Effects of repeated subcutaneous administration of recombinant human insulin-like growth factor I in adults with growth hormone deficiency

1994 ◽  
Vol 131 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Maria C Thorén ◽  
Inga-Lena Wivall-Helleryd ◽  
Werner F Blum ◽  
Kerstin E Hall
Keyword(s):  
Growth Factor ◽  
Subcutaneous Administration ◽  
Metabolic Effects ◽  
Hormone Deficiency ◽  
Insulin Like Growth Factor ◽  
Recombinant Human Insulin ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Igfbp 3

Thorén MC, Wivall-Helleryd I-L. Blum WF, Hall KE. Effects of repeated subcutaneous administration of recombinant human insulin-like growth factor I in adults with growth hormone deficiency. Eur J Endocrinol 1994;131:33–40. ISSN 0804–4643 Insulin-like growth factor I (IGF-I) circulates bound to specific binding proteins (BPs) that modulate its effects at target cells. Hypoglycemia alters the serum levels of insulin-dependent IGFBPs and thus modifies the IGF-I action. We administered recombinant IGF-I (40 μg/kg body wt, from Kabi Pharmacia) in a morning dose (08.00 h) for seven consecutive days to six patients (21–47 years) with panhypopituitarism. This dose did not lead to hypoglycemia. Repeated blood sampling was performed on days 1 and 7, otherwise morning samples were drawn. The mean serum total IGF-I was maximal 3–4 h after the injection. A higher peak and basal value (p < 0.05) was observed on day 7 when compared to that observed on day 1. The concentrations were 237 vs 190 μg/l and 43 vs 22 μg/l. The mean free IGF-I increased concomitantly to 17 and 20 μg/l after 2–3 h on days 1 and 7. After 4 h, IGF-II was decreased (p <0.05) from 340 to 291 μg/l on day 1 and from 341 to 252 μg/l on day 7. The IGF-I area under the curve on days 1 and 7 was correlated to the IGFBP-3 levels. Only the patient with the highest IGFBP-3 level obtained IGF-I levels above 100 μg/l for 24 h. In spite of unchanged glucose levels, there was a modest suppression of insulin levels (p < 0.05) between 0 and 4 h from 102 to 78 pmol/l on day 1 and from 90 to 60 pmol/l on day 7 when the subjects were fasting. A small decline of mean potassium concentrations was found 2–6 h after the injection on day 1. During a week with daily injections, the morning serum IGF-I increased slightly in comparison to basal levels but no significant change in morning values of IGFBP-1, -2, -3, glucose and insulin were observed. Serum urea, creatinine, cholesterol and free fatty acid decreased significantly, indicating metabolic effects of IGF-I. Thus IGF-I has metabolic effects in doses not leading to hypoglycemia. To achieve a normal diurnal IGF-I level, recombinant IGF-I should be administered two or three times per 24 h in subjects with subnormal IGFBP-3 levels. Marja Thorén, Department of Endocrinology and Diabetology, Karolinska Hospital, S-171 76 Stockholm, Sweden

scholarly journals Effects of Recombinant Human Insulin-Like Growth Factor I Administration on Spontaneous and Growth Hormone (GH)-Releasing Hormone-Stimulated GH Secretion in Anorexia Nervosa1

2000 ◽  
Vol 85 (8) ◽  
pp. 2805-2809
Author(s):  
Laura Gianotti ◽  
Angela I. Pincelli ◽  
Massimo Scacchi ◽  
Mimma Rolla ◽  
Deanna Bellitti ◽  
...  
Keyword(s):  
Growth Factor ◽  
Normal Weight ◽  
Insulin Like Growth Factor ◽  
Recombinant Human Insulin ◽  
Releasing Hormone ◽  
Gh Secretion ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Igfbp 3

