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Departments of Physiology (P.L.B.) and Medicine (P.L.B., D.J.D.), Toronto Hospital, and Banting and Best Diabetes Center, University of Toronto, Toronto, Ontario, Canada M5S 1A8; and the Department of Pharmacology, LRL Lilly Research Laboratories, Beiersdorf-Lilly (J.S.), Hamburg, Germany
Address all correspondence and requests for reprints to: Dr. P. L. Brubaker, Room 3366, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8. E-mail: p.brubaker{at}utoronto.ca
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-aminobutyric acid
did not affect release of GLP-1. Long chain monounsaturated fatty acids
(18:1), but not saturated fatty acids (16:0), also stimulated the
release of GLP-1 (by 1.7 ± 0.1-fold at 150 µM;
P < 0.001). Consistent with the presence of a cAMP
response element in the proglucagon gene, activation of the protein
kinase A-dependent pathway with forskolin increased proglucagon
messenger RNA transcript levels by 2-fold (P <
0.05); glucose-dependent insulinotropic peptide and phorbol
12,13-dibutyrate were without effect. Therefore, by comparison with
results obtained using primary L cell cultures or in
vivo models, GLUTag cells appear to respond appropriately to
the regulatory mechanisms controlling intestinal GLP-1 secretion. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A number of in vitro cell culture systems have been developed as models of the intestinal L cell, each of which has both advantages and drawbacks. For example, fetal rat intestinal cell (FRIC) cultures are heterogeneous in their cell population, although they have proven to be an excellent model of the rat L cell otherwise, releasing GLP-1 in response to a wide variety of different signal transduction pathways and extracellular mediators (18, 20, 21, 22, 23, 24). FRIC cells have also been used for studies of changes in proglucagon messenger RNA (mRNA) transcript levels (18), although their heterogeneity has proven to be limiting for more detailed molecular analyses of proglucagon gene expression. An alternative model, the isolated canine L cell (25, 26, 27), provides a more homogeneous cell population, but this culture system requires centrifugal elutriation to prepare and is therefore relatively expensive. A secretin tumor cell line (STC-1) that secretes GLP-1 has also been used as an L cell model (28); however, STC-1 cells are poorly differentiated and multipotential. Hence, the similarity of this intestinal S cell model to the GLP-1-producing L cell is unclear.
The paucity of L cell models encouraged us to develop an L cell line (GLUTag) from intestinal endocrine tumors arising in the large bowel in proglucagon-simian virus 40 large T antigen transgenic mice (29). GLUTag cells express the proglucagon gene at high levels and process proglucagon to a number of proglucagon-derived peptides, including GLP-1. GLUTag cells have been demonstrated to secrete GLP-1 in response to intracellular stimulators of the protein kinase A (PKA) and protein kinase C (PKC) pathways, such as forskolin and phorbol esters, respectively (29). As FRIC cultures also exhibit regulated GLP-1 secretion in response to activation of PKA- and PKC-dependent pathways (18, 20, 21, 22, 23, 24), we hypothesized that the GLUTag cell line would be a good model for further studies of GLP-1 release in response to a variety of potential secretagogues.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-ketoisocaproic acid (KIC),
glucose-dependent insulinotropic peptide (GIP), glucagon,
isoproterenol, somatostatin-14 (S14), carbachol, and -aminobutyric
acid (GABA) were gifts from Eli Lilly Co. (Indianapolis, IN).
Bethanechol was purchased from Merck Frosst Canada (Kirkland, Canada),
and tissue culture reagents were obtained from Life Technologies
(Burlington, Canada). Oleic (18:1) and palmitic (16:0) acids and
phorbol 12-myristate-13-acetate (PMA) were obtained from Sigma Chemical
Co. (St. Louis, MO). To enhance fatty acid solubility (30, 31), stock
solutions were prepared in dimethylsulfoxide and then diluted 1:1000
into serum (albumin)-containing tissue culture medium.
Cell culture
GLUTag cells were grown in DMEM (low glucose) containing 10%
(vol/vol) FBS, as previously described (29). The medium was changed
every 3–4 days. Cells were then trypsinized, plated in 24-well
cultures plates, and allowed to reach 60–80% confluence. On the day
of the experiment, cells were washed twice with HBSS and incubated with
test agents in DMEM containing 0.5% (vol/vol) FBS for 2 h. Each
experiment was repeated on a minimum of two different occasions to make
at least n = 4.
