Insulin action at a molecular level – 100 years of progress

Abstract

The discovery of insulin 100 years ago and its application to the treatment of human disease in the years since have marked a major turning point in the history of medicine. The availability of purified insulin allowed for the establishment of its physiological role in the regulation of blood glucose and ketones, the determination of its amino acid sequence, and the solving of its structure. Over the last 50 years, the function of insulin has been applied into the discovery of the insulin receptor and its signaling cascade to reveal the role of impaired insulin signaling—or resistance—in the progression of type 2 diabetes. It has also become clear that insulin signaling can impact not only classical insulin-sensitive tissues, but all tissues of the body, and that in many of these tissues the insulin signaling cascade regulates unexpected physiological functions. Despite these remarkable advances, much remains to be learned about both insulin signaling and how to use this molecular knowledge to advance the treatment of type 2 diabetes and other insulin-resistant states.

Highlights

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  Insulin receptor signaling involves a complex network that includes tyrosine and serine/threonine phosphorylation events.

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  The first intracellular nodes of insulin action are the IRS proteins, which also serve as critical nodes in feedback and the heterologous regulation that promotes insulin resistance.

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  Insulin signaling is important for insulin action in both classical (liver, muscle and adipose) and unexpected (pancreatic β-cell, brain and vascular endothelium) tissues.

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  Insulin resistance in diabetes and metabolic syndrome is driven by many extrinsic factors and new cell-intrinsic factors that could be new therapeutic targets.