Effects of recombinant insulin-like growth factor I on insulin secretion and renal function in normal human subjects.

Insulin-like growth factor I (IGF-I) is an important mediator of growth hormone (GH) action and it appeared tempting to evaluate possible clinical applications. Recombinant IGF-I was infused s.c. at a dose of 20 micrograms/kg of body weight per hour during 6 days in two healthy adult subjects. Blood glucose and fasting insulin levels remained within normal limits and IGF-II levels were suppressed. In contrast to insulin, fasting C peptide levels were decreased. GH secretion was also suppressed by IGF-I. Our preliminary data allow us to distinguish between the effects of GH per se and those of IGF-I: GH causes hyperinsulinism, whereas IGF-I leads to decreased insulin secretion. Glomerular filtration rate, as estimated by creatinine clearance, increased to 130% of preinfusion values during the IGF-I infusion. Total creatinine and urea excretion remained unchanged. We conclude that IGF-I influences kidney function and, in contrast to GH, exerts an insulin-sparing effect. It may be speculated that the therapeutic spectrum of IGF-I is quite different from that of GH.     

Activation of glucose uptake by insulin and insulin-like growth factor I in Xenopus oocytes.

Xenopus laevis oocytes possess a glucose transport system that is activated 3- to 5-fold by insulin-like growth factor I (Ka = 3 nM) and insulin (Ka = 200-250 nM), properties suggesting activation mediated by an insulin-like growth factor I receptor. This activation increases the Vmax of hexose uptake and has little or no effect on the Km for deoxyglucose (Km = 1-2 mM). Activation by hormone requires about 60 min and is inhibited by cytochalasin B but not by cycloheximide. The dependence of hexose uptake rate on hexose concentration exhibits cooperativity with Hill coefficients of 1.8 and 1.4 for the basal and hormone-activated states, respectively. Microinjection of a monoclonal antibody directed against the tyrosine kinase domain of the human insulin receptor blocks activation of hexose uptake by insulin-like growth factor I and insulin but has no effect on basal uptake. Taken together the results implicate the tyrosine-specific protein kinase activity of a cell-surface insulin-like growth factor I receptor in the activation of glucose transport in the Xenopus oocyte.     

Expression of insulin-like growth factor II and receptors for insulin-like growth factor II, insulin-like growth factor I and insulin in isolated and cultured rat hepatocytes.

Insulin-like growth factor II is believed to play an important role in fetal growth and development. The insulin-like growth factor II gene expression is tissue specific and developmentally regulated. We have previously shown an enhanced level of insulin-like growth factor II messenger RNA and protein in human hepatocellular carcinomas. This led to the suggestion that hepatocytes might be involved in insulin-like growth factor II expression. However, previous studies based on in situ hybridization only showed insulin-like growth factor II messenger RNA in liver sinusoidal cells. This paper reports on the analysis of the expression of insulin-like growth factor II and insulin-like growth factor II, insulin-like growth factor I and insulin receptor messenger RNAs in vivo in isolated rat hepatocytes at various stages of development and in vitro in adult rat hepatocytes primary culture. Our study indicates that isolated rat hepatocytes synthesize insulin-like growth factor II messenger RNA with a switch between fetal and adult messenger RNA profiles occurring 21 days after birth. In addition, adult rat hepatocytes in culture expressed insulin-like growth factor II messenger RNA and protein. Insulin-like growth factor II, insulin-like growth factor I and insulin receptor messenger RNAs were also detected. Therefore these results are consistent with the hypothesis that insulin-like growth factor II acts as an autocrine growth factor for hepatocytes in addition to having a paracrine effect. They also indicate that primary culture of hepatocytes is a good model for further studies on insulin-like growth factor II gene regulation.     

Effects of luteinizing hormone, insulin, insulin-like growth factor-I and insulin-like growth factor small binding protein 1 in the polycystic ovary syndrome.

This study explores the clinical and endocrine implications of hyperinsulinaemia in the polycystic ovary syndrome (PCOS). Oral glucose tolerance tests were performed on 34 lean and 19 obese women with PCOS and on 13 lean women with normal ovaries. Insulin measurements were compared with basal gonadotrophins, androgens, insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein 1 (IGFBP-1). Unselected lean women with PCOS were found to have fasting hyperinsulinaemia and the raised serum insulin concentrations were associated with menstrual disturbance and hyperandrogenaemia. In addition, serum insulin concentrations in lean women with PCOS correlated positively with serum IGF-I and negatively with serum IGFBP-1 concentrations. Ovarian stimulation by insulin appears to be independent of luteinizing hormone (LH) and is an important feature in 30% of lean women with PCOS.     

