Insulin-like Growth Factor I Infusion Research Articles

IGF-I inhibits burst mass of pulsatile insulin secretion at supraphysiological and low IGF-I infusion rates.

Insulin-like growth factor I (IGF-I) shares structural and functional features with insulin, affects carbohydrate metabolism, and inhibits insulin secretion. Insulin secretion is pulsatile, and it is regulated by changing frequency and/or mass of secretory bursts. To examine the mechanism of IGF-I's inhibition of insulin secretion, eight healthy volunteers were studied three times. During glucose infusion (2.5 mg x kg(-1) x min(-1)) blood was sampled minutely at time 75-200 min for triplicate insulin concentration measurements by enzyme-linked immunosorbent assay (ELISA; coefficient of variation 2.1%). Time 125 min infusion of saline, low-dose IGF-I (0.025 microg x kg(-1) x min(-1)) or high-dose IGF-I (0.15 microg x kg(-1) x min(-1)) was commenced and continued until 200 min. Data were compared before (75-125 min) vs. during infusion (150-200 min). Insulin concentration time series were deconvolved, using validated pulse-detection criteria, to assess insulin secretory burst mass and frequency. During saline infusion no time effect occurred. After IGF-I infusion, serum C-peptide decreased (582 +/- 85 vs. 481 +/- 82 pM, low-dose IGF-I, P < 0.05; 539 +/- 84 vs. 427 +/- 69 pM, high-dose IGF-I, P < 0.01). Total insulin secretion rates decreased by 17 and 21%, respectively, via specific inhibition of the insulin secretory burst mass (31 +/- 8 vs. 20 +/- 4 pmol/ml, low-dose IGF-I, P = 0.06; 22 +/- 4 vs. 17 +/- 3 pmol/ml, high-dose IGF-I, P < 0.05), whereas the frequency was not affected (10.5 +/- 1.3 vs. 10.7 +/- 1.3 pulses/h, low-dose IGF-I, P = 0.85; 8.7 +/- 1.0 vs. 11.1 +/- 1.2 min/pulse, high-dose IGF-I, P = 0.15). We conclude that IGF-I inhibits pulsatile insulin secretion by specific inhibition of mass but not frequency of secretory bursts.

Systemic infusion of IGF-I or LR(3)IGF-I stimulates visceral organ growth and proliferation of gut tissues in suckling rats.

This study describes developmental changes in gastrointestinal response to insulin-like growth factor I (IGF-I) peptide administration. Neonatal rats were infused with IGF-I or long [Arg3]IGF-I (LR(3)IGF-I) for 6.5 days starting on day 6 or 12 postpartum. Peptides were delivered by mini osmotic pumps at 0, 2, 5, or 12.5 microg x g(-1) x day(-1). IGF-I infusion increased plasma IGF-I levels in both age groups but stimulated body weight gain only in the older rats. Infusion of LR(3)IGF-I did not change plasma IGF-I levels. Both peptides enhanced expression of IGF-binding proteins (IGFBP) 1 and 2 and induced IGFBP-3 in the older rats. For both age groups, weights of the kidney and spleen increased by up to 85 and 76%, respectively. IGF-I treatment also stimulated gut weight and length by up to 60 and 32%, respectively, but dose dependency was observed only in the older rats. LR(3)IGF-I was more potent for all growth parameters in both age groups. Histological observations included thickening of the mucosa and muscularis externa after infusion of IGF-I peptides. Thymidine labeling in the younger rats indicated that proliferative activity increased proportionately with crypt cell growth. These results show that IGF-I peptides selectively stimulate growth of gastrointestinal tissues in suckling rats and that the proximal gut was the most peptide-responsive region.

Contrasting effects of growth hormone and insulin-like growth factor I on the biological activities of endotoxin in the rat.

