Insulin-like Growth Factor-1 Infusion Research Articles

Action of long(R 3)-insulin-like growth factor-1 on protein metabolism in beef heifers

Insulin-like growth factor-1 (IGF-1) is perhaps the most important endogenous factor controlling growth. Most studies to date in livestock have shown that IGF-1 has greatest efficacy when animals are in a catabolic state. We have determined the effects of an iv infusion of the IGF-1 analog Long(R 3)-IGF-1 on protein metabolism in beef heifers that were slowly losing liveweight because of restricted feeding. There was a tendency for both whole-body protein and skeletal muscle protein to be conserved in Long(R 3)-IGF-1-treated heifers. Long(R 3)-IGF-1 administration markedly reduced the plasma concentrations of all amino acids measured and glucose. There was a significant change in the profile differences of endogenous plasma IGF-1 concentrations during the 8-hr infusion period, with plasma IGF-1 decreasing sharply in the test group. There was a significant difference in mean profiles for plasma IGF-2 between the test and control groups. Overall, plasma IGF-2 for the control group decreased only slightly over time (about 40 ng/ml), whereas the test group decreased dramatically (by about 140 ng/ml). Increased plasma concentrations of a 31–32-kDa IGF-binding protein (possibly IGF-binding protein-1) in the treated group was detected by radioligand blot. We found that Long(R 3)-IGF-1 infusion tended to preserve whole-body and muscle protein in beef heifers on a low-quality diet, and suggest that further investigation of this treatment may provide an alternative approach to reducing weight loss during the dry season.

Hypoglycemic Effects of Insulin-Like Growth Factor-1 in Experimental Uremia: Can Concomitant Growth Hormone Administration Prevent This Effect?

The risk of hypoglycemia limits the clinical application of insulin-like growth factor-1 (IGF-1). Our studies aimed to evaluate the mode of occurrence as well as the prevention of this side effect. Acute administration (i.v. infusion) of IGF-1 in subtotal nephrectomized uremic (U), sham-operated ad libitum fed control (C) and sham-operated pair-fed control (P) rats led to hypoglycemia, though more expressed in P. Serum glucose levels decreased within 60 min after the IGF-1 administration by 40% in U, by 45% in C and by 52% in P (p < 0.05, U vs. P). Chronic administration (7 days) of 1, 4 and 8 mg/kg/day IGF-1 in U rats led to hypoglycemia in an increasing manner as the dose of IGF-1 increased. On the first day, 2 h after injection, serum glucose levels were 116.5 ± 8.6, 110.4 ± 12.4, 60,3 ± 19.2 and 50.6 ± 18.3 mg/dl, respectively (p < 0.01). One week later, IGF-1 therapy proved to be less hypoglycemic in all the groups. On day 7, 2 h after injection the serum glucose levels were 118.9 ± 23.8, 89.0 ± 23.9 and 66.0 ± 32.0, respectively (in comparison to day 1 for 4 and 8 mg/kg/day IGF-1 p < 0.05). The combined effect of 4 mg/kg/day IGF-1 and 10 IU/kg/day growth hormone (GH) was also studied in U and P animals. Two hours after the first injections of IGF-1 serum glucose levels decreased in U from 120.0 ± 11.3 to 49.2 ± 21.6 mg/dl, while IGF-1 plus GH decreased the glucose level from 122.0 ± 15.5 to 81.3 ± 24.7 mg/dl (p < 0.05 IGF-1 vs. IGF-1 + GH). The hypoglycemic effect of IGF-1 was less expressed by long-term treatment and simultanous administration of GH overcame the glucose-lowering effect of IGF-1 (serum glucose levels on day 11 one hour after the injections: 73.7 ± 15.3 mg/dl with IGF-1, and 111.0 ± 7.8 mg/dl with IGF-1 + GH). Methylprednisolone (MP) did not significantly alter the former effects of IGF-1 and GH. In summary, IGF-1 leads to hypoglycemia in control and uremic rats in a dose-dependent manner. This effect becomes less expressed after prolonged administration. GH attenuates the hypoglycemic effect of IGF-1. This suggests that the combined GH and IGF-1 treatment is more effective and less dangerous in correcting uremic growth failure.