Exaggerated GH and reduced insulin-like growth factor I (IGF-I) levels are common features in anorexia nervosa (AN). A reduction of the negative IGF-I feedback could account, in part, for GH hypersecretion. To ascertain this, we studied the effects of recombinant human (rh)IGF-I on spontaneous and GH-releasing hormone (GHRH)-stimulated GH secretion in nine women with AN [body mass index, 14.1 ± 0.6 kg/m2] and in weight matched controls (normal weight). Mean basal GH concentrations (mGHc) and GHRH (2.0μ g/kg, iv) stimulation were significantly higher in AN. rhIGF-I administration (20 μg/kg, sc) significantly reduced mGHc in AN (P &lt; 0.01), but not normal weight, and inhibited peak GH response to GHRH in both groups; mGHc and peak GH, however, persisted at a significantly higher level in AN. Insulin, glucose, and IGFBP-1 basal levels were similar in both groups. rhIGF-I inhibited insulin in AN, whereas glucose remained unaffected in both groups. IGFBP-1 increased in both groups (P &lt; 0.05), with significantly higher levels in AN. IGFBP-3 was under basal conditions at a lower level in AN (P &lt; 0.05) and remained unaffected by rhIGF-I. This study demonstrates that a low rhIGF-I dose inhibits, but does not normalize, spontaneous and GHRH-stimulated GH secretion in AN, pointing also to the existence of a defective hypothalamic control of GH release. Moreover, the increased IGFBP-1 levels might curtail the negative IGF-I feedback in AN.

Pharmacokinetics of insulin-like growth factor I in hypopituitarism: correlation with binding proteins

1999 ◽  
Vol 277 (4) ◽  
pp. E579-E584 ◽  
Author(s):  
Nelly Mauras ◽  
Valerie Quarmby ◽  
Duane C. Bloedow
Keyword(s):  
Growth Factor ◽  
Half Life ◽  
Binding Proteins ◽  
Hormone Deficiency ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Normal Absorption ◽  
Igf I ◽  
Growth Factor I ◽  
Igfbp 3

We investigated the pharmacokinetics of recombinant human insulin-like growth factor I (rhIGF-I) in growth hormone deficiency (GHD). Nine GHD adults [age 25 ± 3 (SE) yr] received rhIGF-I (60 μg/kg sc) twice, 10 h apart, and blood was sampled over 24 h. IGF-I and free IGF-I concentrations increased, whereas IGF binding protein 3 (IGFBP-3) and acid labile subunit (ALS) were unchanged during treatment. There was no correlation between absorption or terminal half-life of IGF-I and IGFBP-3 or ALS, but negative correlations with IGF-I clearance (CL/F) and volume of distribution (V/F). Positive correlations between both IGFBP-3 and ALS and IGF-I maximal concentration (Cmax) and time of Cmax( T max) were observed. Compared with normal individuals studied similarly (using 80 μg/kg), GHD subjects showed a normal absorption half-life, a faster elimination half-life, lower Cmax, yet normal T maxand V/F. In conclusion, GHD is associated with normal absorption and distribution of IGF-I yet faster elimination kinetics. Additionally, IGFBP-3 and ALS concentrations modulate the peak concentrations of IGF-I achieved and correlate reciprocally with its V/F and CL/F, underscoring the critical importance of binding proteins in modulating the bioavailability of IGF-I in vivo in humans.

Insulin-like growth factor I accelerates protein synthesis in skeletal muscle during sepsis

1995 ◽  
Vol 269 (5) ◽  
pp. E977-E981 ◽  
Author(s):  
C. V. Jurasinski ◽  
T. C. Vary
Keyword(s):  
Protein Synthesis ◽  
Growth Factor ◽  
Peptide Chain ◽  
Translational Efficiency ◽  
Insulin Like Growth Factor ◽  
Recombinant Human Insulin ◽  
Chain Initiation ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Sepsis causes an inhibition of protein synthesis in gastrocnemius that is resistant to the anabolic effects of insulin. The purpose of the present studies was to investigate the effect of recombinant human insulin-like growth factor I (IGF-I) on protein synthesis during a 30-min perfusion of the isolated rat hindlimb from septic rats. Inclusion of IGF-I (1 or 10 nM) in the perfusate stimulated protein synthesis in gastrocnemius of septic rats 2.5-fold and restored rates of protein synthesis to those observed in control rats. The stimulation of protein synthesis did not result from an increase in the RNA content but was correlated with a 2.5-fold increase in the translational efficiency. The enhanced translational efficiency was accompanied by a 33 and 55% decrease in the abundance of free 40S and 60S ribosomal subunits, respectively, indicating that IGF-I accelerated peptide-chain initiation relative to elongation/termination. These studies provide evidence that IGF-I can accelerate protein synthesis in gastrocnemius during chronic sepsis by reversing the sepsis-induced inhibition of peptide-chain initiation.