We previously demonstrated that GH potentiates the biological activities of endotoxin in the rat. In the present study, we wanted to determine if the potentiating effects of GH on the biological activities of endotoxin could be reproduced by insulin-like growth factor I (IGF-I). Endotoxin (5 mg/kg BW) was injected in rats primed with or without GH or IGF-I for 3 days. As expected, endotoxin administration markedly increased circulating tumor necrosis factor (TNF) and interferon-gamma (IFN gamma) and induced organ injury, hypoglycemia, and hyperlipidemia. In GH-primed rats, endotoxin induced a further increase of serum IFN gamma (but not TNF); and five out of six of those rats died within 15 h after giving endotoxin. However, little difference between endotoxin-treated rats with and without IGF-I priming could be seen. Furthermore, IGF-I infusion altered blood glucose, urea, and circulating ICF-I levels more than GH infusion. Therefore, IGF-I does not enhance the biological activities of endotoxin in the rat, suggesting that the enhancement of endotoxin effects by GH is via an IGF-I-independent pathway. Priming rats by GH (but not by IGF-I) induced a further increased response of serum IFN gamma but not TNF to subsequent endotoxin challenge, suggesting that IFN gamma rather than TNF is likely to be involved in this process.

Role for insulin-like growth factor I in the regulation of electrolyte composition of uterine luminal fluid.

A potential role for insulin-like growth factor I (IGF-I) in the regulation of the uterine electrolyte environment was studied in conjunction with hyperoestrogenaemia caused by superovulation. Uterine luminal fluid from immature rats treated with 4 (control), 10, 20 and 40 i.u. (superovulation) pregnant mares' serum gonadotrophin (PMSG, day -2) and the electrolyte composition was determined on day 3 of pregnancy. Superovulation increased total cation content in uterine flushes by more than twofold, suggesting a comparable increase in the uterine luminal fluid volume. Percentages of K+ and HCO-3 content to total cations or anions increased by 27% and 16%, respectively, and those of Na+ and Cl- decreased by 26% and 15%, respectively, after superovulation. Daily injections with 1.0 micrograms or more oestradiol, from day 0 to day 2, in the 4 i.u. PMSG-primed immature rats caused similar changes in total cation content and electrolyte composition of uterine luminal fluid. Anti-IGF-I antibody infusion in the superovulated or oestradiol-treated immature rats restored the alterations in cation composition but had no effect on anion composition and total cation content. IGF-I was infused into adult rats to achieve increased IGF-I action observed after superovulation. IGF-I infusion altered electrolyte composition, as is observed after superovulation or oestradiol treatment, but had no effect on total cation content. In conclusion, hyperoestrogenaemia caused by superovulation may alter the uterine electrolyte environment for preimplantation embryonic development. IGF-I appears to play a central role in mediating this action of oestrogen.

Insulin-like growth factor I inhibits degradation and improves retention of protein in hindlimb muscle of lambs.

We infused recombinant human insulin-like growth factor I (IGF-I) for 4 h at 12.3 micrograms.h-1.kg live weight-1 directly into the left femoral artery and measured the rates of synthesis, degradation, and gain of protein by the treated and contralateral limbs of well-fed (n = 8), feed-restricted (n = 10), and fasted (n = 9) castrated male lambs. Reducing feed intake decreased net protein gain of hindlimb muscle, reduced hindlimb glucose uptake, and lowered arterial plasma concentrations of IGF-I, insulin, glucose, phenylalanine, tyrosine, and isoleucine. The effect of nutrition on IGF-binding proteins (IGFBP) was generally small; IGFBP-2 was more abundant in fasted lambs. Infusion of IGF-I into the left femoral artery increased plasma levels of IGF-I 2- to 4-fold in the left femoral vein and by 1.5- to 3-fold in the artery and right femoral vein. In the treated limb, IGF-I reduced protein degradation, increased protein gain, and increased glucose uptake without altering blood flow or oxygen uptake, regardless of feed intake. Systemically, IGF-I reduced plasma insulin, phenylalanine, tyrosine, isoleucine, and leucine in all nutrition groups. Plasma IGFBP-3 was increased by 4 h of IGF-I treatment in fasted but not in fed lambs. In fed but not fasted lambs, IGF-I increased blood glucose concentration. Effects of IGF-I on protein metabolism in the contralateral limb were affected by nutrition, generally more so in fasted than in unrestricted fed lambs.

Effects of circulating IGF-I on glucose and amino acid kinetics in the ovine fetus.

