Paradoxical associations of insulin resistance with total and cardiovascular mortality in humans

Ki Su Kim, Yu Mi Lee, In Kyu Lee, Dae Jung Kim, David R. Jacobs, Duk Hee Lee

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Background. Insulin resistance is linked to many human chronic diseases. Paradoxically, however, impaired insulin signaling contributes to longevity in various organisms and is suggested as an adaptive mechanism against external stressors, including obesity. We formulated a novel hypothesis that insulin resistance can be beneficial in obese humans, insofar as it does not cause glucose dysmetabolism. Methods. N = 5,241 participants aged ≥40 with normal fasting glucose were combined across the 1988-1994 and 1999-2004 National Health and Nutrition Examination Survey datasets. Mean follow-up period was 6.6 years. Insulin resistance was measured with homeostasis model assessment (HOMA-IR). Outcomes were all causes (n = 724), cardiovascular diseases (CVD, n = 316), and cancer mortality (n = 190). Results. Supporting the hypothesis, obese persons with high HOMA-IR showed a decreased risk of total and CVD mortality compared to those with the lowest HOMA-IR. Adjusted hazard ratios were 1.0, 0.8, 0.4, and 0.4 (p trend =. 02) for all death and 1.0, 0.6, 0.2, and 0.2 (p trend <. 01) for CVD death. On the other hand, lean persons with high HOMA-IR showed about twice the total and CVD mortality compared to persons with the lowest HOMA-IR (p trend <. 01, respectively). Conclusions. Insulin resistance in obese individuals may begin as an adaptive mechanism and can be beneficial if it is not associated with glucose dysmetabolism. In contrast, insulin resistance in lean individuals associated with higher risk of total and CVD mortality. Insulin resistance may be multifaceted and conventional approaches to regard insulin resistance itself as a pathological condition may be reconsidered in this light.

Original languageEnglish (US)
Pages (from-to)847-853
Number of pages7
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Issue number7
StatePublished - 2015

Bibliographical note

Publisher Copyright:
© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America.


  • Adaptation
  • Cardiovascular mortality
  • Insulin resistance
  • Longevity
  • Obesity


Dive into the research topics of 'Paradoxical associations of insulin resistance with total and cardiovascular mortality in humans'. Together they form a unique fingerprint.

Cite this