Effects of ethanol ingestion on glucose tolerance and insulin secretion in normal and diabetic subjects

To investigate the effect of ethanol on carbohydrate homeostasis in circumstances in which food and ethanol are usually ingested, ethanol was administered hourly in the afternoon prior to the ingestion of a glucose load at 5:00 p.m. in a group of normal subjects and in mild diabetics. In both groups the blood glucose levels following the glucose load were $\text{30–80 mg}\text{100 ml}$ lower and the early insulin secretory response (15–45 min) was 35%–40% higher after ethanol ingestion. In contrast, ethanol intake had no effect on the glucagon response to glucose ingestion. These data suggest that ethanol enhances glucose-stimulated insulin secretion. The dampened blood glucose rise observed with ethanol may be related to the augmented insulin response or to decreased gastrointestinal absorption of glucose. In mild diabetic patients, moderate intake of ethanol is without acute deleterious effects on carbohydrate homeostasis and may in some instances improve the blood glucose response to ingested carbohydrate.     

Effect of insulin-like growth factor I on the thyroid axis in patients with Laron-type dwarfism and healthy subjects.

We have evaluated the effect of exogenous administration of IGF-I on the thyroid axis in four separate studies: (1) iv bolus injection; (2) single sc injection; (3) seven days' sc treatment, and (4) four months' treatment. Thirteen patients with Laron-type dwarfism (LTD) participated in the investigations. In studies 1 and 2, 10 healthy subjects were also included. Before and during long-term treatment (study 4) six LTD patients underwent a TRH test. IGF-I was administered in a dose of 75 micrograms.kg-1 iv or 120-150 micrograms.kg-1 sc. Single injections of IGF-I caused significant decreases of serum TSH in LTD patients (iv: 1.7 +/- 0.2 to 1.1 +/- 0.1 mU/l; sc: from 2.1 +/- 0.4 to 1.1 +/- 0.2; p < 0.0005). In controls the decrease was for iv from 1.2 +/- 0.2 to 0.8 +/- 0.2 mU/l (p < 0.02) and for sc from 2.0 +/- 0.5 to 0.8 +/- 0.2 mU/l (p < 0.05). Long-term administration of IGF-I induces a transitory decrease of both serum TSH and fT4, followed by a spontaneous rise to pretreatment or even higher values. No changes in T3 were observed. TSH stimulation by TRH was significantly augmented after four months of IGF-I treatment (p < 0.005). The effects of IGF-I can be explained by an early stimulation of somatostatin release causing a decrease in TSH and followed by the development of compensatory mechanisms. All changes were within the normal ranges, not causing abnormal thyroid function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of gonadotropins, insulin and insulin-like growth factor I on ovarian oxytocin and progesterone production.

Oxytocin is produced in the granulosa-derived cells of the ruminant corpus luteum where its gene is dramatically up-regulated within days of ovulation. Regulation of these processes is poorly understood but oxytocin release can be increased by insulin, insulin-like growth factor I (IGF-I), and gonadotropins. Here we have assessed interactions between these regulatory systems. Follicle-stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotropin (hCG) caused dose-dependent release of oxytocin from bovine granulosa cells cultured in medium containing 100 ng/ml insulin. The gonadotropins also increased oxytocin mRNA levels and their effects were mimicked by forskolin. The effects of these stimuli on oxytocin and progesterone release were synergistically increased by insulin or IGF-I. Binding studies revealed separate binding sites with characteristics of insulin and IGF-I receptors. Insulin potentiated the effects of hCG and forskolin on oxytocin mRNA levels and release of oxytocin and progesterone in cells from follicles containing greater than 50 ng/ml estradiol. In cells from follicles containing less than 5 ng/ml estradiol these stimuli had little effect on oxytocin release although progesterone release was synergistically increased by insulin and forskolin. The data suggest that gonadotropins regulate oxytocin synthesis and release and that these effects are amplified by insulin or IGF-I acting via their own receptors. Changes associated with maturation of the target cells in vitro appear prerequisite for oxytocin production in response to increased cAMP levels in the presence of insulin or IGF-I.     

The pharmacokinetics of free insulin-like growth factor-I in healthy subjects.