To investigate the role of insulin-like growth factor I (IGF-I) in the regulation of fetal metabolism, the kinetics of leucine, phenylalanine, and glucose were assessed in the chronically catheterized ovine fetus (0.85 gestation) before and during infusion of recombinant human IGF-I (rhIGF-I). Substrate kinetics were determined by tracer dilution. rhIGF-I was infused at 6.7 nmol.kg fetus-1.h-1. Fetal insulin and growth hormone concentrations were significantly decreased by 50% during rhIGF-I infusion. Net umbilical glucose uptake was unchanged, and glucose rate of appearance increased in the fed state only. There were no changes in the net umbilical uptakes of leucine or phenylalanine, but the rates of appearance of both declined during rhIGF-I infusion, indicative of decreased fetal protein breakdown (Ra,Leu 45.4 +/- 1.40 to 40 +/- 1.4 mumol/min in the fed state, 43 +/- 1.5 to 37 +/- 1.5 mumol/min in the fasted state; Ra,Phe 10.7 +/- 0.3 to 10.4 +/- 0.3 mumol/min in the fed state and from 10.7 +/- 0.3 to 9.8 +/- 0.3 mumol/min in the fasted state). Leucine oxidation was also decreased (8.90 +/- 0.76 to 6.52 +/- 0.81 mumol/min, P = 0.025), more so in the fasted than the fed state. These results indicate a significant antiproteolytic endocrine effect for IGF-I in the late-gestation mammalian fetus.

Insulin and insulin-like growth factor-I regulate hepatic insulin-like growth factor binding protein-3 by different mechanisms.

Insulin-dependent diabetes mellitus is associated with decreased levels of circulating insulin-like growth factor binding protein-3 (IGFBP-3), which are restored toward normal by treatment with insulin and/or infusion of insulin-like growth factor-I (IGF-I). To understand underlying mechanisms, we studied IGFBP-3 production in cocultures of parenchymal and nonparenchymal cells from the livers of normal rats. Release of IGFBP-3 was measured by ligand blotting and was increased 1.9- and 15-fold by 10(-8) and 10(-8) M Insulin compared with 10(-10) M (P < 0.05 for 10(-6) vs. 10(-10) M). Expression of IGFBP-3 mRNA was increased concomitantly by 23 and 226% (P < 0.05 for 10(-6) M vs. 10(-10) M), consistent with regulation in part at pretranslational levels. To evaluate mRNA stability, transcription was inhibited with 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB): IGFBP-3 mRNA t1/2 was estimated at 13 h and 17 h with addition of 10(-5) M and 10(-10) M insulin, respectively, ruling out regulation at the level of mRNA turnover. IGFBP-3 gene transcription rates were evaluated by nuclear run-on assays and were increased 2,9-fold with the addition of 10(-6) M insulin, as compared with 10(-10) M insulin, comparable to stimulation of expression. Addition of IGF-I at 2.6 x 10(-8) M and 5.3 x 10(-8) M increased IGFBP-3 release by 5.2- and 8.2-fold (both P < 0.05 vs. no IGF-I), with concomitant increase in IGFBP-3 mRNA expression by 14- and 29-fold (both P < 0.05 vs. no IGF-I), suggesting regulation at a pretranslational level. Further studies showed that IGF-I did not have a significant effect on transcription initiation rates but prolonged the apparent half-life of IGFBP-3 mRNA about 2-fold. Stimulation of IGFBP-3 via type 1 IGF-I receptors was evaluated by studies with [QAYL] IGF-I; the analog increased IGFBP-3 mRNA expression 220 +/- 27% above the level obtained without IGF-I (vs. 133 +/- 9% with wild type IGF-I, P < 0.05), suggesting involvement of receptor-mediated synthesis. Insulin stimulates IGFBP-3 gene transcription but provides proportionally greater increases in IGFBP-3 release, consistent with regulation at both transcriptional and posttranslational levels; in contrast, IGF-I alters IGFBP-3 expression by decreasing IGFBP-3 mRNA degradation, consistent with regulation at pretranslational and posttranscriptional levels. Decreased IGFBP-3 levels in conditions of diabetes mellitus may be due to decreased hepatic IGFBP-3 release, and secondary both to decreased gene transcription (caused by insulin deficiency), as well as to decreased IGFBP-3 mRNA half-life (caused by low levels of IGF-I).

Insulin-like growth factor I promotes growth selectively in fetal sheep in late gestation.

