1 Department of Physiology and Pharmacology and 2 Wallenberg Laboratory, Göteborg University, S-405 30 Goteborg, Sweden
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ABSTRACT |
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The effect of insulin-like growth factor I (IGF-I) on insulin-stimulated glucose uptake was studied in adipose and muscle tissues of hypophysectomized female rats. IGF-I was given as a subcutaneous infusion via osmotic minipumps for 6 or 20 days. All hypophysectomized rats received L-thyroxine and cortisol replacement therapy. IGF-I treatment increased body weight gain but had no effect on serum glucose or free fatty acid levels. Serum insulin and C-peptide concentrations decreased. Basal and insulin-stimulated glucose incorporation into lipids was reduced in adipose tissue segments and isolated adipocytes from the IGF-I-treated rats. In contrast, insulin treatment of hypophysectomized rats for 7 days increased basal and insulin-stimulated glucose incorporation into lipids in isolated adipocytes. Pretreatment of isolated adipocytes in vitro with IGF-I increased basal and insulin-stimulated glucose incorporation into lipids. These results indicate that the effect of IGF-I on lipogenesis in adipose tissue is not direct but via decreased serum insulin levels, which reduce the capacity of adipocytes to metabolize glucose. Isoproterenol-stimulated lipolysis, but not basal lipolysis, was enhanced in adipocytes from IGF-I-treated animals. In the soleus muscle, the glycogen content and insulin-stimulated glucose incorporation into glycogen were increased in IGF-I-treated rats. In summary, IGF-I has opposite effects on glucose uptake in adipose tissue and skeletal muscle, findings which at least partly explain previous reports of reduced body fat mass, increased body cell mass, and increased insulin responsiveness after IGF-I treatment.
insulin-like growth factor I; soleus muscle; glycogen; triglyceride; lipid; free fatty acids; C-peptide; L-thyroxine; cortisol
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INTRODUCTION |
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INSULIN-LIKE GROWTH FACTOR I (IGF-I) and insulin are structurally related polypeptides that mediate a similar pattern of biological effects via receptors that display considerable homology (17). The main regulators of IGF-I expression and secretion are nutritional factors and growth hormone (GH) (17). GH regulates the expression and secretion of IGF-I in many tissues, including adipose tissue (44), skeletal muscle (21), and the liver (17). IGF-I is believed to mediate some of the effects of GH via endocrine and paracrine mechanisms (14, 17, 40). However, direct effects of IGF-I in the liver and adipose tissue are unlikely, because these tissues lack functional type I IGF receptors (18, 29). IGF-I inhibits both GH (17, 18, 29) and insulin secretion (18, 27, 29, 36), further indicating an intimate relation between these hormones in the regulation of growth and metabolism.
Acutely, a high dose of IGF-I results in hypoglycemia, decreased serum levels of free fatty acids (FFA), and increased lipogenesis, effects which are similar to those of insulin. However, IGF-I is less potent than insulin (13, 29, 38). Prolonged IGF-I therapy has been shown to ameliorate hyperglycemia in type 1 and type 2 diabetes mellitus as well as in severe insulin-resistant states (7, 18, 29). A decreased GH secretion may only partly play a role for the amelioration of diabetic conditions by IGF-I treatment (7, 20) because IGF-I also reverses insulin resistance induced by GH in the GH-deficient state (19).
In skeletal muscle tissue, IGF-I has direct insulin-like effects via type I IGF receptors. These effects of IGF-I include increased translocation of glucose transporters, increased glucose uptake, and increased glycogen formation (1, 5, 18, 34, 47). The insulin-like effects of IGF-I in skeletal muscle seem to occur both when IGF-I is given acutely and when IGF-I is given for several days (5).
However, several effects of prolonged treatment with IGF-I are not insulin-like, especially those concerning lipid metabolism and adipose tissue. These effects include increased lipolysis in adipose tissue (19), decreased lipoprotein lipase activity in adipose tissue (33), and decreased body fat mass (14, 25, 44). In some studies, serum FFA levels (5, 18, 20) and serum triglyceride levels increased as a result of increased circulating levels of IGF-I (35, 40).
Thus there are indications that prolonged treatment with IGF-I has opposite effects from those of insulin in adipose tissue but insulin-like effects in skeletal muscle tissue. However, the action of IGF-I in adipose tissue is not clear, especially because it does not seem to possess functional IGF receptors. Moreover, the understanding of the mechanism for IGF-I action in vivo is often complicated by its effect on GH secretion, and few studies have addressed the metabolic effects of IGF-I in the GH-deficient state (14, 19, 33, 39, 40).