Regional Blood Flow Dynamics in Response to Insulin and IGF-1 in Diabetic Animals

Vascular changes in diabetes characterized by increased contractile or decreased dilator responses have been demonstrated in isolated blood vessels as well as in vivosystems. Previous studies in our laboratory have demonstrated that insulin and insulin like growth factor-1 (IGF-1) can decrease mean arterial pressure (MAP) and increase blood flow in vascular beds. In this study we evaluated the regional hemodynamic responses to insulin and IGF-1 in normal and diabetic rats. Normal male rats were made diabetic with streptozotocin (55 mg/kg) i.v. and maintained 60 to 70 days. On the day of the study the rats were anesthetized with urethane/chloralose, the femoral artery and vein cannulated for blood pressure monitoring and blood sampling or infusion, respectively. Pulsed-Doppler flow probes were placed around the iliac artery, renal artery and superior mesenteric artery to monitor blood flow. Insulin (16 nmol/kg) was infused as a bolus via the femoral vein and it decreased the MAP approximately 17% in both normal and diabetic rats. Insulin enhanced vascular flow (expressed as conductance) in the iliac and renal vascular bed but not the superior mesenteric vascular bed in normals. In diabetic rats the flow response to insulin compared to normals was attenuated in the iliac and renal vascular beds and increased in the superior mesenteric vascular bed. A bolus infusion of IGF-1 (16 nmol/kg) also decreased the MAP in normals and diabetics. IGF-1 increased vascular flow in all three vascular beds in normals but in the diabetics the response to IGF-1 was artenuated in the iiiac, increased in h e renal vascular bed and suppressed in the superior mesenteric vascularure. From these studies we conciude that diabetes is associated with an anenllared vascular response to insulin and IGF-1 in the iliac and renal vessels while insulin augments and IGF-1 decreases blood flow in the superior mesenteric vasculature

A comparison of changes in whole body and skin amino acid metabolism of sheep in response to 24 h continuous infusions of variants of insulin-like growth factor 1

Because of the economic significance of wool to many sheep production systems, attempts to partition amino acids towards skin and wool protein synthesis have included both nutritional and hormonal methods of manipulation. A variant of insulin-like growth factor 1 (IGF-1) has previously been shown to transiently increase protein synthesis in the skin of sheep and the current study extended that work by comparing the effects of a 24 h, close-arterial, skin infusion of IGF-1, in the form of either recombinant human (rhIGF-1) or an extended variant (LR3IGF-1), on both whole body and skin amino acid metabolism adult, castrated Romney sheep, with three animals allocated to each treatment. There were no differences in food intake between the two treatment groups. The plasma concentration of immunoreactive IGF-1 of sheep infused with rhIGF-1 increased (P &lt; 0.01) with time of administration, but decreased (P &lt; 0.05) after 24 h of LR3IGF-1 infusion. Administration of both IGF-1 variants caused a substantial and sustained decrease in arterial insulin to less than 50% (P &lt; 0.05) of pre-infusion values, while arterial plasma glucose concentrations were only reduced by 7%. Alterations in whole body and skin protein metabolism were assessed from continuous infusions of mixed [U-13C] AA, [2,6 ring 3H]phenylalanine and [35S]cysteine. Within 4 h both AA concentrations and whole body plasma ILR of essential and non-essential AA were decreased (P &lt; 0.05 for seven AA) by IGF-1 infusions. Both IGF1 variants caused acute increases (P &lt; 0.05) in skin blood flow and, for 13 of the 15 AA measured, isotopic transfers (range 50–220%; P &lt; 0.05 for cysteine and tyrosine), which probably reflect increased protein synthesis. By 24 h skin blood flow, AA uptake and protein synthesis had returned to pre-infusion values. Strategies based on exogenous application, or enhanced endogenous production, of IGF-1 are unlikely, therefore, to produce persistent anabolic responses. Key words: Insulin-like growth factor 1, skin, sheep, protein synthesis

Modulation of renal hemodynamics by IGF-1 is absent in spontaneously hypertensive rats

