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Department of Endocrinology (R.G.C., D.L.M., W.B.W., Y.H.M, E.E.T.), Genentech Inc., South San Francisco, California 94080; and Department of Neurophysiology (G.B.T., K.M.F, I.C.A.F.R.), National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom
Address all correspondence and requests for reprints to: Dr. R. G. Clark, Genentech, Inc., Endocrine Research, 390 Point San Bruno Boulevard, Mail Stop #37, South San Francisco, California 94080. E-mail: rossc{at}gene.com
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Initial results with GH secretagogue administration to normal adults suggest that HPA activation is relatively slight and may be of little clinical significance (3). However, consistent stimulation of cortisol together with GH release could be a highly diabetogenic combination in the longer term and could have adverse consequences for the therapeutic use of GHRPs for growth promoting activity in children or metabolic stimulation in elderly or obese adults. The second aim of this study was to compare the diabetogenic activity of a potent GHRP analog with that of GH in an appropriate animal model. Zucker (fa/fa) rats (12) are a well known model of obesity in the rat. A substrain, the Zucker Diabetic Fatty (ZDF) is a rodent model of type II diabetes (13) as it rapidly develops obesity and insulin resistance with progressive ß-cell failure and subsequent frank diabetes (14). Furthermore, the adrenal axis has been shown to have a significant impact on the severity of diabetes in the ZDF rat, as adrenalectomy significantly ameliorates the severity of their diabetes (15). We have therefore examined the growth-promoting and diabetogenic effects of a GHRP analog and of GH, given separately or in combination with IGF-1, to ZDF rats.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Exp 1
Groups of male rats (200–250 g, NIMR:AS strain) were equipped
with chronic indwelling iv catheters under halothane anesthesia and
attached to an automated blood sampling system, as previously described
(16). Several days later the conscious animals, in an undisturbed
state, were given iv injections of saline, ovine CRH, or GHRP analogs,
and blood samples withdrawn for assay of corticosterone.
Exp 2
Obese male ZDF rats (Genetic Models Inc., Indianapolis, IN) at 6
weeks of age were group housed in a room controlled for temperature and
lighting and fed the pelleted rat diet specified by the breeders
(Purina 5008, 6% fat breeder chow) and tap water ad
libitum. The rats were weighed on the day of surgery and
randomized into 6 groups of 8. Ten lean rats from the same strain
served as controls. Blood samples were taken from a tail vein on days
0, 7, and 14. On day 24, a blood sample was withdrawn after a 4-h fast,
a dose of 1.5 U/kg insulin (Iletin, Lilly, Indianapolis) was injected
ip with a second blood sample taken 30 min later. The rats were then
killed, a terminal blood sample obtained, and organs and the inguinal
(sc) and retroperitoneal (visceral) fat pads dissected and weighed.
Hormones
For Exp 1, a selection of GHRP analogs of different structural
classes were chosen from the series recently reported by McDowell
et al. (10) and described in Table 1
. Ovine CRF (2 µg) was given as a
positive control (17). The GHRP analogs were initially dissolved at 1
mg/ml in saline, supplemented with ethanol or DMSO where necessary.
Before use, these stock solutions were then diluted in a citrate/saline
buffer pH 5.6 containing 1 mg/ml mannitol, to give an iv dose ranging
from 2–10 µg/100 µl, which was equipotent for GH release as
previously determined by in vivo bioassay (10), whereas
inactive analogs were given at 30 µg (Table 1).
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) was dissolved in
a 20 mM sodium acetate buffer, pH 5.0, containing mannitol
(0.5 g/liter), and given by twice daily sc injections, using a dose (50
µg/injection, 100 µg/day) shown to cause weight gain in the rat in
a previous study (10). Recombinant human GH (rhGH, Genentech) was given
sc twice daily (250 µg/injection, 500 µg/day). rhIGF-1 (Genentech,
13.8 mg/ml in acetate buffer) was given by sc osmotic minipump
infusions (Alza, Palo Alto CA, model 2ML4) delivering 758 µg/day for
28 days. All rats were given a single ip injection of ketamine (62.5
mg/kg, Ketaset, Fort Dodge Laboratories, Inc., Fort Dodge, IA) and
xylazine (12.5 mg/kg, Rompun, Miles Inc., Shawnee Mission, KS), and the
osmotic pumps were inserted while the rats were anesthetized. Control
groups received injections or infusions of excipients alone so that all
the animals were treated identically in that they were anesthetized,
implanted with pumps, and received twice sc daily injections.
