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

• Published in: The journal of clinical endocrinology and metabolism Vol. 106; no. 2; pp. e520 - e533
• Main Authors: Stanley, Takara L, Fourman, Lindsay T, Zheng, Isabel, McClure, Colin M, Feldpausch, Meghan N, Torriani, Martin, Corey, Kathleen E, Chung, Raymond T, Lee, Hang, Kleiner, David E, Hadigan, Colleen M, Grinspoon, Steven K
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.02.2021
• Subjects: Adult; Binding proteins; Biopsy; Blood glucose; Blood Glucose - metabolism; Clinical s; Dextrose; Double-Blind Method; Fatty liver; Female; Fibrosis; Follow-Up Studies; Glucose; Glucose metabolism; Gonadotropin-Releasing Hormone - analogs & derivatives; Growth hormone-releasing hormone; Growth Hormone-Releasing Hormone - analogs & derivatives; Growth Hormone-Releasing Hormone - therapeutic use; Growth hormones; HIV; HIV (Viruses); HIV Infections - blood; HIV Infections - complications; HIV Infections - drug therapy; HIV Infections - metabolism; Homeostasis; Human immunodeficiency virus; Humans; Insulin resistance; Insulin-Like Growth Factor Binding Proteins - blood; Insulin-Like Growth Factor Binding Proteins - genetics; Insulin-like growth factor I; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factor-binding protein 1; Insulin-like growth factor-binding protein 2; Insulin-like growth factor-binding protein 3; Insulin-like growth factor-binding protein 4; Insulin-like growth factor-binding protein 6; Insulin-like growth factors; Lipid metabolism; Liver diseases; Male; Medical colleges; Middle Aged; mRNA; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Physiological aspects; Protein binding; RNA; RNA sequencing; Severity of Illness Index; Somatotropin; Steatosis; Tesamorelin; Massachusetts; human immunodeficiency virus; insulin-like growth factor-1; glucose; Nonalcoholic fatty liver disease (NAFLD); insulin-like growth factor–binding proteins; nonalcoholic steatohepatitis (NASH)
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgaa792

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.