Changes In Insulin-like Growth Factor Research Articles

Changes in insulin-like growth factor (IGF)-binding proteins after IGF-I injections in noninsulin-dependent diabetics.

Insulin-like growth factor-I (IGF-I) exerts insulin-like effects on fuel metabolism and suppresses insulin secretion in normal subjects. Unlike insulin, circulating IGF-I is bound to high affinity binding proteins (IGFBPs), which modulate IGF action. We have previously shown that IGF-I administration increases IGFBP-1 and -2 and reduces IGFBP-3 in normal subjects. To determine whether similar effects could be demonstrated in an insulin-resistant state, we administered recombinant human IGF-I for 4 days by sc injection to six obese type II diabetics and determined the effects on fasting concentrations of glucose, C-peptide, IGF-I, and IGFBPs. The changes that occurred in glucose C-peptide and IGFBP levels during oral glucose tolerance testing were also quantified. There was no significant decrease in the mean fasting serum glucose or C-peptide level despite a 7-fold increase in mean fasting IGF-I concentrations (P < 0.01). As expected, during oral glucose tolerance testing, the area under the curve of C-peptide was suppressed after an injection of IGF-I (P < 0.05), but the area under the glucose curve did not change significantly. Mean fasting daily IGFBP-1 and -2 rose 2-fold (P < 0.05) and 1.9-fold (P < 0.05), respectively, whereas IGFBP-3 fell by 16% (P < 0.01) after 4 days of injections. IGFBP-1 was suppressed by 32% after oral glucose alone, whereas an injection of IGF-I plus oral glucose were associated with a more marked fall of 53% (despite suppression of C-peptide). In contrast, mean IGFBP-2 concentrations rose by 40% (P < 0.05) after IGF-I and oral glucose, but there was no change in response to oral glucose alone. These changes in IGFBP-1, -2, and -3 could alter the distribution of IGF-I among the various IGFBPs in the circulation. They may also prove to be a marker of metabolic responsiveness to IGF-I. In a substrate-sufficient state, e.g. after oral glucose, IGFBP-1 and -2 show opposite acute responses to IGF-I, and IGF-I has an apparent acute insulin-like effect on IGFBP-1 concentrations that differs from its longer term effect.

Changes in insulin-like growth factor (IGF)-binding proteins after IGF- I injections in noninsulin-dependent diabetics

Changes in insulin-like growth factor (IGF)-binding proteins after IGF- I injections in noninsulin-dependent diabetics

The relationship between the changes in insulin-like growth factor-1 (IGF-1) and the nutritional states evaluated by nitrogen balance in pregnant rats

The effects of nutrition on serum insulin-like growth factor-1 (IGF-1) concentrations during pregnancy of rats were investigated by using rat cultured hepatocytes in vitro, and by the assessment of nitrogen balance in vivo. IGF-1 concentration was measured by radioimmunoassay, and nitrogen balance was calculated by Pregl-Dumas method. The results were as follows: (1) Cultured rat hepatocytes produced IGF-1 in medium and it was significantly stimulated by the addition of various concentrations of glucose (1.1-4.4 mM) and/or several amino acid concentrations in a dose-related manner. (2) Serum IGF-1 concentrations, which indicated 368.6 +/- 143.8 ng/ml in a non-pregnant fed state, markedly decreased in a fasted state, reaching the levels of 143.8 +/- 30.4 ng/ml after 72 hours fasting. Nitrogen balance in these fasted rats also decreased according to the fasted period. (3) In early pregnancy (Day 0-12), serum IGF-1 concentrations were indistinguishable from those of non-pregnant fed rats. It gradually declined after the 13th day of pregnancy and reached the minimum levels of 77.0 +/- 12.1 ng/ml on the 21st day. On the other hand, mean nitrogen balance which was calculated from the difference of nitrogen retention in the maternal body and that in the fetal body, also decreased after 13 days of pregnancy and reached the levels of 14.9 g/day on the 21st day of pregnancy. These results suggested that IGF-1 concentrations in rat serum and conditioned medium might be regulated by nutritional factors, i.e., glucose and/or several amino acids. The curious profiles of IGF-1 concentrations observed in pregnant rats might be due in part to the effects of nutritional changes between the maternal and fetal body, especially, the changes of protein metabolism represented by the nitrogen balance.

