we attempted to report this study in accordance with the meta - analysis of observational studies in epidemiology guidelines ( 24 ) for meta - analyses of observational studies . we searched the pubmed database through january 2011 , using the key word magnesium in combination with diabetes , and examined the reference lists of the obtained articles . no restriction was imposed . when necessary , we contacted authors of original studies for additional data . studies were included if they met the following criteria : the study design was a prospective cohort study ; the exposure of interest was intake of dietary magnesium or total magnesium ( dietary and supplemental ) ; the outcome of interest was incidence of type 2 diabetes ; and the risk estimate of type 2 diabetes related to magnesium intake and associated 95% ci were reported . we used a standardized data collection form to extract the following information : author name ; publication year ; study population , location , and length of follow - up ; number of cases and participants ; assessment of exposure and outcome ; most fully adjusted risk estimate from multivariable model for the highest versus the lowest category of magnesium intake with corresponding 95% ci ; and statistical adjustment for the main confounding factors of interest . in one study ( 8) , we used data from the multivariable model with full control for potential confounders but not for insulin and glucose because magnesium plays an important role in insulin action and glucose homeostasis ( 5 ) , and adjustment for insulin and glucose , therefore , could represent overadjustment for variables on the causal pathway . two authors ( j .- y.d . and l .- q.q . ) independently performed the literature search , study selection , and data extraction . the relative risk ( rr ) was used as the common measure of association across studies , and the hazard ratio and incidence rate ratio were considered directly as rr . homogeneity test was performed with the use of q statistic at the p < 0.10 level of significance . we also calculated the i statistic , a quantitative measure of inconsistency across studies ( 25 ) . because of the presence of heterogeneity across studies , a random - effects model , which considered both within- and between - study variation , was used to compute the summary risk estimate . prespecified subgroup analyses according to geographic region , length of follow - up , sex , family history of diabetes , and bmi were performed to examine the impacts of these factors on the association . to test the robustness of the association , we also performed sensitivity analyses restricted to studies on dietary magnesium only and studies with further adjustment for cereal fiber intake . in addition , we examined the influence of a single study on the summary risk estimate by omitting one study in each turn . we next quantified a potential linear dose - response relationship of magnesium intake to diabetes risk because most individual studies have detected a significant linear trend . we first calculated an rr for every 100 mg / day increment in magnesium intake for each study based on the method proposed by greenland and longnecker ( 26 ) . potential publication bias was assessed by begg rank correlation test and egger linear regression test ( 27,28 ) . all analyses were performed using stata version 11.0 ( statacorp , college station , tx ) . all statistical tests were two - sided and p < 0.05 was considered statistically significant , except where otherwise specified . we attempted to report this study in accordance with the meta - analysis of observational studies in epidemiology guidelines ( 24 ) for meta - analyses of observational studies . we searched the pubmed database through january 2011 , using the key word magnesium in combination with diabetes , and examined the reference lists of the obtained articles . studies were included if they met the following criteria : the study design was a prospective cohort study ; the exposure of interest was intake of dietary magnesium or total magnesium ( dietary and supplemental ) ; the outcome of interest was incidence of type 2 diabetes ; and the risk estimate of type 2 diabetes related to magnesium intake and associated 95% ci were reported . we used a standardized data collection form to extract the following information : author name ; publication year ; study population , location , and length of follow - up ; number of cases and participants ; assessment of exposure and outcome ; most fully adjusted risk estimate from multivariable model for the highest versus the lowest category of magnesium intake with corresponding 95% ci ; and statistical adjustment for the main confounding factors of interest . in one study ( 8) , we used data from the multivariable model with full control for potential confounders but not for insulin and glucose because magnesium plays an important role in insulin action and glucose homeostasis ( 5 ) , and adjustment for insulin and glucose , therefore , could represent overadjustment for variables on the causal pathway . two authors ( j .