iron metabolism is implicated in the incidence of diabetes and associated atherosclerotic disease [ 13 ] .
this causative relationship is underlined by reports of an improvement of glycaemic control in response to a reduction in body iron [ 4 , 5 ] .
body iron stores accumulate by dietary factors that include vitamin c and alcohol intake   as well as dietary iron , which in turn is a public health anxiety given that this essential nutrient influences the development of vascular disease .
diabetes is particularly concentrated on the indian subcontinent   whose dispersed migrant populations have a higher prevalence compared to various indigenous populations [ 914 ] . while studies show that established risk factors such as obesity and urbanised lifestyle  operate  amongst south asians ,
it remains unclear as to how far they explain an increased susceptibility to diabetes and glucose intolerance for this group .
we and others have reported the preservation of high rates of glucose intolerance amongst indian populations both overseas and in india itself [ 10 , 13 , 14 ] . while levels of ferritin and other markers of body iron status are shown to be predictive of diabetes in other populations ,
given that the improvement of body iron status to combat anaemia is a common primary healthcare concern among indian - origin populations ,   we determined whether serum ferritin was associated with diabetes in this group .
we tested the hypothesis that serum ferritin would reflect glucose tolerance and metabolic features of diabetogenesis amongst randomly selected gujaratis living in rural india and their contemporaries living in the uk .
we examined whether the magnitude of diabetes risk from serum ferritin was independent of obesity and lifestyle factors , which included nutritional intake , physical activity , and country of residence .
methodology of this migration study is described in more detail elsewhere . we compared gujarati indians living in sandwell ( uk ) who had migrated from rural villages in navsari ( gujarat , india ) with contemporaries still living in those villages of origin .
ethical approval for the study was obtained in sandwell and gujarat by the respective local research ethics committees .
participants who were invited to the clinic sessions fasted and had 75  g oral - glucose - tolerance tests ( ogtt ) .
blood samples were taken fasting and at 30 and 120  min after glucose challenge ( based on the who criteria ) .
identical procedures for anthropometry in each site included the leicester height measure ( seca ltd . , birmingham , uk ) , weight ( seca ltd . ) , waist , and hip ( metal tapes ) .
the hip circumference was measured over thin clothing as the widest horizontal circumference around the buttocks .
blood pressure was measured 3 times ( using the mean of the last 2 for analysis ) , with a validated semiautomatic monitor , after > 5  min sitting .
measures were rigorously standardised , with fieldworkers locally revalidated monthly , internationally every 4 months .
dietary analysis proceeded with completion of food diaries for four consecutive days ' intake and was done using wisp ( weighed intake software program ) version 1.23 , tinuveil software , llanfechell , uk .
physical activity was monitored using a validated accelerometer  caltrac  ( muscle dynamics , torrance , ca , usa ) worn continuously for 48 hours .
details of separation , storage , and transport of blood and the analysis of lipids , lipoproteins , glucose , insulin , vitamin b12 , serum folate , and c - reactive protein ( crp ) are available elsewhere .
venous blood collected in edta blood bottles was analysed for a full blood count using haematology analysers at either the clinical haematology department , sandwell hospital , uk ( stak s , beckman coulter corp . ,
hialeah , florida ) , or the mankodi laboratory , india ( bayer advia , bayer diagnostics , baroda , india ) .
ferritin was measured on frozen serum using an automated assay on the roche integra 400 + ( basel , switzerland ) .
given the influence of systemic inflammation on serum ferritin levels , subjects with crp concentrations above 5  mg / l , or males with ferritin > 300  ng / ml , or females with ferritin > 200  ng / ml were excluded from these post hoc analyses .
anaemia was defined as a haemoglobin of < 11.5  g / dl in females and < 13.5  g / dl in males .
folate deficiency was defined as a serum folate <3  ng / ml and vitamin b12 deficiency as < 200  pg / ml .
for a statistically significant ( p < 0.05 , 2-sided ) correlation coefficient  r 
( at least 0.20 ) , with a power of 80% , 193 subjects were needed .