To further understand the role of IGF-I for glucose uptake in skeletal muscle and adipose tissue, we have studied the effects of IGF-I treatment of hypophysectomized rats on basal and insulin-stimulated glucose incorporation into lipids and glycogen in adipose tissue and skeletal muscle tissue, respectively.
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MATERIALS AND METHODS |
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Animals. Female Sprague-Dawley rats (Mollegaard Breeding Center, Ejby, Denmark) were used in these experiments. Hypophysectomy (Hx) was performed at Mollegaard Breeding Center when animals were 50 days old. The animals were maintained under standardized conditions of temperature (24-26°C) and humidity (50-60%), with a light period between 0500 and 1900. The rats were given free access to standard rat chow (rat/mouse standard diet, B&K Universal, Sollentuna, Sweden) and tap water. A body weight gain of >0.5 g/day in Hx rats during a 7-day observation period was regarded as a sign of remaining pituitary tissue and used as an exclusion criterion (23).
After a period of hormonal treatment (see next section), the rats were killed by decapitation. All animals were killed in the morning between 0900 and 1100. Blood was collected from the trunk, and serum was separated and stored atHormonal treatment.
After the 7-day observation period, all hormone therapy commenced on
the same day. All Hx rats were given replacement therapy with
L-thyroxine (10 µg · kg1 · day
1;
Nycomed, Oslo, Norway) and cortisol phos-phate (400 µg · kg
1 · day
1;
Solu-Cortef, Upjohn, Puurs, Belgium) diluted in saline. Injections were
given daily subcutaneously at 0800 (31-33). Human recombinant IGF-I was generously provided by Genentech (San Francisco, CA). IGF-I
was diluted in saline (0.9% NaCl) and given as a continuous infusion
via osmotic minipumps, which were implanted subcutaneously between the
scapulae under anesthesia (xylazine 9 mg/kg, Rompun; Bayer,
Lever-Kusen, Germany, and ketamine-hydrochloride 77 mg/kg, Ketalar;
Parke-Davis, Detroit, MI) (33, 40). When the rats were treated with
IGF-I for 6 days (1.25 mg · kg
1 · day
1),
osmotic minipumps (model 2001, Alza, Palo Alto, CA) were used (33, 40).
IGF-I was also given as a continuous infusion for 20 days (0.85 mg · kg
1 · day
1)
with osmotic minipumps (model 2004, Alza).
Serum analysis. Serum glucose concentrations were measured by the glucose-6-phosphate dehydrogenase method (Merck, Darmstadt, Germany). Serum FFA concentrations were measured by an enzymatic colorimetric method (NEFA C, Wako Chemicals, Neuss, Germany). Serum insulin and C-peptide concentrations were determined by RIA (Rat Insulin and Rat C-Peptide RIAs, Linco Research, St. Charles, MO).
Insulin concentrations in serum after Insulatard treatment in vivo were measured with a human insulin RIA (Phedabas, Pharmacia, Uppsala, Sweden) (3). Serum IGF-I concentrations were determined by a hydrochloride acid-ethanol extraction RIA, with human IGF-I for labeling (Nichols Institute Diagnostics, San Juan Capistrano, CA) (42). Analysis of IGF-I binding proteins (IGFBPs) was performed by Western ligand blotting. The method described by Hossenlopp et al. (16) was used with slight modifications. Serum samples were diluted with SDS buffer [0.5 M Tris · HCl (pH 6.8), 1% wt/vol glycerol, 2% wt/vol SDS, and bromphenol blue], heated, applied on a 4.5% stacking gel, and electrophoresed for 12 h at 40 V through a 12.5% polyacrylamide gel. The gels were soaked in transfer buffer [15 mM Tris, 0.12 M glycine (pH 8.3), and 5% methanol] and electroblotted to a nitrocellulose membrane using a transblot cell (Bio-Rad). The air-dried nitrocellulose membrane was soaked for 30 min at 4°C in saline (0.15 M NaCl, 0.01 M Tris · HCl, pH 7.4) containing 3% Nonident P-40 (Sigma Chemical, St. Louis, MO), then incubated for 2 h in saline containing 1% BSA, and finally incubated for 10 min in saline with 0.1% Tween 20. The nitrocellulose membrane was incubated overnight at 4°C with 125I-labeled IGF-I in saline supplemented with 1% BSA and 0.1% Tween 20 (100,000 counts · minGlucose incorporation into lipids. Glucose incorporation into lipids was analyzed in both adipose tissue segments and isolated adipocytes. Adipose tissue was cut into small segments of 10-15 mg, as previously described (10). The tissue was incubated in a Krebs-Ringer-HEPES (KRH) buffer, pH 7.4, containing 0.55 mM glucose [D-(+)-glucose, Sigma] and 1% BSA (fraction V, Sigma).
