The diurnal rhythm of insulin receptor substrate-1 (IRS-1) and Kir4.1 in diabetes: Implications for a clock gene bmal1

Qianyi Luo, Yucheng Xiao, Alpha Alex, Theodore R. Cummins, Ashay D. Bhatwadekar

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

PURPOSE. Diabetes leads to the downregulation of the retinal Kir4.1 channels and Müller cell dysfunction. The insulin receptor substrate-1 (IRS-1) is a critical regulator of insulin signaling in Müller cells. Circadian rhythms play an integral role in normal physiology; however, diabetes leads to a circadian dysrhythmia. We hypothesize that diabetes will result in a circadian dysrhythmia of IRS-1 and Kir4.1 and disturbed clock gene function will have a critical role in regulating Kir4.1 channels. METHODS. We assessed a diurnal rhythm of retinal IRS-1 and Kir4.1 in db/db mice. The Kir4.1 function was evaluated using a whole-cell recording of Müller cells. The rat Müller cells (rMC- 1) were used to undertake in vitro studies using a siRNA. RESULTS. The IRS-1 exhibited a diurnal rhythm in control mice; however, with diabetes, this natural rhythm was lost. The Kir4.1 levels peaked and troughed at times similar to the IRS-1 rhythm. The IRS-1 silencing in the rMC-1 led to a decrease in Kir4.1 and BMAL1. The insulin treatment of retinal explants upregulated Kir4.1 possibly via upregulation of BMAL1 and phosphorylation of IRS-1 and Akt-1. CONCLUSIONS. Our studies highlight that IRS-1, by regulating BMAL1, is an important regulator of Kir4.1 in Müller cells and the dysfunctional signaling mediated by IRS-1 may be detrimental to Kir4.1.

Original languageEnglish (US)
Pages (from-to)1928-1936
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume60
Issue number6
DOIs
StatePublished - May 2019

Keywords

  • Circadian rhythm
  • Diabetic retinopathy
  • Insulin receptor substrate 1
  • Kir4.1 channels
  • Müller cell

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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