FRIC cultures were prepared from term fetal rat intestines, as previously described (18, 20, 21, 22, 23, 24). In brief, intestines from one litter of rats were pooled to make n = 1, and the cells were dispersed by incubation with collagenase (40 mg/dl; SigmaBlend Type H, Sigma Chemical Co.), hyaluronidase (40 mg/dl; type II, Sigma Chemical Co.), and deoxyribonuclease I (5 mg/dl; Sigma Chemical Co.). Cells were plated at a density of 0.6 fetal rat intestines/60-mm dish in DMEM (high glucose) containing 5% (vol/vol) FBS, 50 IU/ml penicillin, and 50 µg/ml streptomycin and were allowed to recover overnight. Cells were then washed with HBSS and incubated for 2 h with test agents in DMEM (low glucose) containing penicillin, streptomycin, and 20 µU/ml insulin.
Peptide extraction and analysis
At the end of the incubation period, medium was collected,
centrifuged to remove any floating cells, and made to 0.1% (vol/vol)
with trifluoroacetic acid. Cells were homogenized in 1 N
HCl containing 5% (vol/vol) HCOOH, 1% (vol/vol) trifluoroacetic acid,
and 1% (vol/vol) NaCl. Peptides and small proteins were then extracted
from cells and cell medium by passage through a cartridge of
C18 silica (Sep-Pak, Waters Associates, Milford, MA). We
have previously reported that this methodology affords a greater than
88% recovery of intact proglucagon-derived peptides (PGDPs) (22, 23).
Samples were subjected to RIA for GLP-1-(36)NH2 using the
GLP-1-(7–36)NH2 antiserum from Affinity Research
(Nottingham, UK) that recognizes GLP-1(7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36)NH2 and
GLP-1-(1–36)NH2 equally. This antiserum does not
cross-react with Gly-extended forms of GLP-1 (19, 32). Previous studies
have demonstrated that GLP-1-(7–36)NH2 is the predominant
form of GLP-1 synthesized by GLUTag cells (29).
We have previously demonstrated that GLP-1 secretion by FRIC cultures occurs in parallel with that of other PGDPs, most notably glucagon-like immunoreactivity (GLI) (20, 21). Therefore, as in previous studies (18, 20, 21, 22, 23, 24), FRIC cultures were subjected to RIA for changes in GLI secretion using antiserum K4023 (Biospecific, Emeryville, CA).
RNA extraction and analysis
Cells were incubated with test agents for 12 h, after which
total cellular RNA was isolated by the guanidium-isothiocyanate method
(33). Total RNA was subjected to electrophoresis using a 1% (wt/vol)
agarose-formaldehyde gel, and the gel was stained with ethidium bromide
to assess the migration and integrity of the RNA. RNA was then
transferred onto a nylon membrane, fixed by exposure to UV light, and
hybridized using a full-length complementary DNA (cDNA) probe for
proglucagon, as previously described (29). To control for loading and
transfer efficiency, the blots were rehybridized with a cDNA for 18S
ribosomal RNA.
Data analysis
Secretion was calculated as the percentage of the total cell
content of peptide (GLP-1 or GLI) that was found in the medium
[100 x medium peptide/(medium + cell peptide)]. The total
content of GLP-1 in control GLUTag cultures (medium plus cells) was
1.9 ± 0.2 ng/well (n = 10), and this was not altered by
treatment with high doses of any of the test agents. Under control
conditions, 8.5 ± 0.8% (n = 10) of the total cell content
was released into the medium during the 2-h incubation period.
