Diabetes Care Publish Ahead of Print, published online September 17, 2010 THE IMPACT OF BODY MASS INDEX AND THE METABOLIC SYNDROME ON THE RISK OF DIABETES IN MIDDLE-AGED MEN Running title: BMI, metabolic syndrome and diabetes risk Johan Ärnlöv, MD 1, 5, PhD, Johan Sundström, MD, PhD 2, 3; Erik Ingelsson, MD, PhD 1, 4; and Lars Lind, MD, PhD 2 1 Department of Public Health and Caring Sciences/Geriatrics, 2 Department of Medical Sciences, and 3 Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; 4 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; and 5 School of Health and Social Studies, Dalarna University, Falun, Sweden Correspondence to: Johan Ärnlöv, MD, PhD Emailo: [email protected], Submitted 17 May 2010 and accepted 10 September 2010. This is an uncopyedited electronic version of an article accepted for publication in Diabetes Care. The American Diabetes Association, publisher of Diabetes Care, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher- authenticated version will be available in a future issue of Diabetes Care in print and online at http://care.diabetesjournals.org. Copyright American Diabetes Association, Inc., 2010 BMI, metabolic syndrome and diabetes risk Objective: The existence of an obese sub-group, with a healthy metabolic profile and low diabetes risk, has been proposed. Yet, long term data is lacking. We aimed to investigate associations between combinations of body mass index (BMI)-categories and metabolic syndrome (MetS), and risk of type 2 diabetes in middle-aged men. Research design and methods: At age 50, cardiovascular risk factors were assessed in 1675 participants without diabetes in the community-based ULSAM-study. According to BMI/MetS- status, they were categorized as normal weight (BMI<25 kg/m2) without MetS (NCEP-criteria, n=853), normal weight with MetS (n=60), overweight (BMI 25-30 kg/m2) without MetS (n=557), overweight with MetS (n=117), obese (BMI>30 kg/m2) without MetS (n=28), and obese with MetS (n=60). We investigated the associations between BMI/MetS-categories at baseline and diabetes incidence. Results: After 20 years, 160 participants had developed diabetes. In logistic regression models adjusting for age, smoking, and physical activity, increased risks for diabetes were observed in normal-weight with MetS (odds ratio [OR] 3.28, 95%CI 1.38-7.81, p=0.007), overweight without MetS (OR 3.49, 95%CI 2.26-5.42, p<0.001), overweight with MetS (OR 7.77, 95%CI 4.44-13.62, p<0.001), obese without MetS (OR 11.72, 95%CI 4.88-28.16, p<0.001) and obese with MetS (OR 10.06, 95%CI 5.19-19.51, p<0.001), compared to normal-weight without MetS. Conclusions: Overweight or obese men without MetS, were at increased risk for diabetes. Our data provide further evidence that overweight and obesity in the absence of the MetS should not be considered a harmless condition. igher body mass index (BMI) has MHO-hypothesis is not undisputed; it was consistently been associated with an recently reported that both overweight and Hincreased risk for type 2 diabetes.(1; obese middle-aged men without the MetS 2) One reason for the major impact of obesity were at increased risk for cardiovascular on the development of type 2 diabetes is that events and total mortality during 30 years of it often is accompanied by the metabolic follow-up.(7) syndrome (MetS) a cluster of hyperglycemia, In a recent report from the Framingham Heart dyslipidemia and hypertension.(3) Study, overweight or obese individuals In recent years it has been proposed that the without the MetS did not portray a association between BMI and the significantly increased risk for diabetes, while development of type 2 diabetes is more participants with the MetS were at complex than a mere a dose-response substantially higher risk for diabetes relationship.(4; 5) The existence of a regardless of BMI status.(8) However, in this metabolically healthy but obese phenotype previous study, the follow-up did not exceed (MHO) has been proposed, an obese sub- 7 years. Thus, data on the long-term impact of group with a healthy metabolic profile and different BMI/MetS-combinations and the with no increased risk for adverse outcomes risk of diabetes are still lacking. such as diabetes or cardiovascular disease.