Three to four segments were incubated in 1 ml buffer with 0.12 µCi D-[U-14C]glucose (Amersham, Buckinghamshire, UK) at 37°C for 60 min under 100% O2 in the absence or presence of different doses of insulin (Actrapid; 16 nMGlucose incorporation into muscle glycogen. The soleus muscle was taken out, rinsed, and preincubated in KRH buffer for 15 min and thereafter incubated with 0.3 µCi D-[U-14C]glucose/ml for 60 min as described above. Total glycogen and insulin-stimulated glucose incorporation into glycogen were measured as previously described (28). Briefly, the muscle tissue (30 mg) was digested in 30% KOH (0.5 ml/mg tissue) at 100°C for 20 min. Glycogen was precipitated with 100 µl of 8% Na2SO4 and 1.2 ml of absolute ethanol. The precipitate was collected by centrifugation at 3,000 rpm for 5 min. The precipitation was repeated once with ethanol only. Thereafter, the collected precipitate was dried at 40°C for 2 h. Glycogen was dissolved in double-distilled water and neutralized to pH 7.0. [14C]glucose incorporation into muscle glycogen was determined by scintillation counting and expressed as nanomoles of glucose incorporated per milligram wet weight. Total glycogen in muscle was measured using a commercial kit (Glucose/GOD-perid, Boehringer Mannheim, Mannheim, Germany). In short, amyloglucosidase (Sigma) was added to the enzyme-buffer solution (5 mg/100 ml) and mixed with 100 µl of dissolved glycogen. Absorbance at 610 nm was then measured 50 min after the addition of the enzyme solution. Background absorbance was subtracted, and the obtained value was plotted against a glycogen standard for determination of glycogen concentration.
Glucose incorporation into lipid fractions. Extractable lipid from adipocytes was subjected to TLC on plates precoated with Silica Gel 60 (Merck, Darmstadt, Germany). The plates were developed with chloroform-acetic acid (96:4, vol/vol). The bands were visualized by staining in iodine vapor. The bands corresponding to the triglyceride and fatty acid standards were extracted from the silica gel with 0.5 ml cyclohexane, and radioactivity was counted in a liquid scintillation counter.
Lipolysis.
Cell suspensions (final lipocrit 1-2%) were added to plastic
vials containing 2 ml Parker Medium 199 (Statens
Bakteriologiska Laboratory, Stockholm, Sweden)
supplemented with 4% BSA (fraction V, Sigma) in the presence or
absence of isoproterenol [106 M,
(
)-isoproterenol, Sigma]. Incubation was continued for 2 h
at 37°C. Thereafter, cells and medium were separated by
centrifugation through silicon oil (Kebo Lab, Spånga, Sweden)
(12). The glycerol content in the medium was measured enzymatically
(26) and taken as an index of lipolysis. Fat cell size was determined
according to Smith et al. (41), and the fat cell lipid weight was
determined according to Hirsch and Gallian (15). Fat cell number was
calculated by dividing the total lipid weight of the sample by the mean
cellular lipid weight.
Statistics. Values are given as means ± SE. Comparisons between groups were performed with Student's t-test, two-way ANOVA, and one-way ANOVA followed by the Student-Newman-Keuls multiple range test. When appropriate, values were transformed to logarithms.
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RESULTS |
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Six days of IGF-I treatment (1.25 mg · kg1 · day
1)
of HX rats resulted in a significant increase in body weight gain,
spleen weight, and IGF-I concentrations. However, no effects on serum glucose or FFA concentrations were observed (Table
1). Analysis of IGFBPs in serum from Hx
rats with Western ligand blotting showed a reduction in the 45-, 40-, and 30-kDa IGFBP bands after Hx compared with those in normal rats
(Fig. 1). IGF-I treatment of Hx rats restored the reduced levels of the 45- and 40-kDa bands to the levels
seen in normal rats and the 30-kDa and 25-kDa bands to even higher
levels than in normal rats.
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In vivo effects of IGF-I on glucose incorporation into lipids in
adipose tissue.
The effect of 6 days of IGF-I treatment of Hx rats on
insulin-stimulated [14C]glucose incorporation
into lipids in adipose tissue segments is shown in Fig.
2. IGF-I treatment resulted in a decrease
in basal and insulin-stimulated glucose incorporation into lipids (P < 0.05, controls vs. IGF-I treatment, 2-way ANOVA).
Insulin had a statistically significant effect (P < 0.05, vs.
different insulin concentrations, 2-way ANOVA). However, the magnitude
of the insulin-stimulated increase in glucose incorporation was similar in adipose tissue segments from the Hx control rats (53%) and IGF-I-treated rats (46%). Thus the difference in glucose incorporation found in basal incubations remained and could not be overcome by
increasing insulin concentrations. To test the possibility that this
effect was retained in isolated adipocytes, adipocytes were isolated
from parametrial adipose tissue after 6 days of IGF-I treatment of Hx
rats. The basal as well as insulin-stimulated glucose incorporation
into lipids was reduced in a similar manner to the adipose tissue
segments (data not shown).
