual SSTRs in regulating hormonal secretion of the endocrine islets.
In conclusion, our data show for the first time that endogenous peptides SST-14 and SST-28 inhibit glucagon and insulin secretion from mouse pancreatic islets mainly via SSTR2 and SSTR5, respectively. We demonstrated an in vitro inhibition of glucagon secretion using nonpeptidyl SST analogs with potent selectivity for human SSTRs. Our data support the idea that SSTRs have distinct roles in the rodent pancreas (29, 30, 32, 50). Our study using a combination of somatostatin receptor subtype knockout animal and subtype selective SST agonists provides the first functional evidence for the crucial role of the SSTR2 in regulating glucagon secretion and of SSTR5 in mediating SST inhibition of insulin secretion.
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Acknowledgments |
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Footnotes |
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Received August 26, 1999.
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 W. Wente, T. Stroh, A. Beaudet, D. Richter, and H.-J. Kreienkamp Interactions with PDZ Domain Proteins PIST/GOPC and PDZK1 Regulate Intracellular Sorting of the Somatostatin Receptor Subtype 5 J. Biol. Chem., September 16, 2005; 280(37): 32419 - 32425. [Abstract] [Full Text] [PDF]
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 E Ludvigsen, M Stridsberg, E T Janson, and S Sandler Expression of somatostatin receptor subtypes 1-5 in pancreatic islets of normoglycaemic and diabetic NOD mice Eur. J. Endocrinol., September 1, 2005; 153(3): 445 - 454. [Abstract] [Full Text] [PDF]
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 P. Collombat, J. Hecksher-Sorensen, V. Broccoli, J. Krull, I. Ponte, T. Mundiger, J. Smith, P. Gruss, P. Serup, and A. Mansouri The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the {alpha}- and {beta}-cell lineages in the mouse endocrine pancreas Development, July 1, 2005; 132(13): 2969 - 2980. [Abstract] [Full Text] [PDF]
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 Y. Segev, R. Eshet, I. Rivkis, C. Hayat, L. Kachko, M. Phillip, and D. Landau Comparison between somatostatin analogues and ACE inhibitor in the NOD mouse model of diabetic kidney disease Nephrol. Dial. Transplant., December 1, 2004; 19(12): 3021 - 3028. [Abstract] [Full Text] [PDF]
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Genetically Modified Animals in Endocrinology Endocr. Rev., August 1, 2004; 25(4): 673 - 677. [Full Text] [PDF]
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A. Muroyama, S. Uehara, S. Yatsushiro, N. Echigo, R. Morimoto, M. Morita, M. Hayashi, A. Yamamoto, D.-S. Koh, and Y. Moriyama A Novel Variant of Ionotropic Glutamate Receptor Regulates Somatostatin Secretion From {delta}-Cells of Islets of Langerhans Diabetes, July 1, 2004; 53(7): 1743 - 1753. [Abstract] [Full Text] [PDF]
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 E. Ludvigsen, R. Olsson, M. Stridsberg, E. T. Janson, and S. Sandler Expression and Distribution of Somatostatin Receptor Subtypes in the Pancreatic Islets of Mice and Rats J. Histochem. Cytochem., March 1, 2004; 52(3): 391 - 400. [Abstract] [Full Text] [PDF]
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J. van der Hoek, W. W. de Herder, R. A. Feelders, A.-J. van der Lely, P. Uitterlinden, V. Boerlin, C. Bruns, K. W. Poon, I. Lewis, G. Weckbecker, et al. A Single-Dose Comparison of the Acute Effects between the New Somatostatin Analog SOM230 and Octreotide in Acromegalic Patients J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 638 - 645. [Abstract] [Full Text] [PDF]
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J. Bertherat, F. Tenenbaum, K. Perlemoine, C. Videau, J. L. Alberini, B. Richard, B. Dousset, X. Bertagna, and J. Epelbaum Somatostatin Receptors 2 and 5 Are the Major Somatostatin Receptors in Insulinomas: An in Vivo and in Vitro Study J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5353 - 5360. [Abstract] [Full Text] [PDF]
