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Metformin Corrects Abnormal Circadian Rhythm and Kir4.1 Channels in Diabetes

Alpha Alex1, Qianyi Luo1, Deepa Mathew1

  • 1,.

Investigative Ophthalmology & Visual Science
|June 24, 2020
PubMed
Abstract

Insights

Metformin treatment improved circadian rhythms and corrected Kir4.1 channel dysfunction in diabetic mice. This suggests metformin may prevent Müller cell dysfunction in diabetic retinopathy.

Area of Science:

  • Ophthalmology
  • Endocrinology
  • Cell Biology

Background:

  • Diabetic retinopathy (DR) is a major cause of vision loss.
  • Müller cell dysfunction, linked to Kir4.1 channel downregulation, contributes to DR.
  • Metformin's mechanism involves AMPK, but its effect on Kir4.1 is unknown.

Purpose of the Study:

  • To investigate metformin's effect on circadian rhythm and Kir4.1 channel function in a diabetic mouse model.
  • To determine if metformin can correct Müller cell dysfunction in diabetic retinopathy.

Main Methods:

  • Administered metformin to db/db mice and assessed wheel-running activity, retinal Kir4.1 levels, and AMPK phosphorylation.
  • Treated rat Müller cell line (rMC-1) with metformin and AICAR to study AMPK activation's impact on Kir4.1.
  • Investigated the role of AMPKα1 by silencing its gene (Prkaa1).

Main Results:

  • Metformin improved circadian activity and corrected Kir4.1 levels in db/db mice.
  • Metformin upregulated clock genes (Opn4, Aanat) and increased Kir4.1 and Bmal-1 protein expression in rMC-1 cells.
  • AMPK activation by metformin/AICAR increased Kir4.1 and Bmal-1; Prkaa1 silencing decreased them.

Conclusions:

  • Metformin corrects circadian rhythm and Kir4.1 channel dysfunction in a type 2 diabetes model.
  • Metformin shows potential as a therapeutic agent to prevent Müller cell dysfunction in human DR.

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