Assays
Serum chemistries, including glucose, cholesterol, and
triglycerides were measured by standard automated procedures. Insulin
was measured by rat specific RIA (Linco Research Inc., St. Charles,
MO). Rat GH was measured using the reagents supplied by the NIDDK.
Plasma corticosterone was assayed using an ImmunoChem double antibody
corticosterone RIA kit (ICN Biomedicals, Costa Mesa, CA). Rat serum was
extracted using acid-ethanol as previously described (18), then IGF-1
was measured using two assays. Rat IGF-I was measured (19) in a
specific rat IGF-1 RIA (DSL-2900, DSL, Webster, TX), that does not
measure human IGF-1, and total IGF-1 concentrations were measured using
an RIA that detects both rat and human IGF-1 (18).
Analysis
Data are presented as mean ± SE of the mean
(SEM), and were subjected to ANOVA, or ANOVA for repeated
measures where appropriate, followed by paired t test or
Duncan’s new multiple range test as appropriate. A P
< 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Ovine CRF, used as a positive
control, raised corticosterone levels 4-fold. In general, the
corticosterone releasing activity paralleled the GH-releasing potency
of GHRP analogs with different sizes and structures (Table 1). For
example, the parent hexapeptide GHRP-6 (no. 1), a tripeptide (no. 2), a
linear tetrapeptide with a sub optimal N-terminus (no. 3), and a cyclic
heptapeptide (no. 4), given at doses equipotent for GH release, all
showed similar corticosterone-releasing activity, whereas similar
tetrapeptide (no. 5), and dipeptide (no. 6), analogs that were inactive
for GH release, were also without effect on corticosterone (Fig. 1).
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Exp 2: effects of G7039, GH, or IGF-1 in ZDF rats
Serum IGF-1.
Serum IGF-1 levels were measured in the blood
samples taken at sacrifice. In the rat-specific IGF-1 RIA (19) levels
in obese (1997 ± 98 ng/ml) and lean rats (2214 ± 71 ng/ml)
were similar, and treatment of the obese rats with G7039 (2008 ±
142 ng/ml) or GH (2315 ± 170 ng/ml) did not increase IGF-1
levels. Treatment with human IGF-1 caused the amount of rat IGF-1 to
fall in rats treated with IGF-1 alone (1293 ± 73 ng/ml,
P < 0.01 vs. obese control) or IGF-1 +
G7039 (1117 ± 72 ng/ml, P < 0.001 vs.
obese control) or IGF-1 plus hGH (1546 ± 113 ng/ml,
P < 0.05), confirming the specificity of the rat IGF-1
assay. Using an assay that measures total serum IGF-1 (both rat and
human IGF-1) the levels for control lean (501 ± 14 ng/ml) and
obese rats (683 ± 87 ng/ml) were not different, and levels were
unchanged after treatment with G7039 (476 ± 16 ng/ml) or hGH
(585 ± 33 ng/ml). Treatment with IGF-1 alone increased total
serum IGF-1 (1639 ± 72 ng/ml) as did treatment with G7039 plus
IGF-1 (1471 ± 154 ng/ml) or hGH plus IGF-1 (1484 ± 66
ng/ml). Therefore, given the specificity of the rat IGF-1 assay and the
fact that human IGF-1 assays underquantitate rat IGF-1 (19), there was
agreement between the assays on the effects of the treatments.
Body weight gain
The body weight gains for ZDF rats over the first 7 days of
treatment are shown in Fig. 2a, whereas
the full time course is illustrated in Fig. 2b. G7039 and IGF-1 induced
significant (P < 0.01) weight gain compared with
vehicle treated rats by day 2 of treatment (G7039 18.3 ± 1.0
g, IGF-1 21.5 ± 0.7 g, obese controls (13.8 ± 0.4
g), whereas hGH did not increase weight gain at this time (13.6 ±
2.5 g). The weight gain in response to G7039 + IGF-1 (26.8 ±
0.8 g) was greater (P < 0.05) than that to the
combination of hGH + IGF-1 (23.3 ± 1.2 g). All these
differences were maintained out to 7 days (Fig. 2a) with the weight
gains in rats treated with G7039 (65.8 ± 1.5 g) or hGH
(62.0 ± 1.5 g) were greater (P < 0.01) than
in rats treated with excipient (56.1 ± 0.8 g). Over the
course of the experiment, the lean control group gained less weight
than the obese groups. By day 24, the weight gains for the groups
treated with G7039 (177.3 ± 1.9 g) or hGH (182.0 ±
3.5 g) were greater (P < 0.05) than for the obese
controls (169.0 ± 1.6 g), whereas all groups treated with
IGF-1 were markedly heavier (Fig. 2b). The weight gain response to
G7039 + IGF-1 (247.4 ± 7.1 g) was similar to that to hGH +
IGF-1 (245.2 ± 4.9 g) but significantly greater
(P < 0.05) than for IGF-1 treatment alone (232 ±
2 g). Thus, in this diabetic model, the effect of treating with
hGH or G7039 alone had only a small effect compared with that of IGF-1,
which when given alone or combination with hGH or G7039 caused a large
weight gain.