- y.d . and l .- q.q . ) independently performed the literature search , study selection , and data extraction . the relative risk ( rr ) was used as the common measure of association across studies , and the hazard ratio and incidence rate ratio were considered directly as rr . homogeneity test was performed with the use of q statistic at the p < 0.10 level of significance . we also calculated the i statistic , a quantitative measure of inconsistency across studies ( 25 ) . because of the presence of heterogeneity across studies , a random - effects model , which considered both within- and between - study variation , was used to compute the summary risk estimate . prespecified subgroup analyses according to geographic region , length of follow - up , sex , family history of diabetes , and bmi were performed to examine the impacts of these factors on the association . to test the robustness of the association , we also performed sensitivity analyses restricted to studies on dietary magnesium only and studies with further adjustment for cereal fiber intake . in addition , we examined the influence of a single study on the summary risk estimate by omitting one study in each turn . we next quantified a potential linear dose - response relationship of magnesium intake to diabetes risk because most individual studies have detected a significant linear trend . we first calculated an rr for every 100 mg / day increment in magnesium intake for each study based on the method proposed by greenland and longnecker ( 26 ) . potential publication bias was assessed by begg rank correlation test and egger linear regression test ( 27,28 ) . all analyses were performed using stata version 11.0 ( statacorp , college station , tx ) . all statistical tests were two - sided and p < 0.05 was considered statistically significant , except where otherwise specified . we identified 13 prospective cohort studies ( 819 ) of magnesium intake and risk of type 2 diabetes  one article ( 11 ) included two separate cohort studies  involving 536,318 participants and 24,516 incident cases . all studies reported type 2 diabetes as the primary outcome except one study ( 17 ) that did not specify diabetes type ( the great majority of participants had type 2 diabetes ) . eight studies were conducted in the united states , three in asia , one in europe , and one in australia . the number of cases diagnosed in the primary studies ranged from 330 to 8,587 , and the number of participants ranged from 4,497 to 85,060 . both men and women were included in seven studies , one study consisted of men only , and five studies consisted of women only . of the studies , nine reported results on dietary magnesium intake , two ( 11 ) on total ( dietary and supplemental ) magnesium intake , and two ( 12,17 ) on both dietary and total magnesium intake . intake of supplemental magnesium was assessed from use of magnesium or multivitamin supplements ; however , dietary magnesium accounted for the majority of total magnesium intake . characteristics of 13 prospective cohort studies of magnesium and type 2 diabetes ffq , food - frequency questionnaire ; mufa , monounsaturated fatty acid ; pufa , polyunsaturated fatty acid ; sfa , saturated fatty acid ; tfa , trans fatty acid ; wc , waist circumference ; whr , waist - to - hip ratio . the mean length of follow - up ranged from 4 to 20 years . diabetes ascertainment was largely based on self - reports of physician diagnosis , but the majority of cases were confirmed in validation studies . the major adjusted confounders included age , bmi , physical activity , total energy intake , alcohol consumption , smoking , education , and family history of diabetes . adjusted dietary confounders were varied across individual studies , whereas cereal fiber intake was adjusted for in five studies ( 9,11,14,17 ) . the multivariable - adjusted rrs of type 2 diabetes for each study and all studies combined for the highest versus the lowest category of magnesium intake are shown in figure 1 . of the 13 selected studies , 9 found a statistically significant inverse association between magnesium intake and diabetes risk . the summary rr of type 2 diabetes was 0.78 ( 95% ci 0.730.84 ) , comparing the highest with the lowest category of magnesium intake . substantial heterogeneity was observed across studies ( pheterogeneity = 0.04 , i = 42.4% ) . forest plot of prospective cohort studies examining magnesium intake and risk of type 2 diabetes . table 2 presents the results of subgroup analyses stratified by characteristics of study designs and populations . overall , the inverse association between magnesium intake and risk of type 2 diabetes was not substantially modified by geographic region , follow - up length , sex , or family history of diabetes . notably , the observed inverse