Role of Insulin-Like Growth Factor I in Maintaining Normal Glucose Homeostasis

Efficacy HORMONE RESEARCH Horm Res 2004;62(suppl 1):77 82 DOI: 10.1159/000080763 Role of Insulin-Like Growth Factor I in Maintaining Normal Glucose Homeostasis David R. Clemmons Department of Medicine, UNC School of Medicine, Chapel Hill, N.C., USA Key Words Adults W Diabetes mellitus W Gene polymorphisms W Glucose metabolism W Growth hormone W Insulin-like growth factor I W Insulin sensitivity Abstract Insulin-like growth factor I (IGF-I) has significant structural homology with insulin. IGF-I has been shown to bind to insulin receptors to stimulate glucose transport in fat and muscle, to inhibit hepatic glucose output and to lower blood glucose while simultaneously suppressing insulin secretion. However, the precise role of IGF-I in maintaining normal glucose homeostasis and insulin sensitivity is not well defined. Studies in patients with diabetes have shown that in insulin-deficient states, serum IGF-I concentrations are low and increase with insulin therapy. Similarly, administration of insulin via the portal vein results in optimization of plasma IGF-I concentrations. A patient with an IGF1 gene deletion was shown to have severe insulin resistance that improved with IGF-I therapy. Studies conducted in experimental animals have shown that if IGF-I synthesis by the liver is deleted, the animals become insulin-resistant, and this is improved when IGF-I is administered. Likewise, deletion of the IGF-I receptor in muscle in mice induces severe insulin resistance. Administration of IGF-I to patients with type 2 diabetes mellitus has been shown to result in an improvement in insulin sensitivity and a reduction in the requirement for exogenously administered insulin to maintain glucose homeostasis. A polymorphism in the IGF1 gene that has been shown to reduce serum IGF-I results in an increased prevalence of type 2 diabetes. Taken together, these findings support the conclusion that IGF-I is necessary for normal insulin sensitivity, and impairment of IGF-I synthesis results in a worsening state of insulin resistance. Introduction Copyright 2004 S. Karger AG, Basel Insulin-like growth factor I (IGF-I) circulates in relatively high concentrations in human serum. Concentrations of IGF-I in serum are dependent upon a balance of hormones, which include growth hormone (GH) secreted by the pituitary gland but also insulin, particularly as it pertains to its actions in the liver. Therefore, normal hepatic insulin action is required for normal rates of IGF-I synthesis [1]. ABC Fax + 41 61 306 12 34 E-Mail karger@karger.ch www.karger.com 2004 S. Karger AG, Basel 0301 0163/04/0627 0077$21.00/0 Accessible online at: www.karger.com/hre Dr. D.R. Clemmons CB 7170 Endocrinology UNC School of Medicine Chapel Hill, NC 27599 (USA) Tel. +1 919 966 4735, Fax +1 919 966 6025, E-Mail endo@med.unc.edu

Fig. 1. Increase in serum IGF-I concentrations following insulin administration. Insulin was given by conventional subcutaneous (S.C.) injections, intensive S.C. injections or portal vein infusion. The results show that portal vein administration results in a much greater increase in serum IGF-I. actions of IGF-I, whereas mature adipocytes and liver appear to be very insensitive to IGF-I and to rely almost solely on insulin receptors to mediate glucose-lowering effects. Therefore, in severely insulin-deficient states, administration of pharmacological amounts of IGF-I is not able to reverse the consequences of insulin deficiency, presumably because it fails to act on adipose tissue and liver. Conversely, in severe IGF-I-deficient states, insulin action in skeletal muscle appears to be impaired [5]. However, one complication in interpreting in vivo studies of IGF-I deficiency is that this condition is invariably accompanied by supraphysiological concentrations of GH. These high GH concentrations lead to anti-insulin effects in both liver and fat, which worsen insulin resistance [6]. Therefore, determining the precise role of IGF-I deficiency in altering insulin action is complicated by these compensatory changes. The recent ability to delete IGF-I synthesis in tissues selectively has shed new light on the mechanisms that mediate these effects. Insulin-Deficient States in Humans When insulin secretion and actions are normal and when normal rates of IGF-I synthesis are maintained, the IGF-I that is present in interstitial fluid binds to both IGF-I receptors and hybrid insulin/igf-i receptors, which are formed by combining one alpha and one beta subunit from the insulin receptor and one alpha and one