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To examine the association of type 2 diabetes mellitus with arm length as a marker for early life environment and development.
This was a cross-sectional analysis of 658 second and third generation Japanese Americans (349 men and 309 women). Different arm length (total, upper and forearm length) and leg length (total and lower leg length) measurements were performed. Type 2 diabetes was defined by use of hypoglycemic medication or a fasting plasma glucose (FPG) ≥7mmol/L or 2 h ≥11.1mmol/L during an OGTT. Persons meeting criteria for impaired glucose tolerance were excluded from these analyses (FPG<7mmol/L and 2 h <11.1 and ≥7.8mmol/L). Multivariable logistic regression was used to estimate associations between diabetes prevalence and limb lengths while adjusting for possible confounders.
145 subjects had diabetes. On univariate analysis arm and leg length were not associated with diabetes. After adjustment for age, sex, CT measured intra-abdominal fat area, height, weight, smoking status and family history of diabetes, total arm length and upper arm length were inversely related to diabetes (Odds Ratio (OR) for a 1 standard deviation increase 0.49; 95% CI 0.29, 0.84 and OR 0.56; 95% CI 0.36, 0.87, respectively). Forearm length, height and leg length were not associated with diabetes after adjustment for confounding variables.
Our findings of associations between arm lengths and type 2 diabetes prevalence supports a role for factors that determine bone growth or their correlates in the development of this condition.
Several studies have shown an inverse relationship between height and type 2 diabetes [1-3]. Recent reports have shown that leg length is the key component for this association since it was related to type 2 diabetes, while trunk length was not [3-5]. It has been hypothesized that short adult leg length, and in particular femur length, is a marker for poor environmental conditions in early life, both intrauterine and during early childhood [6-9]. Previous work showed that adult leg length is sensitive to breastfeeding and energy intake in early childhood, the period in which the legs grow fastest , and that leg length is decreased in chronic childhood illnesses . It was also shown that leg length is associated with psychological stress during childhood . The role of early life diet on leg length is debatable, however, since it was recently shown that nutritional supplementation during pregnancy and early infancy in an undernourished population did not change relative leg length .
One potential explanation for the observed associations between limb lengths and diabetes is that the former serve as markers for nutritional state and stress during the early phases of life when bone development and growth occur. The “thrifty phenotype hypothesis” posits that adverse early life environment influences the development of beta cells (both in mass and function) and insulin resistance, making a subject more prone to develop diabetes in later life . Thus limb length and height may reflect early life development and serve as a means to indirectly test the thrifty phenotype hypothesis.
Arm length shows roughly the same growth pattern as leg length, with growth in utero and spurts during the first two years of life and puberty [13-15]. One can therefore envision that arm length also may be determined by environmental factors. Indeed, it has been shown that arm length is associated with environmental factors during infancy, such as lead poisoning and economic status, and thus may be a marker of early life deprivation or stress [16,17].
Given these observations, we undertook a study to test the hypothesis that arm length is inversely associated with type 2 diabetes prevalence. For this purpose, we used the Japanese American Community Diabetes Study (JACDS) cohort that contains a large number of individuals in whom anthropometric and body composition measurements and assessment of diabetes status were obtained.
The study population consisted of 658 second and third generation Japanese-American men and women of 100% Japanese ancestry who were enrolled in the JACDS. Details about recruitment and enrollment for this study have been described previously . Briefly, subjects were chosen from volunteers through community-wide recruitment from 1983-88 and were representative of Japanese-American residents of King County, WA, in age distribution, residential distribution, and parental immigration pattern. A comprehensive mailing list and telephone directory that included almost 95% of the Japanese-American population of King County, WA, was used to identify potential participants. Subjects were followed over 10 years with repeated study measurements. The study protocol was reviewed and approved by the University of Washington Human Subjects Review Committee and subjects provided written consent. For this analysis, we performed a cross-sectional analysis of data obtained at the time subjects entered the study. Since all subjects with diabetes in this population developed this condition as adults (youngest age of onset 31 years), the onset of diabetes occurred well after bone growth was completed, and thus could not have affected limb lengths.
All evaluations were performed at the General Clinical Research Center, University of Washington. Anthropomorphic parameters were taken with subjects wearing shorts and hospital slippers. Subjects were weighed on a digital recording scale, to the nearest one hundredth of a kilogram. Height was measured to the nearest tenth of a centimeter. Total arm length was defined as the distance in centimeters between the superior border of the acromion process and the tip of the third finger, when the arm and hand were fully extended. Upper arm length was the distance between the head of the radius and the superior border of the acromion process, and forearm length from the head of the radius to the tip of the lateral styloid. Total leg length was measured from the standing surface to the trochanteric landmark, lower leg length was defined as the distance from the inferior border of the lateral malleolus to the lower border of the femoral head. All length measurements were taken on the left side of the body using a tape measure.
