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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. 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. Access through your institution Buy or

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INSULIN AND INSULIN-LIKE GROWTH FACTOR RECEPTOR SIGNALLING Article 10 February 2025 INSULIN RESISTANCE IN TYPE 2 DIABETES MELLITUS Article 17 April 2025 ACTIVATION OF THE HUMAN INSULIN

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PubMed  Google Scholar  Download references 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 AUTHORS AND AFFILIATIONS * Department of Pathology and Cell Biology, Columbia University College of Physicians and

Surgeons, New York, 10032, New York, USA Rebecca A. Haeusler * Departments of Biochemistry and Cardiothoracic Surgery, Weill Cornell Medicine, New York, 10065, New York, USA Timothy E.

McGraw * Department of Medicine, Columbia University College of Physicians & Surgeons, New York, 10032, New York, USA Domenico Accili Authors * Rebecca A. Haeusler View author

publications You can also search for this author inPubMed Google Scholar * Timothy E. McGraw View author publications You can also search for this author inPubMed Google Scholar * Domenico

Accili View author publications You can also search for this author inPubMed Google Scholar 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. CORRESPONDING AUTHOR Correspondence to Domenico Accili. ETHICS DECLARATIONS COMPETING INTERESTS

The authors declare no competing financial interests. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR FIG. 4

POWERPOINT SLIDE FOR FIG. 5 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. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Haeusler, R., McGraw,

T. & Accili, D. Biochemical and cellular properties of insulin receptor signalling. _Nat Rev Mol Cell Biol_ 19, 31–44 (2018). https://doi.org/10.1038/nrm.2017.89 Download citation *

Published: 04 October 2017 * Issue Date: January 2018 * DOI: https://doi.org/10.1038/nrm.2017.89 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

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