Insulin-like growth factor I (IGF-I) is required for normal fetal growth and skeletal maturation in late gestation, because null mutations of the IGF-I gene in mice reduce fetal weight and retard ossification of bones. To determine if, conversely, increased abundance of IGF-I promotes fetal growth and skeletal maturation, fetal sheep were infused intravascularly with recombinant human IGF-I (n = 7) (26 +/- 3 micrograms. h-1.kg-1) from 120 to 130 days gestation and compared with controls (n = 15). IGF-I infusion increased plasma IGF-I concentrations by 140% (P = 0.002) and weights of fetal liver, lungs, heart, kidneys, spleen, pituitary, and adrenal glands by 16-50% (P < 0.05). Weights and/or lengths of the fetus, placenta, gastrointestinal tract, individual skeletal muscles, and long bones were unchanged by IGF-I. However, IGF-I increased the percentage of proximal epiphyses of long bones present (P < 0.05) and their cross-sectional areas by 15 to 38% (P < 0.05). These results show that IGF-I promotes growth of major fetal organs, endocrine glands, and skeletal maturation in vivo, consistent with IGF-I actively controlling and not merely facilitating fetal growth. The variable response of different tissues may partly reflect tissue specificity in growth requirements for additional factors.

The role for the uterine insulin-like growth factor I in early embryonic loss after superovulation in the rat

To examine possible roles of the insulin-like growth factor (IGF) system in increased early embryonic loss after superovulation. Changes in the uterine IGF system were examined in superovulated rats. Insulin-like growth factor I (IGF-I) was infused to the right uterine horns to mimic enhanced IGF-I actions after superovulation. Uterine luminal fluids were collected after IGF-I infusions and embryos were cultured with uterine luminal fluids. Steroid hormones, IGF-I, IGF binding protein (IGFBP), and IGF-I receptor levels, developmental rate, and cell numbers of embryos. Elevated IGF-I levels and suppressed IGFBP levels were found from days 1 to 3 of pregnancy after superovulation. Uterine luminal fluids of the IGF-I infusion and superovulation groups impaired embryo development in vitro. Anti-IGF-I antibody infusions after superovulation reversed detrimental effects of superovulation. Dialysis of uterine luminal fluids of the IGF-I infusion and superovulation groups before culture improved embryo development. Enhanced IGF-I actions in the uterus after superovulation may be responsible for the increase of early embryonic loss. The detrimental factor for embryo development seems a small molecule and is likely a local product of the uterus in which IGF-I actions are enhanced.

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-I enhances immune response in dexamethasone-treated or surgically stressed rats maintained with total parenteral nutrition.

New evidence suggests that insulin-like growth factor-I (IGF-I) is an important regulator of immune response. Our objective was to determine the effects of IGF-I on immune response during total parenteral nutrition (TPN) using two stress models. Male, Sprague-Dawley rats (230 to 250 g) were given TPN with or without coinfusion of recombinant human IGF-I (800 micrograms/d for 6 days) and subjected to either dexamethasone, a synthetic glucocorticoid, or surgical stress, in the form of a midline abdominal incision. In the dexamethasone model, immune response was assessed by total cellularity of the thymus and spleen, in vitro assays of lymphocyte proliferation, and interleukin 6 (IL-6) production, and concentrations of IL-6 and tumor necrosis factor alpha (TNF-alpha) in serum. In the surgical model, flow cytometry was used to identify and quantify splenic populations of T and B lymphocytes and macrophages. In rats immunosuppressed by dexamethasone, IGF-I infusion increased mitogen-induced proliferation of thymocytes, but did not alter cellularity in the thymus; enhanced proliferation and IL-6 production in peripheral blood mononuclear cells following treatment with concanavalin A or lipopolysaccharide; and reduced the serum concentration of IL-6, but not TNF-alpha. In surgically stressed rats, IGF-I infusion restored the splenic populations of immature and mature B lymphocytes, which were decreased by TPN. our data demonstrate that IGF-1 enhances immune response during TPN in rats.

Long R3 insulin-like growth factor-I (IGF-I) infusion stimulates organ growth but reduces plasma IGF-I, IGF-II and IGF binding protein concentrations in the guinea pig