In a randomized cross-over study in five healthy males we compared 75-min constant i.v. infusion of saline, low-dose recombinant human (rh) insulin-like growth factor-I (rhIGF-I; 1.5 microg/kg/h) and high-dose rhIGF-I (9.0 microg/kg/h). Serum samples were analysed for ultrafiltered free IGF-I (fIGF-I), total IGF-I (tIGF-I), tIGF-II and IGF-binding protein-1 (IGFBP-1) and -3.Free and total IGF-I were unchanged during saline infusion. Low-dose rhIGF-I caused a small increment in fIGF-I [+41%, from 0.64 +/- 0.19 (mean +/- SEM) to 0.90 +/- 0.25 microg/l;P< 0.05] and tIGF-I (+9%, from 220 +/- 31 to 239 +/- 33 microg/l;P< 0.05). High-dose rhIGF-I increased tIGF-I by 40% (from 227 +/- 36 to 329 +/- 31 microg/l;P< 0.05), and fIGF-I by 11.5 times (from 0.56 +/- 0.20 to 6.46 +/- 1.39 microg/l;P< 0.05). The pharmacokinetic profile of fIGF-I was calculated after high-dose IGF-I only. The disappearance of fIGF-I followed first order kinetics with an apparent half-life of 14.4 +/- 1.0 [11.2-17.1 (range)] min. The clearance was estimated to 52 +/- 20 (16-128) ml/min/kg and the volume of distribution to 1102 +/- 464 (388-2899) ml/kg. In the three experiments, there were no differences in IGFBP-1, and tIGF-II and IGFBP-3 remained unchanged.In conclusion, fIGF-I remained within the physiological range after low-dose rhIGF-I, whereas high-dose rhIGF-I resulted in supraphysiological concentrations. Since the half-life estimates for each subject were remarkably similar, this parameter most likely does not explain the observed variation in clearance and volume of distribution of fIGF-I. Instead, differences in the circulating and cellular IGF-I binding capacity may be of importance.     

Isolation of the human insulin-like growth factor genes: insulin-like growth factor II and insulin genes are contiguous.

Overlapping recombinant clones that encompass the insulin-like growth factor (IGF) I and II genes have been isolated from a human genomic DNA library. Each gene is present once per haploid genome; the IGF-I gene spans greater than 35 kilobase pairs (kbp) and the IGF-II gene is at least 15 kbp. The exon-intron organization of these genes is similar, each having four exons, which is one more than the related insulin gene. Comparison of the restriction endonuclease cleavage maps of the IGF-II and insulin genes, including their flanking regions and hybridization with an IGF-II cDNA probe, revealed that they are adjacent to one another. The IGF-II and insulin genes have the same polarity and are separated by 12.6 kbp of intergenic DNA that includes a dispersed middle repetitive Alu sequence. The order of the genes is 5'-insulin-IGF-II-3'.     

Effects of recombinant human insulin-like growth factor I and insulin on counterregulation during acute plasma glucose decrements in normal and Type 2 (non-insulin-dependent) diabetic subjects

Summary Insulin-like growth factor I (65 μg/kg) or insulin (0.1 IU/kg) were injected i.v. on two separate occasions in random order in normal and in Type 2 (non-insulin-dependent) diabetic subjects. Insulin-like growth factor I and insulin injection resulted in identical decrements of plasma glucose concentrations after 30 min but in delayed recovery after insulin-like growth factor I as compared to insulin in both groups (p<0.05 insulin-like growth factor I vs insulin). Counterregulatory increases in plasma glucagon, adrenaline, cortisol and growth hormone concentrations after hypoglycaemia (1.9±0.2 mmol/l) in normal subjects were blunted after insulin-like growth factor I administration compared to insulin (p<0.05). Plasma glucose in Type 2 diabetic subjects did not reach hypoglycaemic levels but the acute glucose decrease to 4.5±0.8 mmol/l was associated with significantly lower responses of plasma glucagon and adrenaline but higher cortisol levels after insulin-like growth factor I compared to insulin (p<0.003). Plasma concentrations of non-esterified fatty acids and leucine decreased similarly after insulin-like growth factor I and insulin in both groups. The present results demonstrate that insulin-like growth factor I is capable of mimicking the acute effects of insulin on metabolic substrates (plasma glucose, non-esterified fatty acids, leucine). The decreases of plasma glucose were similar after both peptides in normal and in diabetic subjects who were presumably insulin resistant. Counterregulatory hormone responses to plasma glucose decrements differed, however, between insulin-like growth factor I and insulin and in the diabetic and the control subjects. After insulin-like growth factor I the increases in adrenaline, cortisol, growth hormone and glucagon were blunted in normal subjects despite slightly lower plasma glucose concentrations.     