Beneficial metabolic effects of insulin-like growth factor I in patients with severe insulin-resistant diabetes type A

1994 ◽  
Vol 131 (3) ◽  
pp. 251-257 ◽  
Author(s):  
Peter D Zenobi ◽  
Yvonne Glatz ◽  
Annamarie Keller ◽  
Susanne Graf ◽  
Silvia E Jaeggi-Groisman ◽  
...  
Keyword(s):  
Growth Factor ◽  
Type A ◽  
Metabolic Effects ◽  
Insulin Like Growth Factor ◽  
Severe Insulin Resistance ◽  
Insulin Resistant ◽  
Glucose Levels ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Zenobi PD, Glatz Y, Keller A, Graf S, Jaeggi-Groisman SE, Riesen WF, Schoenle EJ, Froesch ER. Beneficial metabolic effects of insulin-like growth factor I in patients with severe insulin-resistant diabetes type A. Eur J Endocrinol 1994;131:251–7. ISSN 0804–4643 Severe insulin resistance type A is due to mutations in the insulin receptor gene and is characterized by glucose intolerance or diabetes mellitus, despite extreme hyperinsulinemia, virilization and acanthosis nigricans. At present, there is no therapy for this condition. Recently, we showed that glucose levels in three such patients are promptly lowered by an iv bolus of recombinant human insulin-like growth factor I (rhIGF-I). In the present study, we investigated two of these rare patients again and determined fasting and postprandial glucose, insulin, C-peptide, proinsulin and lipid levels during five control, five treatment and three wash-out days while on a constant diet. Treatment consisted of 2 × 150 μg rhIGF-I/kg sc per day, which elevated total IGF-I levels 4.5-fold above the control. Fasting glucose levels (days 1–5) in the two patients were 9.6±1.3 and 9.2 ± 1.2 mmol/l, respectively, and fell to 4.4±0.4 and 5.1±0.5 mmol/l on treatment days 8–10. Fasting insulin (2950±450 and 690±125 pmol/l), C-peptide (2217±183 and 1317±235 pmol/l) and proinsulin control levels (125±35 and 66±0 pmol/l) also decreased by ~65% during rhIGH-I treatment, as did the respective postprandial levels. Lipid levels hardly changed at all. In conclusion, IGF-I appears to correct partially some metabolic sequelae of severe insulin resistance and may, hence, be used as a new therapeutic agent. E Rudolf Froesch, Department of Internal Medicine, University Hospital, Rämistrasse 100, 8091 Zurich, Switzerland

O-Mannosylation of recombinant human insulin-like growth factor I (IGF-I) produced inSaccharomyces cerevisiae

FEBS Letters ◽  
1989 ◽  
Vol 248 (1-2) ◽  
pp. 111-114 ◽  
Author(s):  
Karl Hård ◽  
Wilbert Bitter ◽  
Johannis P. Kamerling ◽  
Johannes F.G. Vliegenthart
Keyword(s):  
Growth Factor ◽  
Human Insulin ◽  
Insulin Like Growth Factor ◽  
Recombinant Human Insulin ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Effects of octreotide on insulin-like growth factor I and metabolic indices in growth hormone-treated growth hormone-deficient patients

1993 ◽  
Vol 129 (5) ◽  
pp. 399-408 ◽  
Author(s):  
Torben Laursen ◽  
Jens OL Jorgensen ◽  
Hans Ørskov ◽  
Jens Møller ◽  
Alan G Harris ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Animal Studies ◽  
Area Under The Curve ◽  
Insulin Like Growth Factor ◽  
Gh Secretion ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Igfbp 3