A 75-gram oral glucose tolerance test was performed in the morning after a 10-hour overnight fast. Diabetes was diagnosed if the fasting glucose was ≥7 mmol/L, the 2-hour value was ≥11.1 mmol/L  or subjects were on oral hypoglycemic medication or insulin. Plasma glucose was assayed by an automated glucose oxidase method. Subjects who developed diabetes in the 10-year follow-up period were classified as nondiabetic at baseline. The comparison group consisted of those subjects without impaired glucose tolerance (IGT), defined as a OGTT 2-hour value between 7.8 and 11.0 mmol/L. All 658 subjects successfully completed an OGTT and hence this information is available for all subjects in the current analysis.
A single 1-cm abdominal slice by CT-scan was obtained at the level of the umbilicus to determine intra-abdominal fat (IAF) area measured within the confines of the transversalis fascia.
Smoking status was defined as current smoker versus former smoker or non-smoker. The family history for diabetes was positive when a first-degree relative had known type 2 diabetes.
Statistical analyses were performed using STATA SE11 (STATA Corp., College Station, TX). Multiple logistic regression was used to estimate the odds ratios for having type 2 diabetes in relation to an increase of 1 standard deviation of the different arm length measurements and other continuous variables. Potential confounders that were added in the models as covariates comprised known risk factors for type 2 diabetes including IAF area or factors related to limb length. The presence of non-linear associations between limb lengths and diabetes odds were assessed using a polynomial regression approach. The presence of effect modification between limb length and a covariate was tested by the insertion of first-order interaction terms in the appropriate models. We calculated the 95% confidence interval (CI) for each odds ratio (OR). A two-sided p-value of <0.05 was considered statistically significant.
Out of the 658 subjects entered into this analysis, 145 had type 2 diabetes. Because 194 subjects had IGT, the remaining 319 subjects were classified as the comparison population, making the total analysis sample size 464. Baseline characteristics by diabetes status and sex are shown in Table 1. Compared to those without diabetes, men and women with type 2 diabetes differed significantly by mean age, weight, height, BMI, IAF area, upper arm length, and (in men only) total arm length and total and lower leg length.
Analyses examining whether potential confounders were associated with both dependent (diabetes) and independent (arm length, leg length and height) variables were performed. Age, weight, IAF area, family history of diabetes and smoking status were significantly associated with both (p<0.05). In addition, sex and height were included in multivariable models because of their associations with limb length.
When controlling for explanatory and confounding variables (age, sex, IAF area, height, weight, smoking status and family history of diabetes) using multivariable logistic regression models, a number of associations between arm length measurements and diabetes became apparent (Table 2). Total arm length (OR 0.49; 95% CI 0.29, 0.84) and upper arm length (OR 0.56; 95% CI 0.36, 0.87) were inversely related to diabetes, while forearm length was positively associated with diabetes (OR 1.24; 95% CI 0,93, 1.65). Total leg length, lower leg length and height did not show a statistically significant association with diabetes after adjustment for potential confounders (age, sex, IAF area, weight, smoking status and family history of diabetes) (Table 3). There were no statistically significant interactions between the different limb length measurements and any of the covariates shown in the fully-adjusted models in Tables 2 and and33 (sex * total arm length, p=0.126; sex * upper arm length, p=0.492; sex * forearm length, p=0.358; sex * total leg length, p=0.223; sex * lower leg length, p=0.157 and sex * height, p=0.598). The quadratic transformations of the limb length measurements were not significant in the multivariable models, therefore a linear relation can be assumed.
Even though there was no significant interaction between sex and arm length measurements, sex-specific analyses for the associations between arm lengths and diabetes were performed. The sex specific findings in adjusted models are shown in Figure 1. The associations between upper and total arm length and diabetes odds are of greater magnitude in men compared to women.
A sensitivity analysis was performed that excluded subjects who had diabetes at baseline or who developed diabetes in the 10-year follow-up period. This analysis yielded similar results to those shown in Tables 2 and and3.3. The analyses in Tables 2 and and33 were re-run after including subjects with IGT in the comparison group, and these results were nearly identical to those described above.
We have shown that, after adjustment for confounding factors, total and upper arm lengths are inversely associated with diabetes prevalence in Japanese Americans. Forearm length, total leg length, lower leg length and height were not associated with diabetes. No significant interaction was seen between limb lengths and sex in the prediction of diabetes prevalence, although differences in the magnitudes of these associations by sex did appear when a sex-specific analysis was conducted. Given the non-significance of the sex-limb length interactions, we believe the evidence does not therefore strongly support a difference in the associations between limb length and diabetes prevalence by sex. To the best of our knowledge, this is the first study in humans to report that shorter arm length is independently associated with a higher prevalence of diabetes.
