Elevated insulin, proinsulin and insulin-like growth factor-binding protein-1 in 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.
References (40)
- et al.
Growth hormone, insulinlike growth factor-1, and insulinlike growth factor binding proteins 1 and 3 in chronic liver disease
Hepatology
(1995) - et al.
Hepatic growth hormone receptor, insulin-like growth factor I, and insulin-like growth factor-binding protein messenger RNA expression in pediataric liver disease
Hepatology
(1997) - et al.
Monoclonal antibodies to the 27–34 K insulin-like growth factor binding protein
Biochem. Biophys. Res. Commun.
(1988) - et al.
High insulin-like growth factor binding protein 1 levels in cirrhosis: link with insulin resistance
Hepatology
(1996) - et al.
Both insulin sensitivity and glucose sensitivity are impaired in patients with non-diabetic liver cirrhosis
Hepatol. Res.
(2000) Are patients with cirrhosis “glucose resistant”?
J. Hepatol.
(1995)- et al.
The contribution of proinsulin and des-31,32 proinsulin to the hyperinsulinemia of diabetic and nondiabetic cirrhotic patients
Metabolism
(1995) - et al.
Alterations of glucose metabolism in chronic liver disease
Diabetes Res. Clin. Pract.
(1990) - et al.
Hyperinsulinemia in pre-ascitic cirrhosis: effects on systemic and renal hemodynamics, sodium homeostasis, forearm blood flow, and sympathetic nervous activity
Hepatology
(1996) - et al.
Diabetes increases the risk of acute hepatic failure
Gastroenterology
(2002)
Regulation and function of insulin-like growth factor-binding protein-1
Proc. Soc. Exp. Biol. Med.
Insulin-like growth factor binding protein-1: recent findings and new directions
Proc. Soc. Exp. Biol. Med.
Insulin-like growth factor-binding protein-1 modulates blood glucose levels
Endocrinology
Insulin regulation of insulin-like growth factor binding protein-1 in obese and non-obese humans
J. Clin. Endocrinol. Metab.
Regulation of insulin-like growth factor binding protein-1 during protracted critical illness
J. Clin. Endocrinol. Metab.
The IGF axis and growth in children with chronic renal failure: a report of the Southwest Pediatric Nephrology Study Group
J. Clin. Endocrinol. Metab.
Concentrations, release and disposal of insulin-like growth factor (IGF)-binding proteins, IGF-I and growth hormone in different vascular beds in patients with cirrhosis
J. Clin. Endocrinol. Metab.
Expression of IGFBP-1 in normal and cirrhotic human livers
J. Endocrinol.
Phosphorylated insulin-like growth factor binding protein1 is increased in pregnant diabetic subjects
Diabetes
Kinetics of insulin-like growth factor (IGF) and IGF-binding protein responses to a single dose of growth hormone
J. Clin. Endocrinol. Metab.
Cited by (22)
Serum IGFBP-1 as a potential biomarker for diagnosis of early-stage upper gastrointestinal tumour
2020, EBioMedicineCitation Excerpt :Most studies have focused on the association between prediagnostic serum levels of IGFBP-1 and cancer risk, and the results in colorectal cancer seem to be contradictory [37-41]. Several reports demonstrated that serum IGFBP-1 levels were increased in some cancers, such as ovarian cancer, hepatocellular carcinoma, and NPC [42-44]. However, these studies were limited by the small sample size and lacked early diagnostic assessment.
Structural changes of fibrinogen as a consequence of cirrhosis
2018, Thrombosis ResearchCitation Excerpt :Since the fibrinogen level increases in inflammatory states [26] and cirrhosis may be accompanied by inflammation, the final concentration of fibrinogen is a result of the equilibrium between two opposing processes (inflammation and reduced synthetic capacity of the liver). An increase in IGFBP-1 concentration due to cirrhosis was detected in several studies [27–30]. Although plasma concentrations of fibrinogen in two study groups were similar, the difference between samples became evident during the isolation of fibrinogen.
Growth Inhibitory Effect of Low Fat Diet on Prostate Cancer Cells: Results of a Prospective, Randomized Dietary Intervention Trial in Men With Prostate Cancer
2010, Journal of UrologyCitation Excerpt :PSA, sex hormones (estradiol and total testosterone), insulin and lipid panels were measured at the UCLA clinical laboratory. IGF I and II, and IGFBP-1, 2 and 3 were measured at the laboratory of one of us (PC) using previously described enzyme-linked immunosorbent assay techniques.14 Serum fatty acid analysis was done at the UCLA center for human nutrition laboratory using established techniques.15
Stabilization of IGFBP-1 mRNA by ethanol in hepatoma cells involves the JNK pathway
2007, Journal of HepatologyCitation Excerpt :Insulin, via inhibition of IGFBP-1 gene expression, is a major determinant of IGFBP-1 levels in the liver and the serum [1]. But IGFBP-1 gene expression is induced by severe catabolic conditions observed during liver disease and critical illness [3,4] as well as by a variety of stress conditions such as amino acid depletion, hypoxia and proinflammatory cytokines [5–7]. We have recently shown that IGFBP-1 is also induced by dioxin, an environmental contaminant and upon endoplasmic reticulum stress [8,9].
Endoplasmic reticulum stress induction of insulin-like growth factor-binding protein-1 involves ATF4
2006, Journal of Biological ChemistryCitation Excerpt :Various observations suggest that the integrated stress response is aimed at providing resistance to stressful conditions and at promoting cell survival (53, 54). Liver IGFBP-1 and circulating IGFBP-1 are up-regulated in a number of catabolic conditions as follows: malnutrition, liver disease, and critical illness (55–57), but little is known about the physiological implication of stress-related induction of IGFBP-1. Because ATF4 target genes are mainly survival genes, this suggests that IGFBP-1 could have such a function under stressful conditions.
Insulin-like growth factor binding protein 1 as a novel specific marker of hepatic insulin sensitivity
2008, Journal of Clinical Endocrinology and Metabolism