J Gerontol A Biol Sci Med Sci. 2014 Oct 17. pii: glu194. [Epub ahead of print]

Paradoxical Associations of Insulin Resistance With Total and Cardiovascular Mortality inHumans.

Kim KS1, Lee YM1, Lee IK2, Kim DJ3, Jacobs DR Jr4, Lee DH5.

Abstract

BACKGROUND:

. Insulin resistance is linked to many human chronic diseases. Paradoxically, however, impairedinsulin 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. Insulinresistance 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 CVDmortality 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 insulinresistance itself as a pathological condition may be reconsidered in this light.