Lower liver IGF-1 expression and specific shifts in IGF-binding proteins are associated with worse fatty liver disease, more fibrosis, and poorer blood sugar control — and growth hormone-releasing hormone treatment can modify these binding proteins.
n=61 with NAFLDIn this clinical trial population, lower hepatic IGF-1 expression was independently associated with worse steatosis, higher disease activity scores, and poorer glucose control — suggesting the liver's own IGF-1 production is a key metabolic signal.
What the researchers found
Hepatic IGF-1 mRNA was significantly lower in individuals with more severe steatosis (fat accumulation) and higher NAFLD Activity Scores, and was inversely related to blood glucose parameters independent of circulating IGF-1 levels. This means the liver's own IGF-1 production — not just what's in the blood — matters for metabolic health.
Among the binding proteins, IGFBP2 and IGFBP4 were lower while IGFBP6 and IGFBP7 were higher with increasing steatosis. Notably, IGFBP7 increased with fibrosis severity, making it a potential marker for scarring. GHRH treatment increased circulating IGFBP-1 and IGFBP-3 while decreasing IGFBP-2 and IGFBP-6, demonstrating that the GH axis can modify these binding protein profiles.
Why it matters
NAFLD affects roughly a quarter of the global population and is a leading cause of liver disease, yet treatment options remain limited. This study reveals that the IGF system in the liver is not just a passive bystander but actively linked to disease progression. The finding that GHRH can modify binding protein profiles opens a potential therapeutic avenue — and the divergent roles of different IGFBPs suggest that targeted approaches, not blanket IGF manipulation, will be needed.
The numbers in context
61 patients; 39 with liver RNA-Seq; IGF1 inversely associated with steatosis/NAS; IGFBP2/4 low in severe disease; IGFBP6/7 high; IGFBP7 increased with fibrosis; GHRH increased IGFBP-1/3, decreased IGFBP-2/6
How the study worked
This was a secondary analysis of data from a randomized clinical trial of GHRH conducted at two US academic medical centers. The 61 participants were HIV-infected adults aged 18-70 with at least 5% liver fat. Of these, 39 had RNA-Seq data from liver biopsies, allowing researchers to measure actual gene expression of IGF-1 and binding proteins in liver tissue and correlate these with histopathology (steatosis, inflammation, fibrosis) and glucose metabolism measures.
Who was studied
61 HIV-infected adults with NAFLD, 39 with liver RNA-Seq data from biopsy, in a randomized GHRH trial
What this study cannot tell us
The associations are cross-sectional and cannot prove causation. The study population was HIV-infected, which may limit generalizability to the broader NAFLD population since HIV and antiretroviral therapy can independently affect metabolism. The liver biopsy subset was small (39 patients), and multiple statistical comparisons increase the risk of false positive findings. GHRH effects on circulating IGFBPs may not reflect hepatic changes.
How to read the evidence
This is a secondary analysis of a randomized clinical trial with liver biopsy data and RNA-Seq. While it provides moderate-quality human evidence with direct tissue measurements, the correlational design and relatively small sample limit causal conclusions.
When this study was published
Published in 2021, this study reflects current understanding of the GH-IGF axis in NAFLD. The field has continued to evolve with growing interest in GHRH analogs and metabolic liver disease, keeping these findings relevant.
The bigger picture
This study connects growth hormone biology to liver disease in a way that goes beyond simple IGF-1 blood levels. By looking at what the liver itself is producing, it reveals a more nuanced picture of how the GH-IGF axis intersects with metabolic liver disease. It also positions GHRH analogs — peptides already used in other contexts — as potential tools for modifying the IGF binding protein landscape in NAFLD patients.
Questions still open
- Would GHRH treatment actually improve liver histology in NAFLD patients, or does it just change binding protein levels without clinical benefit?
- Do these IGF-1 and IGFBP relationships hold true in non-HIV NAFLD populations?
- Could IGFBP7 serve as a non-invasive blood biomarker for liver fibrosis severity?
Common questions
What is IGF-1 and why does it matter for the liver?
Could growth hormone treatments help people with fatty liver disease?
Read the original research
Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease.
The Journal of clinical endocrinology and metabolism, 106(2), e520-e533
Citation
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. (2021). Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease.. The Journal of clinical endocrinology and metabolism, 106(2), e520-e533. https://doi.org/10.1210/clinem/dgaa792