Effects on glucose tolerance,insulin secretion,insulin-like growth factor 1 and its binding protein,IGFBP-1, in a randomized controlled diet and exercise study in healthy,middle-aged men

Abstract. Objectives . To study the effects of advice on diet, exercise and their combination on oral glucose tolerance (OGTT), insulin secretion, insulin-like growth factor-1 (IGF-1) and its binding protein, IGFBP-1. Design . A 6-month, randomized, controlled intervention study. Setting . Primary health care centres in Sollentuna, Stockholm and the Department of Medicine, Karolinska Hospital, Stockholm, Sweden. Subjects . One hundred and fifty-seven normoglycaemic healthy men, mean age 46 years, range 35–60 years, with slightly to moderately raised cardiovascular risk factors. Interventions . Advice on diet (D, n = 40), exercise (E, n = 39) a combination of both (DE, n = 39) and a control group (C. n = 39). Main outcome measures . An OGTT, insulin secretion, IGF-1 and its binding protein, IGFBP-1. Results . The number of pathological OGTTs in the intervention groups decreased from 42/118 to 33/118 whilst the number in the control group did not change. Fasting insulin levels decreased in groups E and DE from 8.8–7.4 mU L^?1 (P < 0.01) and from 8.3–6.7 mU L^?1 (P < 0.01), respectively. Accordingly, the insulin area under the curve decreased from 5278 to 4828 (P < 0.05) in group E, and from 5482 to 4809 (P < 0.01) in group DE. IGF-1 only increased in group D. The most prominent changes were noted for IGFBP-1, which increased in all three intervention groups and to the highest degree in group DE (from 33.7–42.6 μg L^?1, P < 0.001). Conclusions . A combination of increased exercise and improved diet, as well as increased exercise alone, favourably affect glucose and insulin homeostasis in middle-aged men with moderately elevated cardiovascular risk factors. The most marked changes were noted for IGFBP-1, possibly suggesting a decreased insulin secretion and an enhanced insulin sensitivity.     

Effects of epidermal growth factor, insulin and insulin-like growth factor I on rat pancreatic acinar cells cultured in serum-free medium

The effects of epidermal growth factor (EGF), insulin, and insulin-like growth factor I (IGF-I) were examined alone and in combination on rat pancreatic acinar cells cultured 48 h in serum free medium. IGF-I at a concentration of 2.7 nM maintained viability of cultured acinar cells comparably to EGF. In contrast, insulin was less effective in maintaining acinar viability, even at high concentrations (170nM). There were no additive or interactive effects of these growth factors on acinar viability. EGF significantly increased [3H]-phenylalanine incorporation into acinar protein and the specific activity of phenylalanine-acylated transfer RNA (tRNAphe), but did not change the apparent rate of protein synthesis when compared with insulin of IGF-I. EGF with insulin, IGF-I, or both resulted in significantly lower specific activities of tRNAphe when compared to EGF alone, but all had comparable rates of total phe-incorporation. Acinar cells readily degraded insulin, but not EGF or IGF-I. These results demonstrate some specificity in the acinar requirement for growth factors (EGF = IGF-I greater than insulin) in maintaining viability in culture.     

大米不同烹调方法对健康人餐后血糖和胰岛素分泌的影响

动值[(19.7±6.8)mU/L]明显低于大米粥[(27.6±13.1)mU/L,P<0.05]和葡萄糖[(29.9±12.2)mU/L,P<0.05].结论 健康人进食等量大米煮成的大米粥餐后血糖波动比进食大米饭更大,早期胰岛素分泌增加,餐后胰岛素波动增大.     