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Figure 3 shows the wet weights in grams
of the inguinal (Fig. 3a) and retroperitoneal (Fig. 3b) body fat depots
when killed after 24 days of hormone treatment. The rapid weight gain
of the obese control rats is reflected in their depots, which were
several times heavier than the depots of the lean rats. None of the
treatments reduced the fat pad weights of the obese rats to those of
lean controls. However, hGH alone or in combination with IGF-1
significantly reduced inguinal, but not retroperitoneal fat, whereas
IGF-1 treatment increased retroperitoneal, but not inguinal fat. G7039
alone did not affect absolute fat pad weights but increased both depot
weights when given in combination with IGF-1 (Fig. 3). The relative fat
depot size (expressed as grams per 100 g of body weight) was also
increased for the retroperitoneal depot by G7039 plus IGF-1 (control
obese 0.71 ± 02 g/100 g vs. 0.81 ± 0.03 g/100g,
P < 0.05). Thus, for similar total body weight
increases, animals treated with hGH + IGF-1 or G7039 + IGF-1 showed
differential effects on the amount and distribution of body fat
depots.
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shows the changes with time
in fasting blood glucose and insulin levels over the course of
treatment with these peptides alone or in combination. There was no
difference between lean and obese fasting blood glucose values at day 0
of treatment (Fig. 4b). Blood glucose remained well controlled in all
the groups at 7 days, but by 14 days, the obese rats were developing
diabetes (obese controls 218 ± 27 mg/dl, lean controls 140
± 3 mg/dl). This hyperglycemia was exacerbated at 14 days by treatment
with G7039 (386 ± 63 mg/dl), and even more so (P
< 0.05) with hGH (504 ± 38 mg/dl). However, the combination of
G7039 and IGF-1 resulted in a blood glucose marginally lower
(190 ± 27 mg/dl) than the obese controls, and comparable with
that in the rats receiving the combination of hGH and IGF-1 (233
± 49 mg/dl).
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). G7039 +
IGF-1 resulted in a lower blood glucose (301 ± 53 mg/dl) than did
hGH + IGF-1 treatment (512 ± 55 mg/dl). However, the glucose
values in the G7039 + IGF-1 treated group were elevated
(P < 0.05) compared with animals receiving IGF-1 alone
(177 ± 4 mg/dl), which clearly delayed the progression of
diabetes in this model.
Serum insulin levels were also measured in these rats (Fig. 4a). At day
0, the levels in obese rats were elevated compared with lean controls,
indicative of the prediabetic state of these young ZDF rats. Although
after 7 days all the obese animals continued to maintain their blood
sugars within the normal range; this was at the expense of a marked
increase in fasting plasma insulin except in the groups receiving IGF-1
either alone, or in combination with G7039. Note again that IGF-1 alone
significantly reduced serum insulin levels (obese control, 21 ± 2
ng/ml; IGF-1 treated, 8 ± 1 ng/ml) (Fig. 4a). Both G7039 and hGH
elevated serum insulin (39 ± 6 and 48 ± 6 ng/ml,
respectively). However, plasma insulin was significantly lower in the
rats treated with G7039 + IGF-1 compared with those treated with hGH +
IGF-1 (10 ± 2 ng/ml vs. 25 ± 3 ng/ml,
P < 0.05). Thus, G7039, like hGH is clearly
diabetogenic in this model, and this effect can be reduced somewhat
by concomitant IGF-1 treatment.
