Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease

Abstract

Context: Growth hormone (GH) and IGF-1 help regulate hepatic glucose and lipid metabolism, and reductions in these hormones may contribute to development of nonalcoholic fatty liver disease (NAFLD).

Objective: To assess relationships between hepatic expression of IGF1 and IGF-binding proteins (IGFBPs) and measures of glycemia and liver disease in adults with NAFLD. Secondarily to assess effects of GH-releasing hormone (GHRH) on circulating IGFBPs.

Design: Analysis of data from a randomized clinical trial of GHRH.

Setting: Two US academic medical centers.

Participants: Participants were 61 men and women 18 to 70 years of age with HIV-infection, ≥5% hepatic fat fraction, including 39 with RNA-Seq data from liver biopsy.

Main outcome measures: Hepatic steatosis, inflammation, and fibrosis by histopathology and measures of glucose homeostasis.

Results: Hepatic IGF1 mRNA was significantly lower in individuals with higher steatosis and NAFLD Activity Score (NAS) and was inversely related to glucose parameters, independent of circulating IGF-1. Among the IGFBPs, IGFBP2 and IGFBP4 were lower and IGFBP6 and IGFBP7 (also known as IGFBP-related protein 1) were higher with increasing steatosis. Hepatic IGFBP6 and IGFBP7 mRNA levels were positively associated with NAS. IGFBP7 mRNA increased with increasing fibrosis. Hepatic IGFBP1 mRNA was inversely associated with glycemia and insulin resistance, with opposite relationships present for IGFBP3 and IGFBP7. GHRH increased circulating IGFBP-1 and IGFBP-3, but decreased IGFBP-2 and IGFBP-6.

Conclusions: These data demonstrate novel relationships of IGF-1 and IGFBPs with NAFLD severity and glucose control, with divergent roles seen for different IGFBPs. Moreover, the data provide new information on the complex effects of GHRH on IGFBPs.

Trial registration: ClinicalTrials.gov NCT02196831.

Keywords: Nonalcoholic fatty liver disease (NAFLD); glucose; human immunodeficiency virus; insulin-like growth factor-1; insulin-like growth factor–binding proteins; nonalcoholic steatohepatitis (NASH).

© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Associations between hepatic IGF-1 expression and measures of NAFLD severity: A, steatosis grade; B, NAFLD Activity Score; and C, fibrosis stage. Slope from 1-way ANOVA test for linear trend, and r from Pearson correlation.

Figure 2.

Associations between A, hepatic IGFBP7 expression and B, circulating IGFBP-7, and steatosis grade, NAFLD Activity Score, and fibrosis stage. Slopes from 1-way ANOVA test for linear trend, and r values from Pearson correlation.

Figure 3.

Associations between A, hepatic IGF1; B, IGFBP1; C, IGFBP3; and D, IGFBP7 expression and fasting glucose (left) and 2-hour glucose (right). r from Pearson correlation.