Our findings are in keeping with suggestions in the limited literature hypothesizing that arm length may be associated with diabetes. A shorter demi-arm span (measured from the sternal mid-line to the web space between the middle and fourth fingers) was shown not to be associated with diabetes . However, in that study diabetes was defined based on subject self-report, which may have resulted in misclassification of diabetes status without oral glucose tolerance testing to confirm this diagnosis, and furthermore may have had limited statistical power as only 24 subjects with this disorder were included in the analysis. In an animal study using the GK-rat model, those animals with diabetes had shorter humerus lengths compared to those without type 2 diabetes . Finally, arm length has been shown to be inversely associated with dementia (both Alzheimer’s disease and vascular dementia), a condition that appears to be associated with the early life environment, as may also be the case with type 2 diabetes as postulated in the thrifty phenotype hypothesis [17,21].
Though not as extensively studied as leg length, arm length has been shown to be associated with environmental conditions during early childhood [16,17] and therefore can be used as a marker for early exposures and deprivation. The mechanism linking environmental conditions, arm length and diabetes would appear to be in line with the thrifty phenotype hypothesis . According to this hypothesis, poor nutrition in utero and/or in the early childhood period leads to impaired development of the endocrine pancreas and thus an increased susceptibility to develop diabetes in later life due to limited pancreatic beta-cell insulin secretory capacity. Supporting this hypothesis is the finding that there is a decrease in fetal pancreatic beta cells in human pregnancies complicated by intra-uterine growth reduction, often caused by environmental factors (such as smoking, infections, and maternal diet) [22,23]. Our finding that adult total arm length is inversely associated with diabetes provides further indirect support for the hypothesis that environmental factors during the fetal and childhood period are associated with diabetes development.
Different studies have demonstrated an association between leg length, height and diabetes [1,3,5]. Interestingly, we were not able to find such a relation. However, none of these studies focused on Japanese American subjects, who are known to have a different body composition compared to Caucasian Americans . Moreover, heterogeneity between races with regard to associations between health outcomes and body proportions has been shown before by Weitzman et al, who reported that leg length is inversely linked to diabetes in Caucasian subjects, but not African Americans .
The different body composition between Japanese and Caucasians might be a limitation to our study. It has been shown that Japanese college students have relatively short arm to height ratios and thigh lengths compared to their Caucasian American counterparts . Even though our study clearly shows the inverse association of arm length and diabetes in Japanese Americans, it may not be generalizable to other ethnic groups. A second limitation is that we could not correct for possible differences in socio-economic status or level of education, since these variables were not recorded. It is thought however that social status was quite similar in this homogenous study cohort. Lastly, we did not determine the islet cell antibody status of subjects in the study and therefore cannot exclude the fact that some subjects may have had type 1 diabetes. However, given that Japanese are at very low risk for diabetes compared to other ethnic groups , and also that the youngest age of diabetes onset in our population was 31 years, it is likely that all persons in this analysis with diabetes had type 2 disease. Similar results were obtained when the analysis was repeated after excluding the participants who were nondiabetic at baseline but who developed this condition over the 10-year follow-up period.
In conclusion, total and upper arm lengths are inversely associated with diabetes prevalence, while forearm length, height and total and lower leg length were not related to diabetes. Since total arm length is dependent on environmental factors during pregnancy and early childhood, our findings are in keeping with the hypothesis that type 2 diabetes is determined in part by environmental factors in early life. Since height and leg length were related to diabetes in other studies with Caucasian subjects, this suggests possible ethnic differences in these associations. The relationship between limb lengths and diabetes is more complex than previously recognized and further research is needed to better understand these associations.
We appreciate the support and cooperation given by the King County Japanese-American Community to the study. This work was supported by National Institutes of Health Grants DK-31170, HL-49293, and DK-02654; by facilities and services provided by the Diabetes Research Center (DK-17047), Nutrition Obesity Research Center (DK-35816), and the General Clinical Research Center (RR-00037) at the University of Washington. The Department of Veterans Affairs and VA Puget Sound Health Care System provided support to Drs. Boyko and Kahn.
AUTHOR CONTRIBUTIONSM.M.S. analyzed the data, drafted and edited the manuscript E.J.B., K.M.U., S.S., L.A.W., D.L.L., M.J.M., W.Y.F., and S.E.K. helped interpreting the data, contributed to the discussion and reviewed/edited the manuscript. All authors approved the final version.
DUALITY OF CONFLICTS
The authors declare that there is no duality of interest associated with this manuscript.