association was more pronounced among participants with bmi 25 kg / m ( rr 0.73 [ 95% ci 0.660.81 ] ) , and there was little evidence of heterogeneity ( pheterogeneity = 0.21 , i = 28.1% ) . however , no association was observed among those with bmi < 25 kg / m ( rr 1.09 [ 0.761.56 ] ) . subgroup analyses relating magnesium to type 2 diabetes by characteristics of study designs and populations to test the robustness of our findings , we conducted sensitivity analyses . restricting analysis to studies of dietary magnesium intake yielded an rr of 0.80 ( 95% ci 0.700.86 ; n = 11 ) . restricting analysis to studies that controlled for cereal fiber yielded an rr of 0.74 ( 0.680.80 ; n = 5 ) . further analyses investigating the influence of a single study on the overall risk estimate by omitting one study at each turn yielded a narrow range of rrs from 0.77 ( 0.720.82 ) to 0.79 ( 0.740.85 ) . in addition , no single study substantially contributed to the heterogeneity across studies . in the dose - response analysis of the 13 primary studies , the summary rr of type 2 diabetes for every 100 mg / day increment in magnesium intake was 0.86 ( 95% ci 0.820.89 ) , with evidence of heterogeneity among studies ( pheterogeneity = 0.02 , i = 48.4% ) . there was little evidence of publication bias with regard to magnesium intake in relation to risk of type 2 diabetes , as indicated by begg rank correlation test ( p = 0.99 ) and egger linear regression test ( p = 0.95 ) . we identified 13 prospective cohort studies ( 819 ) of magnesium intake and risk of type 2 diabetes  one article ( 11 ) included two separate cohort studies  involving 536,318 participants and 24,516 incident cases . all studies reported type 2 diabetes as the primary outcome except one study ( 17 ) that did not specify diabetes type ( the great majority of participants had type 2 diabetes ) . eight studies were conducted in the united states , three in asia , one in europe , and one in australia . the number of cases diagnosed in the primary studies ranged from 330 to 8,587 , and the number of participants ranged from 4,497 to 85,060 . both men and women were included in seven studies , one study consisted of men only , and five studies consisted of women only . of the studies , nine reported results on dietary magnesium intake , two ( 11 ) on total ( dietary and supplemental ) magnesium intake , and two ( 12,17 ) on both dietary and total magnesium intake . intake of supplemental magnesium was assessed from use of magnesium or multivitamin supplements ; however , dietary magnesium accounted for the majority of total magnesium intake . characteristics of 13 prospective cohort studies of magnesium and type 2 diabetes ffq , food - frequency questionnaire ; mufa , monounsaturated fatty acid ; pufa , polyunsaturated fatty acid ; sfa , saturated fatty acid ; tfa , trans fatty acid ; wc , waist circumference ; whr , waist - to - hip ratio . the mean length of follow - up ranged from 4 to 20 years . diabetes ascertainment was largely based on self - reports of physician diagnosis , but the majority of cases were confirmed in validation studies . the major adjusted confounders included age , bmi , physical activity , total energy intake , alcohol consumption , smoking , education , and family history of diabetes . adjusted dietary confounders were varied across individual studies , whereas cereal fiber intake was adjusted for in five studies ( 9,11,14,17 ) . the multivariable - adjusted rrs of type 2 diabetes for each study and all studies combined for the highest versus the lowest category of magnesium intake are shown in figure 1 . of the 13 selected studies , 9 found a statistically significant inverse association between magnesium intake and diabetes risk . the summary rr of type 2 diabetes was 0.78 ( 95% ci 0.730.84 ) , comparing the highest with the lowest category of magnesium intake . substantial heterogeneity was observed across studies ( pheterogeneity = 0.04 , i = 42.4% ) . forest plot of prospective cohort studies examining magnesium intake and risk of type 2 diabetes . table 2 presents the results of subgroup analyses stratified by characteristics of study designs and populations . overall , the inverse association between magnesium intake and risk of type 2 diabetes was not substantially modified by geographic region , follow - up length , sex , or family history of diabetes . notably , the observed inverse association was more pronounced among participants with bmi 25 kg / m ( rr 0.73 [ 95% ci 0.660.81 ] ) , and there was little evidence of heterogeneity ( pheterogeneity = 0.21 , i = 28.1% ) . however , no association was observed among those with bmi < 25 kg / m ( rr 1.09 [ 0.761.56 ] ) . subgroup analyses relating magnesium to type 2 diabetes by characteristics of study designs and populations to test the robustness of our findings , we conducted sensitivity analyses . restricting analysis to studies of dietary magnesium intake yielded