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In vitro effects of IGF-I on glucose incorporation into lipids in adipocytes. These experiments were conducted to test the possibility that preincubation of isolated adipocytes with IGF-I in vitro affects basal and insulin-stimulated glucose incorporation into lipids in another way from in vivo. The effects of IGF-I and insulin in vitro were studied in isolated adipocytes from normal female rats.
In initial experiments, the effects of different concentrations of IGF-I and insulin on glucose incorporation into lipids in isolated adipocytes were compared. Both hormones increased glucose incorporation into lipids in a concentration-dependent manner. However, the potency of insulin to stimulate glucose incorporation into lipids was ~100-fold higher than that of IGF-I (Fig. 5A). In subsequent experiments, isolated adipocytes were preincubated for 2 h with 3 nM IGF-I (a dose which gives a submaximal effect on glucose uptake) and then exposed to different concentrations of insulin (Fig. 5B). Insulin stimulated glucose incorporation in a similar manner whether or not the cells were preincubated with IGF-I (Fig. 5B). In contrast to the in vivo findings, basal glucose incorporation was higher in cells preincubated with IGF-I. Together, these results show that IGF-I has no direct inhibitory effect on the ability of adipocytes to respond to insulin.
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In vivo effect of IGF-I on lipolysis.
The effect of IGF-I treatment on basal and isoproterenol-stimulated
lipolysis in isolated adipocytes was subsequently studied. Adipocytes
were isolated from Hx rats that had been treated with IGF-I for 6 days
and compared with adipocytes isolated from Hx control rats (Fig.
6). Basal lipolysis was not affected by
IGF-I treatment. However, isoproterenol-stimulated lipolysis was
slightly increased in cells from IGF-I-treated rats, indicating that
IGF-I treatment increases the responsiveness of adipocytes to
catecholamines.
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In vivo effect of IGF-I on glucose incorporation into glycogen in
soleus muscle.
The effect of IGF-I treatment on glycogen content and glucose
incorporation into glycogen of isolated soleus muscle was studied. The
glycogen content of the muscle was higher in IGF-I-treated rats
compared with Hx control rats (1.57 ± 0.2 vs. 0.63 ± 0.2 mg/g
tissue; P < 0.05). There was an overall significant increase in glucose incorporation into glycogen in soleus muscle of
IGF-I-treated rats (P < 0.05, 2-way ANOVA). Basal
glucose incorporation into glycogen was significantly increased (Fig.
7). At a submaximal concentration of
insulin, glucose incorporation was increased in soleus muscles of
IGF-I-treated rats but not in Hx controls, indicating an increased
sensitivity to insulin. At the highest insulin concentration, glucose
incorporation was similar in the two treatment groups, indicating that
IGF-I treatment did not increase the maximal capacity of the soleus
muscle to respond to insulin (Fig. 7).
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DISCUSSION |
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Treatment of Hx rats with IGF-I for 6 or 20 days reduced basal and insulin-stimulated lipogenesis in adipose tissue but increased insulin-stimulated glycogen synthesis in skeletal muscle. It is likely that this inhibitory effect of IGF-I on lipogenesis in adipocytes was caused by decreased insulin secretion (18, 27, 29, 36). This conclusion is based on the following observations. First, C-peptide and insulin levels were decreased in IGF-I-treated Hx rats. Second, insulin treatment of Hx rats increased basal and insulin-stimulated glucose incorporation into lipids in adipocytes. Third, preincubation with IGF-I in vitro did not interfere with the insulin response on glucose incorporation into lipids. However, we cannot rule out the possibility that prolonged exposure of adipocytes to IGF-I interferes directly with the insulin response, because only short-term experiments were possible to perform in vitro.
IGF-I is capable of reproducing most of the effects of insulin in adipocytes at 100-fold higher concentrations (2). Accordingly, the type I IGF receptor seems to be very scarce or absent from rat adipocytes (48). These results indicate that IGF-I can have a direct effect on adipocytes only via the insulin receptor (24, 48). The type I IGF receptor is present in high density in skeletal muscle (34, 47). Moreover, in skeletal muscle, IGF-I is 5-10 times less potent than insulin on glucose transport (8). Therefore, it is likely that the physiological effects of IGF-I in skeletal muscle are via IGF receptors and not insulin receptors. However, the possibility that IGF-I can act partly through the insulin receptor in skeletal muscle cannot be completely ruled out. In conclusion, our observations and those of others are in line with the assumption that the direct metabolic effects of IGF-I are mediated through the insulin receptor in adipose tissue and through IGF-I receptors in muscle tissue.
