The role of insulin-like growth factor I in growth of diabetic rats

Insulin-deficient, streptozotocin-diabetic rats show severe metabolic disturbances and stop growing. Besides insulin, these animals also lack growth hormone and insulin-like growth factor-I. We examined whether or not growth parameters correlate with IGF-I serum levels in young rats with streptozotocin-diabetes of different severity. In the diabetic rats, blood glucose varied between 18.4 and 38.6 mmol/l (healthy controls between 6.1 and 9.3), IGF-I serum levels between 2.6 and 15.6 nmol/l (controls between 19.6 and 26.5), and serum insulin levels between 0.05 and 0.14 nmol/l (controls between 0.36 and 0.55). We found a highly significant linear correlation between IGF-I serum levels and the two investigated growth parameters, tibial epiphyseal width and longitudinal tibial bone growth. The finding that these indices of growth are strongly correlated with IGF-I serum levels in young rats with diabetes of different severity, suggests that IGF-I is a major determinant of growth. This is in keeping with our earlier demonstration that exogenously infused IGF-I promotes growth in diabetic rats.     

Epidermal homeostasis: the role of the growth hormone and insulin-like growth factor systems

GH and IGF-I and -II were first identified by their endocrine activity. Specifically, IGF-I was found to mediate the linear growth-promoting actions of GH. It is now evident that these two growth factor systems also exert widespread activity throughout the body and that their actions are not always interconnected. The literature highlights the importance of the GH and IGF systems in normal skin homeostasis, including dermal/epidermal cross-talk. GH activity, sometimes mediated via IGF-I, is primarily evident in the dermis, particularly affecting collagen synthesis. In contrast, IGF action is an important feature of the dermal and epidermal compartments, predominantly enhancing cell proliferation, survival, and migration. The locally expressed IGF binding proteins play significant and complex roles, primarily via modulation of IGF actions. Disturbances in GH and IGF signaling pathways are implicated in the pathophysiology of several skin perturbations, particularly those exhibiting epidermal hyperplasia (e.g., psoriasis, carcinomas). Additionally, many studies emphasize the potential use of both growth factors in the treatment of skin wounds; for example, burn patients. This overview concerns the role and mechanisms of action of the GH and IGF systems in skin and maintenance of epidermal integrity in both health and disease.     

Midlife plasma insulin-like growth factor I and cognitive function in older men

CONTEXT: Emerging biological and epidemiological evidence suggests possible benefits of higher IGF-I levels in cognitive aging. OBJECTIVE: The objective of the study was to examine the relation of midlife plasma IGF-I levels to late-life cognition. DESIGN, SETTING, AND PARTICIPANTS: We conducted a secondary analysis from the Physicians' Health Study II, a prospective cohort of U.S. male physicians. Participants provided blood samples from 1982 to 1984 (mean age 57 yr). Using stored samples, we measured free IGF-I in 376 men and total IGF-I and IGF binding protein-3 in 460 men. Starting in 2001, we administered telephone-based tests of general cognition [the Telephone Interview of Cognitive Status (TICS)], verbal memory, and category fluency. We estimated multivariable-adjusted mean differences in cognitive performance across levels of free IGF-I and IGF-I to IGF binding protein-3 molar ratio. MAIN OUTCOME MEASURES: Global score (averaging performance across all individual cognitive tests), the TICS, and a verbal memory score were measured. RESULTS: Each sd increment in free IGF-I was associated with a multivariable-adjusted increase of 0.08 U (P = 0.02) on the global score. This mean difference was equivalent to that observed between men 2 yr apart in age: i.e. each sd increase in free IGF-I appeared cognitively equivalent to staying 2 yr younger. No significant mean differences in TICS scores were observed across free IGF-I levels. For verbal memory, each sd increment in free IGF-I was associated with an adjusted mean difference of 0.08 U (P = 0.03). Results appeared consistent for the molar ratio but were not statistically significant. CONCLUSION: Higher midlife free IGF-I may be associated with better late-life cognition.     

