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 Cummins, Ashay Bhatwadekar

Research output: Contribution to journalArticle

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 & visual science
Volume60
Issue number6
DOIs
StatePublished - May 1 2019

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Insulin Receptor Substrate Proteins
Circadian Rhythm
Genes
Insulin
Patch-Clamp Techniques
Small Interfering RNA
Up-Regulation
Down-Regulation
Phosphorylation

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

The Diurnal Rhythm of Insulin Receptor Substrate-1 (IRS-1) and Kir4.1 in Diabetes : Implications for a Clock Gene Bmal1. / Luo, Qianyi; Xiao, Yucheng; Alex, Alpha; Cummins, Theodore; Bhatwadekar, Ashay.

In: Investigative ophthalmology & visual science, Vol. 60, No. 6, 01.05.2019, p. 1928-1936.

Research output: Contribution to journalArticle

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abstract = "Purpose: Diabetes leads to the downregulation of the retinal Kir4.1 channels and M{\"u}ller cell dysfunction. The insulin receptor substrate-1 (IRS-1) is a critical regulator of insulin signaling in M{\"u}ller 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 M{\"u}ller cells. The rat M{\"u}ller 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 M{\"u}ller cells and the dysfunctional signaling mediated by IRS-1 may be detrimental to Kir4.1.",
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