Abstract
HMGA1 (high mobility group A1) is a nonhistone architectural chromosomal protein that functions mainly as a dynamic regulator of chromatin structure and gene transcription. As such, HMGA1 is involved in a variety of fundamental cellular processes, including gene expression, epigenetic regulation, cell differentiation and proliferation, as well as DNA repair. In the last years, many reports have demonstrated a role of HMGA1 in the transcriptional regulation of several genes implicated in glucose homeostasis. Initially, it was proved that HMGA1 is essential for normal expression of the insulin receptor (INSR), a critical link in insulin action and glucose homeostasis. Later, it was demonstrated that HMGA1 is also a downstream nuclear target of the INSR signaling pathway, representing a novel mediator of insulin action and function at this level. Moreover, other observations have indicated the role of HMGA1 as a positive modulator of the Forkhead box protein O1 (FoxO1), a master regulatory factor for gluconeogenesis and glycogenolysis, as well as a positive regulator of the expression of insulin and of a series of circulating proteins that are involved in glucose counterregulation, such as the insulin growth factor binding protein 1 (IGFBP1), and the retinol binding protein 4 (RBP4). Thus, several lines of evidence underscore the importance of HMGA1 in the regulation of glucose production and disposal. Consistently, lack of HMGA1 causes insulin resistance and diabetes in humans and mice, while variations in the HMGA1 gene are associated with the risk of type 2 diabetes and metabolic syndrome, two highly prevalent diseases that share insulin resistance as a common pathogenetic mechanism. This review intends to give an overview about our current knowledge on the role of HMGA1 in glucose metabolism. Although research in this field is ongoing, many aspects still remain elusive. Future directions to improve our insights into the pathophysiology of glucose homeostasis may include epigenetic studies and the use of “omics” strategies. We believe that a more comprehensive understanding of HMGA1 and its networks may reveal interesting molecular links between glucose metabolism and other biological processes, such as cell proliferation and differentiation.
Highlights
Glucose homeostasis is essential for life, and its maintenance is ensured through evolutionarily conserved regulatory mechanisms, that implicate complex and fine-tuned interplays between a variety of organs, tissues, hormones, receptors, nutrients, sensors, enzymes, and other molecules that may act locally and systemically [1, 2]
As a step toward understanding the molecular basis of regulation of the insulin receptor (INSR) gene, a nuclear binding protein that interacted with, and activated the INSR gene promoter, was identified previously, during muscle and adipose cell differentiation [88]. This DNA binding protein was identified as HMGA1, and its expression was markedly reduced in two unrelated patients with either the Type A syndrome or the common form of type 2 diabetes, in whom cell surface INSRs were decreased and INSR gene transcription was impaired despite the fact that the INSR genes were normal, indicating defects in INSR gene regulation [15, 89, 133]
Based on the above-mentioned findings, among the many tasks that HMGA1 can perform, there is its role in the transcriptional regulation of gene and gene networks involved in INSR signaling and glucose metabolism
Summary
HMGA1 is involved in a variety of fundamental cellular processes, including gene expression, epigenetic regulation, cell differentiation and proliferation, as well as DNA repair. Many reports have demonstrated a role of HMGA1 in the transcriptional regulation of several genes implicated in glucose homeostasis. It was proved that HMGA1 is essential for normal expression of the insulin receptor (INSR), a critical link in insulin action and glucose homeostasis. This review intends to give an overview about our current knowledge on the role of HMGA1 in glucose metabolism. Research in this field is ongoing, many aspects still remain elusive.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