We recently reported that attenuation of vasoactive agent-induced calcium signal and cell contraction of mesangial cell by insulin-like growth factor 1 (IGF-1), observed in normal mesangial cells, is totally abolished in spontaneously hypertensive rat (SHR) mesangial cells. This phenomenon might be related to the well-known aberrant regulation of SHR glomerular hemodynamics. Since it has been reported that in vivo IGF-1 infusion increases renal plasma flow (RPF) and glomerular filtration rate (GFR), we examined whether the modulation of renal function by IGF-1 is altered in SHR. We performed in vivo renal clearance studies using eight-week-old SHR and control Wistar Kyoto rats (WKY) before and after IGF-1 (5 micrograms/kg) infusion into the left renal artery for 20 minutes. Mean arterial pressure was not affected by IGF-1 in both WKY and SHR. In WKY, IGF-1 increased GFR and RPF, and decreased renal vascular resistance (RVR). However, GFR, RPF, and RVR were not altered by IGF-1 in SHR, while systemic infusion of angiotensin II antagonist, CV-11974, increased GFR and RPF. The present data show that the modulation of renal hemodynamics by IGF-1 is absent in SHR. This might be related the pathophysiology of the development of hypertension.

Intravenous infusion of insulin-like growth factor I in fetal sheep reduces hepatic IGF-I and IGF-II mRNAs

Liver contains the highest concentrations of insulin-like growth factor (IGF) I mRNA in adult rats and sheep and is a major source of circulating IGF-I. In rats, inhibition of hepatic IGF-I production by exogenous IGF-I has been reported. In fetal sheep, skeletal muscle and liver are major sites of IGF-I synthesis and potential sources of circulating IGF-I. To determine whether feedback inhibition of IGF gene expression in fetal liver or muscle by IGF-I occurs, IGF-I and IGF-II mRNAs were measured in these tissues after intravenous infusion of recombinant human IGF-I into fetal sheep. Infusion of IGF-I (26 +/- 4 micrograms.h-1.kg-1; n = 6) or saline (n = 6) commenced on day 120 of pregnancy (term = 150 days) and continued for 10 days. Plasma concentrations of IGF-I were threefold higher in infused fetuses at 130 days of gestation (P < 0.0003), whereas those of IGF-II were unchanged. IGF-I infusion reduced the relative abundance of IGF-I mRNA (P < 0.0002) and IGF-II mRNA (P < 0.01) in fetal liver by approximately 50% but did not alter IGF-I or IGF-II mRNA in skeletal muscle. These results indicate that IGF-I inhibits the expression of both IGF-I and IGF-II genes in fetal liver and that IGF gene expression in fetal liver and muscle is differentially regulated by IGF-I.

Insulin-like growth factor I modulates c- fos induction and astrocytosis in response to neurotoxic insult

Insulin-like growth factor I participates in the cellular response to brain insult by increasing its messenger RNA expression and/or protein levels in the affected area. Although it has been suggested that insulin-like growth factor I is involved in a variety of cellular responses leading to homeostasis, mechanisms involved in its possible trophic effects are largely unknown. Since activation of c- Fos in postmitotic neurons takes place both in response to insulin-like growth factor I and after brain injury, we have investigated whether this early response gene may be involved in the actions of insulin-like growth factor I after brain insult. Partial deafferentation of the cerebellar cortex by 3-acetylpyridine injection elicited c-Fos protein expression on both Purkinje and granule cells of the cerebellar cortex. This neurotoxic insult also triggered gliosis, as determined by an increased number of glial fibrillary acidic protein-positive cells (reactive astrocytes) in the cerebellar cortex. When 3-acetylpyridine-injected animals received a continuous intracerebellar infusion of either a peptidic insulin-like growth factor I receptor antagonist or an insulin-like growth factor I antisense oligonucleotide for two weeks through an osmotic minipump, c- Fos expression was obliterated while reactive gliosis was greatly increased. On the contrary, continuous infusion of insulin-like growth factor I significantly decreased reactive gliosis without affecting the increase in c- Fos expression. These results indicate that insulin-like growth factor I is involved in both the neuronal (c- Fos) and the astrocytic (glial fibrillary acidic protein) activation in response to injury.

