IGFs/somatomedins: significance for growth.
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Acromegaly↗
Biomedical subjects
J Zapf
Publications and source records attributed to J Zapf.
Biological and immunological properties of insulin-like growth factors (IGF) I and II.
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Adipose Tissue↗
Insulin-like growth factor I in the dog: a study in different dog breeds and in dogs with growth hormone elevation.
A radioimmunoassay (RIA) devised for the measurement of human insulin-like growth factor I (IGF I) was employed for the measurement of canine IGF I. Canine IGF I was extracted from plasma specimens by gel chromatography. Columns were eluted with 1 M acetic acid and the fractions representing the 55 to 85% bed volume were pooled, lyophilized and reconstituted with assay buffer. Serial dilutions of canine IGF I from both normal and acromegalic dogs when added to the RIA system gave a similar displacement pattern of human [125I]IGF I as the one obtained by the addition of unlabelled human IGF I. The dose-response curve obtained by canine IGF I paralleled the one obtained by human IGF I. Logit-log transformation and least squares fitting resulted in straight line fitting of the standard curve between 0.039 and 5 ng IGF I added per tube. The within-assay coefficient of variation (CV) was 16.7% and the between-assay CV was 21.8%. Plasma IGF I concentrations in normal dogs appeared to be a function of body size. The concentrations were 36 +/- 27 ng/ml in Cocker Spaniels, 87 +/- 33 ng/ml in Beagles, 117 +/- 34 ng/ml in Keeshonds, and 280 +/- 23 ng/ml in German Shepherds (mean +/- SEM). The mean IGF I level in a group of dogs with growth hormone (GH) elevation was 700 +/- 90 ng/ml. Though this group of dogs comprised both small and large dogs, the mean IGF I level significantly differed from the one found in German Shepherds, the largest breed studied (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Acromegaly↗
Effect of glycemic control on serum insulin-like growth factors in diabetes mellitus.
We investigated the effect of improving glycemic control on serum concentrations of insulin-like growth factors I and II (IGF-I and IGF-II). In 22 adults followed during an intensive home glucose monitoring program for 6 mo, no effect of improving control was seen on either IGF-I or IGF-II. Similar results were obtained in young diabetic children less than 10 yr of age and in diabetic adolescents with detectable puberty before entering the study. In older diabetic children without evidence of puberty before treatment (Tanner prepubertal stage 1), initial IGF-I concentrations were low, but increased during establishment of glycemic control. Puberty developed during therapy in this latter group. Our data do not support a "global" effect of glycemic control on serum IGF-I in diabetic patients. Increases of IGF-I with better glycemic control appear most likely to occur when the metabolic consequences of diabetes have suppressed normal pubertal increases of IGF-I. IGF-II concentrations were unaffected by glycemic control in all subjects.
Adolescent↗
Insulin-like growth factors I and II, prolactin, and insulin in 19 growth hormone-deficient children with excessive, normal, or decreased longitudinal growth after operation for craniopharyngioma.
We studied insulin-like growth factors (IGF) I and II, prolactin, and the insulin response to arginine in 19 children with craniopharyngioma and documented growth hormone deficiency. Patients were divided into three groups according to their growth rate during the first postoperative year. Seven patients with excessive growth (Group A) had hyperinsulinism, normal IGF values, elevated basal prolactin levels, and a delayed thyrotropin response to thyrotropin-releasing hormone, which was compatible with hypothalamic lesions. In the six patients with normal growth (Group B), the insulin level was low; all other hormone values were similar to those of Group A. In the six patients with decreased growth (Group C), levels of IGF I, insulin, prolactin, and thyrotropin were low, indicating the presence of severe pituitary damage and explaining the failure to grow. Patients in all groups had low or undetectable basal levels of growth hormone. We conclude that in Group B, normal IGF permitted normal growth, and prolactin hypersecretion may have been responsible for normal IGF I values. Excessive growth in Group A may have been caused by hyperinsulinism associated with hyperphagia and obesity of hypothalamic origin.
Adolescent↗
[Diagnosis in acromegaly. Insulin-like growth factor as a parameter of activity].