beta subunit from the IGF-I receptor [2]. As the affinity of the insulin receptor homodimer for IGF-I is 200-fold lower than that for insulin, it is doubtful whether IGF-I exerts its actions through the insulin receptor homodimer. However, hybrid receptors have a 20-fold higher affinity for IGF-I compared with insulin, and they have been shown to activate insulin receptor-linked signalling mechanisms [3]. Therefore, this provides a mechanism whereby physiological concentrations of IGF-I may stimulate insulinlike actions. Regardless of the receptor subtype that is utilized, in most tissues IGF-I has been shown to stimulate insulinlike actions in vitro, including stimulation of glucose transport, glucose oxidation and translocation of the glucose transporter GLUT-4 to the plasma membrane [4]. The extent to which IGF-I, as opposed to insulin, participates in this process under basal conditions has been difficult to define. There appear to be major differences among tissues in the capacity of IGF-I to exert these actions. Skeletal muscle is an insulin target tissue that appears to be particularly sensitive to the insulin-like Severe insulin deficiency is accompanied by low serum IGF-I concentrations [7]. When patients with type 1 diabetes mellitus who had not received insulin therapy were assessed, their blood IGF-I concentrations were below the lower limit of normal. In response to insulin injections, IGF-I concentrations rose 2.5-fold in a 3-day period. Similarly, experimental studies in rats have shown that normal IGF-I synthesis by the liver requires normal portal vein insulin secretion [8]. This finding has been confirmed in humans. Patients with type 1 diabetes who received insulin by portal vein infusion for 6 months were compared with control volunteers who received intensive insulin therapy by peripheral injection, and plasma IGF-I concentrations were measured. IGF-I was at least 60% higher at steady state in the controls who received portal vein insulin (fig. 1) [9]. This suggests that optimum insulinization of the liver is necessary for optimal IGF-I plasma concentrations. Similarly, IGF-binding protein 1 (IGFBP-1), whose synthesis is suppressed by insulin and, importantly, controls the concentrations of free IGF-I that are available to bind to receptors, was optimally suppressed with portal vein insulin, whereas peripheral vein insulin resulted in suboptimal suppression. Thus, free IGF-I concentrations would be expected to be disproportionately increased in the patients who received portal vein insulin. This increase in IGF-I may be required for optimum insulin sensitization in the periphery. 78 Horm Res 2004;62(suppl 1):77 82 Clemmons

Studies of patients with rare genetic syndromes have also furthered our understanding of the necessity for normal IGF-I concentrations to maintain normal insulin sensitivity in humans. A single patient who had a severe IGF1 gene deletion has been described. This patient had serum IGF-I concentrations that were!2% of normal, and GH injections failed to stimulate growth. The patient had a 3.6-fold reduction in insulin sensitivity compared with normal age-matched controls. After 6 months of IGF-I therapy, this defect in insulin sensitivity was completely reversed, suggesting that maintenance of normalto-high serum IGF-I concentrations resulted in optimization of insulin action [10]. Similarly, long-term studies in patients with severe insulin resistance caused by mutations in the insulin receptor show that IGF-I is capable of lowering haemoglobin A1c by 1.8% over a 9-month treatment interval [11]. This strongly suggests that, in the absence of normal insulin action, IGF-I is able to augment insulin-like signalling, which leads to improvement of glucose metabolism. Tissue-Specific Gene Deletions in Mice The ability to selectively alter IGF-I synthesis in tissues has led to new insights into the role of IGF-I in maintaining insulin sensitivity and the role of blood transport of IGF-I compared with autocrine/paracrine-synthesized IGF-I, which occurs in peripheral tissues. Elimination of IGF-I synthesis specifically in hepatocytes leads to an 80% reduction in serum IGF-I in mice [12]. While these animals have a minimal growth retardation, for example only a 6% reduction in final adult length, they show significant abnormalities in carbohydrate metabolism. When an insulin tolerance test was performed, the animals that had low serum IGF-I concentrations had impaired glucose clearance compared with control animals, and the impaired glucose clearance was observed in spite of a 3.2- fold increase in plasma insulin