INSULIN-LIKE GROWTH FACTOR-1 LOWERS mRNA LEVEL OF PHOSPHOENOLPYRUVATE CARBOXYKINASE (PEPCK) GENE, BUT DOES NOT SUPPRESS AMYLIN GENE EXPRESSION IN NEWBORN DOGS ▴ 1836

Insulin-like growth factor-1 (IGF-1) exerts insulin-like effects on glucose homeostasis. Amylin is a newly discovered pancreatic hormone which may impair insulin action. IGF-1 has been reported to reduce plasma amylin level in adult rats. In the present study, the effects of IGF-1 on the expression of the liver phosphoenolpyruvate carboxykinase (PEPCK) gene and the pancreatic amylin gene in newborn dogs were tested to determine the effects on neonatal glucose metabolism by IGF-1. After C-section delivery, euglycemic hyper-IGF-1 clamps(IGF-1 infusion rate: 10 μg/kg/min) were performed in newborn dogs (N=3). Total RNAs were isolated from frozen liver and pancreas. Northern blottings were performed using a rat PEPCK cDNA probe and a dog amylin cDNA probe to measure the mRNA levels of the PEPCK and amylin genes. The mRNA bands were quantitatively analyzed by a densitometer. The plasma concentration of amylin and IGF-1 were analyzed by radioimmunoassay. Results: 1) After the clamps, the plasma IGF-1 concentration was sharply increased to 2,822.2± 539.5 ng/ml from 128.3 ± 15.4 ng/ml (basal), whereas the plasma glucose level (143.0 ± 13.7 mg/dl) was kept at basal level(138.3 ± 18.1) by a variable infusion of glucose; 2) IGF-1 lowered the liver PEPCK mRNA level (75.1 ± 2.8) by 45.7%, compared to control(138.4 ± 41.2%); 3) IGF-1 inhibited neither amylin mRNA level (106.7± 14.2%) compared with the basal (100.0 ± 5.9%) nor the plasma amylin level (56.6 ± 3.8 pg/ml) compared to the basal (60.3 ± 5.5 pg/ml). The results suggest that IGF-1 may effectively suppress neonatal gluconeogenesis but that the unaffected amylin expression in newborn dogs by IGF-1 may be a counterregulatory factor for inducing insulin resistance in neonatal mammalians.

Changes in blood and red cell volume in the neonatal lamb and the effect of insulin-like growth factor I.

1. Blood volume was measured weekly using [51Cr]-labelled red cells in 10 lambs from 3 to 10 weeks of age. Red cell and plasma volumes were calculated using the measured blood volume and haematocrit. Other parameters, including plasma erythropoietin, urea, creatinine and glucose, were measured twice weekly. The results were compared to a group of five lambs that received an infusion of insulin-like growth factor I (IGF-I). 2. In control lambs, plasma volume increased linearly by 47 +/- 7 mL/week over the experimental period. Red cell volume only increased by 10 +/- 2 mL/week during weeks 3-7, but then increased by 25 +/- 2 mL/week over weeks 7-10. Haematocrit declined from 28.0 +/- 1.6 to 24.7 +/- 1.7% over weeks 3-7 and then increased to 30.7 +/- 1.1% by week 10. 3. In 10 control lambs infused for 8 days (starting at 22-26 days of age) with 10 mmol/L HCl, there was a decrease in plasma IGF-I concentrations, 3 days after the start of infusion. In five lambs infused for 8 days with IGF-I (6 microg/kg per h) plasma IGF-I concentration was maintained significantly (P <0.01) higher than that of the controls. 4. There was no significant difference in haematocrit, red cell or plasma volumes between the treatment groups and no reticulocytosis was observed. Plasma erythropoietin concentrations did not change over the infusion period in either group. 5. Serum urea decreased significantly in the IGF-I infused group but serum creatinine did not change in either group during the infusion period. In both the groups, there was a significant decrease in glucose, urea and creatinine over weeks 3-10 after birth. There was no difference in growth rates between the two groups. 6. Thus, it appears that the observed changes in haematocrit are due to a constant increase in plasma volume with varying rates of red cell volume increases. 7. IGF-I infused at a dose that maintains physiological concentrations and alters protein metabolism does not result in increased erythropoietin or erythropoiesis during the neonatal period of the lamb.