We have tested whether an animal with substantial amounts of both IGF-I and IGF-II in circulation, such as the guinea pig, would respond to chronic IGF infusion in the same manner as the adult rat, which has negligible amounts of IGF-II in blood. Female guinea pigs of 350 g body weight were continuously infused for 7 days with recombinant guinea pig IGF-I or -II (120 or 360 micrograms/day) or long R3 IGF-I (LR3IGF-I) (120 micrograms/day), an analogue which has much reduced affinities for IGF binding proteins. IGF-I or IGF-II infusion led to substantial increases in plasma IGF-I or IGF-II respectively in comparison with vehicle-infused animals. Nevertheless, body weight gain, feed intake, feed conversion efficiency and carcass composition were not significantly affected by any treatment (significance was deemed to be P < 0.05). Amongst the tissues examined only the fractional weight (g/kg body weight) of the adrenals was increased, and that only by the higher dose (360 micrograms/day) of IGF-I. However, the fractional weight of adrenals, gut, kidneys and spleen were significantly increased by LR3IGF-I, but again overall growth was not stimulated. A possible explanation for the lack of IGF-I effects is that total circulating IGF concentrations were not increased by these treatments. IGF-II significantly raised total IGF concentrations at the higher dose only. Plasma IGF-I was reduced by IGF-II infusion, as was plasma IGF-II by IGF-I infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the effects of human recombinant insulin-like growth factor I and insulin on plasma amino acid concentrations and leucine kinetics in humans

We examined the effects of recombinant human insulin-like growth factor I (IGF-I) and insulin on the plasma amino acid (AA) profile and leucine kinetics in eight normal subjects. IGF-I was infused at 52 pmol.kg-1.min-1, in combination with prime-continuous [1-14C] leucine infusion, to obtain steady-state plasma concentrations of total (54 +/- 3 nmol/l) and free (7.3 +/- 1 nmol/l) IGF-I (study 1). In response to IGF-I, plasma AA levels declined by 37 +/- 3% (1975 +/- 198 to 1368 +/- 120 mumol/l) and total branched chain amino acids (BCAA) declined by 34 +/- 3% (390 +/- 21 to 256 +/- 13 mumol/l). This hypoaminoacidaemic effect was associated with a decline in endogenous leucine flux of 17 +/- 2% (1.88 +/- 0.05 to 1.57 +/- 0.04 mumol.kg-1.min-1) and leucine oxidation of 17 +/- 1% (0.31 +/- 0.02 vs 0.26 +/- 0.02 mumol.kg-1.min-1) (both p < 0.01 vs basal). The same subjects underwent a second study (study 2) in which insulin was infused at 6.22 pmol.kg-1.min-1 to obtain a steady-state plasma insulin concentration of 530 +/- 25 pmol/l while maintaining euglycaemia. The infusion rate was designed to match the declines in plasma BCAA levels and leucine turnover observed during IGF-I infusion. The rates of glucose infusion necessary to maintain euglycaemia during IGF-I and insulin infusion were 4.9 +/- 1.0 and 7.8 +/- 0.6 mg.kg-1.min-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the effects of human recombinant insulin-like growth factor I and insulin on plasma amino acid concentrations and leucine kinetics in humans

We examined the effects of recombinant human insulin-like growth factor I (IGF-I) and insulin on the plasma amino acid (AA) profile and leucine kinetics in eight normal subjects. IGF-I was infused at 52 pmol·kg−1·min−1, in combination with prime-continuous [1-14C] leucine infusion, to obtain steady-state plasma concentrations of total (54±3 nmol/l) and free (7.3±1 nmol/l) IGF-I (study 1). In response to IGF-I, plasma AA levels declined by 37±3% (1975±198 to 1368±120 Μmol/l) and total branched chain amino acids (BCAA) declined by 34±3% (390±21 to 256±13 Μmol/l). This hypoaminoacidaemic effect was associated with a decline in endogenous leucine flux of 17±2% (1.88±0.05 to 1.57±0.04 Μmol·kg−1·min−1) and leucine oxidation of 17±1% (0.31±0.02 vs 0.26±0.02 Μmol·kg−1·min−1) (both p<0.01 vs basal). The same subjects underwent a second study (study 2) in which insulin was infused at 6.22 pmol·kg−1·min−1 to obtain a steady-state plasma insulin concentration of 530±25 pmol/l while maintaining euglycaemia. The infusion rate was designed to match the declines in plasma BCAA levels and leucine turnover observed during IGF-I infusion. The rates of glucose infusion necessary to maintain euglycaemia during IGF-I and insulin infusion were 4.9±1.0 and 7.8±0.6 mg·kg−1 ·min−1, respectively. During insulin infusion total BCAA declined by 39% from 369±23 to 226±20 Μmol/l, leucine flux declined by 16±2% from 1.90±0.05 to 1.61±0.03 Μmol·kg−1·min−1, and leucine oxidation declined by 19±2% from 0.32±0.02 to 0.26±0.02 Μmol·kg−1·min−1. On a molar basis IGF-I was 7.3% as potent as insulin in inhibiting proteolysis. These results demonstrate that in humans: (i) the hypoaminoacidaemic response to IGF-I can be entirely ascribed to the inhibition of proteolysis; (ii) qualitatively, the effects of IGF-I and insulin on plasma AA profile and protein metabolism are similar; (iii) quantitatively, IGF-I is 14-fold less potent than insulin in suppressing protein degradation.