We cannot exclude the possibility that other metabolic changes induced by IGF-I therapy can change the insulin responsiveness of adipocytes. One such possibility is a changed expression of IGFBPs. Our results show that Hx decreases and IGF-I treatment for 7 days increases 45-kDa and 40-kDa IGFBPs in Hx rats. These results are in agreement with previous findings (4). Both 30-kDa and 25-kDa IGFBPs seem to be negatively regulated by insulin (2). In our model, IGF-I treatment reduces both serum insulin and C-peptide concentrations, which could explain an increase in 30-kDa and 25-kDa binding proteins (2). As IGF actions are modified by IGFBPs, the induction of binding proteins by IGF-I may act as a regulator of IGF-I effects in target tissues. However, it is unclear whether these effects of IGF-I on circulating IGFBPs affect glucose uptake in adipose tissue or skeletal muscle.
Basal lipolysis and the proportion of labeled fatty acids to triglycerides were not changed in cultured adipocytes after IGF-I treatment of Hx rats, indicating that the apparent decreased lipogenesis was not due to an increased lipolysis. Thus it can be concluded from the present results that the decreased lipogenesis after IGF-I treatment is mainly due to a decreased capacity of glucose metabolism in adipocytes. After Hx, when basal and stimulated insulin serum levels are decreased (11, 40), basal and insulin-stimulated lipogenesis and glucose oxidation in adipose tissue have been shown to be decreased (9, 11). When Hx rats were treated with insulin, these changes were partly reversed, as shown in this study and previously (9, 11). These results indicate that insulin is important for the long-term regulation of the lipogenic capacity of adipose tissue. A further decrease in insulin secretion induced by IGF-I, as shown in this study and by others (18, 27, 29, 36), may thus contribute to the low lipogenic capacity of adipose tissue. The decreased lipogenic capacity explains observations from both experimental and clinical studies, which showed that long-term treatment with IGF-I reduces fat depots (14, 25, 44).
In contrast to lipogenesis in adipose tissue, glycogen content and insulin-stimulated glycogen synthesis in muscle tissue were increased by IGF-I treatment. Our results are in line with those reported by Dimitriadis et al. (5), who showed that prolonged treatment of normal rats with IGF-I resulted in increased glucose utilization and glycogen synthesis in the soleus muscle.
Human IGF-I, with 3 of 70 amino acids different from rat IGF-I, is more
potent in vitro than rat IGF-I on rat adipocytes (42). The doses used
in our experiments increased body weight to the same range as in
previous reports (14, 39, 40). IGF-I treatment of Hx rats does not
affect food intake (40). Moreover, the doses resulted in serum
concentrations of IGF-I similar to those of normal rats (40). Glucose
concentrations were not altered by IGF-I treatment, indicating that the
treatment did not induce hypoglycemia. This result is in agreement with
the observation that more frequent injections of IGF-I had no effect on
blood glucose concentrations, whereas few daily doses resulted in
hypoglycemia (45). The dose of thyroxine (10 µg · kg1 · day
1)
has been shown to be physiological with respect to plasma
concentrations of thyroxine (30) and longitudinal bone growth (43). A
dose of 500 µg/kg cortisone per day has been shown to be within the physiological range with respect to body growth and longitudinal bone
growth (22) and GH binding (9).
Although these results indicate that the effects of GH on body composition may be partly mediated via increased circulating levels of IGF-I, the effect of IGF-I treatment of Hx rats differs in some aspects from effects of GH. We have shown that GH treatment of Hx rats increased lipoprotein lipase activity in skeletal muscle but did not affect this activity in adipose tissue. In contrast, IGF-I treatment had no effect on muscle lipoprotein lipase activity but decreased lipoprotein lipase activity in adipose tissue (33). Thus it is possible that the inhibition of lipoprotein lipase activity in adipose tissue after IGF-I treatment is also due to the decreased serum insulin levels.
Moreover, GH-treated Hx rats and human GH transgenic mice have unaltered or decreased serum triglyceride levels, whereas IGF-I-treated Hx rats and IGF-I transgenic mice have increased serum triglyceride levels (32, 35, 40). Thus several effects of GH on lipid metabolism are not mediated via IGF-I; rather, IGF-I may modulate the effect of GH both at the level of GH secretion and insulin secretion.
However, IGF-I and GH may also act in concert, e.g., decrease body fat
mass. For example, GH treatment of Hx rats increased catecholamine-stimulated lipolysis, an effect that has been shown to be
partly due to an increase in -adrenergic receptor numbers (46). Thus
it is possible that the increased lipolytic responsiveness induced by
GH may be partly mediated via IGF-I.