(4- We hypothesized that overweight and obesity, 6) It should, however, be noted that the regardless of MetS-status, as well as the 2 BMI, metabolic syndrome and diabetes risk MetS, regardless of BMI-status, would be assayed by enzymatic techniques. Fasting associated with long-term increased risk for blood glucose was determined by an oxidase diabetes. We tested our hypothesis by method and insulin by radioimmunoassay. investigating the associations of combinations Supine systolic and diastolic blood pressures of BMI-categories and presence/absence of were measured twice in the right arm after 10 the MetS to long-term risk of type 2 diabetes minutes rest, and means were calculated. using data from a cohort study of middle-aged In the present study we used a modified men followed for 20 years. As a secondary version of the National Cholesterol Education aim, we investigated the association between Program (NCEP) definition of the MetS(3) combinations of BMI-categories and (Table 1). As waist circumference was only presence/absence of insulin resistance (IR) to measured in a subsample of the participants future risk of diabetes as some previous (n=480), the NCEP definition was modified investigators have defined MHO as obesity in by using a body mass index (BMI) cut-point the absence of insulin resistance.(4; 9; 10) instead of the NCEP waist circumference criterion (>102 cm). In the subsample with MATERIAL AND METHODS data on waist circumference, a waist Study Sample. In 1970 to 1973, all men born circumference of 102 cm corresponded to a in 1920 to 1924 and residing in the county of BMI of 29.4 kg/m2 in a linear regression Uppsala were invited to a health survey (at analysis (regression equation: BMI age 50) aimed at identifying risk factors for [kg/m2]=0.298 x waist circumference [cm] – cardiovascular disease; 82% of the invited 1.027). This BMI-cut point is similar to BMI men participated (n=2322). The cohort was cut-points used in previous modified NCEP reinvestigated after 10 and 20 years when the definitions of the metabolic subjects were approximately 60 and 70 years syndrome(12)BMI did not differ between this old, respectively. The design and selection subsample (25.2 kg/m2, SD 3.1) and the rest criteria for the cohort have been described of the cohort (25.0 kg/m2, SD 3.3, p=0.32). previously.(11) Participants were excluded for We used the homeostasis model (HOMA, the following reasons: diabetes mellitus at [fasting glucose*fasting insulin]/22.5)(13) baseline (n=124), unavailable data on MetS and defined IR as HOMA-IR in the top components or covariates (n=523), leaving quartile of the distribution in participants 1675 men as the present study sample. Of without diabetes (> 3.43). Leisure time these, data on IR was available in 1375 physical activity was estimated using a participants. The baseline characteristics and questionnaire containing four physical the event rates of diabetes were similar in the activity categories; Sedentary, Moderate, present study sample compared to those Regular, and Athletic(11) participants who were excluded due to By defining normal weight as BMI < 25 missing data at baseline (data not shown). kg/m2, overweight as BMI 25-30 kg/m2, and Informed written consent was obtained and obesity as BMI > 30 kg/m2, we could the Uppsala University Ethics Committee categorize the participants as, normal weight approved the study. without MetS (n=853), normal weight with Baseline Examinations and MetS Definition. MetS (n=60), overweight without MetS The examination at age 50 has been described (n=557), overweight with MetS (n=117), in detail previously.(11) Blood samples for obese without MetS (MHO, n=28) and obese fasting concentrations were drawn in the with MetS (n=60). In secondary analyses, we morning after an overnight fast. Cholesterol also categorized participants according to and triglyceride concentrations in serum were BMI/IR-categories: normal weight without IR 3 BMI, metabolic syndrome and diabetes risk (n=652), normal weight with IR (n=103), RESULTS overweight without IR (n=389), overweight Baseline characteristics for the different BMI- with IR (n=172), obese without IR (n=21) and MetS categories are shown in Table 2. obese with IR (n=48). BMI/MetS-categories and type 2 diabetes Endpoint definitions. Diabetes was defined incidence. During the 20 year follow-up, 160 according to current WHO criteria using participants had developed type 2 diabetes. fasting concentrations of glucose (fasting The risk of diabetes was higher in the blood glucose ≥6.1 mmol/l at the baseline overweight and obesity categories and with investigation and 10-year reinvestigation prevalent MetS compared to normal weight [which corresponds to fasting plasma glucose individuals without the MetS in both crude ≥ 7.0 mmol/l] or fasting plasma glucose ≥7.0 and multivariable models adjusting for age at mmol/l at the 20-year reinvestigation) or the baseline, smoking status, and physical activity use of anti-diabetic medication at any (Table 3). Obese participants regardless of investigations.(14) Of the present study MetS-status had a more than ten-fold sample, 1364 participants attended the 10- increased risk for diabetes as compared to year reinvestigation and in 967 participants normal weight individuals without the MetS.