Changes in insulin-like growth factor 1 receptor density after transient cerebral ischemia in the rat. Lack of protection against ischemic brain damage following injection of insulin-like growth factor 1.

Binding of 125I-insulin-like growth factor-1 (125I-IGF-1) to rat brain slices was studied after 15 min of two-vessel occlusion ischemia and 1 h to 4 days of recirculation. Ligand binding in the hippocampus increased at 6 h post ischemia in the CA1 and CA3 regions and the dentate gyrus, suggesting that the IGF-1 receptors were up-regulated, while no change was seen in neocortex and striatum. Intracerebroventricular injections of IGF-1 (2 micrograms) prior to and after transient cerebral ischemia did not reduce neuronal damage. The increased up-regulation on IGF-1 receptors and the absence of neuroprotection by IGF-1 suggest that the intracellular signal transduction chain activated by the IGF-1 receptor may be interrupted.

Plasminogen activator inhibitor-1 antigen concentrations during insulin and oral glucose tolerance tests in obese man

In vitro studies have shown that insulin increases plasminogen activator inhibitor-1 (PAI-1) synthesis and secretion in cells of hepatic origin. However, in vivo studies have failed to demonstrate an acute or chronic effect of insulin infusions on PAI-1 concentrations in man. To investigate the effects of exogenous insulin infusion compared to endogenous insulin secretion, 8 obese subjects underwent an insulin tolerance test (ITT) and an oral glucose tolerance test (OGTT). During ITT, insulin levels rose from (median, range) 8 (5–18) μU ml −1 at time 0 to 140 (40–500) μU ml −1 after 30 min before falling to 12.5 (6–32) μU ml −1 at 90 min. Plasma glucose fell from 3.9 (3.1–4.7mmol −1 at time 0 to 1.8 (1.1–2.6)mmol 1 −1 after 30min. During OGTT plasma insulin rose from 6·5 (5–26) μU ml −1 at time 0 to 102 (9–300) μU ml −1 after 60 min and 74 (17–25) μU ml −1 after 2h. Plasma glucose was 4.3 (3.6–4.7) mmol l −1 at time 0 and 8.1 (2.0–10.3) and 6.2 (4–9.8) mmol 1 −1 after 60 and 2 h respectively. During OGTT growth hormone levels were 1.8 mU l −1 at time 0 and fell gradually to 0.8 mU l −1 after 90 min and were 1.1 (0.6–11) at 2h. During ITT growth hormone rose from 1.0 mU I −1 at time 0 to 50.5 mU 1 −1 after 60min. There were no changes in insulin-like growth factor-1 in either group. PAI-1 concentrations were 31.1 ng ml −1 at time 0 and showed a gradual fall to 22.3 and 18 ng ml −1 after 60 and 120min of OGTT. During ITT PAI-1 was 15.4ng ml −1 at time 0 and 14.8 and 18.4ng ml −1 after 60 and 90min. The results confirm that exogenous insulin does not acutely regulate PAW concentrations. The high portal (endogenous) insulin concentrations seen during OGTT in these patients do not seem to have measurable effects on hepatic PAI-1 output.

Insulin-like growth factor I receptor binding in brains of Alzheimer's and alcoholic patients.

Patients with chronic alcoholism and/or Alzheimer's disease show degenerative changes in the cerebral cortex and hippocampus. To investigate possible changes in insulin-like growth factor I receptor binding sites in brain tissue of patients with these pathological conditions, the number of 125I-insulin-like growth factor I binding sites was determined in tissues obtained from control patients and those with Alzheimer's and/or with a history of alcoholism. The four experimental groups examined consisted of patients from similar age groups. Postmortem histology and a clinical history were used for the diagnosis of Alzheimer's disease and alcoholism, respectively. Careful clinical records were kept concerning other variables such as immediate cause of death and medications administered before death. Specific binding of 125I-insulin-like growth factor I to homogenates prepared from cerebral cortex of Alzheimer's, alcoholic, alcoholic Alzheimer's, and age-matched control patients was similar, although Alzheimer's patients tended to have slightly higher binding values. No significant differences in insulin-like growth factor I binding in cerebral cortex were found with regard to age of patients, the interval between death and autopsy, and CNS-active medications. No statistical differences in 125I-insulin-like growth factor I binding were noted in hippocampal tissue from the four patient groups. Thus, human insulin-like growth factor I binding sites in cerebral cortex and hippocampus appear unaffected by several variables.