Our results suggest that IGF-I reduces body fat mass via an inhibition of the lipogenic capacity of adipocytes. IGF-I probably reduces lipogenesis in adipose tissue via inhibition of insulin secretion. Moreover, an increased catecholamine-inducible lipolysis may also contribute to reduced body fat mass. In view of the present results and previous reports, it seems appropriate to conclude that IGF-I plays an important role in the regulation of intermediary metabolism, serving as a modulator of the effects of GH and insulin in this regulation. The potential of IGF-I for treatment of type II diabetes is further substantiated in this study by the findings of a decreased lipogenesis in adipose tissue and an insulin-like effect in skeletal muscle.
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ACKNOWLEDGEMENTS |
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We thank Birgitta Odén and Barbro Basta for excellent technical assistance, and Genentech, Inc., for the generous gift of IGF-I.
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FOOTNOTES |
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The study was supported by grants from the Swedish Medical Research Council (8269), the Nordisk Insulin Foundation, the Handlaren Hjalmar Svenssons Foundation, the Magnus Bergvalls Foundation, the Åke Wibergs Foundation, the King Gustav V's and Oueen Victoria's Foundation, the Tore Nilson Foundation, and The Swedish Medical Society.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: S. Edén, Dept of Physiology, Göteborg University, Box 434, S-405 30 Göteborg, Sweden (E-mail: staffan.eden{at}fysiologi.gu.se).
Received 24 June 1999; accepted in final form 8 November 1999.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Bilan, PJ,
Mitsumoto Y,
Ramlal T,
and
Klip A.
Acute and long-term effects of insulin-like growth factor 1 on glucose transporters in muscle cells.
FEBS Lett
298:
285-290,
1992[ISI][Medline].
2.
Binoux, M.
The IGF system in metabolism regulation.
Diabete Metab
21:
330-337,
1995[ISI][Medline].
3.
Carlsson, L,
Nilsson I,
and
Oscarsson J.
Hormonal regulation of liver fatty acid-binding protein in vivo and in vitro: effects of growth hormone and insulin.
Endocrinology
139:
2699-2709,
1998
4.
Clemmons, DR,
Thissen JP,
Maes M,
Ketelslegers JM,
and
Underwood LE.
Insulin-like growth factor-I (IGF-I) infusion into hypophysectomized rats induces specific IGF-binding proteins in serum.
Endocrinology
125:
2967-2972,
1989[Abstract].
5.
Dimitriadis, G,
Parry-Billings M,
Dunger D,
Bevan S,
Colquhoun A,
Taylor A,
Calder P,
Krause U,
Wegener G,
and
Newsholme EA.
Effects of in-vivo administration of insulin-like growth factor-1 on the rate of glucose utilization in the soleus muscle of the rat.
J Endocrinol
133:
37-43,
1992[Abstract].
6.
Dole, VP,
and
Meinerz H.
Microdetermination of long-chain fatty acids in plasma and tissues.
J Biol Chem
235:
2595-2599,
1960[ISI][Medline].
7.
Dunger, DB,
Cheetman TD,
and
Crowne EC.
Insulin-like growth factors (IGFs) and IGF-1 treatment in the adolescent with insulin-dependent diabetes mellitus.
Metabolism
44:
119-123,
1995[ISI][Medline].
8.
Froesch, ER,
Schmid C,
Schwander J,
and
Zapf J.
Actions of insulin-like growth factors.
Annu Rev Physiol
47:
443-467,
1985[ISI][Medline].
9.
Gause, I,
Edén S,
DiGirolamo M,
and
Smith U.
Changes in growth hormone binding and metabolic effects of growth hormone in rat adipocytes following hypophysectomy.
Acta Physiol Scand
124:
229-238,
1985[ISI][Medline].
10.
Gause, I,
Edén S,
Jansson JO,
and
Isaksson O.
Effects of in vivo administration of antiserum to rat growth hormone on body growth and insulin responsiveness in adipose tissue.
Endocrinology
112:
1559-1566,
1983[Abstract].
11.
Gause, I,
Isaksson O,
Lindahl A,
and
Edén S.
Effect of insulin treatment of hypophysectomized rats on adipose tissue responsiveness to insulin and growth hormone.
Endocrinology
116:
945-951,
1985[Abstract].
12.
Gliemann, J,
Österlind K,
Vinten J,
and
Gammeltoft S.
A procedure for measurement of distribution spaces in isolated fat cells.
Biochim Biophys Acta
286:
1-9,
1972[ISI][Medline].
13.
Guler, HP,
Zapf J,
and
Froesch ER.
Short-term metabolic effects of recombinant human insulin-like growth factor 1 in healthy adults.
N Engl J Med
317:
137-140,
1987[Abstract].