Effects of ethanol on the intraovarian insulin-like growth factor-1 system in the prepubertal rat

Insulin-like growth factor-1 (IGF-1) is considered to play an important role during ovarian development and function. Because ethanol (ETOH) is a gonadal toxin in men, as well as male and female rats, we hypothesized that this drug may be having detrimental effects in the ovary by altering the intraovarian actions of IGF-1. In support of this notion, the present study was undertaken to examine the chronic effects of ETOH on the ovarian IGF-1 system in prepubertal female rats. Each rat was implanted with a gastric cannula on day 24 and began receiving either a control or ETOH liquid diet on day 29. The animals were killed on day 34, confirmed to be in the late juvenile stage of development, and their ovaries and blood were collected. Using an RNase protection assay, we determined the expression of mRNAs encoding IGF-1 and the Type 1 IGF receptor in the ovaries of control and ETOH-treated rats. Results indicate that the ETOH-treated rats showed an increase in the ovarian expression of IGF-1a (p < 0.0001) and IGF-1b (p < 0.001) mRNA, the two alternatively spliced forms of the IGF-1 gene. Conversely, ovarian IGF-1 protein levels were depressed (p < 0.05) in ETOH-treated rats as determined by radioimmunoassay. Furthermore, ETOH-treated rats showed a decrease (p < 0.01) in the expression of Type-1 IGF receptor mRNA with a subsequent decrease (p < 0.05) in the ovarian levels of IGF-1 receptor protein, as determined by Western blot analysis. Also, using Western immunoblotting, we determined increases in immunoreactive IGF-binding proteins-3 (p < 0.05) and 5 (p < 0.01), but not 4, in ETOH-treated rats as compared with controls. Furthermore, we observed a concomitant decrease (p < 0.01) in the serum levels of estradiol. These results demonstrate for the first time that chronic ETOH administration is capable of altering the prepubertal intraovarian IGF-1 signaling system. We suggest that, at least in part, these effects contribute to altered prepubertal ovarian function after chronic exposure to ETOH.     

Characterisation of insulin-like growth factor I receptor in skeletal muscles of normal and insulin resistant subjects

Summary The insulin-like growth factor I receptor and the activity of its associated tyrosine kinase activity were characterised in wheat germ agglutinin extracts from skeletal muscle biopsies from nine control and ten obese Type 2 (non-insulin-dependent) diabetic subjects, who had marked peripheral in vivo insulin resistance for glucose disposal and hyperinsulinaemia. In parallel studies, the concentration of the insulin receptor and its tyrosine kinase activity were examined in the biopsy extracts and compared to the findings for the insulin-like growth factor I receptor system. Specific binding sites for insulin-like growth factor I were detected. The receptor binding of insulin-like growth factor I was not changed in the obese diabetic subjects as compared to binding activity in the biopsies from the control subjects. The molecular weight of the insulin-like growth factor I receptor alpha subunit was similar in both groups (135 kDa). The insulin-like growth factor I stimulated tyrosine kinase activity was also similar for the two groups. In contrast, insulin binding activity was 30% less in the receptor extracts from the in vivo insulin resistant group when compared to the control group. Moreover, insulin-stimulated tyrosine kinase activity was reduced in the former group by 40% when the value was corrected for insulin binding. Thus, specific insulin-like growth factor I receptors are present in human skeletal muscle. These receptors are normal in insulin resistant obese Type 2 diabetic subjects. The findings argue that alterations in the insulin receptor number and tyrosine kinase activity of muscle, which may underlie the marked insulin resistance found in obese Type 2 diabetic patients for glucose disposal, are quite specific for the insulin receptor, since the closely related insulin-like growth factor I receptor was not affected in these patients.     

Effect of beer,yeast-fermented glucose,and ethanol on pancreatic enzyme secretion in healthy human subjects

The effect of beer, ethanol (4% v/v), and corresponding volumetric (water), caloric (glucose 5.76% w/v), and osmotic (glucose 11.5% w/v) control solutions on pancreatic enzyme output and release of gastrin and cholecystokinin (CCK) were studied in six healthy human subjects. As a simpler model of beer, yeast-fermented glucose solution (11.5% w/v) was also studied and compared with unfermented glucose (11.5% w/v). Among the control solutions, the two glucose solutions, but not water, significantly (P<0.05) increased the 150-min integrated trypsin and amylase output over basal levels. Beer and fermented glucose caused a significantly higher increase in trypsin and amylase output compared to water or glucose. Ethanol (4% v/v) failed to stimulate pancreatic enzyme output. Fermented glucose and beer, but not the control solutions, significantly increased plasma gastrin levels above basal values. Isotonic and hypertonic glucose, beer, and fermented glucose significantly increased plasma levels of cholecystokinin (CCK), but the effect was significantly higher after hypertonic glucose than after isotonic glucose, beer, or fermented glucose. Ethanol and water had no effect on plasma levels of gastrin and CCK. We conclude that: (1) in the doses studied intragastric beer and fermented glucose but not ethanol (4% v/v) stimulate pancreatic enzyme output and release of gastrin and CCK; (2) the lack of effect of ethanol indicates that nonalcoholic ingredients of beer and fermented glucose are responsible for this stimulatory effect; and (3) CCK could be one of the major mediators of the stimulation of pancreatic enzyme output after ingestion of beer and fermented glucose.     