Statistical differences were determined by ANOVA using n-1 custom
hypotheses tests on an SAS program (Statistical Analysis Systems, Cary,
NC) for IBM computers.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The forskolin
response was linear within the dose range tested, reaching 2.3 ±
0.5-fold of control values at 100 µM (P
< 0.01). Treatment of GLUTag cells with the cAMP phosphodiesterase
inhibitor, IBMX, similarly increased GLP-1 release, to a maximum of
186 ± 37% of the control value (P < 0.05) at 10
µM (Fig. 1). GLP-1 secretion was also stimulated by
treatment with PDBU; the response to this phorbol ester was highly
significant, reaching 426 ± 61% of the control value at 0.3
µM (P < 0.001). Treatment with a
second phorbol ester, PMA (1 µM), also increased peptide
release, to 1.7 ± 0.2-fold of the control value
(P < 0.001), whereas down-regulation of PKC via 24-h
pretreatment with PMA completely abrogated this response (91 ±
9% of the control value; Fig. 1). In contrast to the PKA and PKC
pathways, incubation with KIC decreased the release of GLP-1 in a
biphasic fashion, with inhibition occurring at low (10–30
µM; P < 0.05–0.01), but not higher
(100–300 µM), concentrations. KIC is an amino acid
metabolite that has been reported to stimulate phospholipase C in islet
cells (34). As the effect of KIC on FRIC cultures has not previously
been reported, a similar dose-response curve was tested in this system
(Fig. 2). KIC had no effect on PGDP
secretion by FRIC cultures, although the positive control (forskolin
plus IBMX) indicated that the cells were responsive to
secretagogues.
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). GIP
increased GLP-1 secretion in a dose-dependent fashion, with a
significant increment to 227 ± 24% of the control value at 0.1
µM (P < 0.001). GLUTag cells were
unresponsive to the structurally related peptide, glucagon, at all
doses tested; however, GLP-1 release was increased in response to
treatment with the highest dose of S14 (0.01 µM;
P < 0.05).
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). As FRIC cultures have previously been
found to be sensitive to the muscarinic agonist bethanechol (24), this
agent was also tested with GLUTag cells and was found to stimulate
GLP-1 release in the same dose range as carbachol (P <
0.05). Although the incremental response to 1000 µM
bethanechol appeared to be reduced compared with that for 1000
µM carbachol, this difference did not reach statistical
significance. GLP-1 secretion was not altered by treatment of GLUTag
cells with either isoproterenol or GABA. Studies in FRIC cultures
similarly indicated a lack of effect of GABA on the L cell (Fig. 2
).
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). Treatment with the monounsaturated
fatty acid stimulated GLP-1 secretion by 1.7 ± 0.1-fold
(P < 0.001) at a dose of 150 µM, whereas
the saturated fatty acid appeared to have either a slight inhibitory or
no effect.
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). In
paired control experiments, forskolin/IBMX treatment increased the
levels of proglucagon mRNA transcripts (by 2-fold; P <
0.05), whereas PDBU was without effect.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several regulatory peptides that activate PKA-dependent pathways through the seven-transmembrane domain, G protein-linked receptors were tested for their effects on GLP-1 release by GLUTag cells, including GIP (35) and glucagon (36). Of these, only GIP was found to stimulate GLP-1 release; glucagon was without effect on the GLUTag cells, consistent with the results of studies using FRIC cultures (24). Studies using models as diverse as FRIC cultures (20, 24), isolated perfused rat ileum (37, 38), and the anesthetized rat (39), have all indicated that GIP can stimulate secretion by the rat intestinal L cell. Interestingly, this effect appears to be species specific, as the human L cell is not stimulated by GIP in vivo (1, 4). Very recently, we demonstrated that the effects of physiological concentrations of GIP on the rat L cell in vivo are exerted indirectly, through the vagus nerve (40). At supraphysiological concentrations, however, the effects of GIP on the L cell are not prevented by vagotomy. Thus, our finding that the GLUTag cells are responsive to GIP at relative high concentrations only (0.03–0.1 µM) is consistent with the in vivo sensitivity of the L cell to this peptide.
