Diabetes Metab J.  2021 May;45(3):285-311. 10.4093/dmj.2020.0250.

Hyperinsulinemia in Obesity, Inflammation, and Cancer

• Zhang AM
• Wellberg EA
• Kopp JL
• Johnson JD

• KMID: 2516332
• DOI: http://doi.org/10.4093/dmj.2020.0250

Abstract

The relative insufficiency of insulin secretion and/or insulin action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute increase in circulating insulin, a state known as hyperinsulinemia. Studies are beginning to elucidate the cause-effect relationships between hyperinsulinemia and numerous consequences of metabolic dysfunctions. Here, we review recent evidence demonstrating that hyperinsulinemia may play a role in inflammation, aging and development of cancers. In this review, we will focus on the consequences and mechanisms of excess insulin production and action, placing recent findings that have challenged dogma in the context of the existing body of literature. Where relevant, we elaborate on the role of specific signal transduction components in the actions of insulin and consequences of chronic hyperinsulinemia. By discussing the involvement of hyperinsulinemia in various metabolic and other chronic diseases, we may identify more effective therapeutics or lifestyle interventions for preventing or treating obesity, diabetes and cancer. We also seek to identify pertinent questions that are ripe for future investigation.

Keyword

Breast neoplasms; Diabetes mellitus, type 2; Insulin; Longevity; Metabolic syndrome; Pancreatic neoplasms

Figure

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  Fig. 1. Trade-offs with insufficient and excessive circulating insulin levels. "Updated on 30 July 2021"

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  Fig. 2. Possible cellular targets of hyperinsulinemia in pancreatic cancer. (A) Violin plot showing insulin receptor (Insr) expression in pancreatic cells and immune cells. The data is based on single-cell gene expression analysis of mouse pancreas in Ptf1aCreER; LSL-KrasG12D; Ins1−/− genetic background generated using 10x Genomics. Background mRNA contamination was cleaned by R packages SoupX and the single-cell gene expression data was analyzed by Seurat 4.0 (Satija Lab). (B) Possible cellular targets of hyperinsulinemia in pancreatic cancer initiation and/or progression.

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  Fig. 3. Multiple links between insulin signaling and breast cancer. Insulin/Igf1 receptor signaling interacts with master regulators of breast cancer cell fate, including estrogen receptor signaling, core cell-cycle regulators, and metabolism. Virtually all proteins in this signaling network are regulated by phosphorylation. RTK, receptor tyrosine kinase; Erbb2, proto-oncogene Neu/Her2; Fgfr, fibroblast growth factor receptor; Insr, insulin receptor; Esr1, estrogen receptor 1; Grb2, growth factor receptor-bound protein 2; Irs, insulin receptor substrate; PI3K, phosphoinositide 3-kinase; Tsc2, tuberous sclerosis complex 2; Pten, phosphatase and tensin homolog; Glut1, glucose transporter 1; Hk, hexokinase; mTORC, mammalian target of rapamycin complex; Erk, extracellular signal-regulated kinase; Tp53, tumor protein p53; Gsk3b, glycogen synthase kinase 3b; Hif1a, hypoxia-inducible factor 1a; Pfk, phosphofructokinase; Pk, pyruvate kinase; Cdkn1, cyclin-dependent kinase inhibitor-1; Ampk, AMP-activated protein kinase; Pgr, progesterone receptor; Foxm1, forkhead box M1; Ccnd1/3, cyclin-dependent kinase 1/3; Myc, myc oncogene; Foxo, forkhead family box O; Cdk, cyclin-dependent kinase; Rb, retinoblastoma; E2f1, E2F transcription factor 1.

• 

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