14.
Guler, HP,
Zapf J,
Schweiwiller E,
and
Froesch ER.
Recombinant human insulin-like growth factor 1 stimulates growth and has distinct effects on organ size in hypophysectomized rats.
Proc Natl Acad Sci USA
85:
4889-4893,
1988[Abstract].
15.
Hirsch, J,
and
Gallian E.
Methods for the determination of adipose cell size in man and animals.
J Lipid Res
9:
110-119,
1968
16.
Hossenlopp, P,
Seurin D,
Segovia-Quinson B,
Hardouin S,
and
Binoux M.
Analysis of serum insulin-like growth factor binding proteins using Western blotting: use of the method for titration of the binding proteins and competitive binding studies.
Anal Biochem
154:
138-143,
1986[ISI][Medline].
17.
Humbel, RE.
Insulin-like growth factor 1 and II.
Eur J Biochem
190:
445-462,
1990[ISI][Medline].
18.
Hussain, MA,
Schmitz O,
Christiansen JS,
Zapf J,
and
Froesch ER.
Metabolic effects of insulin-like growth factor-1: a focus on insulin sensitivity.
Metabolism
44:
108-112,
1995[ISI][Medline].
19.
Hussain, MA,
Schmitz O,
Mengel A,
Glatz Y,
Christiansen JS,
Zapf J,
and
Froesch ER.
Comparison effects of growth hormone and insulin-like growth factor 1 on substrate oxidation and on insulin sensitivity in growth hormone-deficient humans.
J Clin Invest
94:
1126-1133,
1994[ISI][Medline].
20.
Hussain, MA,
Schmitz O,
Mengel A,
Keller A,
Christiansen JS,
Zapf J,
and
Froesch ER.
Insulin-like growth factor 1 stimulates lipid oxidation, reduces protein oxidation, and enhances insulin sensitivity in humans.
J Clin Invest
92:
2249-2256,
1993[ISI][Medline].
21.
Isgaard, J,
Carlsson L,
Isaksson OP,
and
Jansson J.
Pulsatile intravenous growth hormone (GH) infusion to hypophysectomized rats increases insulin-like growth factor 1 messenger RNA in skeletal tissues more effectively than continuous GH infusion.
Endocrinology
123:
2605-2610,
1988[Abstract].
22.
Jansson, JO,
Albertsson-Wikland K,
Edén S,
Thorngren KG,
and
Isaksson O.
Circumstantial evidence for a role of the secretory pattern of growth hormone in control of body growth.
Acta Endocrinol
99:
24-30,
1982[ISI][Medline].
23.
Jansson, JO,
Albertsson-Wikland K,
Edén S,
Thorngren KG,
and
Isaksson O.
Effect of frequency of growth hormone administration on longitudinal bone growth and body weight in hypophysectomized rats.
Acta Physiol Scand
114:
261-265,
1982[ISI][Medline].
24.
King, GL,
Kahn CR,
Rechller MM,
and
Nissley SP.
Direct demonstration of separate receptors for growth and metabolic activities of insulin and multiplication stimulating activity (an insulin-like growth factor) using antibodies to the insulin receptors.
J Clin Invest
66:
130-140,
1980[ISI][Medline].
25.
Laron, Z,
Avitzur Y,
and
Klinger B.
Carbohydrate metabolism in primary growth hormone resistance (Larons syndrome) before and during insulin-like growth factor-1 treatment.
Metabolism
44:
113-118,
1995[ISI][Medline].
26.
Laurell, S,
and
Tibbling G.
An enzymatic fluorometric micromethod for the determination of glycerol.
Clin Chem Acta
13:
317-322,
1966[ISI][Medline].
27.
Leahy, JL,
and
Vandekerkhove KM.
Insulin-like growth factor-1 at physiological concentrations is a potent inhibitor of insulin secretion.
Endocrinology
126:
1593-1598,
1990[Abstract].
28.
Lundholm, K,
and
Scherstén T.
Gluconeogenesis in human liver tissue; an in vitro method for the evaluation of gluconeogenesis in man.
Scand J Clin Lab Invest
36:
339-345,
1976[ISI][Medline].
29.
Moses, AD.
Recombinant insulin-like growth factor-1 as therapy of altered carbohydrate homeostasis.
Curr Op Endocrinol Diabetes
4:
16-25,
1997.
30.
Mälkönen, M,
and
Manninen V.
Faliure of thyoid hormones to maintain normal lipoprotein patterns after removal of the pituitary gland.
Atherosclerosis
38:
121-128,
1981[ISI][Medline].
31.
Oscarsson, J,
Olofsson S,
Bondjers G,
and
Edén S.
