SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the lung, liver, adipose tissue, and pancreatic cells via IRF1

Jihoon Shin, Shinichiro Toyoda, Shigeki Nishitani, Toshiharu Onodera, Shiro Fukuda, Shunbun Kita, Atsunori Fukuhara, Iichiro Shimomura

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background: COVID-19 can cause multiple organ damages as well as metabolic abnormalities such as hyperglycemia, insulin resistance, and new onset of diabetes. The insulin/IGF signaling pathway plays an important role in regulating energy metabolism and cell survival, but little is known about the impact of SARS-CoV-2 infection. The aim of this work was to investigate whether SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the host cell/tissue, and if so, the potential mechanism and association with COVID-19 pathology. Methods: To determine the impact of SARS-CoV-2 on insulin/IGF signaling pathway, we utilized transcriptome datasets of SARS-CoV-2 infected cells and tissues from public repositories for a wide range of high-throughput gene expression data: autopsy lungs from COVID-19 patients compared to the control from non-COVID-19 patients; lungs from a human ACE2 transgenic mouse infected with SARS-CoV-2 compared to the control infected with mock; human pluripotent stem cell (hPSC)-derived liver organoids infected with SARS-CoV-2; adipose tissues from a mouse model of COVID-19 overexpressing human ACE2 via adeno-associated virus serotype 9 (AAV9) compared to the control GFP after SARS-CoV-2 infection; iPS-derived human pancreatic cells infected with SARS-CoV-2 compared to the mock control. Gain and loss of IRF1 function models were established in HEK293T and/or Calu3 cells to evaluate the impact on insulin signaling. To understand the mechanistic regulation and relevance with COVID-19 risk factors, such as older age, male sex, obesity, and diabetes, several transcriptomes of human respiratory, metabolic, and endocrine cells and tissue were analyzed. To estimate the association with COVID-19 severity, whole blood transcriptomes of critical patients with COVID-19 compared to those of hospitalized noncritical patients with COVID-19. Results: We found that SARS-CoV-2 infection impaired insulin/IGF signaling pathway genes, such as IRS, PI3K, AKT, mTOR, and MAPK, in the host lung, liver, adipose tissue, and pancreatic cells. The impairments were attributed to interferon regulatory factor 1 (IRF1), and its gene expression was highly relevant to risk factors for severe COVID-19; increased with aging in the lung, specifically in men; augmented by obese and diabetic conditions in liver, adipose tissue, and pancreatic islets. IRF1 activation was significantly associated with the impaired insulin signaling in human cells. IRF1 intron variant rs17622656-A, which was previously reported to be associated with COVID-19 prevalence, increased the IRF1 gene expression in human tissue and was frequently found in American and European population. Critical patients with COVID-19 exhibited higher IRF1 and lower insulin/IGF signaling pathway genes in the whole blood compared to hospitalized noncritical patients. Hormonal interventions, such as dihydrotestosterone and dexamethasone, ameliorated the pathological traits in SARS-CoV-2 infectable cells and tissues. Conclusions: The present study provides the first scientific evidence that SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in respiratory, metabolic, and endocrine cells and tissues. This feature likely contributes to COVID-19 severity with cell/tissue damage and metabolic abnormalities, which may be exacerbated in older, male, obese, or diabetic patients.

Original languageEnglish (US)
Article number155236
JournalMetabolism: clinical and experimental
Volume133
DOIs
StatePublished - Aug 2022
Externally publishedYes

Keywords

  • Adipose tissue
  • COVID-19
  • Cytokine
  • Dexamethasone
  • Diabetes
  • Dihydrotestosterone
  • Insulin resistance
  • Insulin signaling
  • Insulin/IGF signaling pathway
  • Interferone
  • IRF1
  • Liver
  • Lung
  • Male sex
  • Metabolic abnormality
  • Multiorgan dysfunction
  • Obesity
  • Older age
  • Pancreatic cell
  • SARS-CoV-2 infection
  • Tissue damage

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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