The peripheral actions of growth hormone (STH) are mediated by somatomedins or "insulin-like growth factors" (IGF I and II). In untreated acromegaly (n = 24) IGF I was always found increased, IGF II, however, was unchanged. The mean IGF-I-level (+/- SEM) was 553 +/- 75 (range 319-1066) ng/ml in active acromegaly and 193 +/- 10 (range 120-300) ng/ml in control persons. The corresponding IGF-II-values were 533 +/- 38 (range 187-720) and 647 +/- 21 (range 400-900) ng/ml. After treatment of acromegaly IGF I followed changes of the basal STH level with a delay of 4-8 weeks independent of the mode of treatment. This was in contrast to behaviour of IGF II. When STH was suppressible below 1 ng/ml after oral administration of 100 g glucose IGF I was never increased. STH after glucose of more than 5 ng/ml was always associated with increased IGF I. STH values between 1 and 5 ng/ml after glucose were combined with IGF-I-increases in 3 out of 6 cases. Thus, IGF I represents a valuable diagnostic criterion for assessment of activity of acromegaly, particularly in borderline cases, in contrast to IGF II. The criterion of normal somatotrophic function is suggested to be suppressibility of STH level below 1 ng/ml after oral administration of 100 g glucose.
Acromegaly↗
Insulin-like growth factors. Studies in diabetics with and without retinopathy.
To determine whether two insulin-like growth factors (IGF I and IGF II) influence the course of diabetic retinopathy, we measured the concentrations of these factors in 80 adult patients with diabetes and in 62 control subjects. In seven patients with Type I diabetes and rapidly deteriorating vision as a result of proliferative and exudative retinopathy, the serum concentration of IGF I was 722 +/- 41 ng per milliliter (mean +/- S.E.M.), as compared with 381 +/- 48 ng per milliliter in 26 patients who had Type I diabetes without retinopathy or with less severe forms of it, and 302 +/- 15 ng per milliliter in the controls (P less than 0.001 for both comparisons). Serum concentrations of IGF II were normal in subjects with Type I diabetes but were somewhat depressed in those with Type II disease. Whether elevated serum concentrations of IGF I cause the accelerated development of retinopathy in some patients remains to be determined. Such levels do appear to identify patients at high risk for rapid deterioration of vision, and hence may be useful in selecting patients for more intensive or alternative forms of therapy.
Adult↗
Resistance to subcutaneous and intramuscular insulin associated with deficiency of insulin-like growth factor (IGF) 2.
A diabetic patient is described whose serum was deficient in IGF 2. The patient responded appropriately to intravenous insulin but was resistant to subcutaneous and intramuscular insulin. His serum degraded insulin in vitro. This degradation was inhibited by IGF 2 and to a lesser extent by IGF 1 and insulin. We propose that this patient inactivated insulin at the injection site because of an insulin protease in his tissues that would normally be inhibited by serum IGF 2.
Adult↗
Regulation of rat adipocyte glucose transport by growth hormone: no mediation by insulin-like growth factors.
Growth hormone (GH) in vivo is responsible for normal glucose transport in isolated rat fat cells: In fat cells of hypophysectomized (hypox) rats basal glucose transport is maximal and insulin-insensitive. GH treatment of hypox rats restores the basal glucose transport rate towards normal and renders it again insulin-sensitive. The aim of this study was to find out whether these are direct effects of GH or effects that are mediated by GH-dependent insulin-like growth factors (IGF) I or II. Whereas IGF I and II infused into hypox rats stimulate growth, they do not normalize the glucose transport system in fat cells. Thus, the restriction of basal glucose transport in adipocytes seems to be directly controlled by GH.
Adipose Tissue↗
Synthesis and secretion of insulin-like growth factor and its binding protein by the perfused rat liver: dependence on growth hormone status.