, chicago , il ) using standard and nonparametric tests ( as determined by kolmogorov - smirnov normality plots ) amongst men and women .
central tendencies and variation for parametric data are presented as mean ( standard deviation ( sd ) ) or geometric means ( 95% ci ) for nonparametric data .
comparisons were made by t - test , mann whitney test , or chi square tests .
partial correlation analysis ( two - tailed ) was used to adjust the effects of gender and site .
linear regression models and binary logistic models were developed to test the strength of association , beta ( 95% ci ) of potential independent predictors of glucose intolerance .
the standardised beta coefficients presented allowed direct comparison ( along a scale of 0 - 1 ) of the strength of each association within the model .
the percentage prevalence of diabetes ( known and newly detected ) was similar across sites ( 7.7% , and 10.7% ) , respectively , for india and the uk .
with respect to impaired glucose tolerance , in navsari ( india ) it was 20.4% and in the sandwell ( uk ) it was 5.4% .
overall , the percentage of indians with normal glucose tolerance in navsari was 71.9% and in sandwell it was 83.9% .
thirty - three subjects from sandwell and 29 subjects from navsari were excluded due to either high crp or ferritin , leaving 114 men and 163 women from navsari and 109 men and 118 women in sandwell . of subjects with high crp or ferritin ,
41% had either diabetes ( all newly detected ) or impaired glucose tolerance during ogtt ( a higher proportion than those with normal crp or ferritin , p < 0.001 ) . amongst subjects with normal crp or ferritin ,
levels of ferritin were higher amongst diabetics ( p = 0.005 ) irrespective of site ( figure 1 ) .
levels of ferritin were higher amongst those with glucose intolerance , both in the presence ( p = 0.04 ) or in the absence of central obesity ( p = 0.02 ) ( figure 2 ) . across a gradient of deteriorating glucose tolerance ( normal to impaired glucose to frank diabetes ) , levels of ferritin increased ordinally independently of gender and migration status ( pseudo r = 0.04 , p < 0.008 ) .
the age - adjusted prevalence of iron deficiency was greater amongst women ( p < 0.01 ) at 79.6 ( 72.786.5)% in navsari women and 49.5 ( 39.659.4)% in sandwell women , compared to 25.7 ( 17.733.7)% in navsari men and 17.6 ( 9.825.3)% in sandwell men .
measures of anthropometry and blood pressure were significantly lower amongst those with low levels of ferritin ( < 20  ng / ml ) , compared to normal ferritin , ( for both men and women , table 1 ) .
metabolic factors such as glucose during ogtt , fasting nonesterified fatty acids ( nefa ) , insulin , hdl cholesterol , and triglycerides were also lower amongst those with low ferritin , significantly so for fasting triglycerides and nefa .
diabetes was less common amongst those with low ferritin ( p = 0.008 ) , where the risk estimate was 0.35 ( 0.150.81 ) .
on univariate analysis , levels of ferritin were associated with a range of metabolic factors , including fasting glucose ( r = 0.114 , p < 0.001 ) , serum triglycerides ( 0.270 , p < 0.001 ) , apolipoprotein b ( 0.189 , p < 0.001 ) , insulin levels ( 0.113 , p < 0.04 ) , nefa concentrations ( 0.238 , p < 0.001 ) , waist ( 0.318 , p < 0.001 ) and hip circumferences ( 0.148 , p < 0.001 ) , waist to hip ratio ( 0.424 , p < 0.001 ) , and bmi ( 0.190 , p < 0.001 ) .
these associations remained unchanged on separate analysis of gujaratis at each site , except for insulin level , waist and hip circumferences , and bmi , which were no longer related to ferritin . to control confounding from central obesity , on a subgroup analysis of nonobese gujaratis ( excluding men with a waist girth
 94  cm and women  80  cm ) , associations between ferritin and fasting glucose ( p = 0.03 ) , blood pressure ( p < 0.002 ) , and triglycerides ( p < 0.01 ) were conserved .
the magnitude of the relationship between ferritin and serum triglyceride levels was stronger in those with diabetes ( r = 0.13 , p < 0.001 ) and impaired glucose tolerance ( r = 0.20 , p < 0.001 ) compared to normal glucose ( r = 0.05 , p < 0.001 ) .
the age - adjusted prevalence of anaemia was significantly less common in sandwell ( p < 0.01 ) and greater amongst women compared to men .
iron deficiency anaemia was more common amongst those in navsari , particularly the women ( table 2 ) .