IGF-I stimulation of muscle protein synthesis in the awake rat: permissive role of insulin and amino acids.

Infusion of insulin-like growth factor I (IGF-I) lowers plasma amino acid and insulin concentrations, which may limit the capacity of IGF-I to promote muscle protein synthesis in vivo. We measured heart and skeletal muscle incorporation of continuously infused L-[ring-2,6-3H]phenylalanine in awake postabsorptive rats receiving 4-h intravenous infusions of saline (n = 11), IGF-I (1 microgram.kg-1.min-1) with (n = 10) or without (n = 11) amino acid replacement, or IGF-I with insulin replacement (n = 8). There were no significant increases in muscle protein synthesis during the infusion of IGF-I alone, which was associated with decreases in both plasma insulin (52 +/- 5%, P < 0.001) and amino acids (25 +/- 5%, P < 0.05). When IGF-I was given together with amino acids, protein synthesis was significantly increased in gastrocnemius (4.7 +/- 0.4 vs. 2.5 +/- 0.3%/day, P < 0.001), oblique (4.5 +/- 0.4 vs. 2.8 +/- 0.4%/day, P < 0.05), and soleus (8.8 +/- 0.7 vs. 6.4 +/- 0.3%/day, P < 0.01) and tended to be higher than saline control values in heart (10.9 +/- 0.9 vs. 8.8 +/- 0.7%/day, P = 0.08). Amino acid replacement prevented plasma concentrations from falling and also blunted the decline in plasma insulin (22 +/- 5%, P < 0.01 vs. IGF-I alone). When IGF-I and insulin replacement were given, protein synthesis was increased in heart (13.0 +/- 0.6%/day), gastrocnemius (4.7 +/- 0.4%/day), and oblique (4.5 +/- 0.4%/day) (P < 0.001 for each, compared with saline). We conclude that the action of IGF-I to acutely stimulate muscle protein synthesis in the awake rat is limited by the fall in circulating insulin and/or amino acid concentrations that accompanies IGF-I infusion in vivo and is prevented by co-infusion of insulin or amino acids.

Insulin-like growth factor-1 (IGF-1) enhances recovery from HgCl2-induced acute renal failure

Several growth factors have been found to play an important role in the recovery from acute renal failure (ARF). The effect of the continuous subcutaneous infusion of human recombinant insulin-like growth factor (IGF)-1 (125 micrograms daily by osmotic minipumps) in a rat model of mercuric chloride (HgCl2)-induced ARF was examined. HgCl2 (4 mg/kg) induced ARF with a mortality that was unaffected by IGF-1. However, IGF-1 significantly enhanced functional and histologic recovery in the survivors, as measured by serum creatinine and creatinine clearance and by histologic scoring. Solution hybridization RNAase protection assays showed that renal IGF-1 mRNA, IGF-1 receptor (IGF-1R) mRNA, and IGF-binding protein-1 (IGFBP-1) mRNA were unaffected by exogenous IGF-1, but this treatment significantly increased renal IGF-1 in ARF rats compared with normal rats and ARF rats not receiving IGF-1. After ARF renal mRNA for IGF-1 was decreased, IGF-1R was unchanged and IGFBP-1 was increased. Similar changes occurred in IGF-1-infused ARF rats. Thus, (1) IGF-1 enhances recovery from nephrotoxic ARF both functionally and histologically; (2) in nephrotoxic ARF, there is (a) a reduction in IGF-1 mRNA expression that is not prevented by IGF-1 infusion, and (b) an increase in renal IGFBP-1 mRNA. This may allow a significant increase in renal IGF-1 levels in IGF-1-infused ARF rats, despite the decrease in renal IGF-1 mRNA. A local increase in renal IGFBP-1 and IGF-1 may explain the accelerated recovery from ATN in this model. It was concluded that HgCl2-induced ARF is amenable to improvement by IGF-1 infusion and that the increase in renal IGFBP-1 mRNA may be an important modulator in the recovery of the kidney.

