Insulin-like growth factor (IGF)-I and IGF binding proteins axis in diabetes mellitus

Abstract

Increasing evidence suggests an important role of the insulin-like growth factor (IGF)-IGF binding protein (IGFBP) axis in the maintenance of normal glucose and lipid metabolism. Significant changes occur in the local IGF-I-IGFBPs environment in response to the diabetic milieu. A significant reduction of serum IGF-I levels was observed in patients with type 1 diabetes mellitus (T1DM). Inversely, considerably increased serum levels of IGF-I and IGFBP-3 levels were detected in individuals with glucose intolerance including T2DM. Recently, several prospective studies indicated that baseline levels of IGF-I and IGFBPs are associated with the development of diabetes. These findings suggest that disturbances in insulin and IGF-I-IGFBP axis can affect the development of glucose intolerance including diabetes.

Introduction

The insulin-like growth factor (IGF)-system plays critical roles in regulating the somatic growth in an endocrine manner and in the proliferation as well as differentiation of normal and malignant cells in a paracrine-autocrine manner1). IGF-I has a significant structural homology with proinsulin. However, IGF-I and insulin have distinct receptors, which are tyrosine kinase-containing receptors with approximately 60% of amino acid sequence homology2,3). The affinity of the IGF receptor for IGF-I is 1,000 times greater than that for insulin, while the insulin receptor shows 100 folds greater affinity towards insulin than that for IGF-I. The IGF system includes growth hormone (GH), IGF-I/II peptide, type 1 and 2 receptors, IGF binding proteins (IGFBPs), and IGFBP proteases4,5,6). A total of six high-affinity binding proteins have been identified (IGFBP-1 to -6). The hepatic IGF-I circulates almost entirely in the IGFBP-bound form. IGFBP-3, a major IGFBP species in the serum, binds more than 90% of the circulating IGF-I in a large ternary complex consisting of IGFBP-3, acid labile subunit, and IGFs7). IGFBP-3 also has been shown to stimulate cell growth and carry out other functions in an IGF-independent manner in a variety of cell types8).

The IGF-I-IGFBP axis and glucose and lipid metabolism

Although IGF-I is classically considered an important growth factor, it also has major metabolic effects. This metabolic effect of IGF-I is to provide a signal to cells that adequate nutrient is available to avoid apoptosis, enhance cellular protein synthesis, enable cells to undergo hypertrophy in response to an appropriate stimulus and stimulate cell division. Insulin is the primary regulator of glucose metabolism, but the IGF axis also might play a role in maintaining glucose homeostasis. Many laboratory studies have found that IGF-I can promote glucose uptake in peripheral tissues9,10). It has been shown also that IGF-I can suppress hepatic glucose production11,12). Furthermore, a significant positive correlation between the sensitivity to insulin and endogenous IGF-I concentration in patients with varying degree of glucose intolerance was reported13). In addition, exogenous IGF-I administration has been shown to reduce serum glucose levels in healthy individuals and patients with various glucose intolerance states9,14). These findings indicate that serum IGF-I and IGFBPs levels may influence the risk of developing type 2 diabetes mellitus (T2DM).

IGFBPs may also have a role in glucose metabolism. In particular, IGFBP-1 may acutely regulate glucose levels through its effects on free IGF-I15). Insulin suppresses IGFBP-1 gene transcription and changes in insulin concentration are correlated with relatively acute changes in circulating IGFBP-1 levels16). Exogenous IGFBP-1 injections have been shown to cause reductions in free IGF-I and circulating glucose levels17). In addition, reduced IGFBP-1 synthesis and circulating levels are observed in obesity18). IGFBP-3, the most abundant IGFBP in circulation, may play a role in glucose regulation, and its metabolic effects are largely opposite to those of IGF-I19). IGFBP-3 inhibits the biological activity of IGF-I by sequestrating IGF-I into a circulating reservoir, thereby reducing levels of free IGF-I in circulation and increases the risk of diabetes14,19). It has been reported that IGFBP-3 binds to the nuclear receptor, RXR-α, which interacts with the peroxisome proliferator-activated receptor-gamma nuclear protein that is involved in the regulation of glucose and lipid metabolism20). Studies on transgenic animal showed that overexpression of IGFBP-3 was associated with fasting hyperglycemia and impaired glucose tolerance (IGT)21).