In keeping with a role for the vagus in modulating GLP-1 release in the rat in vivo, both carbachol and bethanechol were found to stimulate peptide secretion by GLUTag cells at doses of 500-1000 µM. The dose-response curve for these effects was identical to that of a previous study using bethanechol with FRIC cultures (24). However, in the perfused rat ileum model, cholinergic agonists stimulate the release of GLP-1 at substantially lower concentrations (10–100 µM) (37, 38). The reasons for the differences between the two in vitro models and the in situ setting are not clear; however, the possible involvement of other mediators cannot be discounted in the perfused rat ileum model. Nonetheless, a cholinergic pathway does appear to be important for GLP-1 secretion in humans, as atropine treatment prevents GLP-1 secretion during an oral glucose tolerance test (41). Interestingly, this effect is also species specific, as carbachol is actually inhibitory to the canine L cell in vitro (25, 26). Finally, as bethanechol acts through muscarinic receptors only, whereas carbachol binds to both muscarinic and nicotinic receptors, the present findings suggest a role for a muscarinic receptor in the regulation of GLP-1 secretion. Although the secretin tumor (STC-1) cell line is not a true model of the L cell, studies using these cells have indicated an involvement of the M3 receptor subtype in modulating GLP-1 release (28). Further investigations to determine the receptor subtype expressed by the GLUTag cells are therefore clearly warranted.
In contrast to the stimulatory effects of muscarinic agonists on both FRIC cultures and GLUTag cells, other neuromodulators, including the ß-adrenergic agonist isoproterenol and the chloride channel inhibitor GABA, had no effect on peptide secretion in these culture systems (present data and Ref. 24). These findings are consistent with those reported for the perfused rat ileum (37, 38). However, as for the regulation by other secretagogues, the lack of effect of the ß-adrenergic agonist is species dependent, as it has been reported that the canine L cell is stimulated by epinephrine (25, 26).
The intestinal neuropeptide S14 is a known inhibitor of the L cell in
FRIC cultures (24), canine L cells in vitro (25, 26, 27), and
both rats and dogs in vivo (42, 43). Studies in FRIC
cultures (24) have suggested the presence of SSTR5, a
somatostatin-28-preferring subtype on the L cell, rather than SSTR2,
the S14-preferring receptor (44). The results of the present study
suggest that neither of these receptors is present on GLUTag cells, as
both should be associated with decreased GLP-1 release through
inhibition of the PKA pathway. Although it remains to be established
why GLP-1 secretion by the GLUTag cells was actually increased by
treatment with high doses of S14, this finding is not without
precedent, as stimulatory effects of somatostatin have been observed in
the neuroendocrine GH4C1 cells via release of
the Gß-subunit from inhibitory G proteins (45, 46).
Finally, GLP-1 secretion was also found to be stimulated by a long
chain monounsaturated fatty acid (18:1), but not by a similar length
saturated fatty acid (16:0), consistent with our previous results using
FRIC cultures (21, 24). Oleic acid has also been reported to stimulate
the canine L cell in vitro over a similar dose range (27).
These findings are consistent with several reports of stimulation of
the rat ileal L cell in vivo by mixed fats (39) and
therefore suggest that diets enriched in long chain monounsaturated
fatty acids, such as olive oil, may be a useful approach to enhance the
release of GLP-1 in vivo. A summary of the similarities and
differences between the secretory responses of the primary rat L cell
in culture (e.g. FRIC cultures) and the GLUTag cell line is
shown in Table 1.
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TC2 islet cell line (47). However, the results
of the present study indicate a total lack of effect of PDBU on
proglucagon mRNA transcript levels in the enteroendocrine GLUTag cell
line. We have similarly reported that activation of the PKC-dependent
pathway in GLUTag cells with cholecystokin (29) or in FRIC cultures
with PMA (18) does not augment total PGDP or proglucagon mRNA
transcript levels. Taken together, therefore, these observations
highlight the importance of the cAMP-dependent pathway in the
regulation of both proglucagon gene expression and GLP-1 secretion by
the intestinal L cell. The results of the present study indicate that the GLUTag cells appear to represent a good model of the intestinal L cell; they exhibit appropriate responses to known stimulators of GLP-1 secretion and are unaffected by factors that do not modulate GLP-1 release in other systems. Thus, these cells should be useful for further studies to evaluate potential GLP-1 secretagogues.
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Acknowledgments |
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Footnotes |
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2 Scientist of the Medical Research Council of Canada.
Received January 15, 1998.
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References |
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-subunits in neuroendocrine cells. Mol Cell Endocrinol 132:61–71[CrossRef][Medline]
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