Acute effect of human recombinant insulin-like growth factor I on renal function in humans.

We examined the acute effects of insulin-like growth factor I (IGF-I) on renal function in 8 normal subjects who received a 3-hour intravenous infusion of IGF-I at a rate of 0.4 micrograms/kg.min. After starting the IGF-I infusion, the plasma IGF-I concentration rose quickly and achieved a plateau after 90 min that was threefold above the basal value. During IGF-I infusion, progressive rises in glomerular filtration rate (from 93 +/- 4 to 121 +/- 6 ml/173 m2.min; p < 0.01) and renal plasma flow (from 529 +/- 31 to 703 +/- 55 ml/1.73 m2.min; p < 0.01) were observed, with no change in filtration fraction. The plasma levels of potassium and phosphate decreased significantly during the last 90 min of the study, while the plasma sodium concentration remained unchanged. A significant decrease in the fractional excretion of sodium, potassium, and phosphate was observed during the last 90 min of the IGF-I infusion period. The heart rate rose modestly with no change in mean arterial pressure. These findings show that, when administered acutely, IGF-I is a potent renal vasodilator, but is antinatriuretic. IGF-I also enhances potassium and phosphate uptake by extrarenal tissues and reduces renal potassium and phosphate excretion.

IGF-I alters energy expenditure and protein metabolism during parenteral feeding in rats

In this study, 20 micrograms.kg.-1.h-1 of recombinant human insulin-like growth factor I (IGF-I) was infused into normal healthy rats to examine the effects of IGF-I on glucose, protein, and energy metabolism in either overnight-fasting or parenteral-feeding states. The fed state was maintained by continuous intravenous feeding of a complete diet containing 838 kJ.kg-1.d-1, 2 g N.kg-1.d-1, and no fat. At each nutritional state, one-half of the animals received IGF-I infusion while the other half received saline as control. [14C-1]leucine and [3H-6]glucose were used to determine the effects of IGF-I on protein and glucose kinetics during fed and fasting states. The results showed that 1) infusion of IGF-I at this amount did not alter plasma glucose appearance and only marginally decreased plasma glucose concentrations in both nutritional states; 2) during fasting, IGF-I did not show anabolic effects on protein metabolism either at the whole-body level or in individual tissues. However, during feeding, IGF-I significantly stimulated exogenous nitrogen utilization by the whole body; and 3) IGF-I reduced the thermogenic effect of feeding. The results suggest that parenteral feeding may be an important variable in the response of protein anabolism to IGF-I in vivo.

Insulin-like growth factor-I inhibits insulin and amylin secretion in conscious rats.

Human recombinant insulin-like growth factor-I (IGF-I) exerts insulin-like antidiabetic properties in vitro and in vivo. To determine the effects of IGF-I infusion on insulin and amylin release, plasma glucose of freely moving undisturbed rats was constantly maintained at 13.9 mmol/liter by variable glucose infusion for 120 min in three groups of fasted Sprague-Dawley rats (hyperglycemic clamp technique). Group A, vehicle infusion (control group); group B, bolus 0.39 nmol plus 0.39 nmol/h IGF-I continously; and group C, bolus 1.96 nmol plus 1.96 nmol/h IGF-I continuously. During the steady-state phase of the experiment, IGF-I dose dependently reduced plasma insulin (pmol/liter: A, 718 +/- 58; B, 613 +/- 35, NS vs. A; C, 408 +/- 21, P < 0.01 vs. A; dose-response effect: P < 0.0001), plasma amylin (pmol/liter: A, 10.2 +/- 0.6; B, 8.8 +/- 0.5, NS vs. A; C, 5.8 +/- 0.4, P < 0.01 vs. A; dose-response effect: P < 0.0001), and net glucose uptake (mumol/kg.min: A, 188 +/- 12; B, 160 +/- 12, NS vs. A; C, 134 +/- 7, P < 0.01 vs. A; dose-response effect: P < 0.0025). At the same time, the ratio of plasma insulin/plasma amylin (mol/mol: A, 72 +/- 6; B, 71 +/- 5; C, 74 +/- 9; NS), the ratio of net glucose uptake/plasma insulin (mumol/kg.min per pmol/liter: A, 0.28 +/- 0.03; B, 0.27 +/- 0.02; C, 0.36 +/- 0.04; NS), and glycogen content of liver, heart, and various hindlimb muscles remained unaffected. The results demonstrate that IGF-I is a potent inhibitor of insulin and amylin release in healthy rats exposed to hyperglycemia and suggest that IGF-I infusion inhibits hormone secretion from pancreatic beta cells at infusion rates that do not affect insulin-stimulated glucose uptake by peripheral tissues.