using various categories of anaemia , there was no influence of these exposures on diabetes status save iron deficiency anaemia ( p = 0.01 ) , which had a modest protective influence . on partial correlation analysis ( controlling for the effects of gender and country of residence ) , levels of ferritin
were positively related to total calorie intake ( 0.49 , p < 0.001 ) , energy derived from fat ( 0.50 , p < 0.001 ) , dietary iron ( 0.32 , p < 0.001 ) , and alcohol intake ( 0.26 , p < 0.001 ) and negatively related to energy derived from carbohydrate ( 0.39 , p < 0.001 ) .
levels of ferritin were unrelated to energy derived from protein ( p = 0.64 ) and showed modest association with energy expenditure from caltrac ( 0.17 , p = 0.04 ) and vitamin c intake ( 0.16 , p = 0.06 ) . on linear regression analysis , ferritin levels
were independently associated with residence in india ( beta ( 95% ci ) 0.78 ( 1.040.52 ) ) , male gender ( 1.16 ( 1.380.93 ) ) , anaemia ( 0.434 ( 0.1930.676 ) ) , age ( 0.015 ( 0.0060.024 ) ) , and serum triglycerides ( 0.258 ( 0.0640.451 ) ) ( or apolipoprotein b ) , all p < 0.001 , in models that also included waist to hip ratio , fasting plasma glucose , and systolic blood pressure .
fasting glucose was also predictive of ferritin ( p = 0.02 ) independently of gender , site , and waist to hip ratio , but not when measures of triglycerides or apolipoprotein b were added to regression models . on multivariate logistic analysis , the presence of diabetes was independently associated with age ( beta = 1.06 ( 1.021.10 ) , p < 0.001 ) and serum ferritin levels ( 2.11 ( 1.343.12 ) , p = 0.001 ) in a model that included migration status , gender , waist to hip ratio , anaemia , serum triglycerides , serum insulin , hdl cholesterol , and systolic blood pressure .
within indian gujarati men and women , serum ferritin , a marker of body iron status and inflammation , was consistently associated with glucose intolerance and indices of diabetes independently of lifestyle and metabolic risk factors .
serum ferritin concentrations may reflect an increased risk of diabetes amongst populations originating from the indian subcontinent , and it is an important consideration , given the heightened prevalence of anaemia in this group .
ferritin is an acute phase reactant , and inflammation may play a role in the inferred relationship between body iron stores and the risk of diabetes [ 18 , 19 ] . potentially , chronic inflammation is associated with diabetogenic risk factors such as obesity .
however , in our study , lean gujaratis with raised ferritin were still more likely to have diabetes than obese gujaratis with normal ferritin , and obesity per se was not associated with ferritin . in a white european population ,
the predictive value of ferritin with respect to diabetes disappeared once other metabolic risk factors were adjusted for .
the cross - sectional nature of our study may limit our interpretation of an independent relationship between ferritin and glucose intolerance .
our inclusion of participants with only normal crp and ferritin levels was an attempt to control for confounding from inflammation , but residual confounding from other inflammatory pathways or markers could persist .
the measurement of soluble transferrin receptor , the expression of which is interpreted as a demand for cellular iron , is a more accurate measure of body iron status than serum ferritin alone . as such , while high levels of ferritin may reflect a predisposition to diabetes in this population , the converse may also be true ( a susceptibility to glucose intolerance results in higher ferritin ) .
however , due to the cross - sectional nature of our study , the possibility of the raised serum ferritin levels caused by insulin intolerance or type 2 diabetes mellitus ( reverse causation ) can not be ruled out .
we found that high levels of ferritin are associated with insulin resistance independent of lifestyle changes and gender .
however , studies in other populations show that the development of type 2 diabetes mellitus is associated with dietary heme - iron intake [ 3 , 20 ] .
similarly , people with a family history of diabetes exhibit high levels of ferritin irrespective of glucose tolerance status . in a cross - sectional study of 12  090 korean subjects ,
however , they observed that raised serum ferritin concentrations were associated with type 2 diabetes mellitus , ifg , insulin resistance , and metabolic syndrome in men , yet only with ifg in women .
iron is a potent metal , which could potentially interfere with insulin synthesis and secretion in the pancreas , leading to insulin resistance or reduced insulin secretion [ 23 , 24 ] .
for example , amongst patients with haemochromatosis undergoing ogtt , hepatic iron overload is reported to result in impaired insulin extraction . while the pathophysiological mechanism is unclear , levels of triglycerides and dietary fat in this study were closely related to ferritin .
