diabetes mellitus is a major complication of iron overload in patients with beta thalassemia major . this is a descriptive study conducted in a tertiary care teaching hospital to analyze beta cell function and insulin resistance , and their relation to iron overload status in beta thalassemia major . fasting glucose , two - hour post load glucose , fasting insulin , alanine amino transaminase ( alt ) , and ferritin were used as outcome measures . the homeostatic model assessment ( homa model ) of the 30 cases , 20% had impaired fasting glucose , 3.3% had impaired glucose tolerance , and none had diabetes . fasting glucose was not significant between the cases and controls ( p = 0.113 ) . fasting insulin ( p = 0.001 ) , ferritin ( p = 0.001 ) , and alt ( p = 0.001 ) levels were significantly high in the cases . insulin resistance index was significantly higher in the cases ( p = 0.001 ) as also the beta cell function ( p = 0.001 ) . with increase in age and the number of units transfused there is a decline in beta cell function , fasting insulin , and insulin resistance after attaining the maximum level . this suggests that initial insulin resistance is followed by insulin depletion due to loss of beta cell function , leading to diabetes mellitus . impaired glucose tolerance ( igt ) and insulin resistance precede the onset of insulin - dependent diabetes and adequate chelation therapy is essential for delaying the onset or for prevention of diabetes . thalassemia major ( tm ) or cooley 's anemia is widespread throughout the mediterranean region , africa , middle east , indian subcontinent , and south east asia . in india , every year 10,000 children are born with thalassemia , contributing to 10% of the global burden and the frequency of tm ranges between 3 and 15% in the general population . iron overload of tissue , if not adequately treated , is the most important complication of tm and is the major focus of management . inadequate or absence of chelating therapy leads to progressive dysfunction of the heart , liver , and endocrine glands . over the years iron deposition may lead to pulmonary hypertension and osteopenia . diabetes mellitus is one of the major endocrine problems and prevalence of impaired glucose tolerance and diabetes varies from 8.5 to 12.2% and 5.4 to 19.5% , respectively . this study was done to find out the incidence of abnormal glucose tolerance and diabetes in tm patients , who were on long - term transfusion , and also to provide an insight into the possible mechanism of occurrence of diabetes . various parameters of glycemic indices were correlated with the indicators of iron overload , such as ferritin , and the total number of units transfused . patients with tm undergoing regular transfusions were recruited from the department of pediatrics in a tertiary care teaching hospital in mangalore , from february 2007 to august 2008 . the sample size was 40 , with 30 cases of tm and 10 age- and sex - matched controls . those eligible for this study included tm diagnosed by hemoglobin electrophoresis and on regular transfusion , of age between five and seventeen years , and absence of any other known endocrinological problem . patients with a family history of diabetes in first - degree relatives , on treatment with drugs causing diabetes , and presence of chronic illness , were excluded from the study . ten normal children between five and seventeen years of age , with no family history of tm , and absence of diabetes in first - degree relatives were included as controls . informed consent from a parent and approval from the institutional ethics committee were obtained prior to the study . a detailed history was taken , such as , age at diagnosis , age at first transfusion , total number of transfusions , compliance with transfusion , and details of chelation therapy . physical examination including pallor , icterus , skin changes , liver and spleen size , and a systemic examination the investigations undertaken were fasting plasma glucose ( fpg ) , two - hour post load glucose , fasting insulin ( fi ) , ferritin , alanine amino transferase ( alt ) , and hemoglobin . fasting plasma glucose was done from a blood sample collected after overnight fasting of eight hours . an oral glucose load of 1.75 g / kg was then administered and a repeat sample collected after two hours , for two - hour post - load glucose . the test was done using riak-1 ( radio immunoassay kit for insulin ) supplied by the baba atomic research center , mumbai . the american diabetes association ( ada ) criterion 2007 , was used for diagnosis of diabetes . fasting plasma glucose ( fpg ) < 100 mg / dl ( 5.6 mmol / l ) = normal fasting glucosefpg 100 - 125 mg / dl ( 5.6 - 6.9 mmol / l ) = impaired fasting glucose ( ifg)fpg  126 mg / dl ( 7.0 mmol / l ) = provisional diagnosis of diabetes 