Animal studies have demonstrated that in addition to inhibiting growth hormone (GH) secretion octreotide inhibits in a direct manner hepatic or peripheral insulin-like growth factor I (IGF-I) generation. To test this hypothesis in humans we studied ten GH-deficient patients with frequent blood sampling during 38 h on two occasions. Regular GH therapy was discontinued 72 h prior to each study period. At the start of each study a subcutaneous (sc) injection of GH (3 IU/m2) was given (at 18.00 h). In a single-blinded crossover design, patients received a continuous sc infusion of either octerotide (200 μg/24 h) or placebo (saline). The pharmacokinetics of GH were similar on the two occasions. The area under the curve±sem of serum GH was 142.5±53.6 μg·l−1·h−1 (octreotide) and 144.8±41.8 μg·l−1·h−1 (placebo), (p=0.73); Cmax (μg/l) was 12.5±1.47 (octreotide) and 12.8±1.42 (placebo) (p=0.83), and Tmax (h) was 6.1±0.97 (octreotide) and 5.2±0.65 (placebo) (p=0.49). Growth hormone administration was associated with an increase in serum IGF-I (μg/l), which was identical during the two studies, from 85.3±19.4 to 174.25±30.3 for octreotide and from 97.0±26.4 to 158.8±28.2 for placebo. Mean IGF-I levels (μg/l) were 138.2±25.1 (octreotide) and 134.5±28.6 (placebo) (p=0.78). Similarly, the increase in IGF binding protein 3 (IGFBP-3) levels was identical. Mean IGFBP-3 levels (μg/l) were 2303±323 (octreotide) and 2200±361 (placebo) (p=0.25). Mean insulin levels were significantly lower during octreotide treatment (39.9±17.9 mU/l) than during placebo (59.7±17.8 mU/l) (p<0.05). Mean blood glucose levels were elevated significantly during octreotide infusion (5.98±0.23 mmol/l for octreotide and 5.07±0.16 mmol/l for placebo; p=0.001). Glucagon levels decreased non-significantly (p=0.07) and IGFBP-1 levels tended to increase during infusion of octreotide although not significantly (p=0.41). Levels of the lipid intermediates were identical on the two occasions. Alanine and lactate levels were significantly increased during octreotide infusion. Mean levels of blood alanine (μmol/l) were 470.8±24.2 (octreotide) and 360.1±17.8 (placebo) (p<0.02). Mean levels of blood lactate were 1038±81.0 (octreotide) and 894.4±73.8 (placebo) (p<0.04). We conclude that short-term continuous sc infusion of octreotide has no direct effect on the generation of IGF-I or the pharmacokinetics of exogenous GH in GH-deficient man.

scholarly journals Effects of Recombinant Human Insulin-Like Growth Factor I Administration on Growth Hormone (GH) Secretion, Both Spontaneous and Stimulated by GH-Releasing Hormone or Hexarelin, a Peptidyl GH Secretagogue, in Humans1

1999 ◽  
Vol 84 (1) ◽  
pp. 285-290
Author(s):  
E. Ghigo ◽  
L. Gianotti ◽  
E. Arvat ◽  
J. Ramunni ◽  
M. R. Valetto ◽  
...  
Keyword(s):  
Growth Factor ◽  
Negative Feedback ◽  
Inhibitory Effect ◽  
Insulin Like Growth Factor ◽  
Recombinant Human Insulin ◽  
Gh Secretion ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Hypothalamic Level

