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Related Experiment Videos

A fatty acid-induced decrease in pyruvate dehydrogenase activity is an important determinant of beta-cell dysfunction

Y P Zhou1, P O Berggren, V Grill

  • 1Department of Molecular Medicine, Karolinska Hospital and Institute, Stockholm, Sweden.

Diabetes
|May 1, 1996
PubMed
Summary

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Elevated free fatty acids (FFAs) in db/db mice impair insulin secretion by inhibiting glucose oxidation via a glucose-fatty acid cycle. This mechanism involves reduced pyruvate dehydrogenase (PDH) activity and increased PDH kinase activity, impacting glucose metabolism and insulin release.

Area of Science:

  • Metabolic research
  • Endocrinology
  • Molecular biology

Background:

  • Obesity, hyperglycemia, and hyperinsulinemia are characteristic of db/db mice.
  • Elevated serum free fatty acid (FFA) levels are observed in db/db mice compared to controls.
  • Glucose-induced insulin release from db/db islets is significantly impaired.

Purpose of the Study:

  • To investigate the impact of fatty acid oxidation on insulin secretion in db/db mice.
  • To elucidate the molecular mechanisms underlying the observed effects.
  • To explore the role of the glucose-fatty acid cycle in impaired insulin secretion.

Main Methods:

  • Utilized db/db mice and age/sex-matched db/+ controls.
  • Assessed glucose-induced insulin release from isolated islets.

Related Experiment Videos

  • Employed etomoxir, a carnitine palmitoyltransferase I inhibitor.
  • Measured islet glucose oxidation and pyruvate dehydrogenase (PDH) activity.
  • Analyzed PDH kinase activity.

    • Main Results:

    • Etomoxir ameliorated glucose-induced insulin release in db/db islets, indicating a role for fatty acid oxidation.
    • Fatty acid oxidation inhibition by etomoxir enhanced glucose oxidation and the ratio of glucose oxidation to utilization.
    • db/db islets showed decreased PDH activity and increased PDH kinase activity.
    • These molecular abnormalities were partially reversed by etomoxir treatment.

    Conclusions:

    • Elevated FFA levels in db/db mice diminish glucose-induced insulin secretion.
    • A glucose-fatty acid cycle inhibits glucose oxidation by decreasing PDH activity and increasing PDH kinase activity.
    • These findings highlight a key mechanism contributing to impaired insulin secretion in diabetes models.