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Stimulation of insulin secretion induced by low 4-cresol dose involves the RPS6KA3 signalling pathway

François Brial1,2, Géraldine Puel3, Laurine Gonzalez4

  • 1Université Paris Cité, INSERM U1132 Biologie de l'os et du cartilage (BIOSCAR), Paris, France.

Plos One
|October 24, 2024
PubMed

Insights

4-cresol, a compound linked to improved diabetes health, enhances insulin sensitivity and secretion. It targets the RPS6KA3 kinase, suggesting a novel mechanism for regulating blood sugar and insulin release in diabetes.

Area of Science:

  • Metabolomics
  • Endocrinology
  • Pharmacology

Background:

  • 4-cresol (4-methylphenol) is a xenobiotic metabolite inversely correlated with type 2 diabetes.
  • Preclinical models suggest 4-cresol has health benefits in diabetes.

Purpose of the Study:

  • To elucidate the physiological role of 4-cresol.
  • To identify signaling mechanisms underlying 4-cresol's effects on glucose metabolism and insulin secretion.

Main Methods:

  • In vitro studies on human adipocytes and mouse myoblasts to assess insulin sensitivity.
  • Experiments on isolated mouse islets to evaluate glucose-stimulated insulin secretion.
  • Screening of GPCRs and kinases for 4-cresol binding.
  • In vivo studies using diabetic rats and Rps6ka3 deficient mice.

Main Results:

  • 4-cresol did not impair insulin sensitivity in adipocytes and enhanced it in myoblasts.
  • 4-cresol potentiated glucose-induced insulin secretion in isolated islets.
  • 4-cresol selectively bound to TNK1, EIF2AK4 (GCN2), and RPS6KA3 (RSK2) kinases.
  • RPS6KA3 kinase expression decreased in islets of 4-cresol-treated diabetic rats.
  • Rps6ka3 deficient mice showed reduced body weight, fasting glycemia, and improved glycemic control with enhanced insulin release.
  • Inhibition of RPS6KA3 mimicked low-dose 4-cresol effects on insulin secretion and beta-cell proliferation.

Conclusions:

  • 4-cresol plays a beneficial role in glucose homeostasis and insulin secretion.
  • The kinase RPS6KA3 is a key mediator of 4-cresol's effects.
  • Low doses of 4-cresol regulate insulin secretion and beta-cell function via RPS6KA3.

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