Anatomy of the pituitary insulin-like growth factor system.

In situ hybridization was used to map patterns of gene expression for components of the insulin-like growth factor (IGF) system, including IGF-I and -II, IGF-binding proteins 1-5 (IGFBP1-5), the IGF-I receptor, and GH in the rat pituitary. IGF-I mRNA was concentrated in isolated cells scattered throughout the gland with features typical of nonendocrine folliculo-stellate cells. IGF-II mRNA was abundant in neural (NL) and intermediate lobe (IL) capillaries, and low levels were present in endocrine cells of anterior lobe (AL) and IL. IGFBP1 mRNA was not detected in the pituitary. IGFBP2 mRNA was concentrated in epithelial cells lining AL follicles and in astroglial-like cells (pituicytes) of the NL. IGFBP3 mRNA was localized in isolated cells scattered throughout the AL and NL. IGFBP4 mRNA was relatively abundant in NL pituicytes and was diffusely expressed in the AL. IGFBP5 mRNA was equally abundant in NL and AL, and was localized in folliculo-stellate and epithelial cells of the AL and pituicytes and capillaries of the NL. Neither IGF-I nor IGFBP1-5 were detected in the IL. IGF-I receptor mRNA was abundant and homogeneously distributed throughout the AL and IL, compatible with expression by endocrine cells. There was overlap, but no particular correlation, between IGF system gene expression and GH-producing cells, which were clustered in the dorsal-lateral wings of the AL. In summary, IGF system gene expression is bountiful in the rat pituitary, but does not correlate with sites of GH synthesis. IGF-I receptor mRNA, which might have been expected to localize to somatotrophs, appears to be equally abundant in all of the endocrine cells of both AL and IL; the other constituents of the IGF system are localized in connective tissue and support elements that demonstrate no special anatomical relationship to somatotrophs. Finally, there is remarkably abundant gene expression for IGFBP2, -4, and -5 in the NL.     

Nutrition and the insulin-like growth factor system

Nutritional status is a key regulator of the circulating and tissue insulin-like growth factor (IGF) system. IGF-I mRNA and protein levels decrease in tissues such as liver and intestine with fasting and are restored with refeeding. Additional studies suggest that the level of protein and calorie intake independently regulate plasma IGF-I concentrations in man. The level of nutrition effects the biological actions of recombinant growth hormone (GH) and IGF-I administration in humans. Limited data demonstrate that plasma and tissue levels of the insulin-like growth factor binding proteins (IGFBPs) are also sensitive to nutrient intake. Specific micronutrients, such as potassium, magnesium and zinc also appear to be important for optimal IGF-I synthesis and anabolic effects in animal models. Malnutrition is common in elderly patients, however, the interaction between specific nutrients, general nutritional status and the aging process on the IGF system is incompletely understood. Mechanisms of nutrient-IGF systeminteractions which may affect the biological actions of IGF-I, IGF-II, and the IGFBPs are increasingly being determined in basic studies. The effects of underlying nutritional status and responses to dietary intake will be important to evaluate in clinical studies of the IGF system and exogenous growth factor therapy.     

Growth hormone, the insulin-like growth factor axis, insulin and cancer risk

Growth hormone (GH), insulin-like growth factor (IGF)-I and insulin have potent growth-promoting and anabolic actions. Their potential involvement in tumor promotion and progression has been of concern for several decades. The evidence that GH, IGF-I and insulin can promote and contribute to cancer progression comes from various sources, including transgenic and knockout mouse models and animal and human cell lines derived from cancers. Assessments of the GH-IGF axis in healthy individuals followed up to assess cancer incidence provide direct evidence of this risk; raised IGF-I levels in blood are associated with a slightly increased risk of some cancers. Studies of human diseases characterized by excess growth factor secretion or treated with growth factors have produced reassuring data, with no notable increases in de novo cancers in children treated with GH. Although follow-up for the vast majority of these children does not yet extend beyond young adulthood, a slight increase in cancers in those with long-standing excess GH secretion (as seen in patients with acromegaly) and no overall increase in cancer with insulin treatment, have been observed. Nevertheless, long-term surveillance for cancer incidence in all populations exposed to increased levels of GH is vitally important.