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Is insulin resistance a cause or a consequence of aging?

Image credit: Park et al, 2015 https://europepmc.org/article/med/26219845

Shubhankar Kulkarni
Shubhankar Kulkarni Aug 05, 2020
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Is the problem still unsolved?


Is it concisely described?

Insulin resistance was previously considered a cause of type 2 diabetes. Recent studies have suggested other mechanisms that precede insulin resistance and that they have a role in establishing insulin resistance. If we consider type 2 diabetes as an age-related disorder, we might consider insulin resistance as a consequence of aging.

We know for certain that insulin resistance and longevity are associated. Metabolic syndrome consists of metabolic defects associated with increased risks of reduced longevity and other age-related disorders. The metabolic syndrome of aging was originally called insulin resistance syndrome, pointing to insulin resistance as the key factor. In older persons, age-related rise of visceral adiposity and accumulation of senescent cells with inflammatory phenotype results in high blood levels of proinflammatory cytokines that probably interfere with insulin signaling. Insulin resistance contributes to increased cardiovascular morbidity in part through impairments in lipid uptake and storage of circulating lipids leading to increased plasma levels of very-low-density lipoprotein (proatherogenic apoB-containing/triglyceride-rich lipoproteins). Due to its high prevalence and strong association with many adverse outcomes, insulin resistance is often considered to have a causal role in many adverse aging phenotypes and age-related conditions, and counteracting insulin resistance could be an effective “anti-aging” intervention. This is suported by the use of metformin (an anti-diabetic drug) to combat other aging-related disorders and increase longevity. This view is, however, in contrast with the widely accepted notion that a downregulation (by genetic modulation) of the insulin signaling pathway in invertebrates is associated with exceptional longevity. Furthermore, it is suggested that in mammals, enhanced insulin sensitivity is neither a necessary nor a sufficient step towards increased longevity. Therefore, to answer whether insulin resistance is a cause or a consequence of aging, we need answers to:

  1. Is type 2 diabetes an age-related disorder?
  2. What molecular pathways connect insulin resistance and aging?

The answer to whether insulin resistance is a cause or consequence of aging may help in treating either with the medications used to treat the other.

[1]Watve M. Doves, diplomats and diabetes: a Darwinian interpretation of type 2 diabetes and related disorders. New York: Springer, 2013

[2]Corkey B. Banting Lecture 2011: Hyperinsulinemia: Cause or Consequence? Diabetes. 2011;61:4–13. doi: 10.2337/db11-1483.

[3]Ford ES, Giles WH, Dietz WH. Prevalence of the Metabolic Syndrome Among US Adults. JAMA [Internet]. 2002 Jan 16;287(3):356. Available from: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.287.3.356

[4]Sepe A, Tchkonia T, Thomou T, Zamboni M, Kirkland JL. Aging and Regional Differences in Fat Cell Progenitors – A Mini-Review. Gerontology [Internet]. 2011;57(1):66–75. Available from: https://www.karger.com/Article/FullText/279755

[5]Barzilai N, Ferrucci L. Insulin Resistance and Aging: A Cause or a Protective Response? Journals Gerontol Ser A Biol Sci Med Sci [Internet]. 2012 Dec 1;67(12):1329–31. Available from: https://academic.oup.com/biomedgerontology/article-lookup/doi/10.1093/gerona/gls145

[6]Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox JP, Schernthaner G, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes, Obes Metab [Internet]. 2014 Nov;16(11):1165–73. Available from: http://doi.wiley.com/10.1111/dom.12354

[7]Tatar M, Bartke A, Antebi A. The Endocrine Regulation of Aging by Insulin-like Signals. Science (80- ) [Internet]. 2003 Feb 28;299(5611):1346–51. Available from: https://www.sciencemag.org/lookup/doi/10.1126/science.1081447

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