Insulin sensitivity
The blood glucose responses to an insulin challenge were assessed
at day 24 of treatment (Fig. 5). Thirty
minutes after the insulin challenge, blood glucose values were higher
in the obese vs. lean animals (277 ± 42 mg/dl
vs. 84 ± 8 mg/dl), and in G7039 treated animals were
reduced to levels (323 ± 67 mg/dl) not significantly different
from those of the obese controls. In hGH-treated rats, blood glucose
remained significantly elevated (533 ± 55 mg/dl,
P < 0.05) compared with obese controls or G7039
treated rats (Fig. 5). Similarly, the blood glucose levels were
significantly (P < 0.05) lower in G7039 + IGF-1
treated rats (238 ± 47 mg/dl) than in hGH + IGF-1 treated rats
(388 ± 48 mg/dl).
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illustrates the serum
cholesterol and triglyceride levels in the rats. The most striking
finding was the immediate and sustained increase in these metabolites
in the animals given G7039 alone or in combination with IGF-1.
Cholesterol concentrations were not different at baseline but were
raised by G7039 after 7 days (control 100 ± 3 mg/dl
vs. 122 ± 5 mg/dl, P < 0.05), after
14 days (control 104 ± 2 mg/dl vs. 122 ± 4
mg/dl, P < 0.05) and 24 days (control 126 ± 3
mg/dl vs. 138 ± 3 mg/dl, P < 0.05).
The combination of G7039 and IGF-1 gave the highest cholesterol (day
24, IGF-1, 132 ± 3 mg/dl vs. IGF-1 plus G7039,
163 ± 8 mg/dl, P < 0.05). Cholesterol
concentrations were not affected by treatment with hGH. Triglyceride
concentrations were increased by G7039 after 7 days (control, 281
± 30 mg/dl vs. 488 ± 60 mg/dl, P <
0.05), after 14 days (control, 673 ± 53 mg/dl vs.
1218 ± 76 mg/dl, P < 0.05) and remained elevated
at day 24 (control, 1058 ± 73 vs. 1412 ± 44
ng/ml, P < 0.05). In contrast, the triglyceride
concentrations on day 24 were reduced in the rats treated with hGH
(501 ± 46 mg/dl, P < 0.05 vs.
control) or hGH plus IGF-1 (634 ± 52 mg/dl, P <
0.05 vs. control). Treatment with IGF-1 alone restrained the
rise in triglycerides (day 0; control, 209 ± 35 mg/dl, IGF-1,
236 ± 20 mg/dl, NS: day 24; control, 1058 ± 73 mg/dl,
IGF-1, 666 ± 33 mg/dl, P < 0.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The major novel finding from this study is that the GH secretagogue G7039, given at a dose (100 µg/day) and regimen (twice daily sc injections) that stimulated weight gain in normal adult rats, was also highly diabetogenic, raising blood glucose and insulin levels in ZDF rats within 14 days of treatment. This was somewhat surprising because Zucker rats have been reported to be hyporesponsive to GH secretagogues for GH release (22), and one might expect that direct sc administration of a large dose of GH twice daily would be more effective than the release of endogenous GH by G7039. GHRP-6 has previously been given (in combination with GHRH) to nondiabetic obese Zucker (fa/fa) rats, but significant increases in plasma IGF-1, insulin, or blood glucose levels over obese controls were not reported (22).
It was interesting to compare the anabolic effects of GH and G7309. Both agents increased even further the rapid weight gain of these obese animals, but this effect was small compared with the response in normal animals treated with frequent injections of this dose of G7039 (10) or of GH (23) over a similar period (4). It is likely that the reduced growth response in ZDF rats is due to the evident deterioration in their diabetic state caused by GH or G7039, which would render them GH resistant (24). Adding IGF-1 to either treatment ameliorates the diabetic state and allows a large growth response (25). Analogous observations have been made in type 1 diabetic rats, whose growth retardation and insensitivity to GH can be overcome by IGF-1 treatment (24) .
