There is currently widespread interest in the IGFs (IGF-I and IGF-II) and their roles in the regulation of growth and differentiation of an ever increasing number of tissues are being reported. This selective review focused on the current state of our knowledge about the structure of mammalian IGFs and the multiple forms of mRNAs which arise from alternative splicing and promoter sites which arise from gene transcription. Current progress in the immunological measurement of the IGF is reviewed including different strategies for avoiding binding protein interference. The results of measurements of serum IGF-I and IGF-II in fetus and mother and at various stages of postnatal life are described. Existing knowledge of the concentration of these peptides in body fluids and tissues are considered. Last, an attempt is made to indicate circumstances in which the IGFs are exerting their actions in an autocrine/paracrine mode and when endocrine actions predominate. In the latter context it was concluded that an important role for GH action on skeletal tissues via hepatic production of IGF-I and endocrine action of IGF-I on growth cartilage is likely.

Insulin-Like Growth Factors I and II. Peptide, Messenger Ribonucleic Acid and Gene Structures, Serum, and Tissue Concentrations

Nutrition is one of the main regulators of circulating IGF-I. In humans, serum IGF-I concentrations are markedly lowered by energy and/or protein deprivation. Both energy and proteins are critical in the regulation of serum IGF-I concentrations. Indeed, after fasting, optimal intake of both energy and protein is necessary for the rapid restoration of circulating IGF-I. We believe, however, that in adult humans energy may be somewhat more important than protein in this regard. While the lowest protein intake is able to increase IGF-I in the presence of adequate energy, there is a threshold energy requirement below which optimal protein intake fails to raise IGF-I after fasting. When energy intake is severely reduced, the carbohydrate content of the diet is a major determinant of responsiveness of IGF-I to GH. The essential amino acid content of the diet is also critical for the optimal restoration of IGF-I after fasting, when protein intake is reduced. The exquisite sensitivity of circulating IGF-I to nutrients, the nycthemeral stability of its concentrations and its relative short half-life constitute the basis for its use as a marker of both nutritional status and adequacy of nutritional rehabilitation. For these indications, IGF-I measurement is more sensitive and more specific than measurement of the other nutrient-related serum proteins (albumin, prealbumin, transferrin, retinol-binding protein). Animal models have been developed to investigate the mechanisms responsible for the nutritional regulation of IGF-I. There is no doubt that many mechanisms are involved (Fig. 12). Decline of serum IGF-I in dietary restriction is independent of the diet-induced alterations in pituitary GH secretion. The role of the liver GH receptors is dependent on the severity of the nutritional insult. In severe dietary restriction (fasting), a marked decrease of the number of somatogenic receptors supports the role of a receptor defect in the decline of circulating IGF-I. In contrast, in less severe forms of dietary restriction (protein restriction), the decline of IGF-I results from a postreceptor defect in the GH action at the hepatic level. Nutritional deprivation decreases hepatic IGF-I production by diminishing IGF-I gene expression. Decline in IGF-I gene expression is mainly caused by nutrient deficiency and less importantly by the nutritionally induced hormonal changes (insulin and T3). Diet restriction also increases the clearance and degradation of serum IGF-I through changes in the levels of circulating IGFBPs.(ABSTRACT TRUNCATED AT 400 WORDS)

Nutritional Regulation of the Insulin-Like Growth Factors*

The Wisconsin epidemiologic study of diabetic retinopathy. VI: Retinal photocoagulation

Diabetes mellitus is a disease of metabolic dysregulation, most notably abnormal glucose metabolism, accompanied by characteristic long-term complications. The complications that are specific to diabetes include retinopathy, nephropathy, and neuropathy. Patients with all forms of diabetes of sufficient duration, including insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), are vulnerable to these complications, which cause serious morbidity (Table 1 and Table 2). Retinopathy is so characteristic of diabetes that its presence has been incorporated into the nosologic definition of NIDDM. Only hyperglycemia of sufficient magnitude to be associated with retinopathy is classified as NIDDM, while lower levels of hyperglycemia that are . . .

Long-term complications of diabetes mellitus

Three different lines of research and three entirely different observations have led to the discovery of the insulin-like growth factors (IGFs). In 1957, Salmon & Daughaday carried out an important experiment (44). They observed that serum stimulated the incorporation of 35S into incubated cartilage. Serum of hypophysectomized rats was devoid of this sulfation activity. It could not be reconstituted by addition of growth hormone to the incubation medium but reappeared after administration of growth hormone to hypophysectomized rats (44). These observations led Daughaday to postulate that growth hormone itself does not stimulate growth processes in vitro and in vivo, but rather induces the formation of factors that mediate the message of growth hormone. These factors-first called sulfation factors, later soma­ tomedins-Iead to sulfation of cartilage in vitro, which reflects growth in vivo. As we shall see, this hypothesis has been proven to be valid. Most cultured cells need serum to grow. Several growth factors in serum are responsible for growth-promoting effects, an aspect that will be discussed below in more detail. In 1972, Pierson & Temin extracted factors from serum, which they called multiplication-stimulating activity (MSA) (37). These fac­ tors had molecular weights below 10,000. When added to culture medium, they stimulated cells to replicate. Later it was found that cultured liver cells secrete MSA into the culture medium (10). This was the first demonstration that MSA is produced in the liver and that MSA may lead to autocrine stimulation of the same cells by which it is secreted. The third road towards the discovery of insulin-like growth factors departed from an entirely different observation: Serum exerts insulin-like effects on

Actions of Insulin-Like Growth Factors

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.

Insulin-like growth factors. Studies in diabetics with and without retinopathy.

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.

Insulin-like growth factors in the fed and fasted states.

Insulin-like growth factors (IGFs) I and II, which are present in normal human beings, were measured in serum samples from 11 pygmies from the Central African Republic, 31 controls, and 12 patients with growth hormone deficiency. The mean serum concentration of IGF-I (+/- S.E.M.) was 68.6 +/- 8 ng per milliliter in pygmies, as compared with 193 +/- 10 ng per milliliter in controls (P less than 0.001) and 24 +/- 4 ng per milliliter in patients with growth hormone deficiency (P less than 0.05). Mean serum concentrations of IGF-II in controls, pygmies, and growth hormone-deficient patients were 647 +/- 22, 503 +/- 37, and 252 +/- 29 ng per milliliter, respectively. The serum IGF-I concentration was within the normal range in only one pygmy, whereas IGF-II values were within the normal range in 10 of 11. Pygmies appear to have a major defect in the production of IGF-I.

Dwarfism in the pygmy. An isolated deficiency of insulin-like growth factor I.

We investigated the effect of improving glycemie 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 <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 glycemie control. Puberty developed during therapy in this latter group.

Our data do not support a “global” effect of glycemie control on serum IGF-I in diabetic patients. Increases of IGF-I with better glycemie 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 glycemie control in all subjects.

Effect of Glycemic Control on Serum Insulin-like Growth Factors in Diabetes Mellitus

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. (J Clin Endocrinol Metab 54: 1101, 1982)

E R Froesch

Papers

Insulin-like growth factors. Studies in diabetics with and without retinopathy.

Insulin-like growth factors in the fed and fasted states.

Dwarfism in the pygmy. An isolated deficiency of insulin-like growth factor I.

Effect of Glycemic Control on Serum Insulin-like Growth Factors in Diabetes Mellitus

Insulin-like growth factor in pregnancy: studies in a growth hormone-deficient dwarf.