  fasting plasma glucose ( fpg ) < 100 mg / dl ( 5.6 mmol / l ) = normal fasting glucose fpg 100 - 125 mg / dl ( 5.6 - 6.9 mmol / l ) = impaired fasting glucose ( ifg ) fpg  126 mg / dl ( 7.0 mmol / l ) = provisional diagnosis of diabetes the corresponding categories when the oral glucose tolerance test ( ogtt ) is used are the following : 
 two - hour post - load glucose < 140 mg / dl ( 7.8 mmol / l ) = normal glucose tolerancetwo - hour post - load glucose 140 - 199 mg / dl ( 7.8 - 11.1 mmol / l ) = impaired glucose tolerance ( igt)two - hour post - load glucose  200 mg / dl ( 11.1 mmol / l ) = provisional diagnosis of diabetes 
  two - hour post - load glucose < 140 mg / dl ( 7.8 mmol / l ) = normal glucose tolerance two - hour post - load glucose 140 - 199 mg / dl ( 7.8 - 11.1 mmol / l ) = impaired glucose tolerance ( igt ) two - hour post - load glucose  200 mg / dl ( 11.1 mmol / l ) = provisional diagnosis of diabetes patients with ifg and/or igt are now referred to as having  pre - diabetes indicating the relatively high risk for development of diabetes in these patients . all cases and controls were evaluated for beta cell function index and insulin resistance index using homeostasis model assessment ( homa ) . test of significance was done by applying the students unpaired t - test between the cases and controls . pearson 's correlation co - efficient ( r ) was employed to assess the strength of association as well as linear relation between the variables . the mean age among the cases was 10.16 years and that of the controls was 10.10 years . among the cases 46.7% were males and 53.3% were females . age at first transfusion varied between three and eighteen months with the mean at 9.9 months . deferoxamine was not taken routinely , due to the higher cost involved ; 73.3% had poor compliance with chelation therapy . left ventricular dysfunction was found in one child who had stopped chelation therapy ; 53.3% of the cases had characteristic clay - colored skin . the mean liver span was 12 cm and the mean splenic size was 4.3 cm . patient characteristics ( mean values ) impaired fasting glucose was seen in six cases ( 20% ) . there was no significant difference in fasting glucose between the cases and controls ( p = 0.113 ) and the mean glucose value was within normal limits in both groups . a statistically significant difference was observed in fasting insulin ( p = 0.001 ) , beta cell function ( p = 0.001 ) , iri ( p = 0.001 ) , alt ( p = 0.001 ) , and ferritin ( p = 0.001 ) when compared with the controls . fasting glucose had a good correlation with the other glycemic indices , such as , fasting insulin ( r = 0.434 , p = 0.017 ) , insulin resistance index ( r = 0.544 , p = 0.002 ) , and beta cell function index ( r = 0.389 , p = 0.034 ) . fasting insulin was significantly higher in the cases compared to the controls ( p = 0.001 ) . it correlated well with other glycemic indices like fasting glucose ( r = 0.434 , p = 0.017 ) , beta cell function ( r = 0.614 , p = 0.001 ) , and iri ( r = 0.944 , p = 0.001 ) . the insulin resistance index was higher in cases compared to controls and the difference was highly significant ( p = 0.001 ) . it correlated well with other glycemic indices like fasting glucose ( r = 0.544 , p = 0.002 ) , fasting insulin ( r = 0.944 , p = 0.001 ) , and beta cell function ( r = 0.430 , p = 0.018 ) . the beta cell function index was also significantly higher in the cases compared to the controls ( p = 0.001 ) . the beta cell function also correlated with other glycemic indices like fasting glucose ( r = -0.389 , p = 0.034 ) , fasting insulin ( r = 0.614 , p = 0.001 ) , and insulin resistance index ( r = 0.0.430 , p = 0.018 ) . however , the glycemic indices such as fasting glucose , fasting insulin , beta cell function , and iri did not correlate with the indicators of iron overload , such as , ferritin and number of transfusions . there was also no correlation between the glycemic indices and age . the number of transfusions received in the cases correlated with the age ( r = 0.687 , p = 0.001 ) and serum ferritin ( r = 0.385 , p = 0.036 ) . similarly ferritin , although significantly high in the cases ( p = 0.001 ) did not correlate with the parameters of the glycemic indices [ tables 2 and 3 ] . correlation among fasting glucose , fasting insulin ( fi ) , beta cell function , and insulin resistance index ( iri ) correlation of the number of units transfused with age and ferritin an interesting observation was found when internal grouping was done with the total number of transfusions < 100 , 100 - 150 , and > 150 units . there was a progressive increase in beta