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Ormdl3 regulation of specific ceramides is dispensable for β-cell function and glucose homeostasis under obesogenic

Liam D Hurley1, Hugo Lee1, Gina Wade2

  • 1Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA.

Biorxiv : the Preprint Server for Biology
|February 17, 2023
PubMed

Insights

Loss of ORMDL3 in pancreatic beta cells did not affect glucose homeostasis or insulin secretion. However, it altered very long chain ceramide levels in islets under high-fat diet conditions.

Area of Science:

  • Endocrinology
  • Metabolic Disease Research
  • Cell Biology

Background:

  • Sphingolipids are crucial for cellular function, and their chronic elevation is linked to pancreatic beta-cell failure.
  • ORMDL3 is a key regulator of sphingolipid homeostasis, but its specific role in beta-cell pathophysiology is not well understood.

Approach:

  • Generated a mouse model with beta-cell specific deletion of Ormdl3 (Ormdl3β-/-).
  • Assessed metabolic parameters (glucose tolerance, insulin sensitivity), insulin secretion, and islet morphology under standard and high-fat diet conditions.
  • Utilized lipidomics to analyze ceramide levels in islets.

Key Points:

  • Loss of beta-cell Ormdl3 did not impact glucose tolerance, insulin sensitivity, insulin secretion, or islet morphology on a standard diet.
  • High-fat diet challenge in Ormdl3β-/- mice revealed significantly higher levels of very long chain ceramides in islets.
  • No alterations in overall metabolic parameters or islet architecture were observed in Ormdl3β-/- mice even under high-fat diet.

Conclusions:

  • Loss of Ormdl3 alone is insufficient to impair beta-cell function or whole-body glucose and insulin homeostasis.
  • Ormdl3 deficiency specifically alters very long chain ceramide levels within pancreatic islets.
  • Further research is needed to elucidate the precise role of ORMDL3 in sphingolipid metabolism and beta-cell health.

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