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  • Review Article
  • Published:

The manifold roles of protein S-nitrosylation in the life of insulin

Nature Reviews Endocrinology volume 18, pages 111–128 (2022)Cite this article

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Abstract

Insulin, which is released by pancreatic islet β-cells in response to elevated levels of glucose in the blood, is a critical regulator of metabolism. Insulin triggers the uptake of glucose and fatty acids into the liver, adipose tissue and muscle, and promotes the storage of these nutrients in the form of glycogen and lipids. Dysregulation of insulin synthesis, secretion, transport, degradation or signal transduction all cause failure to take up and store nutrients, resulting in type 1 diabetes mellitus, type 2 diabetes mellitus and metabolic dysfunction. In this Review, we make the case that insulin signalling is intimately coupled to protein S-nitrosylation, in which nitric oxide groups are conjugated to cysteine thiols to form S-nitrosothiols, within effectors of insulin action. We discuss the role of S-nitrosylation in the life cycle of insulin, from its synthesis and secretion in pancreatic β-cells, to its signalling and degradation in target tissues. Finally, we consider how aberrant S-nitrosylation contributes to metabolic diseases, including the roles of human genetic mutations and cellular events that alter S-nitrosylation of insulin-regulating proteins. Given the growing influence of S-nitrosylation in cellular metabolism, the field of metabolic signalling could benefit from renewed focus on S-nitrosylation in type 2 diabetes mellitus and insulin-related disorders.

Key points

  • Post-translational modification of insulin signalling proteins by S-nitrosylation is an under-appreciated, but widely used, control mechanism in health and disease.

  • S-nitrosylation of ion channels and exocytotic machinery regulates insulin secretion from pancreatic β-cells.

  • S-nitrosylation of the insulin receptor and its signalling partners modulates insulin sensitivity in normal health.

  • Obesity-driven insulin resistance is associated with increased S-nitrosylation of insulin signalling proteins.

  • Cellular stress-driven insulin resistance is associated with increased S-nitrosylation of stress response proteins.

  • Modulation of the S-nitrosylation state of many insulin-regulatory proteins might provide novel therapeutic opportunities in metabolic disorders and diabetes mellitus.

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Fig. 1: Working model of protein S-nitrosylation and denitrosylation.
Fig. 2: Role of S-nitrosylation in insulin secretion from β-cells.
Fig. 3: The facilitatory role of S-nitrosylation in the AKT branch of insulin signal transduction.
Fig. 4: Mechanisms of inflammation-mediated insulin resistance.
Fig. 5: Mechanisms of insulin resistance mediated by aberrant S-nitrosylation of proteins in insulin signalling cascades.
Fig. 6: The role of aberrant protein S-nitrosylation in endoplasmic reticulum stress-mediated insulin resistance.

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Acknowledgements

The authors acknowledge the support of National Institutes of Health grants DK119506, HL158507, DK128347 and HL157151.

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Authors and Affiliations

  1. Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Hua-Lin Zhou, Richard T. Premont & Jonathan S. Stamler

  2. Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Hua-Lin Zhou, Richard T. Premont & Jonathan S. Stamler

  3. Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA

    Hua-Lin Zhou, Richard T. Premont & Jonathan S. Stamler

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J.S.S., H.-L.Z. and R.T.P. contributed substantially to the discussion of the content and reviewed and/or edited the article before submission. H.-L.Z. researched data for the article and wrote the article.

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Glossary

Thiol

A sulfhydryl group (SH) in the amino acid cysteine. The thiol group in proteins is the site of post-translational modification by S-nitrosylation.

LMW SNOs

Low molecular weight S-nitrosothiols, which serve as cofactors in protein denitrosylases. Common examples include S-nitrosoglutathione (GSNO) and S-nitroso-co-enzyme A (SNO-CoA), which serve as substrates in GSNO reductases and SNO-CoA reductases, respectively.

Quantal size

The elementary unit of synaptic transmission elicited by the release of neurotransmitters from a single vesicle. Changes in quantal size might be regulated by postsynaptic modification of receptor sensitivity and/or alterations in vesicle filling.

Weibel–Palade bodies

Storage granules in endothelial cells containing and releasing von Willebrand factor and P-selectin to regulate haemostasis and inflammation.

Nitrosative stress

A state of cellular stress characterized by excessive S-nitrosylation of proteins. Nitrosative stress is usually caused by either increased production of nitric oxide or decreased metabolism of S-nitrosothiols.

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Zhou, HL., Premont, R.T. & Stamler, J.S. The manifold roles of protein S-nitrosylation in the life of insulin. Nat Rev Endocrinol 18, 111–128 (2022). https://doi.org/10.1038/s41574-021-00583-1

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