Elevated insulin, proinsulin and insulin-like growth factor-binding protein-1 in liver disease

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Abstract

Insulin-like growth factor-binding protein-1 (IGFBP-1) is one of six soluble binding proteins that regulate the actions of the insulin-like growth factors (IGFs). Liver is the major source of IGFBP-1 in non-pregnant humans. In normal physiology, IGFBP-1 transcription is potently inhibited by insulin and serum levels are limited by a rapid clearance rate. Elevated levels of IGFBP-1 in liver disease have been attributed to insulin resistance; however, the relationships between these analytes have not been defined. We studied insulin, proinsulin and IGFBP-1 in normal subjects (NL, N=47, 43 ± 12 yr), cirrhosis (CIR, N=29, 54 ± 14 yr), hepatocellular carcinoma (HCC, N=42, 61 ± 11 yr), and other liver tumors (TUM, N=8, 60 ± 17 yr). All three analytes were significantly increased in liver disease (mean ± SEM; p-values relative to normals): IGFBP-1 (NL 24 ± 4 ng/ml; CIR 235 ± 53, p<0.0001; HCC 505 ± 105, p<0.0001; TUM 118 ± 36, p<0.0001), insulin (NL 72 ± 4 pM; CIR 261 ± 62, p<0.0002; HCC 180 ± 25, p<0.0001; TUM 189 ± 58, p<0.0001), proinsulin (NL 6.5 ± 0.7 pM; CIR 36.8 ± 7.7, p<0.0001; HCC 26.2 ± 3.8, p<0.0001; TUM 32.1 ± 9.7, p<0.0001). The ratio of proinsulin to insulin was also significantly elevated in liver disease. A typical curvilinear inverse relationship of insulin and IGFBP-1 was observed, but was shifted several fold higher for the liver disease groups. Our results demonstrate that insulin and proinsulin are elevated in liver disease. However, these elevations are paradoxically accompanied by elevated IGFBP-1 levels, indicating disruption of normal regulatory mechanisms. IGFBP-1 is postulated to play a dynamic role in metabolic substrate utilization via regulation of free IGF. Therefore, inappropriate elevation of IGFBP-1 could play an important role in the metabolic disturbances associated with liver disease.

Introduction

Insulin-like growth factor-binding protein-1 (IGFBP-1) is one of six soluble binding proteins that regulate the actions of the insulin-like growth factors (IGFs) [1], [2]. Liver is the major source of IGFBP-1 in non-pregnant humans. In normal physiology, IGFBP-1 is present almost exclusively in the serum compartment and has a rapid clearance rate (T1/2∼10 min) [3]. Serum levels are regulated primarily via insulin inhibition of IGFBP-1 transcription and are dynamically and inversely related to estimates of the free fraction of IGF-1 [2], indicating that IGFBP-1 may regulate the metabolic actions of this growth factor in the circulation. In addition, infusion of IGFBP-1 into rats leads to increased serum glucose concentrations [3], supporting the hypothesis that IGFBP-1 may be involved in glucose counter-regulation perhaps by regulating the insulin-like actions of circulating free IGF-I.

Serum IGFBP-1 levels are abnormally low in obesity and hyperinsulinemic conditions, and are inversely related to insulin concentrations [2], [4]. Elevated levels of IGFBP-1 have been demonstrated in fasting, malnutrition and insulin deficiency and are probably related to low insulin levels. However, in prolonged critically ill patients, the high serum levels of IGFBP-1 are not affected by intensive insulin therapy despite the lowered blood glucose [5]. IGFBP-1 levels are also elevated in renal failure [6] and in liver diseases [7]. In liver disease, the increased serum IGFBP-1 levels may be due to increased hepatic synthesis [8], although no relationship to hepatic IGFBP-1 mRNA expression has been observed [9], [10].

To further explore the relationships of insulin and IGFBP-1 in liver disease, we measured serum levels of IGFBP-1, insulin and proinsulin in non-diabetic, non-alcoholic patients with cirrhosis, hepatocellular carcinoma and other liver tumors to determine the interrelationships of these three analytes. Our results indicate that an inverse relationship of insulin and IGFBP-1 is present in liver disease, but at a considerably higher setpoint as compared to normal.

Section snippets

Subjects

The involvement of human subjects in this study was approved by the Institutional Review Boards of the Fooyin University and Yuan’s General Hospital, Kaohsiung, Taiwan, and informed consent was obtained from the study subjects. The study population consisted of the following groups: (1) Normals (NL): n=47, no liver disease (M/F=32/15, age 43 ± 12 yr, range 22–86 yr); (2) Cirrhosis (CIR), n=29 (M/F=19/10, age 54 ± 14 yr, range 29–76 yr); hepatocellular carcinoma (HCC), n=42 (M/F=33/9, age 61 + 11 yr,

Assays

Insulin was measured by a two-site chemiluminescent immunoassay using paired mouse anti-human insulin monoclonal antibodies (BiosPacific, Emeryville, CA). The detection antibody was labeled with acridinium ester (Assay Designs, Ann Arbor, MI). For the solid phase capture, 1 μg of the paired antibody dissolved in 200 μl of coating buffer (50 mM sodium bicarbonate, pH 9.6) was applied to each well (96-well white microtiter plates, Nunc, Denmark) and incubated at 4 °C overnight. The wells were

Results

Fasting IGFBP-1 levels were significantly increased in CIR (235 ± 53 ng/ml, p<0.0001), HCC (505 ± 105, p<0.0001) and TUM (118 ± 36, p<0.0001) as compared to NL (24 ± 4 ng/ml) (Fig. 1A). Among the liver disease groups, IGFBP-1 levels were significantly higher in HCC as compared to CIR or TUM (p<0.05).

Fasting insulin concentrations were also significantly elevated in CIR (261 ± 62 pM, p<0.0002), HCC (180 ± 25 pM, p<0.0001) and TUM (189 ± 58 pM, p<0.0001) as compared to NL (72 ± 4 pM) (Fig. 1B). There were no

Discussion

Unlike the other five IGFBPs, serum IGFBP-1 displays dynamic variability due to its short serum half-life coupled with potent transcriptional down-regulation of IGFBP-1 expression by insulin [2], [13]. The regression lines for the inverse relationship between fasting IGFBP-1 and insulin are characteristically curvilinear, apparently due to a critical inhibitory concentration of insulin for IGFBP-1 production superimposed on a relatively invariant and rapid clearance rate. For instance, in a

Acknowledgements

This work was supported by a medical technology educational grant from the Ministry of Education of Taiwan. Technical assistance of I-Wen Huang is greatly appreciated.

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