Isolated livers of normal and hypophysectomized (hypox) rats with or without GH replacement therapy were perfused in an erythrocyte-free recirculating perfusion system for 4 h in the presence of [35S]cysteine. Albumin secretion and synthesis increased in a parallel and linear fashion over 4 h. The albumin secretion rates were 0.53 and 0.21 mg/g liver h-1 in normal and hypox animals, respectively. Insulin-like growth factor (IGF) secretion, measured as insulin equivalents in the fat cell assay as well as in a competitive protein binding assay, and IGF synthesis, as determined from [35S]cysteine incorporation into immunoprecipitable IGF, likewise increased linearly and in parallel throughout the perfusion time. The IGF secretion rate was 50 microU/g liver h-1. The secreted IGF had a molecular weight of approximately 7700 daltons. Secretion and synthesis of IGF were reduced to 11% in hypox rats and were largely restored by human GH replacement therapy (to 86% of normal). A single specific binding protein with an approximate molecular weight of 35,000 was detected in the perfusate. The binding protein was measured by covalent cross-linkage to [125I]IGF I by dimethylsuberimidate. The secretion of this binding protein was 62% of normal in hypox animals and 79% in GH-treated hypox rats. The data suggest that IGF is continuously synthesized and released by the liver. Assuming a half-life for IGF of 3 h in the normal rat, a plasma volume of 8 ml, and a liver weight of 8.5 g, the rate of IGF production by the perfused normal rat liver (50 microU/g liver h-1) would be sufficient to maintain serum IGF at the concentration determined in normal rat serum (approximately 130 microU/ml). This suggests that the liver is the major site of IGF production in the rat.
Albumins↗
Progesterone-controlled growth hormone overproduction and naturally occurring canine diabetes and acromegaly.
Female pet dogs exhibiting either glucose intolerance alone or glucose intolerance and acromegaly were investigated. Some dogs developed the disorder(s) during dioestrus and some animals developed the disorder(s) after they were given medroxyprogesterone acetate (MPA). Elevated fasting plasma glucose levels (12.3 +/- 1.9 mM, mean +/- SEM) were accompanied by fasting hyperinsulinaemia (144 +/- 21 microU/ml, mean +/- SEM) and drastic elevation of plasma growth hormone (GH) levels (112.6 +/- 45 ng/ml, mean +/- SEM). An iv glucose tolerance test (IVGTT) performed on all dogs revealed non-suppressibility of GH levels and glucose intolerance. Plasma concentrations of glucose, insulin and GH during IVGTT in affected dogs differed significantly from the concentrations measured in normal dogs during the same test. MPA withdrawal and/or ovariohysterectomy (OVx-HYx) in affected animals was followed by reversal of GH levels to normal and improved glucose tolerance. Acromegaly associated soft tissue changes were also reversible after MPA withdrawal and/or OVx-HYx when GH levels had dropped. In 5 dogs which had developed diabetes during dioestrus and in which a spontaneous decrease in plasma progesterone occurred during the investigation a concomittant decrease in GH levels was observed. Plasma GH measured at different stages of pregnancy in 45 dogs was found to be elevated in one animal only. The results show that the development of spontaneous diabetes/acromegaly occurring in some female dogs is related to progestagen (progesterone/MPA) exposure and that reversal of the signs is achieved by progesterone/MPA withdrawal. The results suggest that diabetes/acromegaly in the dogs studied was caused by progesterone/MPA-evoked GH elevation. Finally, the findings also suggest that the GH axis normally not appreciably responsive to progestagen exposure in some dogs becomes and/or is paradoxically controlled by physiologic levels of endogenous progesterone or low doses of MPA.
Acromegaly↗
Hypoglycemia associated with non-islet-cell tumor and insulin-like growth factors.
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Humans↗
Insulin-like growth factor I stimulates growth in hypophysectomized rats.
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Animals↗
Glucose transport in adipocytes and its control by growth hormone in vivo.
Previous results showed maximally enhanced basal glucose transport in adipocytes of hypophysectomized rats and restoration to normal after human growth hormone (hGH) administration. The data suggested a hGH-dependent "limiting factor" for glucose transport in the adipocyte membrane, which is acutely inhibited by insulin resulting in enhanced glucose transport. In this study the effect of hGH was investigated with respect to dose and time dependence. hGH was administered by continuous infusion from subcutaneously implanted Alzet minipumps. A significant decrease of basal glucose transport was obtained at the lowest hGH dose of 50 mU/day for 6 days. This effect of hGH was strictly correlated to the effects on growth (tibial epiphyseal width, DNA synthesis, body weight, serum level of insulin-like growth factor). The effect of hGH on basal glucose transport was already observed after 12 h of infusion, and it increased to a maximum after 3 days. The data support the concept that GH regulates the glucose transport system in adipose tissue in vivo.