The Effects of Thyroid Hormone on Insulin-Like Growth Factor (IGF) and IGF-Binding Protein (IGFBP) Expression in the Neonatal Rat: Prolonged High Expression of IGFBP-2 in Methimazole- Induced Congenital Hypothyroidism*

In the rat a developmental switch in the serum insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) profile takes place during the first 3 postnatal weeks. The fetal expression pattern of high IGF-II and IGFBP-2 is replaced by the adult pattern of low levels of IGF-II and IGFBP-2 and high levels of IGF-I and IGFBP-3. The regulatory mechanisms mediating these changes are unknown, but may include perinatal changes in endocrine function. To study the effects of thyroid function and the perinatal thyroid secretory burst on IGF and IGFBP expression, we established a rat model of congenital hypothyroidism, leading to marked postnatal growth retardation during the perinatal period. The hypothyroid animals lacked the steep rise in serum IGF-I levels normally occurring during the third week of life, showing only a modest rise to approximately 50% of control levels. The pattern of serum IGF-II decline in hypothyroid animals was slightly different from that in controls, with lower IGF-II levels during the second week of life and a slower decline down to the very low final levels. The hypothyroid pups continued to express high levels of IGFBP-2 up to the age of 19 days, while the control animals, after a slow initial decline, showed an abrupt fall of IGFBP-2 serum levels during the third week of life. Liver IGFBP-2 mRNA levels reflected the serum changes, with elevated IGFBP-2 mRNA in hypothyroid animals. The expression of other IGFBPs did not differ from that in the control group. At the age of 18 days, serum GH levels in the hypothyroid animals were approximately one third of control GH levels, which suggests a role for GH as a possible mediator of thyroid hormone actions on the IGF system. The changes in growth parameters and in the IGF and IGFBP profile of hypothyroid pups could be abolished by thyroid hormone replacement from birth. We conclude that thyroid hormone is, directly or indirectly, essential for some of the neonatal changes in IGF and IGFBP profiles.

Supplemental growth hormone alters body composition, muscle protein metabolism and serum lipids in fit adults: characterization of dose-dependent and response-recovery effects

Using double-blind, placebo-controlled procedures, the effects of low and high therapeutic dosages of methionyl-human growth hormone (met-hGH) on body composition, muscle protein metabolism and serum lipids were studied in 7 fit adults without growth hormone (GH) deficiency. Dose-dependent changes in body composition were observed that in part appeared to be influenced by a response-recovery effect, as measured by responses factored according to the duration of washout between exposure to the low and high dosages of met-hGH (6 weeks vs. 12 weeks vs. 18 weeks). Increases in fat-free weight were accompanied by an increase in skeletal muscle protein metabolism. Basal levels of cholesterol were inversely related to peak levels of GH in response to exercise stimulation and IGF-I, while GH supplementation lowered levels of total cholesterol and high- and low-density lipoproteins. A dose-dependent effect occured for total cholesterol, and the percent change in cholesterol was related to the percent change in insulin-like growth factor I (IGF-I). Endogenous levels of GH were attenuated in response to stimulation and IGF-I levels were increased after treatment with GH, but no dose-dependent changes were observed. We conclude that met-hGH alters body composition and muscle protein metabolism, and decreases stored and circulating lipids in fit adults with a preexisting supranormal body composition. The physiological profile of the person was not as important as the treatment conditions in determining the somatic and physiological response outcomes.

Insulin-Like Growth Factor-I in the Parenterally Fed Low Birth Weight Infant

Postnatal change in insulin-like growth factor-1 (IGF-I) was studied longitudinally in 9 very low birth weight infants (less than 1,200 g, less than 30 weeks at birth) who were receiving 85% or more of their nutrient intake via the parenteral route. There was no apparent relationship between IGF-I, nitrogen intake, energy intake, or nitrogen retention. In 6/9 infants IGF-I decreased with postnatal age. A low IGF-I may reflect the poor nutritional status and growth rate commonly seen in sick preterm infants.