Intravenous infusion of insulin-like growth factor-1 into fetal sheep reduces the barrier to diffusion and the impedance of umbilical-placental blood flow

Intravenous infusion of insulin-like growth factor-1 into fetal sheep reduces the barrier to diffusion and the impedance of umbilical-placental blood flow

Insulin-like growth factor-1 lowers protein oxidation in patients with thermal injury.

The effect of insulin-like growth factor-1 (IGF-1) on energy expenditure and protein and glucose metabolism in a group of patients with thermal injury was determined. Accelerated protein catabolism is a constant feature of the hypermetabolic response to thermal injury. Insulin-like growth factor-1 has been reported to minimize protein catabolism and normalize energy expenditure in animal models of thermal injury. To determine the efficacy of IGF-1 in human burn patients, resting energy expenditure (metabolic cart), whole body protein kinetics (N15 Lysine), and glucose disposal (glucose tolerance test) were assessed in eight burn patients before and after a 3-day infusion of IGF-1 (20 micrograms/kg/hr). All patients were fluid-resuscitated uneventfully and were without obvious infection at the time of study. Enteral nutrition was administered at a constant rate before and during the IGF-1 infusion. Resting energy expenditure was not altered by IGF-1 (40.3 +/- 2.2 vs. 39.1 +/- 2.3 kcal/kg/day). However, glucose uptake was promoted, and protein oxidation decreased significantly (0.118 +/- 0.029 vs. 0.087 +/- 0.021 g/kg/d, p < 0.05) by IGF-1. In addition, insulin secretion, in response to a glucose challenge, was blunted. Insulin-like growth factor-1 therapy has a beneficial effect in preserving lean body mass during severe stress conditions by minimizing the flux of amino acids toward oxidation.

Insulin-like growth factor 1 alters feto-placental protein and carbohydrate metabolism in fetal sheep.

Insulin-like growth factor 1 (IGF-1) is an anabolic hormone in postnatal life and may be an important endocrine regulator of fetal growth. However, its effects on fetal metabolism in vivo have not previously been determined. We studied the effect of 50 micrograms/h.kg IGF-1 infusion in 12 chronically catheterized fetal sheep. Fetal blood amino nitrogen concentrations fell 10% and maternal 7%, consistent with a rise in feto-placental amino acid uptake. Fetal amino acid oxidation, measured by fetal urea production fell by 30% (44.4 +/- 10.5 to 30.9 +/- 8.0 mumol/min). Fetal and maternal blood glucose concentrations both fell by 0.1 mM, consistent with increased feto-placental glucose uptake. Placental lactate production fell 30% (114 +/- 15 to 78 +/- 11 mumol/min), as did fetal and uterine lactate uptake. There was no change in umbilical or uterine blood flows, nor in placental transfer by simple or facilitated diffusion. We conclude that IGF-1 has anabolic effects on feto-placental protein and carbohydrate metabolism. Circulating IGF-1 may in part mediate the regulation of fetal growth in response to fetal nutrient supply.

Insulin-like growth factor 1 alters feto-placental protein and carbohydrate metabolism in fetal sheep

Insulin-like growth factor 1 (IGF-1) is an anabolic hormone in postnatal life and may be an important endocrine regulator of fetal growth. However, its effects on fetal metabolism in vivo have not previously been determined. We studied the effect of 50 micrograms/h.kg IGF-1 infusion in 12 chronically catheterized fetal sheep. Fetal blood amino nitrogen concentrations fell 10% and maternal 7%, consistent with a rise in feto-placental amino acid uptake. Fetal amino acid oxidation, measured by fetal urea production fell by 30% (44.4 +/- 10.5 to 30.9 +/- 8.0 mumol/min). Fetal and maternal blood glucose concentrations both fell by 0.1 mM, consistent with increased feto-placental glucose uptake. Placental lactate production fell 30% (114 +/- 15 to 78 +/- 11 mumol/min), as did fetal and uterine lactate uptake. There was no change in umbilical or uterine blood flows, nor in placental transfer by simple or facilitated diffusion. We conclude that IGF-1 has anabolic effects on feto-placental protein and carbohydrate metabolism. Circulating IGF-1 may in part mediate the regulation of fetal growth in response to fetal nutrient supply.