The role of insulin-like growth factor binding proteins

Insulin-like growth factors (IGFs) are fundamental cell regulators with an evolutionary conserved role synchronising tissue growth, development and function according to metabolic conditions. Although structurally very similar to insulin, the IGFs act in a very different way as cell regulators. Whereas insulin is stored in a specific gland and released when needed, the IGFs are stored outside of cells with soluble binding proteins. A very complex system of six IGF binding proteins, each of which exists in various modified states and interacts with other proteins, provides a sophisticated system for conferring specificity to provide a finely tuned system for local regulation at the tissue level.     

The role of growth hormone in growth, lipid homeostasis, energy utilization and partitioning in rainbow trout: interactions with leptin, ghrelin and insulin-like growth factor I

The growth-promoting effects of in vivo growth hormone (GH) treatment were studied in relation to size and lipid content of energy stores including liver, mesentery, white muscle and belly flap in rainbow trout. In order to elucidate endocrine interactions and links to regulation of growth, adiposity and energy metabolism, plasma levels of GH, insulin-like growth factor I (IGF-I), leptin (Lep) and ghrelin, were assessed and correlated to growth and energy status. In addition tissue-specific expression of lepa1 mRNA was examined. Juvenile rainbow trout were implanted with sustained-release bovine GH implants and terminally sub-sampled at 1, 3 and 6 weeks. GH increased specific growth rate, reduced condition factor (CF) and increased feed conversion efficiency resulting in a redistribution of energy stores. Thus, GH decreased mesenteric (MSI) and liver somatic index (LSI). Lipid content of the belly flap increased following GH-treatment while liver and muscle lipid content decreased. Independent of GH substantial growth was accompanied by an increase in muscle lipids and a decrease in belly flap lipids. The data suggest that the belly flap may function as an energy buffering tissue during episodes of feeding and lean growth. Liver and muscle lipids were positively correlated to body weight, indicating a size-dependent change in adiposity. Hepatic lepa1 mRNA positively correlated to MSI and CF and its expression decreased following GH treatment, coinciding with decreased hepatic lipid content. Plasma Lep was positively correlated to MSI and belly flap lipid content, suggesting that Lep may communicate energy status. In summary, the observed GH tissue-specific effects on lipid metabolism in rainbow trout highlight the complex physiology of the energy reserves and their endocrine control.     

A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I

This study examines whether the serine/threonine protein kinase, Akt, is involved in the cross-talk between epidermal growth factor (EGF) and insulin-related growth factor I (IGF-I) receptors and ER-alpha. Treatment of MCF-7 cells with either EGF or IGF-I resulted in a rapid phosphorylation of Akt and a 14- to 16-fold increase in Akt activity, respectively. Akt activation was blocked by inhibitors of phosphatidylinositol 3-kinase, but not by an inhibitor of the ribosomal protein kinase p70S6K. Stable transfection of cells with a dominant negative Akt mutant blocked the effects of EGF and IGF-I on ER-alpha expression and activity, whereas stable transfection of cells with a constitutively active Akt mutant mimicked the effects of EGF and IGF-I. In the latter cells, there was a decrease in the amount of ER-alpha protein and messenger RNA (70-80%) and an increase in the amount of progesterone receptor protein, messenger RNA (4- to 9- and by 3.5- to 7-fold, respectively) and pS2 (3- to 5-fold). Coexpression of wild-type ER-alpha and the dominant negative Akt mutant in COS-1 cells also blocked the growth factor-stimulated activation of ER-alpha, but coexpression of the wild-type receptor with the constitutively active Akt mutant increased ER-alpha activity. Receptor activation was blocked by an antiestrogen. Studies using mutants of ER-alpha demonstrated that Akt increased estrogen receptor activity through the amino-terminal activation function-1 (AF-1). Serines S104 S106, S118, and S167 appear to play a role in the activation of ER-alpha by Akt.     

