title: Paradoxical Associations of Insulin Resistance With Total and Cardiovascular Mortality in Humans.
abstract: 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.
authors.affiliation: Department of Preventive Medicine and.
authors.forename: Ki-Su
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Preventive Medicine and.
authors.forename: Yu-Mi
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Department of Endocrinology, School of Medicine, Kyungpook National University, Daegu, Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Dae-Jung
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis.
authors.forename: David R
authors.initials: DR
authors.lastname: Jacobs
authors.affiliation: Department of Preventive Medicine and BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Korea. lee_dh@knu.ac.kr.
authors.forename: Duk-Hee
authors.initials: DH
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000097:blood / Q000150:complications / Q000401:mortality*; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008136:Longevity; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000150:complications / Q000401:mortality; D009749:Nutrition Surveys; D009765:Obesity / Q000150:complications / Q000378:metabolism* / Q000401:mortality*; D014481:United States
chemical_list: D001786:Blood Glucose
keywords: Adaptation; Cardiovascular mortality; Insulin resistance; Longevity; Obesity.