title: Adipose tissue, muscle, and function: potential mediators of associations between body weight and mortality in older adults with type 2 diabetes.
abstract: OBJECTIVE
  Studies in type 2 diabetes report both increased mortality for normal weight and no evidence of an obesity paradox. We aimed to examine whether adipose tissue, muscle size, and physical function, which are known to vary by weight, mediate associations between BMI and mortality.
  
  
  METHODS
  The AGES-Reykjavik cohort comprised participants aged 66-96 years with diabetes defined by fasting glucose, medications, or self-report. BMI was determined from measured height and weight and classified as normal (18.5-24.9 kg/m(2), n = 117), overweight (25.0-29.9 kg/m(2), n = 293, referent group) or obese (≥30.0 kg/m(2), n = 227). Thigh muscle area and intermuscular, visceral, and subcutaneous adipose tissues were assessed with computed tomography. Function was assessed from gait speed and knee extensor strength. Hazard ratios (HRs) and 95% CIs were estimated by Cox proportional hazards regression adjusted for demographics and diabetes-related risk factors.
  
  
  RESULTS
  The median follow-up was 6.66 years, and there were 85, 59, and 44 deaths among normal weight, overweight, and obese participants, respectively. There was no mortality risk for obese participants and an increased risk among normal weight compared with overweight participants (HR 1.72 [95% CI 1.12-2.64]). Associations remained with adjustment for adipose tissues and knee extensor strength; however, mortality risk for normal weight was attenuated following adjustment for thigh muscle (HR 1.36 [95% CI 0.87-2.11]) and gait speed (HR 1.44 [95% CI 0.91-2.27]). Linear regression confirmed with bootstrapping indicated that thigh muscle size mediated 46% of the relationship between normal weight and mortality.
  
  
  CONCLUSIONS
  Normal weight participants had elevated mortality risk compared with overweight participants. This paradoxical association was mediated in part by muscle size.
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD rachel.murphy@nih.gov.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Murphy
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD.
authors.forename: Ilse
authors.initials: I
authors.lastname: Reinders
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Garcia
authors.affiliation: Icelandic Heart Association Research Institute, Kopavogur, Iceland.
authors.forename: Gudny
authors.initials: G
authors.lastname: Eiriksdottir
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD.
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.affiliation: Landspitali National University Hospital, Reykjavik, Iceland.
authors.forename: Rafn
authors.initials: R
authors.lastname: Benediktsson
authors.affiliation: Icelandic Heart Association Research Institute, Kopavogur, Iceland.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Department of Geriatrics, Landspitali National University Hospital and Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Palmi V
authors.initials: PV
authors.lastname: Jonsson
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD.
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology; D001823:Body Composition; D001835:Body Weight / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism / Q000401:mortality*; D005260:Female; D006801:Humans; D008297:Male; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000378:metabolism / Q000401:mortality; D050177:Overweight / Q000150:complications / Q000378:metabolism / Q000401:mortality; D012307:Risk Factors