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

J Clin Endocrinol Metab. 2021 Jan 23;106(2):e520-e533. doi: 10.1210/clinem/dgaa792.


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: 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).

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Glucose / metabolism*
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Gonadotropin-Releasing Hormone / analogs & derivatives
  • Growth Hormone-Releasing Hormone / analogs & derivatives*
  • Growth Hormone-Releasing Hormone / therapeutic use
  • HIV
  • HIV Infections / blood
  • HIV Infections / complications
  • HIV Infections / drug therapy
  • HIV Infections / metabolism
  • Humans
  • Insulin-Like Growth Factor Binding Proteins / blood*
  • Insulin-Like Growth Factor Binding Proteins / genetics
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism*
  • Male
  • Middle Aged
  • 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
  • Severity of Illness Index


  • Blood Glucose
  • IGF1 protein, human
  • Insulin-Like Growth Factor Binding Proteins
  • Gonadotropin-Releasing Hormone
  • Insulin-Like Growth Factor I
  • Growth Hormone-Releasing Hormone
  • tesamorelin

Associated data