Effect of insulin-like growth factor 1 on host response to tumor.

Oncology patients suffer multiple detrimental metabolic alterations. Among these are catabolism of tumor free body mass to supply nutrients to feed the tumor. This results not only in enhanced tumor growth but also poor wound healing and immunosuppression of the tumor host. Efforts are therefore being directed at finding methods for improving the nutritional status of the tumor host without enhancing tumor growth. We investigated the ability of two hormones, insulin-like growth factor-1 (IGF-1) and insulin, to improve physiologic function in tumor-bearing animals. Tumor-bearing animals received a continuous infusion of IGF-1 (2.20 mg/kg/day), insulin (820 microns/kg/day) or placebo via an osmotic minipump for 7 days. All animals were pair fed to eliminate nutritional intake as a variable. The placebo group lost 31.37 +/- 4.3 g of tumor free body mass during the study period. The insulin treated group lost 26.34 +/- 7.42 g and the IGF-1 group lost 5.07 +/- 3.25 g (P < 0.001, ANOVA). IGF-1 treatment failed to alter plasma glucose, lactate, or total amino acid concentration and failed to alter hepatic ketone body concentrations, but did improve hepatic mitochondria redox potential. Finally, IGF-1 improved splenic weight by 110% and splenic lymphocyte count by 300%. In conclusion IGF-1 appears to offer potential in supporting tumor free host body mass without stimulating tumor growth.

Insulinlike growth factor 1 (IGF-1) reduces gut atrophy and bacterial translocation after severe burn injury.

Bacterial translocation after severe burns is associated with gut mucosal atrophy and increased mucosal permeability. Insulinlike growth factor 1 (IGF-1) levels are low after trauma and do not respond to growth hormone treatment. Since IGF-1 receptors have been demonstrated in gut mucosa, we proposed that treatment with IGF-1 would reduce mucosal atrophy and bacterial translocation. Rats received 50% total body surface area full-thickness burn or sham burn. They were treated with a continuous, subcutaneous infusion of either IGF-1 (approximately 3 mg/kg per day) or placebo (0.01 mol of acetate) for up to 5 days after receiving the burn. The mesenteric lymph node and liver were cultured for gram-negative bacteria. The small intestinal mucosa was scraped, weighed, and analyzed for DNA and protein content. Treatment with IGF-1 improved body weight, spleen weight, and gut mucosal weight. It stimulated mucosal DNA and protein content and reduced the incidence of bacterial translocation to the mesenteric lymph node from 89% to 30%. Insulinlike growth factor may reduce gut barrier failure by decreasing mucosal atrophy and subsequent barrier failure. In addition to its general anabolic effects, recombinant human IGF-1 may improve gut mucosal function and reduce infectious morbidity in severely traumatized or septic patients by reducing gut atrophy and reducing bacterial translocation.

Effects of continuous infusion of insulin-like growth factor I and II, alone and in combination with thyroxine or growth hormone, on the neonatal hypophysectomized rat