an rr of 0.80 ( 95% ci 0.700.86 ; n = 11 ) . restricting analysis to studies that controlled for cereal fiber yielded an rr of 0.74 ( 0.680.80 ; n = 5 ) . further analyses investigating the influence of a single study on the overall risk estimate by omitting one study at each turn yielded a narrow range of rrs from 0.77 ( 0.720.82 ) to 0.79 ( 0.740.85 ) . in the dose - response analysis of the 13 primary studies , the summary rr of type 2 diabetes for every 100 mg / day increment in magnesium intake was 0.86 ( 95% ci 0.820.89 ) , with evidence of heterogeneity among studies ( pheterogeneity = 0.02 , i = 48.4% ) . there was little evidence of publication bias with regard to magnesium intake in relation to risk of type 2 diabetes , as indicated by begg rank correlation test ( p = 0.99 ) and egger linear regression test ( p = 0.95 ) . in the past decade , the role of magnesium in development of type 2 diabetes has been increasingly recognized . the present updated meta - analysis of 13 prospective cohort studies involving 536,318 participants and 24,516 cases determined a significant inverse association between magnesium intake and risk of type 2 diabetes in a dose - response manner . substantial heterogeneity was observed across studies , which was expected given the between - study variation , such as inconsistent data collecting methods , various nutrient databases , and different ethnic populations . in our subgroup analyses , the results were not substantially affected by geographic region , follow - up length , sex , or family history of diabetes , whereas the association tended to be stronger in overweight than in normal - weight individuals . the absence of heterogeneity in the stratified analyses by bmi indicated that bmi may , at least partially , contribute to the overall between - study variation . more important , bmi may serve as an effect modifier of the magnesium and diabetes association . all included cohort studies have adjusted for bmi , but only six studies ( 11,12,1719 ) have assessed the impacts of bmi on the association between magnesium intake and diabetes risk . among them , three studies ( 12,17,18 ) found more pronounced associations in overweight individuals than in normal - weight ones , yet only one ( 12 ) reached statistical significance in interaction tests . in our stratified analyses , the effect of bmi on the association was apparent , although the test for interaction was not statistically significant ( pinteraction = 0.13 ) , which was likely the result of insufficient statistical power . of note , it is plausible that high magnesium intake may have greater effects on improving insulin sensitivity in overweight individuals who are prone to insulin resistance ( 12 ) . in this regard , waist circumference and waist - to - hip ratio , which are suggested to be better predictors of insulin resistance than bmi ( 29 ) , may have more pronounced effects on the magnesium and diabetes association . because magnesium intake highly correlated to other healthy lifestyle and dietary factors , such as cereal fiber and calcium intakes , it is difficult to isolate the effect of magnesium intake on diabetes risk from other factors . consequently , the potential influences of these factors deserve consideration while interpreting the results . higher cereal fiber intake has been shown to be associated with a reduced diabetes risk ( 14 ) . in our analysis restricted to five studies ( 9,11,14,17 ) with control for cereal fiber intake , the inverse association between magnesium intake and diabetes risk persisted and remained statistically significant . in addition , limited evidence suggests calcium intake may play a role in preventing diabetes ( 23 ) . however , in the black women s health study ( 13 ) that mutually adjusted for magnesium and calcium , the association between calcium intake and risk of type 2 diabetes disappeared , whereas an inverse association with magnesium intake remained . moreover , physical activity ( 11,15 ) and smoking ( 15,18 ) , two important and modifiable risk factors for diabetes ( 30,31 ) , appeared not to have appreciable impacts on the association . taken together , existing evidence to date from observational cohort studies supports an independent , protective role of magnesium intake against type 2 diabetes . indeed , experimental and metabolic studies have provided convincing evidence in support of direct effects of magnesium intake on insulin resistance and type 2 diabetes . intracellular magnesium deficiency may result in disorders of tyrosine kinase activity during insulin signaling and glucose - induced insulin secretion , leading to impaired insulin sensitivity in muscle cells and adipocytes ( 32,33 ) . in animal studies , magnesium supplementation has been shown to protect against fructose - induced insulin resistance ( 6 ) and reduce the development of diabetes in rat models ( 7 ) . furthermore , evidence from randomized controlled