Low circulating insulin-like growth factor I bioactivity in elderly men is associated with increased mortality

CONTEXT: Low IGF-I signaling activity prolongs lifespan in certain animal models, but the precise role of IGF-I in human survival remains controversial. The IGF-I kinase receptor activation assay is a novel method for measuring IGF-I bioactivity in human serum. We speculated that determination of circulating IGF-I bioactivity is more informative than levels of immunoreactive IGF-I. OBJECTIVE: Our objective was to study IGF-I bioactivity in relation to human survival. DESIGN, SETTING, AND STUDY PARTICIPANTS: We conducted a prospective observational study at a clinical research center at a university hospital of 376 healthy elderly men (aged 73-94 yr). MAIN OUTCOME MEASURES: IGF-I bioactivity was determined by the IGF-I kinase receptor activation assay. Total and free IGF-I were determined by IGF-I immunoassays. Mortality was registered during follow-up (mean 82 months). RESULTS: During the follow-up period of 8.6 yr, 170 men (45%) died. Survival of subjects in the highest quartile of IGF-I bioactivity was significantly better than in the lowest quartile, both in the total study group [hazard ratio (HR) = 1.8; 95% confidence interval (95% CI) = 1.2-2.8; P = 0.01] as well as in subgroups having a medical history of cardiovascular disease (HR = 2.4; 95% CI = 1.3-4.3; P = 0.003) or a high inflammatory risk profile (HR = 2.3; 95% CI = 1.2-4.5; P = 0.01). Significant relationships were not observed for total or free IGF-I. CONCLUSION: Our study suggests that a relatively high circulating IGF-I bioactivity in elderly men is associated with extended survival and with reduced cardiovascular risk.     

The role of the insulin-like growth factors and their binding proteins in glucose homeostasis

The insulin like growth factors (IGF-I and -II) are structurally and functionally related to insulin. While insulin is a key regulator of glucose homeostasis over the short term, emerging evidence suggests that the IGFs are involved in the longer term glucose homeostasis, possibly by modulating insulin sensitivity. Unlike insulin, the IGFs are present in most biological fluids as complexes with high affinity binding proteins, the insulin-like growth factor binding proteins (IGFBPs). The IGFBPs regulate the bioavailability of the IGFs. Of the six IGFBPs identified there is evidence from studies in transgenic mice that both IGFBP-1 and IGFBP-3 may have a role in glucose regulation.     

The role of the growth hormone-insulin-like growth factor axis in glucose homeostasis.

Homeostatic mechanisms normally maintain the plasma glucose concentration within narrow limits despite major fluctuations in supply and demand. There is increasing evidence that the growth hormone (GH)-insulin-like growth factor (IGF) axis may play an important role in glucose metabolism. GH has potent effects on intermediary metabolism, some of which antagonize the actions of insulin. In contrast, IGF-I has insulin-like actions, which are, in the case of glucose metabolism, opposite to those of GH. There is often deranged glucose metabolism in situations where GH is deficient or in excess. The clinical administration of GH or IGF-I results in altered glucose metabolism and changes in insulin resistance. Despite these observations, the precise role of GH and IGF-I and their interactions with insulin in controlling normal glucose homeostasis are unknown. In diabetes, GH secretion is abnormally increased as a result of reduced portal insulin resulting in impaired hepatic IGF-I generation. Evidence suggests that this may contribute to the development of diabetic microvascular complications. IGF-I 'replacement' in diabetes is under investigation and new methods of delivering IGF-I as a complex with IGFBP-3 offer exciting new prospects.     