In this study, we examined the effects of systemically administered insulin-like growth factor (IGF)-I and -II on growth of the hypophysectomized (Hx) neonatal rat. Neonatal Wistar rats were Hx or sham Hx on postnatal day (PND) 6 and implanted sc with Alzet pumps on PND 10. Recombinant human IGF-I or -II were infused between PND 10 and 18 at an average dose of 1.9 micrograms/g body weight (BW) per day. In addition, some groups received daily sc injections of recombinant human GH or thyroxine (T4) at 2.5 micrograms and 25 ng/g BW per day, respectively. Pups were sacrificed on PND 18 and serum IGF levels determined. Despite restoration of serum IGF-I levels to sham control values in the Hx pups infused with IGF-I, no significant increase in BW occurred, although some increase in individual organ growth was observed (spleen, kidney, lung). Similarly, administration of IGF-II proved ineffective as a growth promoter in the neonatal Hx rat. In contrast, GH alone stimulated BW gain (P less than 0.001). T4 proved most potent in increasing skeletal growth (50% increase over Hx controls, P less than 0.001), without increasing serum IGF-I or -II levels. IGF-I and GH were equally effective in promoting a small yet statistically significant (17% over Hx controls, P less than 0.05) increase in skeletal growth. A synergistic effect on BW was observed with combined administration of T4 plus IGF-I to the Hx pups (P less than 0.05). The effects of hormonal therapy on serum IGF binding proteins (IGFBPs) was assessed by Western ligand blots. Administration of IGF-I, but not GH, resulted in increased levels of IGFBP-3, the predominant IGFBP of the adult rat. We conclude that systemically administered IGFs in doses that result in normalization of serum levels are ineffective promoters of somatic growth in neonatal rats. While normalization of serum IGF-I levels does result in modest skeletal growth, selective organ growth and increased serum IGFBP-3, growth stimulation does not equal that seen with GH (body weight) or thyroid hormone (skeletal growth). Differences in IGFBP profiles fail to account for the increased potency of GH as a promoter of BW gain. Thus, our data do not support a major endocrine role for IGF-I or -II in neonatal growth, but are consistent with an autocrine/paracrine action of IGF in the mediation of neonatal mammalian growth.

Effects of continuous infusion of insulin-like growth factor I and II, alone and in combination with thyroxine or growth hormone, on the neonatal hypophysectomized rat.

In this study, we examined the effects of systemically administered insulin-like growth factor (IGF)-I and -II on growth of the hypophysectomized (Hx) neonatal rat. Neonatal Wistar rats were Hx or sham Hx on postnatal day (PND) 6 and implanted sc with Alzet pumps on PND 10. Recombinant human IGF-I or -II were infused between PND 10 and 18 at an average dose of 1.9 micrograms/g body weight (BW) per day. In addition, some groups received daily sc injections of recombinant human GH or thyroxine (T4) at 2.5 micrograms and 25 ng/g BW per day, respectively. Pups were sacrificed on PND 18 and serum IGF levels determined. Despite restoration of serum IGF-I levels to sham control values in the Hx pups infused with IGF-I, no significant increase in BW occurred, although some increase in individual organ growth was observed (spleen, kidney, lung). Similarly, administration of IGF-II proved ineffective as a growth promoter in the neonatal Hx rat. In contrast, GH alone stimulated BW gain (P less than 0.001). T4 proved most potent in increasing skeletal growth (50% increase over Hx controls, P less than 0.001), without increasing serum IGF-I or -II levels. IGF-I and GH were equally effective in promoting a small yet statistically significant (17% over Hx controls, P less than 0.05) increase in skeletal growth. A synergistic effect on BW was observed with combined administration of T4 plus IGF-I to the Hx pups (P less than 0.05). The effects of hormonal therapy on serum IGF binding proteins (IGFBPs) was assessed by Western ligand blots. Administration of IGF-I, but not GH, resulted in increased levels of IGFBP-3, the predominant IGFBP of the adult rat. We conclude that systemically administered IGFs in doses that result in normalization of serum levels are ineffective promoters of somatic growth in neonatal rats. While normalization of serum IGF-I levels does result in modest skeletal growth, selective organ growth and increased serum IGFBP-3, growth stimulation does not equal that seen with GH (body weight) or thyroid hormone (skeletal growth). Differences in IGFBP profiles fail to account for the increased potency of GH as a promoter of BW gain. Thus, our data do not support a major endocrine role for IGF-I or -II in neonatal growth, but are consistent with an autocrine/paracrine action of IGF in the mediation of neonatal mammalian growth.

Effects of the Infusion of Insulin-Like Growth Factor I in a Child with Growth Hormone Insensitivity Syndrome (Laron Dwarfism)

Effects of the Infusion of Insulin-Like Growth Factor I in a Child with Growth Hormone Insensitivity Syndrome (Laron Dwarfism)