The IGF axis may also affect lipid metabolism. Although mature adipocytes are devoid of IGF-I receptor, preadipocytes express them in abundance and IGF-I stimulates preadipocyte differentiation10). In vitro studies have shown that IGF-I may have insulin-like effects in promoting the uptake of free fatty acid (FFA) into adipocytes, hepatocytes, and stimulating lipogenesis10,22). Human studies reported that exogenous IGF-I administration significantly lowered FFA levels23,24). Overall, FFA uptake is thought to be the primary effect of the IGF axis on FFA turnover, whereas the promotion of lipogenesis plays only a minor role. In addition, a number of studies have shown an independent association between low levels of IGF-I and cardiovascular disease25,26).

The IGF-I-IGFBP axis and diabetes mellitus

The GH-IGF-I axis has been reported to be altered in patients with type 1 diabetes mellitus (T1DM)27). T1DM is a disease of insulin deficiency that results from the autoimmune-mediated destruction of pancreatic beta cells. Whereas spontaneous GH secretion is increased, low serum IGF-I levels have been reported, suggesting that GH resistance is present in T1DM. The major part of serum IGF-I derives from liver in response to GH stimulation, and IGF-I synthesis in the liver is also regulated by insulin28). Therefore, the lack of adequate intraportal insulin supply leads to a major suppression of hepatic IGF-I biosynthesis in DM. Furthermore, a low portal vein insulin concentration contributes to elevated IGFBP-1 levels in patients with T1DM29). IGFBP-3 is the principal binding protein of IGF-I in serum, and its concentration is increased in response to GH. Changes in IGFBP profiles result in an alteration of IGF-I availability in DM. These abnormalities not only exacerbate hyperglycemia in T1DM patients, but may contribute to the pathogenesis of diabetes-specific complications30). Although serum IGF-I axis has been largely studied in T1DM patients, there is limited evidence in the literature of a possible relationship between serum IGF-I and IGFBP-3 levels and the clinical variables associated with T1DM.

Several lines of evidence suggest that the IGF-I-IGFBPs axis has an important role in the maintenance of normal glucose homeostasis and may contribute to the etiopathogenesis of T2DM31,32). Although there are conflicting data regarding the relationship between IGF-I and IGFBPs levels and T2DM, many studies have found that free IGF-I and IGFBP-3 concentrations are elevated, whereas, IGFBP-1 levels are low in subjects with IGT and T2DM32,33). The association of high serum IGF-I level with IGT and DM may be either causal or pathological. Early T2DM and IGT are usually characterized by insulin resistance and hyperinsulinemia. Insulin stimulates hepatic IGF-I synthesis, suppresses hepatic IGFBP-1 synthesis, and increases GH expression in the liver, which could lead to increase circulating concentration of total or free IGF-I. Therefore, high serum IGF-I levels in subjects with T2DM may be due to high insulin concentrations rather than because of some specific biological impact of IGF axis on DM pathogenesis. However, elevated IGFBP-1 levels in patients with T2DM have been frequently reported. This would be expected because the loss of hepatic sensitivity to insulin and decreased insulin levels allow for uncontrolled IGFBP-1 secretion. Recently, a large prospective study found strong associations of incident diabetes with baseline levels of IGFBP-1, 2, 3 and free IGF-I suggesting a modulatory effect of the IGF-IGFBP axis on the risk of DM34). These data indicate a protective effect of IGF-I against the development of IGT/T2DM. Although serum IGF-I levels were thought to be dependent on the degree of glucose control in patients with T2DM, prior studies examining clinical correlations of IGF-I or IGFBP-3 levels in diabetes have yielded mixed results35,36,37). Table 1 depicts results of several studies that examined serum IGF-I and IGFBP-1-3 levels and association of the IGF-I axis with clinical variables in patients with DM.

Table 1. Selected studies on serum IGF-IGFBP axis in patients with diabetes mellitus.

IGF, insulin-like growth factor; IGFBP, IGF binding protein; HbA1c, glycosylated hemoglobin; GH, growth hormone; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; F, free; T, total; ND, not done.

^a)Prospective study; serum IGF-I, IGFBPP-1, 2, & 3 levels at base line and evaluates correlation between IGF-I axis and T2DM.

Conclusions

IGF-I is an important growth factor and has major metabolic effects. Many studies suggest that the IGF-I-IGFBPs axis is important for the maintenance of normal glucose homeostasis and its disturbance are associated with the risk of diabetes. Cross-sectional studies indicate that IGF-I and IGFBPs levels are altered in patients with obesity and glucose intolerance including DM. Furthermore, large prospective studies found strong associations between baseline IGF-I and IGFBPs levels and the risk of developing DM. In addition, the use of recombinant human IGF-I to improve peripheral insulin sensitivity in subjects with DM has been promising. However, further studies are necessary to reveal biological mechanism of IGF-I-IGFBP-3 axis impact on the development of glucose intolerance and T2DM.