The large effects of IGF-1 on whole body size were reflected in large increases in the weight of body organs known to be responsive to either GH or IGF-1 (26, 27). In comparison, G7039 did not increase organ weights; in fact, when given alone it reduced the weight of the spleen and also it reduced the response to IGF-1 of the thymus. Lymphoid tissues are particularly sensitive to stress hormones, raising the possibility that these effects were due to G7039 increasing the release of adrenal steroids. Despite the dramatic increases in body weight, changes in individual fat depots were not marked, although GH treatment either alone or in combination with IGF-1 did reduce inguinal fat (28, 29) whereas G7039 + IGF-1 increased this fat depot. There was evidence for differential effects on fat depots, implying that they may respond differentially to metabolic hormones in this ZDF model. Differential effects on distribution of fat and mobilization have been reported in humans treated with GH (30) or IGF-1 (31) and in Zucker (fa/fa) rats treated with GH and IGF-1(29). The Zucker (fa/fa) obese rats have a mutation in the leptin receptor that renders the animals insensitive to leptin (32). The susceptibility of ZDF rats and leptin-deficient (ob/ob) mice (33) to the diabetogenic effects of GH suggests interactions between leptin and GH, though our data in ZDF rats show that an intact leptin receptor axis is not required for GH to decrease body fat.
By the end of the experiment, serum cholesterol and triglycerides were elevated in obese ZDF animals compared with lean controls. GH treatment alone or in combination with IGF-1 had no effect on serum cholesterol and reduced serum triglycerides compared with untreated ZDF rats. Surprisingly, G7039 treatment, alone or in combination with IGF-1, increased even further these serum lipids. Because the GH releasing activity of G7039 alone cannot explain this difference, an additional property of G7039, not shared by hGH, must also be responsible for this adverse effect on lipids. Again, it is well known (33) that corticosteroids exacerbate the diabetogenic effects of GH, and all GHRPs after acute administration raise cortisol in normal individuals, so we suggest that activation of the HPA axis in combination with a stimulation of GH most simply explains the differential diabetogenic effects of G7039 in this model.
It is well known that the in vivo vs. in vitro potency of active GHRP analogs for GH release varies widely (10), though whether this reflects differences in metabolic stability or relative access to pituitary vs. hypothalamic targets in unclear. GHRPs do not stimulate cortisol release in hypophysectomized animals (34), suggesting that they do not directly affect the adrenals, nor do they stimulate ACTH release from pituitary cells in vitro (9, 11). In addition the ACTH response to GHRP is abrogated in pituitary stalk sectioned animals (35). Rather, just as they activate hypothalamic mechanisms controlling GH release (36), GHRPs also seem to activate hypothalamic mechanisms controlling ACTH release, either by releasing CRH or AVP or by synergizing with their actions on ACTH release (17). Because only a single GHRP receptor has been identified to date (37), it is uncertain whether the in vivo ACTH-releasing and GH-releasing activities of GHRPs can be separated. We therefore tested the corticosterone-releasing activity of a range of novel GHRP analogs of different size and structures, whose in vivo and in vitro potency for GH release in the rat had already been well documented (10).
Whereas all the potent GH secretagogues tested had some corticosterone-releasing activity, and inactive analogs did not, the relative amounts of corticosterone release varied quite widely. One analog had a high in vitro potency but low in vivo potency for GH release, and this had no effect on corticosterone release, again suggesting that direct pituitary stimulation is unlikely to be involved in ACTH release. We cannot be sure that the differences observed reflect intrinsic potency differences, or the difference between solely hypothalamic activation of ACTH vs. hypothalamic and pituitary activation for GH. It could also reflect differences in access to the separate hypothalamic centers that control ACTH or GH release. Now that the GHRP receptor has been identified, it should be possible to identify the neuronal target that mediates activation of the HPA axis by GHRPs and to establish whether this stimulation can be separated from GH release by further analog development.
Even if the ACTH- and GH-releasing activities are intrinsic to the same receptor activation pathway, the relative magnitude of GH and ACTH release may vary markedly. For example, the combination of GHRPs with GHRH produce a synergistic effect on GH release but not on ACTH release, effectively enhancing the specificity of the response several fold (38), whereas the negative feedback effects of raised cortisol may be more pronounced on ACTH than on GH responses to GHRPs. Elevations in fasting blood glucose have been reported in elderly subjects dosed with an orally active GHRP for 4 weeks (39), so further work is clearly needed because even a small but consistent rise in cortisol accompanying GH stimulation could provide an undesirable extra diabetogenic drive in susceptible individuals. Finally, if ACTH release is an intrinsic property of GHRP receptor activation, then it is an intriguing possibility that when the endogenous GHRP ligand(s) are identified they may prove to play a role in the endogenous endocrine mechanisms controlling ACTH release as well as GH release, perhaps regulating the very same metabolic interactions between adrenal steroids and GH in normal subjects that they exaggerate in diabetes-prone individuals.
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Acknowledgments |
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Footnotes |
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Received March 14, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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