a potential pathway for the intersection of body iron status and dietary fat metabolism is that ferritin can regulate the secretion of apo b .
the porphyrin ring structure of apo b allows the direct binding of ferritin proteins   and we are tempted to speculate that iron delivery is a normal physiological outcome of lipoprotein metabolism , which is moderated by the action of insulin .
the restriction of dietary iron and fat improves pathological states such as nonalcoholic fatty liver , which in itself is a risk factor for diabetes .
elsewhere , we have reported that insulin resistance is related to the suppression of nefa during ogtt in this gujarati indian population . in the present analysis ,
the relationship between ferritin and absolute measures of nefa and insulin during ogtt was greater in magnitude than the association between ferritin and nefa suppression .
another possible mechanism is proposed in a recent spanish - population based cross - sectional study , suggesting that iron metabolism may contribute to the initiation of insulin resistance through inhibition of adiponectin and osteocalcin proteins involved in body glucose level regulation .
our results show that when compared with the nonmigrant population ( living in gujarati villages of india ) , the gujarati people who have immigrated to the uk have a higher ferritin level and less anaemia , but similar rates of diabetes .
firstly , the migration to the uk is more likely to involve a greater likelihood of nonvegetarianism , as opposed to the traditional gujarati vegetarian diet .
secondly , a nonspecific marker like ferritin could be linked to the chronic inflammatory states that are associated with obesity , which would also be exacerbated by dietary changes .
finally , the changes in prevalence could be due to a higher availability of medical resources in sandwell ( compared to gujarati villages ) , so more routine blood counts have been undertaken .
this may therefore result in more patients being treated for anaemia diagnosed on the serum results rather than on clinical presentation alone , thus more ferrous sulphate prescribed to the population .
this would result in a higher serum ferritin and lower prevalence of anaemia in this group of people .
the implication of these findings is that the interpretation of serum ferritin amongst people from the indian subcontinent is an important concern , not only for the treatment of anaemia   but also for the paradoxical risk of diabetes .
according to a study done on -thalassaemia major patients , which investigated the effects of chelation therapy on glucose levels , treating patients with deferoxamine and deferiprone ( combined chelation for lowering ferritin levels ) resulted in an improvement of glucose metabolism disorders in -thalassaemia major patients .
the increased risk of diabetes is potentially a consideration for clinician treating particular ethnic groups with iron replacement therapy .
this study raises concerns as to whether reference ranges for serum ferritin in south asians are sensitive to a potential risk of diabetes .
however , the present study design would be unsuitable and underpowered to answer such questions . in summary ,
levels of ferritin are associated with diabetes and metabolic factors amongst indian gujaratis , and this relationship is independent of site and gender and remains independent of the effects on obesity .
further work is warranted to determine the prognostic and diagnostic implications of body iron status within this population .
 
 background . 
 serum ferritin predicts the onset of diabetes ; however , this relationship is not clear amongst south asians , a population susceptible to glucose intolerance and anaemia . objective . 
 this study tests whether ferritin levels reflect glucose tolerance in south asians , independent of lifestyle exposures associated with indian or british residence 
 . methods . 
 we randomly sampled 227 gujaratis in britain ( 49.8 ( 14.4 ) years , 50% men ) and 277 contemporaries living in gujarati villages ( 47.6 ( 11.8 ) years , 41% men ) . 
 both groups underwent a 75  g oral - glucose - tolerance test . 
 we evaluated lifestyle parameters with standardised questionnaires and conducted comprehensive clinical and lab measurements . 
 results . across sites , 
 the age - adjusted prevalence of diabetes was 9.8% . 
 serum ferritin was higher amongst diabetics ( p = 0.005 ) , irrespective of site , gender , and central obesity ( p  0.02 ) , and was associated with fasting and postchallenge glucose , anthropometry , blood pressure , triglycerides , and nonesterified fatty acids ( p < 0.001 ) . 
 diabetes was less in those with low ferritin ( < 20  mg / ml ) , p < 0.008 , and risk estimate = 0.35 ( 95% ci 0.150.81 ) , as were blood pressure and metabolic risk factors . 
 on multivariate analysis , diabetes was independently associated with ferritin ( p = 0.001 ) and age ( p < 0.001 ) . 
 conclusion . 
 ferritin levels are positively associated with glucose intolerance in our test groups , independent of gender and indian or uk lifestyle factors . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion