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Chronotherapeutic effect of orexin antagonists on glucose metabolism in diabetic mice

Kanta Kon1, Hiroshi Tsuneki2, Hisakatsu Ito3

  • 1K Kon, Department of Clinical Pharmacology, University of Toyama, Toyama, Japan.

The Journal of Endocrinology
|August 9, 2019
PubMed

Insights

Orexin receptor antagonists improved glucose intolerance in diabetic mice, with some acting via sleep and others independently. These findings suggest potential chronotherapeutic strategies for type 2 diabetes linked to sleep disruption.

Area of Science:

  • Neuroscience
  • Endocrinology
  • Metabolic Diseases

Background:

  • Disrupted sleep is linked to an increased risk of type 2 diabetes.
  • The orexin system, crucial for wakefulness, is implicated in insomnia when overactive.
  • Previous studies showed dual orexin receptor antagonists (DORAs) improve sleep and glucose intolerance in diabetic mice, but mechanisms are unclear.

Purpose of the Study:

  • To investigate the functional link between sleep and glucose metabolism by comparing orexin antagonists with varying sleep-promoting effects.
  • To explore potential chronotherapeutic mechanisms for type 2 diabetes associated with sleep disturbances.

Main Methods:

  • Administered orexin-1 receptor antagonists (1-SORA-1), orexin-2 receptor antagonists (2-SORA-MK1064), and dual orexin receptor antagonists (DORA-12) to db/db mice (type 2 diabetic model) and streptozotocin-induced diabetic mice (type 1 model).
  • Evaluated effects on sleep-wake behavior, glucose intolerance, body weight, food intake, locomotor activity, and energy expenditure.
  • Assessed expression levels of proinflammatory factors in liver and white adipose tissue.

Main Results:

  • 2-SORA-MK1064 and DORA-12 improved non-rapid eye movement sleep and glucose intolerance in db/db mice when given during the resting phase; 1-SORA-1 had no effect on sleep but improved glucose intolerance.
  • Chronic administration of these drugs improved glucose intolerance without altering body weight, food intake, activity, or energy expenditure.
  • Proinflammatory factors were reduced in the liver by 2-SORA-MK1064 and DORA-12, and in white adipose tissue by 1-SORA-1 and DORA-12.
  • No effects were observed when drugs were administered during the awake phase or in type 1 diabetic mice.

Conclusions:

  • Both sleep-independent (1-SORA-type) and possibly sleep-dependent (2-SORA-type) mechanisms can yield chronotherapeutic benefits for type 2 diabetes linked to sleep disturbances.
  • Orexin receptor antagonists show promise for treating type 2 diabetes, with distinct pathways influencing metabolic improvements.

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