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Study of In Vivo Glucose Metabolism in High-fat Diet-fed Mice Using Oral Glucose Tolerance Test OGTT and Insulin Tolerance Test ITT
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Liver insulinization as a driver of triglyceride dysmetabolism

Joshua R Cook1, Meredith A Hawkins2, Utpal B Pajvani3

  • 1Naomi Berrie Diabetes Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Columbia University College of Physicians & Surgeons, New York City, NY, USA. jrc2175@cumc.columbia.edu.

Nature Metabolism
|July 17, 2023
PubMed

Insights

Metabolic dysfunction-associated fatty liver disease (MAFLD) is linked to insulin resistance. Even mild insulin elevations can drive fat accumulation in the liver due to selective insulin resistance.

Area of Science:

  • Hepatology
  • Endocrinology
  • Metabolic Diseases

Background:

  • Metabolic dysfunction-associated fatty liver disease (MAFLD) is highly prevalent and associated with insulin resistance and type 2 diabetes.
  • The precise mechanisms linking MAFLD and impaired insulin action are not fully understood.
  • Insulin resistance is a hallmark of metabolic syndrome, affecting glucose and lipid metabolism.

Purpose of the Study:

  • To review human data and elucidate the etiological role of insulin in MAFLD.
  • To investigate the selective preservation of insulin's stimulation of triglyceride biosynthesis in MAFLD.
  • To explain the phenomenon of 'selective insulin resistance' in the context of MAFLD and hyperinsulinemia.

Main Methods:

  • Review of existing human data and clinical studies.
  • Analysis of insulin signaling pathways in hepatocytes.
  • Focus on the differential regulation of hepatic glucose production and triglyceride biosynthesis by insulin.

Main Results:

  • Insulin's ability to suppress hepatic glucose production (HGP) is impaired in insulin resistance.
  • Insulin's stimulation of hepatic triglyceride (TG) biosynthesis is relatively preserved.
  • Hepatocellular processes for TG accumulation may require less insulin signaling ('insulinization') than those regulating HGP.

Conclusions:

  • Hyperinsulinemia in insulin-resistant states may sufficiently maintain hepatic TG biosynthesis.
  • Sustained, even modest, insulin elevations in a pro-lipogenic environment can lead to significant hepatic TG accumulation.
  • This selective insulin resistance contributes to the pathogenesis of MAFLD in individuals with metabolic derangements.

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