Affiliations 

  • 1 Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine and Animal Science, University of Peradeniya, Peradeniya, Sri Lanka
  • 2 Department of Livestock and Avian Sciences, Faculty of Livestock, Fisheries, and Nutrition, Wayamba University of Sri Lanka, Makandura, Sri Lanka
  • 3 Department of North Indian Music, Faculty of Music, University of the Visual and Performing Arts, Colombo, Sri Lanka
  • 4 China-ASEAN College of Marine Sciences, Xiamen University Malaysia, Sepang, Selangor, Malaysia
  • 5 Faculty of Sciences and Engineering, University of Nottingham Malaysia, Semenyih, Malaysia
  • 6 Department of Clinical Medicine, Faculty of Medicine, University of Ruhuna, Galle, Sri Lanka
  • 7 Department of Psychiatry, Faculty of Medicine, University of Ruhuna, Galle, Sri Lanka
  • 8 Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
  • 9 Department of Community Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
Front Endocrinol (Lausanne), 2022;13:1028846.
PMID: 36479211 DOI: 10.3389/fendo.2022.1028846

Abstract

The paradoxical action of insulin on hepatic glucose metabolism and lipid metabolism in the insulin-resistant state has been of much research interest in recent years. Generally, insulin resistance would promote hepatic gluconeogenesis and demote hepatic de novo lipogenesis. The underlying major drivers of these mechanisms were insulin-dependent, via FOXO-1-mediated gluconeogenesis and SREBP1c-mediated lipogenesis. However, insulin-resistant mouse models have shown high glucose levels as well as excess lipid accumulation. As suggested, the inert insulin resistance causes the activation of the FOXO-1 pathway promoting gluconeogenesis. However, it does not affect the SREBP1c pathway; therefore, cells continue de novo lipogenesis. Many hypotheses were suggested for this paradoxical action occurring in insulin-resistant rodent models. A "downstream branch point" in the insulin-mediated pathway was suggested to act differentially on the FOXO-1 and SREBP1c pathways. MicroRNAs have been widely studied for their action of pathway mediation via suppressing the intermediate protein expressions. Many in vitro studies have postulated the roles of hepato-specific expressions of miRNAs on insulin cascade. Thus, miRNA would play a pivotal role in selective hepatic insulin resistance. As observed, there were confirmations and contradictions between the outcomes of gene knockout studies conducted on selective hepatic insulin resistance and hepato-specific miRNA expression studies. Furthermore, these studies had evaluated only the effect of miRNAs on glucose metabolism and few on hepatic de novo lipogenesis, limiting the ability to conclude their role in selective hepatic insulin resistance. Future studies conducted on the role of miRNAs on selective hepatic insulin resistance warrant the understanding of this paradoxical action of insulin.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.