In vivo and in vitro effects of insulin-like growth factor-I (IGF-I) on femoral mRNA expression in old rats

The in vivo response of bone to IGF-I infusion in a marrow ablation model and the effect of IGF-I on bone marrow stromal cells in vitro was evaluated. IGF-I (25 ng/day), infused directly into femur, stimulated the expression of alkaline phosphatase, procollagen ∝ 1 (I) and osteopontin mRNA, while osteocalcin mRNA was not affected. The dose dependency to IGF-I was bi-phasic, with stimulation at 25 and 50 ng but not at 150 ng/day. The effect of IGF-I was observed in the aged but not in the adult rat femur. However, the elevated mRNA levels in old bones with IGF-I treatment were still below those observed in adult bones. The effect of IGF-I was also examined in cultured stromal cells. IGF-I (50 ng/ml) stimulates the expression of alkaline phosphatase, procollagen ∝ 1 (I), osteopontin and osteocalcin mRNA in stromal cells from both adult and old rats. These results suggest that the lack of response of adult bone to IGF-I in vivo was not due to the impaired response of the stromal cells to IGF-I. Differences in the responses of stromal cells from adult and old animals were noted. In the presence of serum (10%), stromal cells from adult rats were stimulated to synthesize DNA at lower levels of IGF-I than stromal cells from old animals. Our results show that IGF-I can stimulate mRNA expression of osteoblast markers in vivo in aged rats in a marrow ablation model and enhance DNA synthesis and gene expression in cultured marrow stromal cells from old rats. Thus, it is possible that exogenous IGF-I could be beneficial in treating age-associated osteopenia.

The effects of subcutaneous insulin-like growth factor-I infusion in insulin-dependent diabetes mellitus.

Insulin-dependent diabetes can be associated with low insulin-like growth factor-I (IGF-I) levels despite normal or even high GH secretion. The basis of the diabetic abnormalities in GH-IGF dynamics that contribute to insulin resistance and impaired fuel metabolism are not well understood. To further investigate these matters, this study evaluated baseline IGF system parameters and responses to recombinant human IGF-I in four diabetic adolescents and six pubertal stage-matched controls. Spontaneous overnight and arginine-stimulated GH secretion, insulin, IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 levels were measured before, during, and after daily 10-h sc infusions of saline or IGF-I (20 micrograms/kg.h). Baseline overnight GH secretion and IGFBP-1 and -3 levels were not significantly different in the two groups, but IGF-I levels were significantly lower and IGF-II levels were higher in diabetic subjects. IGF-I infusion produced a 3-fold increase in serum IGF-I levels and a reciprocal profound reduction in IGF-II levels in both groups. IGFBP-1 levels increased dramatically in diabetics and modestly in normal subjects in response to IGF-I infusion, but IGFBP-3 levels were not significantly altered. Spontaneous overnight and arginine-stimulated GH secretion were suppressed by about 50% in both groups after IGF-I infusion. Insulin requirements were substantially reduced in diabetics receiving IGF-I, and insulin secretion was suppressed in normal subjects, with no evidence of a change in insulin half-life. Blood glucose remained stable in both groups throughout saline and IGF-I infusions, and no hypoglycemia or other adverse effect occurred during IGF-I infusions. Further studies are necessary to determine whether the addition of IGF-I to insulin replacement therapy may stably reduce the insulin requirement, maintain normal GH levels, and perhaps achieve better metabolic and anabolic balance in the treatment of insulin-dependent diabetes.

The effects of subcutaneous insulin-like growth factor-I infusion in insulin-dependent diabetes mellitus

The effects of subcutaneous insulin-like growth factor-I infusion in insulin-dependent diabetes mellitus