• Rachel A Murphy, Ilse Reinders, Melissa E Garcia, Gudny Eiriksdottir, Lenore J Launer, Rafn Benediktsson, Vilmundur Gudnason, Palmi V Jonsson, Tamara B Harris, and Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik).
• Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD rachel.murphy@nih.gov.
• Diabetes Care. 2014 Dec 1;37(12):3213-9.

ObjectiveStudies 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.Research Design And MethodsThe 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.ResultsThe 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.ConclusionsNormal weight participants had elevated mortality risk compared with overweight participants. This paradoxical association was mediated in part by muscle size.© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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