Differential effects of continuous vs. intermittent administration of growth hormone to hypophysectomized female rats on serum lipoproteins and their apoproteins.
Endocrinology
125:
1638-1649,
1989[Abstract].
32.
Oscarsson, J,
Olofsson SO,
Vikman K,
and
Edén S.
Growth hormone regulation of serum lipoproteins in the rat: different growth hormone regulatory principles for apolipoprotein (apo) B and the sexually dimorphic apo E concentrations.
Metabolism
11:
191-198,
1991.
33.
Oscarsson, J,
Ottosson M,
Vikman-Adolfsson K,
Frick F,
Enerbäck S,
Lithell H,
and
Edén S.
Growth hormone but not IGF-1 or insulin increases lipoprotein lipase activity in muscle tissues of hypophysectomized rats.
J Endocrinol
160:
247-255,
1999
34.
Poggi, C,
Le Marchand-Brustel Y,
Zapf J,
Froesch ER,
and
Freychet P.
Effects and binding of insulin-like growth factor 1 in the isolated soleus muscle of lean and obese mice: comparison with insulin.
Endocrinology
105:
723-730,
1979[ISI][Medline].
35.
Quaife, CJ,
Mathews LS,
Pinkert CA,
Hammer R,
Brinster RL,
and
Palmiter RD.
Histopathology associated with elevated levels of growth hormone and insulin-like growth factor 1 in transgenic mice.
Endocrinology
124:
40-48,
1989[Abstract].
36.
Rennert, NJ,
Caprio S,
and
Sherwin RS.
Insulin-like growth factor 1 inhibits glucose-stimulated insulin secretion but does not impair glucose metabolism in normal humans.
J Clin Endocrinol Metab
76:
804-806,
1993[Abstract].
37.
Rodbell, M.
Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis.
J Biol Chem
239:
375-380,
1964
38.
Schmitz, F,
Hartmann H,
Stümpel F,
and
Creutzfeldt W.
In vivo metabolic action of insulin like growth factor 1 in adult rats.
Diabetologia
34:
144-149,
1991[ISI][Medline].
39.
Schoenle, E,
Zapf J,
Humbel R,
and
Froesch ER.
Insulin-like growth factor 1 stimulates growth in hypophysectomized rats.
Nature
296:
252-253,
1982[ISI][Medline].
40.
Sjöberg, A,
Oscarsson J,
Olofsson SO,
and
Edén S.
Insulin-like growth factor and growth hormone have different effects on serum lipoproteins and secretion of lipoproteins from cultured rat hepatocytes.
Endocrinology
135:
1415-1421,
1994[Abstract].
41.
Smith, U,
Sjöström L,
and
Björntorp P.
Comparison of two methods of determining human adipose cell size.
J Lipid Res
13:
822-824,
1972
42.
Tamura, K,
Kobayashi M,
Ishii Y,
Tamura T,
Hashimoto K,
Nakumara S,
Niwa M,
and
Zapf J.
Primary structure of rat insulin-like growth factor-1 and its biological activities.
J Biol Chem
264:
5616-5621,
1989
43.
Thorngren, KG,
and
Hansson LI.
Effect of thyroxine and growth hormone on longitudinal bone growth in the hypophysectomized rat.
Acta Endocrinol
74:
24-40,
1973[ISI][Medline].
44.
Tomas, FM,
Knowles SE,
Owens PC,
Chandler CS,
Francis GL,
and
Ballard FJ.
Insulin-like growth factor-1 and more potent variants restore growth of diabetic rats without inducing all characteristic insulin effects.
Biochem J
291:
781-786,
1993[ISI][Medline].
45.
Woodall, SM,
Breier BH,
O'Sullivan U,
and
Gluckman PD.
The effect of the frequency of subcutaneous insulin-like growth factor-1 administration on weight gain in growth hormone deficient mice.
Horm Metab Res
23:
581-584,
1991[ISI][Medline].
46.
Yang, S,
Björntorp P,
Xinglu L,
and
Edén S.
Growth hormone treatment of hypophysectomized rats increases catecholamine-induced lipolysis and the number of -adrenergic receptors in adipocytes: no differences in the effects of growth hormone on different fat depots.
Obes Res
4:
471-478,
1996[Abstract].
47.
Yu, KT,
and
Czech MP.
The type 1 insulin-like growth factor receptor mediates the rapid effects of multiplication-stimulation activity on membrane transport systems in rat soleus muscle.
J. Biol. Chem.
259:
3090-3095,
1984
48.
Zapf, J,
Schoenle E,
Waldvogel M,
Sand I,
and
Froesch ER.
Effect of trypsin treatment of rat adipocytes on biological effects and binding of insulin and insulin-like growth factors.
Eur. J. Biochem.
113:
605-609,
1981[Abstract].