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. 2021 Nov 1;14(11):dmm049340.
doi: 10.1242/dmm.049340. Epub 2021 Nov 29.

Insulin at 100 years - is rebalancing its action key to fighting obesity-related disease?

Gemma V Brierley  1   2 , Robert K Semple  3
Affiliations

Insulin at 100 years - is rebalancing its action key to fighting obesity-related disease?

Gemma V Brierley et al. Dis Model Mech. .

Abstract

One hundred years ago, insulin was purified and administered to people with diabetes to lower blood glucose, suppress ketogenesis and save lives. A century later, insulin resistance (IR) lies at the heart of the obesity-related disease pandemic. Multiple observations attest that IR syndrome is an amalgamation of gain and loss of insulin action, suggesting that IR is a misnomer. This misapprehension is reinforced by shortcomings in common model systems and is particularly pronounced for the tissue growth disorders associated with IR. It is necessary to move away from conceptualisation of IR as a pure state of impaired insulin action and to appreciate that, in the long term, insulin can harm as well as cure. The mixed state of gain and loss of insulin action, and its relationship to perturbed insulin-like growth factor (IGF) action, should be interrogated more fully in models recapitulating human disease. Only then may the potential of rebalancing insulin action, rather than simply increasing global insulin signalling, finally be appreciated.

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Conflict of interest statement

Competing interests The authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
The common insulin resistance syndrome and type 2 diabetes exhibit features of gain and loss of insulin action and adipose failure. Features of insulin deficiency, excess insulin action and adipose failure are indicated, drawing on observations of untreated type 1 diabetes, fully compensated insulin resistance (IR) and lipodystrophy, respectively. Bracketed features are rare and only seen in the most severe degrees of insulin deficiency. Overlapping syndromes are numbered. (1) Characteristic of type 2 diabetes or lipodystrophy while insulin concentrations are still high. Some features from all three groups can be seen. (2) Seen in the early stages of decompensation of a proximal insulin signalling defect, e.g. due to INSR mutation. Features of excess insulin action with hyperglycaemia are most common; other features of insulin deficiency rarely develop due to residual insulin production. (3) Seen in obesity- or lipodystrophy-related IR before beta-cell decompensation. Commonly includes all features of lipotoxicity and excess insulin action. (4) Seen in more advanced stages of beta-cell decompensation in obesity- or lipodystrophy-related IR. Reversible features of excess insulin action disappear progressively as beta-cell failure progresses. PCOS, polycystic ovary syndrome.
Fig. 2.
Fig. 2.
Examples of endocrine and cellular crosstalk between insulin and growth hormone/IGF-I action. (1) Insulin and IGFs exert negative feedback on growth hormone secretion at the hypothalamus, and pituitary (2) insulin upregulates hepatic growth hormone expression. (3) Insulin suppresses IGFBP1. (4) High concentrations of insulin or IGF-I can cross-activate each other's receptors. Hybrid insulin/IGF-I receptors will also be present and activated but are not shown here. (5) Close similarities of intracellular signalling cascades for insulin and IGF-I raise the possibility of mutual signalling potentiation. GH, growth hormone; GHRH, growth hormone-releasing hormone; IGF, insulin-like growth factor; IGFBP, IGF-binding protein; IGF-IR, insulin-like growth factor receptor; Ins, Insulin; INSR, insulin receptor; IRS, insulin-responsive gene.
None
Robert Semple (left) and Gemma Brierley (right)
See this image and copyright information in PMC

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References

    1. Accili, D., Drago, J., Lee, E. J., Johnson, M. D., Cool, M. H., Salvatore, P., Asico, L. D., José, P. A., Taylor, S. I. and Westphal, H. (1996). Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat. Genet. 12, 106-109. 10.1038/ng0196-106 - DOI - PubMed
    1. Belfiore, A., Malaguarnera, R., Vella, V., Lawrence, M. C., Sciacca, L., Frasca, F., Morrione, A. and Vigneri, R. (2017). Insulin receptor isoforms in physiology and disease: an updated view. Endocr. Rev. 38, 379-431. 10.1210/er.2017-00073 - DOI - PMC - PubMed
    1. Besic, V., Shi, H., Stubbs, R. S. and Hayes, M. T. (2015). Aberrant liver insulin receptor isoform a expression normalises with remission of type 2 diabetes after gastric bypass surgery. PLoS ONE 10, e0119270. 10.1371/journal.pone.0119270 - DOI - PMC - PubMed
    1. Biddinger, S. B. and Kahn, C. R. (2006). From mice to men: insights into the insulin resistance syndromes. Annu. Rev. Physiol. 68, 123-158. 10.1146/annurev.physiol.68.040104.124723 - DOI - PubMed
    1. Bliss, M. (1982). The Discovery of Insulin: The Twenty-fifth Anniversary Edition. University of Toronto Press.

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