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K. Cejvan, D. H. Coy, and S. Efendic Intra-Islet Somatostatin Regulates Glucagon Release via Type 2 Somatostatin Receptors in Rats Diabetes, May 1, 2003; 52(5): 1176 - 1181. [Abstract] [Full Text] [PDF]
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 A.-Y. Gong, P. S. Tietz, M. A. Muff, P. L. Splinter, R. C. Huebert, M. Z. Strowski, X.-M. Chen, and N. F. LaRusso Somatostatin stimulates ductal bile absorption and inhibits ductal bile secretion in mice via SSTR2 on cholangiocytes Am J Physiol Cell Physiol, May 1, 2003; 284(5): C1205 - C1214. [Abstract] [Full Text] [PDF]
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 M. Z. Strowski, M. Kohler, H. Y. Chen, M. E. Trumbauer, Z. Li, D. Szalkowski, S. Gopal-Truter, J. K. Fisher, J. M. Schaeffer, A. D. Blake, et al. Somatostatin Receptor Subtype 5 Regulates Insulin Secretion and Glucose Homeostasis Mol. Endocrinol., January 1, 2003; 17(1): 93 - 106. [Abstract] [Full Text] [PDF]
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K. Cejvan, D. H. Coy, J. J. Holst, E. Cerasi, and S. Efendic Gliclazide Directly Inhibits Arginine-Induced Glucagon Release Diabetes, December 1, 2002; 51(90003): S381 - 384. [Abstract] [Full Text] [PDF]
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C. Chisholm and G. R. Greenberg Somatostatin-28 regulates GLP-1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures Am J Physiol Endocrinol Metab, August 1, 2002; 283(2): E311 - E317. [Abstract] [Full Text] [PDF]
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G. Tulipano, D. Soldi, M. Bagnasco, M. D. Culler, J. E. Taylor, D. Cocchi, and A. Giustina Characterization of New Selective Somatostatin Receptor Subtype-2 (sst2) Antagonists, BIM-23627 and BIM-23454. Effects of BIM-23627 on GH Release in Anesthetized Male Rats after Short-Term High-Dose Dexamethasone Treatment Endocrinology, April 1, 2002; 143(4): 1218 - 1224. [Abstract] [Full Text] [PDF]
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 J. Gromada, M. Hoy, K. Buschard, A. Salehi, and P. Rorsman Somatostatin inhibits exocytosis in rat pancreatic {alpha}-cells by Gi2-dependent activation of calcineurin and depriming of secretory granules J. Physiol., September 1, 2001; 535(2): 519 - 532. [Abstract] [Full Text] [PDF]
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E. Ballare, L. Persani, A. G. Lania, M. Filopanti, E. Giammona, S. Corbetta, S. Mantovani, M. Arosio, P. Beck-Peccoz, G. Faglia, et al. Mutation of Somatostatin Receptor Type 5 in an Acromegalic Patient Resistant to Somatostatin Analog Treatment J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3809 - 3814. [Abstract] [Full Text] [PDF]
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P. A Smith, L. A Sellers, and P. P A Humphrey Somatostatin activates two types of inwardly rectifying K+ channels in MIN-6 cells J. Physiol., April 1, 2001; 532(1): 127 - 142. [Abstract] [Full Text] [PDF]
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M. Afargan, E. T. Janson, G. Gelerman, R. Rosenfeld, O. Ziv, O. Karpov, A. Wolf, M. Bracha, D. Shohat, G. Liapakis, et al. Novel Long-Acting Somatostatin Analog with Endocrine Selectivity: Potent Suppression of Growth Hormone But Not of Insulin Endocrinology, January 1, 2001; 142(1): 477 - 486. [Abstract] [Full Text] [PDF]
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 C. Chisholm and G. R. Greenberg Somatostatin receptor subtype-5 mediates inhibition of peptide YY secretion from rat intestinal cultures Am J Physiol Gastrointest Liver Physiol, November 1, 2000; 279(5): G983 - G989. [Abstract] [Full Text] [PDF]
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