concentrations. This suggested that the animals were significantly insulin-resistant and that this defect resulted from plasma IGF-I deficiency. This possibility was confirmed by administering IGF-I to these animals, which resulted in increased plasma IGF-I and restoration of the glucose response to an acute insulin injection to normal. This strongly suggests that maintenance of a normal plasma IGF-I concentration is required for normal insulin sensitivity. However, these studies are complicated by the observation that GH secretion is also elevated in these animals due to a lack of normal feedback suppression of GH synthesis. To analyse this model further, these investigators deleted hepatic synthesis of the acid-labile subunit (ALS), a component of the IGF-I/IGFBP-3/ALS complex. They also created animals in which there was reduced hepatic synthesis of both IGF-I and ALS. Plasma IGF-I was further reduced in these animals, and this resulted in a decrease in adult size of approximately 30%. These severely IGF-I-deficient animals had an increase in free IGF-I in their serum, probably because their amount of IGFBP-3 was disproportionately reduced because of rapid clearance caused by loss of the IGF-I/IGFBP-3/ALS complex. These animals had less impairment of glucose intolerance, probably due to maintenance of relatively high free IGF-I concentrations [13]. A further model that was studied was deletion of the IGF-I receptor in skeletal muscle. This was complicated by the observation that deletion of the IGF-I receptor in skeletal muscle also results in deletion of the hybrid insulin/igf-i receptor [5]. When both of these receptors were deleted, however, the animals developed glucose intolerance at age 8 weeks and overt diabetes at 3 months. These animals were significantly insulin-resistant. This finding suggests that, at least in skeletal muscle, some IGF-I- or hybrid receptor-related signalling is necessary to maintain normal glucose homeostasis. This is important because these animals did not have elevated plasma GH concentrations. Therefore, it appears in mice that both normal GH secretion and adequate IGF-I action in skeletal muscle are required for maintenance of normal glucose homeostasis. Other experimental models have reinforced these conclusions. Specifically, the creation of IGFBP-1 transgenic mice has been associated with abnormal glucose dynamics. These animals are important because they do not have elevated GH concentrations [14]. In this state, when serum IGFBP-1 concentrations are elevated because of transgenic forced overexpression, they develop impaired glucose tolerance and the blood glucose-lowering effect of an IGF-I injection is less than in control animals, suggesting that the binding protein is functioning to affect the ability of IGF-I to increase insulin sensitization. Furthermore, when intraperitoneal glucose tolerance tests were conducted, the sensitivity of these animals to an insulin injection was impaired, and this resulted in higher blood glucose concentrations with higher concomitant serum insulin levels. Finally, when the IGFBP-1 transgenic mice were studied at various ages, and simple glucose tolerance tests were performed, there was an age-dependent deterioration in glucose tolerance, with animals at 44 weeks showing a diabetic glucose tolerance test compared with the control animals at IGF-I in Glucose Homeostasis Horm Res 2004;62(suppl 1):77 82 79

44 weeks. This suggests that maintenance of normal free IGF-I concentrations is required for maintenance of normal glucose homeostasis in aged animals. Human Studies Human studies are by definition more complex because of the inability to create selective tissue deficits in IGF-I secretion or action. However, administration of IGF-I for 6 weeks to patients with type 2 diabetes resulted in lowering of blood glucose concentrations throughout the day (fig. 2) and lowering of serum insulin levels. Formal insulin sensitivity testing showed a 3.4-fold improvement in insulin sensitivity that resulted in improvement in the insulin sensitivity index values to near normal (fig. 3) [15]. Confirmation of this finding was obtained in 228 adult volunteers who received IGF-I therapy for 12 weeks at four different dosages. The two highest dosages resulted in substantial lowering of fasting and mean daily blood glucose. Haemoglobin A1c was improved by 1.6% compared with control participants, who received no IGF-I [16]. This strongly suggested that IGF-I was improving insulin sensitivity, which resulted in improvements in glucose metabolism. The molecular mechanism by which IGF-I enhances insulin