Abstract
Type 2 diabetes mellitus is characterized by subclinical systemic inflammation and impaired regulation of blood glucose levels. Interestingly, impairment of glycemic control occurs despite substantial insulin secretion early in the course of this disease. Dysfunction of several organs (including pancreatic islets, liver, skeletal muscle, adipose tissue, gut, hypothalamus and the immune system) has been implicated in the pathogenesis of type 2 diabetes mellitus. However, diabetes-promoting lifestyle factors do not inevitably cause disease in all persons exposed. Hence, defense mechanisms must exist that can keep the detrimental influence of these risk factors at bay. Hormesis describes the phenomenon that exposure to a mild stressor confers resistance to subsequent, otherwise harmful, conditions of increased stress. This Review discusses the emerging concept that the effectiveness of an adaptive (hormetic) response to detrimental lifestyle factors determines the extent of protection from progression to type 2 diabetes mellitus. Further analysis of these protective hormetic responses at the molecular level should help to identify novel targets for preventive or therapeutic intervention in patients at risk of developing type 2 diabetes mellitus or those with overt disease.
Key Points
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Not all persons exposed to diabetes-promoting lifestyle factors develop type 2 diabetes mellitus
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Even individuals with obesity or metabolic syndrome might not progress to overt type 2 diabetes mellitus
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Defense mechanisms must exist that maintain insulin sensitivity and/or pancreatic β-cell survival despite long-term metabolic stress
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Such defense mechanisms comprise protective responses to inflammatory stress, mitochondrial dysfunction, oxidative stress and endoplasmic reticulum stress
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Defense responses exhibit properties of hormesis; for example, mild or transient stress induces an adaptive response that provides protection from increased, otherwise damaging stress
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Pharmacological intervention might promote protective hormetic responses, which suggests novel research avenues for the prevention and/or treatment of type 2 diabetes mellitus
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Acknowledgements
H. Kolb's research is supported by the Gesellschaft von Freunden und Förderern der Heinrich-Heine-Universität Düsseldorf. D. L. Eizirik's research work is supported by grants from the European Union (Projects Eurodia and Naimit within Framework Programs 6 and 7 of the European Community), Fonds National de la Recherche Scientifique, Actions de Recherche Concerteé de la Communauté Française, Belgium, and from the Program on Interuniversity Poles of Attraction initiated by the Belgian State (IUAP P5/17 and P6/40). The authors also thank M. L. Colli for preparing Figure 4.
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Kolb, H., Eizirik, D. Resistance to type 2 diabetes mellitus: a matter of hormesis?. Nat Rev Endocrinol 8, 183–192 (2012). https://doi.org/10.1038/nrendo.2011.158
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DOI: https://doi.org/10.1038/nrendo.2011.158
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