3-O-Methylglucose↗
Insulin-like growth factor in pregnancy: studies in a growth hormone-deficient dwarf.
Serum concentrations of insulin-like growth factors I and II (IGF I and IGF II) were measured before, during and after pregnancy in a GH-deficient dwarf. At no time during these periods did the patient secrete GH in response to an arginine infusion or insulin tolerance test. IGF I and IGF II concentrations before pregnancy were low and similar to those of patients deficient only in GH. During the 35th week of gestation, IGF I and IGF II serum concentrations were within the normal range (165 and 127 ng/ml for IGF I and 740 and 860 ng/ml for IGF II). Abnormally low values of IGF I and IGF II were again recorded 36 h postpartum and 35 days later. These data indicate that some material, probably of placental origin, stimulates the secretion of not only IGF I, but IGF II as well. Alternatively, the human placenta may produce IGF. Such secretion can occur without the prior maternal secretion of pituitary GH.
Arginine↗
Is extrapancreatic tumor hypoglycemia associated with elevated levels of insulin-like growth factor II?
We have tried to answer the still controversial question of whether or not extrapancreatic tumor hypoglycemia is associated with elevated levels of insulin-like growth factor II (IGF II), keeping in mind that controversial results may be due to methodological differences. Serum levels of IGF II were determined by a rat liver membrane radioreceptor assay and by RIA. Serum samples were gel filtered at acidic pH, and some sera were also tested after acid-ethanol extraction as an alternative method for dissociating and separating IGF from the IGF carrier protein. Additionally, the radioreceptor assay was performed with a labeled partially purified IGF preparation [nonsuppressible insulin-like activity soluble in acid-ethanol (NSILA-s "70")] that was used by a group reporting elevated NSILA-s levels in about 40% of their patients with tumor hypoglycemia. Mean serum levels of receptor-reactive IGF II and immunoreactive IGF II (+/- SD) were 436 +/- 169 and 540 +/- 256 ng/ml in 22 patients with tumor hypoglycemia, as compared with 578 +/- 155 and 647 +/- 217 ng/ml in 28 normal adults. This pattern of slightly, but not significantly lower mean IGF II values in tumor hypoglycemia was unchanged when a less pure IGF preparation (NSILA-s 70) was used as a tracer or when the sera were extracted with acid-ethanol. Thus, hypoglycemia resulting from extrapancreatic tumors is not likely to be associated with increased receptorreactive or immunoreactive IGF II levels.
Adolescent↗
Insulin-like growth factors in the fed and fasted states.
The effect of GH administration (5 mg twice daily for 5 days) on the serum concentration of insulin-like growth factors I and II (IGF I and IGF II) was compared in GH-deficient subjects during a period of fasting and a period of normal food intake. Before treatment with GH, the mean concentration of IGF I was 35.2 +/- 7.5 ng/ml. After 5 days of GH treatment in the fed state, IGF I increased nearly 10-fold to 317.4 +/- 55.9 ng/ml (P less than 0.001 vs. pretreatment value). During fasting, identical treatment of the group resulted in only a modest increase of IGF I to 81 +/- 23 ng/ml (P less than 0.001 vs. fed state response). The serum concentration of IGF II before therapy was reduced to only 174 +/- 37 ng/ml. With GH given in the fed state, IGF II increased to 793 +/- 171 ng/ml. These data suggest that IGF II, like IGF I, is GH dependent and, hence, a somatomedin. GH therapy in the fasted state increased IGF II to 437 +/- 70 ng/ml (P = 0.05 vs. fed state response). In a second study, six normal subjects were fasted for 72 h. The integrated serum IGF I concentration (24 samples/subject) decreased 42% by the third day of fasting; IGF II decreased 27% during the same period. The data from both studies are consistent with the conclusion that the metabolic milieu of fasting inhibits IGF secretion in man. IGF I appears to be affected more than IGF II.
Adult↗