The negative feedback exerted by insulin-like growth factor I (IGF-I) on GH secretion occurs at the pituitary, as well as the hypothalamic level, via stimulation of SS and/or inhibition of GHRH release. In fact, recombinant human IGF-I (rhIGF-I) administration inhibits basal GH secretion, at least in fasted humans, though its effect on the GH response to GHRH is still controversial. GH secretagogues (GHS) are peptidyl and nonpeptidyl molecules that act on specific receptors at the pituitary and/or the hypothalamic level. Contrary to GHRH, the GH-releasing activity of GHS is strong, reproducible, and even partially refractory to inhibitory influences such as exogenous somatostatin. We studied the effects of rhIGF-I administration (20μ g/kg sc at 0 min) on GH secretion, either spontaneous or stimulated by GHRH (2 μg/kg iv at +180 min) or Hexarelin (HEX, 2.0 μg/kg iv at+ 180 min), a GHS, in eight normal young women (age, mean ± sem, 28.3 ± 1.2 yr; body mass index, 20.1± 0.5 kg/m2). rhIGF-I administration increased IGF-I levels (peak vs. baseline: 420.3 ± 30.5 vs. 274.4 ± 25.3 μg/L, P &lt; 0.05) within the physiological range from +120 to +300 min. No variation in glucose or insulin levels was recorded. rhIGF-I did not reduce spontaneous GH secretion [areas under curves (AUC)0–300 min 140.6± 66.3 vs. 114.6 ± 32.1 μg/L·h], whereas it inhibited the GH response to both GHRH (AUC180–300 min 447.7 ± 159.4 vs. 715.9 ± 104.3 μg/L·h, P &lt; 0.05) and HEX (620.3 ± 110.4 vs. 1705.9 ± 328.9 μg/L·h, P &lt; 0.03). The percent inhibitory effect of rhIGF-I on the GH response to GHRH (41.7 ± 12.8%) was lower than that on the response to HEX (57.7 ± 11.0%). In fact, the GH response to GHRH alone was clearly lower than that to HEX alone (P &lt; 0.05), whereas the GH responses to GHRH and HEX were similar after rhIGF-I. Our findings show that the sc administration of low rhIGF-I doses inhibits the GH response to GHRH and, even more, that to HEX; whereas, at least in this experimental design in fed conditions, it does not modify the spontaneous GH secretion. Because GHS generally show partial refractoriness to inhibitory inputs, including exogenous somatostatin, the present results point toward a peculiar sensitivity of GHS to the negative feedback action of IGF-I.

scholarly journals Hyperlipidemia is associated with altered levels of insulin-like growth factor-I

2008 ◽  
pp. 919-925
Author(s):  
J Malík ◽  
T Štulc ◽  
D Wichterle ◽  
V Melenovský ◽  
E Chytilová ◽  
...  
Keyword(s):  
Growth Factor ◽  
Coronary Atherosclerosis ◽  
Molar Ratio ◽  
Insulin Like Growth Factor ◽  
Premature Atherosclerosis ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Mixed Hyperlipidemia ◽  
Igfbp 3

Previous studies revealed altered levels of the circulating insulin-like growth factor-I (IGF-I) and of its binding protein-3 (IGFBP-3) in subjects with coronary atherosclerosis, metabolic syndrome and premature atherosclerosis. Hyperlipidemia is a powerful risk factor of atherosclerosis. We expected IGF-I and IGFBP-3 alterations in subjects with moderate/severe hyperlipidemia but without any clinical manifestation of atherosclerosis. Total IGF-I and IGFBP-3 were assessed in 56 patients with mixed hyperlipidemia (MHL; cholesterol >6.0 mmol/l, triglycerides >2.0 mmol/l), in 33 patients with isolated hypercholesterolemia (IHC; cholesterol >6.0 mmol/l, triglycerides <2.0 mmol/l), and in 29 healthy controls (cholesterol<6.0 mmol/l, triglycerides<2.0 mmol/l). The molar ratio of IGF-I/IGFBP-3 was used as a measure of free IGF-I. IHC subjects differed from controls by lower total IGF-I (164+/-60 vs. 209+/-73 ng/ml, p=0.01) and IGF-I /IGFBP-3 ratio (0.14+/-0.05 vs. 0.17+/-0.04, p=0.04). Compared to controls, MHL subjects had lower total IGF-I (153+/-54 ng/ml, p=0.0002) and IGFBP-3 (2.8+/-0.6 mg/ml, p<0.0001), but higher IGF-I/IGFBP-3 ratio (0.25+/-0.06, p<0.0001). Differences remained significant after the adjustment for clinical and biochemical covariates, except for triglycerides. Patients with both IHC and MHL have lower total IGF-I compared to controls. The mechanism is presumably different in IHC and MHL. Because of prominent reduction of IGFBP-3 in patients with MHL, they have reduced total IGF-I despite the actual elevation IGF-I/IGFBP-3 ratio as a surrogate of free IGF-I.

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