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Published on: January 7, 2018
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A Microphysiological Model of Progressive Human Hepatic Insulin Resistance.
Dominick J Hellen1, Jessica Ungerleider1, Erin Tevonian1
1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 US.
Biorxiv : the Preprint Server for Biology
|January 20, 2025
Summary
High insulin levels cause insulin resistance in liver cells, worsened by high glucose and fats. This condition, seen in Type 2 diabetes (T2D) and fatty liver, is partly reversible.
Area of Science:
- Hepatology
- Metabolic Diseases
- Endocrinology
Background:
- Hepatic insulin resistance is key in Type 2 Diabetes (T2D) and metabolic dysfunction-associated fatty liver disease (MAFLD).
- In vivo studies struggle to isolate factors like nutrients, hormones, and inflammation due to complex systemic interactions.
- A human liver microphysiological system (MPS) was used to model insulin response and nutrient perturbations.
Purpose of the Study:
- To establish a physiologically relevant, insulin-responsive metabolic baseline in a human liver MPS.
- To investigate hepatocyte responses to controlled variations in insulin, glucose, and free fatty acids (FFAs).
- To understand the mechanisms underlying hepatic insulin resistance in T2D and MAFLD.
Main Methods:
- Liver MPS were cultured for up to 3 weeks with normal (200 pM) or T2D-level (800 pM) insulin.
- Cells were exposed to normal/hyperglycemic glucose and normal/elevated FFA levels, alone or combined.
- Key assessments included glucose production, signaling pathways, insulin clearance, transcriptomics, and lipid/bile acid accumulation.
Main Results:
- Hyperinsulinemia alone induced insulin resistance within one week.
- Hyperglycemia and elevated FFAs significantly worsened the insulin-resistant phenotype.
- Combined hyperinsulinemia, hyperglycemia, and elevated FFAs altered metabolic and immune signaling, predisposing hepatocytes to insulin resistance.
- Observed phenotypes were partially reversible upon return to normal conditions.
Conclusions:
- The enhanced liver MPS model accurately replicates key aspects of human insulin resistance.
- This model provides valuable insights into the mechanisms of T2D and MAFLD.
- The findings highlight the partial reversibility of metabolic dysfunction in hepatocytes.