Essential role of insulin-like growth factor I receptor in insulin-induced fetal brown adipocyte differentiation

To define the specific role of IGF-I receptor (IGF-IR) in adipogenic and thermogenic differentiation of brown adipocytes during late fetal life, we have established immortalized brown adipocyte cell lines from fetuses of IGF-IR-deficient mice (IGF-IR(-/-)) as well as from wild-type mice (IGF-IR(+/+)). IGF-IR(-/-) cells showed an increased insulin sensitivity regarding insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation despite a substantial reduction in IRS-1 protein content. Furthermore, insulin-induced total and IRS-1-associated phosphatidylinositol 3-kinase activities were augmented in IGF-IR-deficient cells compared with wild-type cells. Downstream phosphatidylinositol 3-kinase activation of Akt, but not p70s6 kinase, were elicited at lower doses of insulin in IGF-IR(-/-) brown adipocytes. Activation of protein kinase Czeta by insulin was similar in both cell types as was insulin-induced glucose uptake. Treatment of wild-type brown adipocytes with insulin for 12 h up-regulated fatty acid synthase (FAS) and adipocyte determination and differentiation (ADD1/SREBP) mRNAs; this effect was impaired in the absence of IGF-IR. At the protein level, insulin increased FAS content and the amount of the mature form of adipocyte determination and differentiation (ADD1/SREBP) in the nucleus in wild-type cells, but not in IGF-IR(-/-) cells. Furthermore, 24 h of insulin stimulation induced the expression of both uncoupling protein-1 and CCAAT/enhancer-binding protein alpha (C/EBPalpha) in wild-type brown adipocytes; these effects were abolished in IGF-I-R(-/-) cells. Retrovirus-mediated reexpression of peroxisomal proliferator-activated receptor gamma (PPARgamma) in IGF-IR(-/-) brown adipocytes could overcome FAS mRNA impairment, bypassing insulin signaling. However, insulin further increased FAS mRNA expression in C/EBPalpha-IGF-IR(-/-) cells, but not in PPARgamma-IGF-IR(-/-) cells. In addition, fetal brown adipocytes lacking IGF-IR up-regulated uncoupling protein-1 expression in the absence of insulin when PPARgamma, but not C/EBPalpha, was overexpressed. These data provide strong evidence for a critical role of IGF-IR in the differentiation of the brown adipocyte phenotype in fetal life; this effect is mimicked by PPARgamma in an insulin-independent manner.     

The role of the type I insulin-like growth factor receptor (IGF-IR) in glomerular integrity.

Insulin-like growth factors (IGFs) have been implicated in normal mammalian kidney development. To confirm a role for the IGF system in podocyte and glomerular integrity, we generated a transgenic mouse that expresses a dominant-negative type 1 IGF receptor (IGF-IR) and determined the structural and functional consequences. Using a 4.25kb fragment of the murine nephrin promoter, the dominant-negative construct was expressed exclusively in the kidney, confirmed by Southern blot and RT-PCR analysis. IGF-Ir486(FLAGstop) protein localized specifically to the glomerular podocyte based on FLAG immunohistochemistry and on co-localization with nephrin and podocin. Wild type and transgenic glomeruli expressed both the alpha- and beta-subunits of the endogenous IGF-IR, with normal expression of both nephrin and podocin. Although the animals were viable and phenotypically normal, histological analysis of the kidneys revealed abnormal and small glomeruli with dilated glomerular capillaries and condensed podocyte nuclei, while ultra-structural examination revealed diffuse but segmental podocyte foot process broadening, fusion, and effacement. Explanted glomeruli from transgenic animals demonstrated a significant inhibition of podocyte cell outgrowth when compared to controls. These studies suggest that IGF signaling is essential for maintaining the integrity of the podocyte and that alterations of IGF signaling may play a role in progressive glomerular disease.     