studies suggests that magnesium supplementation may exert beneficial effects on glucose control in patients with type 2 diabetes ( 34 ) and improve insulin sensitivity in nondiabetic subjects ( 3537 ) . our findings confirmed results from previous meta - analyses ( 14,20 ) . with the accumulative evidence , we were able to enhance the precision of the risk estimates and perform subgroup analyses to explore sources of heterogeneity , thereby increasing the clinical relevance of our findings ( 38 ) . also , all included studies used a prospective cohort design , which minimized the likelihood of recall and selection biases . in addition , the presence of dose - response relationship strengthened the association of magnesium intake with risk of type 2 diabetes . first , observational studies can not establish causal association , and residual confounding remains a concern . a wide range of potential confounders , including demographic and lifestyle factors , were adjusted for in the primary studies , whereas dietary factors were not sufficiently considered . therefore , we could not fully exclude the possibility that unmeasured or inaccurately measured dietary factors are responsible for the observed association . second , misclassification bias may have weakened the strength of the association . because dietary assessment was based on self - administered questionnaires , misclassification of dietary magnesium intake misclassification of diabetes cases is also likely to occur given that diabetes ascertainments in most studies were based on self - reports . few studies ( 11,15,17,19 ) repeated dietary assessment during the follow - up period , which may also result in misclassification . third , we could not completely rule out the influences of changes in diet on the risk estimate in those with subclinical diabetes at baseline . sensitivity analyses that excluded cases diagnosed within the initial several years of follow - up would help examine these influences and achieve more reliable results , but they were performed in few studies ( 15 ) . apart from adequate control for potential confounders , particularly dietary factors , subsequent cohort studies of magnesium intake and type 2 diabetes should take the potential effect modification by bmi into consideration . individual - level meta - analyses ( 39 ) with more power to detect effect modification than study - level meta - analyses may also be pursued . to date , large scale , randomized , placebo - controlled trials , which provide the strongest evidence for establishing a causal relation ( 40 ) , have not been carried out to directly evaluate the effect of magnesium on diabetes incidence . given the compelling evidence from the observational studies , such trials are anticipated to draw definitive conclusions . as for public health , increased consumption of magnesium - rich foods , such as whole grains , nuts , and green leafy vegetables , may bring considerable benefits in diabetes prevention , especially in those at high risk . in conclusion , the present meta - analysis of prospective cohort studies provides further evidence in support of a significant inverse association between magnesium intake and risk of type 2 diabetes , consistent with a dose - response relationship .
objectiveemerging epidemiological evidence suggests that higher magnesium intake may reduce diabetes incidence . 
 we aimed to examine the association between magnesium intake and risk of type 2 diabetes by conducting a meta - analysis of prospective cohort studies.research design and methodswe conducted a pubmed database search through january 2011 to identify prospective cohort studies of magnesium intake and risk of type 2 diabetes . 
 reference lists of retrieved articles were also reviewed . 
 a random - effects model was used to compute the summary risk estimates.resultsmeta-analysis of 13 prospective cohort studies involving 536,318 participants and 24,516 cases detected a significant inverse association between magnesium intake and risk of type 2 diabetes ( relative risk [ rr ] 0.78 [ 95% ci 0.730.84 ] ) . 
 this association was not substantially modified by geographic region , follow - up length , sex , or family history of type 2 diabetes . 
 a significant inverse association was observed in overweight ( bmi 25 kg / m2 ) but not in normal - weight individuals ( bmi < 25 kg / m2 ) , although test for interaction was not statistically significant ( pinteraction = 0.13 ) . in the dose - response analysis , the summary rr of type 2 diabetes for every 100 mg / day increment in magnesium intake was 0.86 ( 95% ci 0.820.89 ) . 
 sensitivity analyses restricted to studies with adjustment for cereal fiber intake yielded similar results . 
 little evidence of publication bias was observed.conclusionsthis meta - analysis provides further evidence supporting that magnesium intake is significantly inversely associated with risk of type 2 diabetes in a dose - response manner .