Short-term met-hGH infusion inhibits somatotroph response to growth hormone releasing hormone (1–44)

To determine whether the short-term administration of growth hormone inhibits pituitary responsiveness to h-GHRH we measured the somatotroph response to h-GHRH-44 (0.3 μg/kg) stimulation in ten normal subjects from the third to the fifth hour of an infusion of met-hGH (2 μg/kg/h) or saline. Insulin, insulin-like growth factors (IGF), somatomedins, free fatty acids (FFA), glycerol, and glucose levels also were assessed during the first 3 hours of infusion. Steady-state GH levels of 5 to 20 ng/mL were achieved during met-hGH infusion. No significant changes in IGF, insulin, or glucose levels measured at the beginning and again after three hours of infusion occurred within or between conditions. Infusion of met-hGH was associated with a significantly greater increase in FFA levels (69 ± 50 μmol/L following saline v 433 ± 57 μmol/L following three hours of met-hGH infusion ( P < .001)). The somatotroph response to h-GHRH-44 was significantly blunted during met-hGH infusion (incremental area under the GH/time curve decreasing from 1,196 ± 183 (ng/mL) × min to 380 ± 139 (ng/mL) × min ( P < .005)). These data demonstrate that this blunting can occur following short-term exogenous GH administration and at serum GH levels comparable to those achieved during naturally occurring bursts of GH secretion. They also suggest that acute mediation of GH release must occur, at least in part, at the pituitary somatotroph level and that IGFs and/or insulin may not be the primary inhibitors. This phenomenon may be directly or indirectly due to GH-dependent metabolic factors such as FFA or glycerol. The lipolytic effect of GH in conjunction with the inhibitory effect of lipolytic products on GH secretion may represent an important feedback loop in the physiologic control of GH release.

Dynamic changes in insulin-like growth factor I immunoreactivity correlate to repair events in rat ear after freeze-thaw injury

The distribution of the trophic peptide insulin-like growth factor I (IGF-I) in the rat ear was mapped after freeze-thaw injury. Immunocytochemical methods and antisera specific to human IGF-I were used. In the ear of normal adult rats scattered basal epidermal cells and a few cells in the underlying connective tissue and elastic cartilage expressed IGF-I immunoreactivity. Within 1 day after injury and reaching maximum in 3 days, all epidermal cells became stained as did invading macrophages and some of the other inflammatory cells. Concomitantly, there were hypertrophic changes. The staining leveled off after 1–2 weeks. Perichondrial cells became IGF-I immunoreactive in increasing frequency during the first week, reached maximal intensity and frequency in 2 weeks, and remained stained for at least 4 weeks. New cartilage was formed concomitantly on both sides of the old one. It is proposed that IGF-I is a substance of general importance for cell maintenance and tissue repair.

Changes in insulin-like growth factors I and II and their binding protein after a single intramuscular injection of growth hormone.

The concentrations of insulin-like growth factors I and II (IGF-I and IGF-II) and their binding proteins in serum were measured in 10 GH-deficient patients before and after a single 6-IU injection of GH. Serum IGF-I concentrations were initially low, increased significantly by 8 and 24 h, and decreased to pretreatment levels 48 and 72 h after GH administration. Serum IGF-II concentrations also were low initially and did not increase by 8 and 24 h, but were, however, significantly higher 48 and 72 h after GH administration. In GH-deficient patients before GH administration, binding of IGF-I or IGF-II to serum proteins was restricted primarily to proteins of 50K mol wt. Little or no binding to proteins of 150,000 mol wt was found. By 8 and 24 h after GH injection, IGF-I, but not IGF-II, bound primarily to a protein(s) of 150K mol wt, as in normal subjects. IGF-II remained bound to a 50K mol wt protein. By 48 and 72 h after administering GH, however, the binding pattern was reversed, and IGF-II, but not IGF-I, bound predominantly to a protein(s) of 150K mol wt. Our data demonstrate both a temporal dissociation in the responses of IGF-I and IGF-II to GH and a similar temporal dissociation in the binding of IGF-I and IGF-II to the large mol wt (150K) binding protein. This dissociation, particularly the latter, may provide a means for better characterization of protein fractions in binding IGF, particularly in terms of specificity.