sensitivity in humans has been analysed, but not completely delineated. IGF-I is capable of binding to hybrid insulin/igf-i receptors in skeletal muscle. This binding to the hybrid receptor selectively stimulates phosphorylation of the insulin receptor beta subunit and activation of insulin receptor substrate 1, the principal downstream signalling molecule activated by insulin binding [3]. This results in enhancement of insulin-stimulated glucose transport in this tissue, an important insulin-like action. The effect can be blocked with an antibody that is specific for IGF-I binding to the IGF-I receptor, which suggests that the effect is truly mediated through the hybrid receptor. The human studies up to this point have analysed the effect of pharmacological doses of IGF-I, and therefore they do not shed much light on the role of normal IGF-I ± ± ±....... Fig. 2. Modal day glucose values in type 2 diabetes before and after IGF-I administration. IGF-I, 40 Ìg/kg, bid was given subcutaneously to 13 patients with type 2 diabetes. Glucose values were measured at the times shown before treatment and after 6 weeks of therapy. The arrows denote the times of meals. Reprinted with permission from Moses et al. [15], from the American Diabetes Association. Copyright 1996 American Diabetes Association. Fig. 3. Change in insulin sensitivity after IGF-I administration. Insulin sensitivity was measured following a frequently sampled intravenous glucose tolerance test. The changes in the mean values and those for each individual are shown. Reprinted with permission from Moses et al. [15], from the American Diabetes Association. Copyright 1996 American Diabetes Association. 80 Horm Res 2004;62(suppl 1):77 82 Clemmons

secretion and maintenance of normal insulin action. Recent epidemiological studies have suggested, however, that maintenance of normal serum IGF-I may be required for maintenance of normal insulin sensitivity. Studies from The Netherlands have shown that 12% of Caucasians have a polymorphism in the promoter region of the IGF1 gene [17]. This results in a reduction in serum IGF-I of approximately 40% in affected individuals. More importantly, these individuals had a prevalence of type 2 diabetes increased by 1.7-fold and prevalence of myocardial infarction increased by 3.4-fold, compared with agematched controls 160 years of age, who do not have the polymorphism. These individuals are also approximately 2.1 cm shorter than controls [18]. The findings suggest that this polymorphism results in some attenuation of final adult height and increased insulin resistance, which leads to a higher rate of development of type 2 diabetes and vascular disease. The findings further suggest that maintenance of normal serum levels of IGF-I is required for long-term maintenance of normal insulin sensitivity, and IGF-I deficiency leads to an increased prevalence of insulin resistance and the development of type 2 diabetes. impaired are associated with lower serum IGF-I concentrations. Conversely, lowering of serum IGF-I concentration increases insulin resistance and restoration of serum IGF-I to normal ameliorates insulin resistance both in experimental animals and humans. In these states, however, it has not been possible to completely delineate the mechanism of action by which IGF-I improves insulin sensitivity. The ability of IGF-I to enhance insulin sensitivity in liver and adipocytes is indirect, and its major effect appears to be mediated through lowering serum GH concentrations, which reduces the anti-insulin actions of GH that are mediated in these tissues. In skeletal muscle, however, reduction of insulin sensitivity may also be due in part to loss of direct effects of IGF-I. Specifically, IGF-I binds to hybrid insulin/igf-i receptors in skeletal muscle, which may result in enhanced insulin-like signalling in this tissue. It is also possible that other peripheral tissues require IGF-I action to maintain normal insulin sensitivity. Future studies will be required to further determine the role of IGF-I in maintaining normal sensitivity to insulin and in reducing the effects of supraphysiological concentrations of GH on deterioration of glucose metabolism. Conclusion IGF-I is an important signalling molecule for maintenance of normal insulin sensitivity. States in which insulin secretion is reduced or insulin action is markedly Acknowledgements The author wishes to thank Ms. Laura Lindsey for her help in the preparation of the manuscript. This work was supported by a grant from the National Institutes of Health HL-56850. 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