Liver insulinization as a driver of triglyceride dysmetabolism

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) has been on the rise, commonly coexisting with insulin resistance, a hallmark of type 2 diabetes mellitus. Despite the growing awareness of this connection, the exact mechanistic link between MAFLD and impaired insulin action remains an enigma. In this insightful perspective, the authors delve into human data to shed light on insulin's role in the development of MAFLD. 

A key focus of their analysis is the intriguing observation of "selective insulin resistance." It is well-established that as insulin resistance sets in, the body's response to insulin diminishes, leading to compromised insulin function in various metabolic processes. However, the authors highlight a peculiar phenomenon: while insulin's ability to regulate hepatic glucose production (HGP) weakens, its stimulation of triglyceride (TG) biosynthesis seems to remain relatively intact. 

To understand this selective insulin resistance, the authors propose an intriguing theory. They suggest that the processes within hepatocytes responsible for TG accumulation require less insulin signal transduction, or "insulinization," compared to those involved in regulating HGP. As a result, even in the face of declining insulin efficacy in controlling glucose production, the hepatocytes can still respond sufficiently to insulin's influence on TG biosynthesis. 

This discrepancy in insulin responsiveness can have profound implications. In states of insulin resistance, where the body's response to insulin is impaired, insulin levels may rise in an attempt to compensate for the aberrant HGP. These elevated insulin levels, though modest, persist throughout the day and night, creating a heavily pro-lipogenic metabolic milieu. In this context, the hepatocytes, despite being relatively resistant to insulin's effect on glucose production, continue to be responsive to insulin's role in TG biosynthesis. This sustained and contextually inappropriate insulin stimulation in a metabolically conducive environment can lead to significant cumulative TG biosynthesis in the insulin-resistant state. 

Cook, J.R., Hawkins, M.A. & Pajvani, U.B. Liver insulinization as a driver of triglyceride dysmetabolism. Nat Metab 5, 1101–1110 (2023). https://doi.org/10.1038/s42255-023-00843-6

The authors' perspective opens new avenues for understanding the complex interplay between insulin resistance and MAFLD. It offers valuable insights into the factors contributing to hepatic lipid accumulation and may pave the way for targeted therapeutic interventions to address the growing burden of MAFLD in individuals with type 2 diabetes mellitus. By unraveling the intricacies of insulin's role in MAFLD, this Perspective contributes to the advancement of knowledge in the field of metabolic disorders and holds promise for improving patient outcomes in the future. Jason & Rita. . . aka Dr. De Leon and Dr. Gillespie