Review Article | Published:

Biochemical and cellular properties of insulin receptor signalling

Nature Reviews Molecular Cell Biology volume 19, pages 3144 (2018) | Download Citation

Abstract

The mechanism of insulin action is a central theme in biology and medicine. In addition to the rather rare condition of insulin deficiency caused by autoimmune destruction of pancreatic β-cells, genetic and acquired abnormalities of insulin action underlie the far more common conditions of type 2 diabetes, obesity and insulin resistance. The latter predisposes to diseases ranging from hypertension to Alzheimer disease and cancer. Hence, understanding the biochemical and cellular properties of insulin receptor signalling is arguably a priority in biomedical research. In the past decade, major progress has led to the delineation of mechanisms of glucose transport, lipid synthesis, storage and mobilization. In addition to direct effects of insulin on signalling kinases and metabolic enzymes, the discovery of mechanisms of insulin-regulated gene transcription has led to a reassessment of the general principles of insulin action. These advances will accelerate the discovery of new treatment modalities for diabetes.

Key points

  • Formally started in 1971 with the discovery of the insulin receptor, the field of insulin signalling has by now resolved many questions related to the cellular, biochemical foundation of the hormone's biological effects.

  • The three major biochemical steps in insulin signalling are: tyrosine phosphorylation of the receptor and its direct substrates; activation of the lipid kinase, PI3K; and activation of multiple serine/threonine kinases, the most important of which is AKT.

  • Through various combinations of these signalling modules in different cell types, with different time and dose dependence after insulin binding, innumerable combinations of signalling complexes can be obtained. This diversity likely underpins the pleiotropism of insulin action, as well as the pathogenesis of insulin resistance.

  • Key recent discoveries in the field include the delineation of a pathway to insulin-dependent glucose transport, the emergence of two central pathways for regulation of gene expression, the interaction of insulin and leptin signalling in the CNS to facilitate energy homeostasis, and the role of inflammation as a regulator of insulin signalling.

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Acknowledgements

The authors thank U. Pajvani and R. Leibel for stimulating discussions and helpful comments. Supported by NIH grants DK57539, DK64819, DK58282, HL81723, DK52852 and HL125649.

Author information

Affiliations

  1. Columbia University College of Physicians and Surgeons, Department of Pathology and Cell Biology, New York, New York 10032, USA.

    • Rebecca A. Haeusler
  2. Weill Cornell Medicine, Departments of Biochemistry and Cardiothoracic Surgery, New York, New York 10065, USA.

    • Timothy E. McGraw
  3. Columbia University College of Physicians & Surgeons, Department of Medicine, New York, New York 10032, USA.

    • Domenico Accili

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Contributions

R.A.H., T.E.M. and D.A. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Domenico Accili.

Glossary

Anorexigenic

Appetite-suppressant.

Paracrine

A mechanism by which neighbouring cells influence each other by way of a secreted factor.

Diacylglycerol

A glycerol molecule with two fatty acid chains present in food or produced primarily in the liver, adipose tissue and intestine, diacylglycerol is best known for its signalling properties to activate protein kinase C but also functions as a precursor molecule in the synthesis of triglycerides and prostaglandins.

Haploinsufficiency

A phenotype caused by a heterozygous loss-of-function mutation, or by a mutation partly affecting levels and/or activity of a gene product.

Post-absorptive state

The state following food absorption by the gut, hence the fasting state.

RABGAP

A protein activating the GTPase activity of RAB, a component of secretory vesicles involved in intracellular transport.

Exocyst

An octamer assembled to promote intracellular vesicle transport.

COPII complex

A complex of proteins assembled around coat protein II (COPII), required for anterograde transport from the endoplasmic reticulum to the Golgi.

Transcytocis

The transport of proteins across the interior of a cell.

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https://doi.org/10.1038/nrm.2017.89

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