The bovine placenta: a specific radioreceptor assay for both insulin-like growth factor I and insulin-like growth factor II

Binding of labelled IGF-I and IGF-II was studied to bovine, ovine and human placental cell membranes. The data show a preponderance of type I receptors in human placental membranes, and of type II receptors in ovine placental membranes, confirming reported data. In contrast, bovine placental membranes are rich in both type I and type II receptors. Therefore, the bovine placenta offers a good model for measuring specifically IGF-I (cross-reactivity with IGF-II 7%) and IGF-II (cross-reactivity with IGF-I 4%). By Scatchard analysis the apparent Kd (1-1.36 nmol/l) for the high affinity binding sites of the type I receptor is similar in all three preparations. Total binding capacity in ovine placental membranes is, however, 4 times lower. The affinity for the type II receptor is lower than for type I, whereas total binding capacity is higher. Affinity cross-linking confirms the competition experiments, showing binding of IGF-I to typical type I and of IGF-II to type II receptors.     

Demonstration of insulin-like growth factor I in human urine

Immunoreactive and receptor-reactive insulin-like growth factor I (IGF-I) was demonstrated in human urine. Thirty percent of the IGF-I immunoreactivity in urine was free, and the remainder was a high mol wt form (approximately 43K). Urinary IGF-I was quantitated by RIA after extraction with octadecylsilyl silica cartridges (Sep-Pak C18 cartridge), a method that measures only free IGF-I. The mean urinary immunoreactive IGF-I levels in normal adults (n = 8) and patients with acromegaly (n = 10) or hypopituitarism (n = 9) were 72 +/- 7 (+/- SEM), 225 +/- 34, and 19 +/- 4 pg/mg creatinine, respectively; these mean values were significantly different from one another. The results indicate that IGF-I is present in human urine and that the quantity in urine is altered in patients with GH excess and deficiency.     

A transgenic model to determine the physiological role of liver-derived insulin-like growth factor I

Insulin-like growth factor-I (IGF-I) has important growth promoting and metabolic effects and is expressed in virtually every tissue of the body. The highest expression is found in the liver but the physiological role of liver-derived IGF-I is unknown. It has been difficult to separate the endocrine effects of liver-derived IGF-I from the autocrine/paracrine effects of locally produced IGF-I in peripheral tissues. Therefore, we have developed a mouse model with a liver-specific inducible deletion of the IGF-I gene. The liver-IGF-I deficient mouse have dramatically reduced (>80%) serum IGF-I levels, demonstrating that the major part of serum IGF-I is liver-derived. Surprisingly, liver-IGF-I deficient mice demonstrate a normal appendicular skeletal growth up to at least 12 months of age despite the dramatic decrease in circulating IGF-I levels, indicating that liver-derived IGF-I is not required for appendicular skeletal growth. However, the adult axial skeletal growth is clearly reduced in the liver-IGF-I deficient mice. Furthermore, the amount of cortical bone is reduced due to decreased radial growth of the cortical bone while the amount of trabecular bone is unchanged in the liver-IGF-I deficient mice. The decreased levels of circulating IGF-I are associated with increased serum levels of growth hormone (GH), indicating a role for liver-derived IGF-I in the negative feedback regulation of GH secretion. Measurements of factors regulating GH-secretion in the pituitary and in the hypothalamus revealed an increased expression of growth hormone releasing hormone (GHRH) and growth hormone secretagogue (GHS) receptors in the pituitary of liver-IGF-I deficient mice. This in turn results in an increased sensitivity to systemically administered GHRH and GHS, demonstrating that the regulatory action of liver-derived IGF-I on GH secretion is at the pituitary rather than at the hypothalamic level. The liver is an important metabolic organ and liver-IGF-I deficient mice are markedly hyperinsulinemic and yet normoglycemic, consistent with an adequately compensated insulin resistance. Interestingly, liver-IGF-I deficient mice display a reduced age-dependent fat mass accumulation compared with control mice. In conclusion, liver-derived IGF-I is important for carbohydrate- and lipid-metabolism and for the regulation of GH-secretion at the pituitary level. Furthermore, it regulates adult axial skeletal growth and cortical radial growth while it is not required for appendicular skeletal growth.