cell function , fasting insulin , and iri with an increase in the number of units transfused , and age followed with a decline , as shown in the graphs . a similar relationship was obtained with increasing age when compared with the beta cell function , fasting insulin , and insulin resistance index [ figures 1 and 2 ] . number of units transfused with fasting insulin and iri number of units transfused with beta cell function the mean age of thalassemic children in our study was 10.1  2.38 years , with the age distribution ranging between five and seventeen years . our study population had a relatively younger age group when compared to other studies , where the mean age among the cases were 14.8  6.9 and 21.7  1.2 years , respectively . however , the mean age almost matched that of the study from india , which was 10.89 years . the size of the liver and spleen did not correlate with any of the parameters like age , ferritin , number of transfusions or glycemic indices , like fasting glucose , fasting insulin , beta cell function , and iri . there was no significant difference in fasting glucose between the cases and controls of our study . however , a significant difference in the fasting glucose levels in thalassemic children ( p < 0.05 ) was observed by others , and this might be due to the inclusion of only post pubertal subjects , more than 18 years of age . they also demonstrated a progressive reduction of circulating insulin levels , which could lead to glucose intolerance . our study population had a relatively younger age group similar to the study by suvarna et al . features of chronic active hepatitis occurred with alt values of 52.5  19.7 and features of cirrhosis occurred with values of 106.7  50.3 , which needed confirmation by liver biopsy . this liver dysfunction due to iron overload was one of the important pathogenetic mechanisms for abnormal glucose tolerance and diabetes . we did not evaluate the raised alt with other tests , and liver biopsy was not done , as it was beyond the scope of the study . impaired fasting glucose was seen in 20% of the cases and impaired glucose tolerance was seen in 3.3% . this was higher than the reported incidence in the study conducted in 2001 - 2002 , where none of the thalassemic children had abnormal glucose tolerance . among 74 greek cases of tm , the prevalence of igt was 12.2% and that of diabetes 5.4% . however , all were aged above 10 years , with a mean age of 20.5  5.2 years . the proposed risk factors for the development of glucose intolerance in tm were elevated ferritin levels , hepatitis c infection , age , family history of diabetes , and splenectomy . the mean age of onset of diabetes , assessed in a large set of cases in italy , was 18.1 years . another smaller study also reported the onset of diabetes to occur after 18 years of age . chelation therapy delayed the onset of diabetes and reportedly the incidence , which was 19% in 1974 was 4.9% in 1995 , and it also improved glucose tolerance . all the cases in this study were on chelation therapy , at least on oral deferiprone , but compliance was poor in a majority ( 73.3% ) , which was one of the reasons for the high incidence of ifg and igt . one of the cases had left ventricular dysfunction due to complete cessation of the chelation therapy , but showed improvement following intensive chelation therapy . although our patients did not have diabetes , the fasting insulin and insulin resistance indices were high , with normal fasting glucose , which was suggestive of the occurrence of insulin resistance before the onset of diabetes . similar findings of the occurrence of insulin resistance before the onset of diabetes were reported by others . the occurrence of insulin resistance may be due to , ( a ) direct effect of iron overload or ( b ) hepatic dysfunction leading to reduced hepatic extraction of insulin , as a result of which the liver , which is the principal site of gluconeogenesis , continues to produce excess glucose into the bloodstream . insulin resistance was not seen in pre - pubertal patients , which made researchers conclude that insulin resistance was acquired rather than genetic in origin . likewise , these researchers found an increased insulin response to hyperglycemia in pubertal subjects and concluded that an elevated insulin level was due to the hypersecretion of insulin , as the c - peptide levels were also elevated . insulin resistance increases with age and beta cell function reduces with age , and the mechanism behind this has not been explained , probably because there has been no abnormal glucose tolerance in their study . however , the present study has no such correlation and supports the results and hypothesis by merkel et al . as the iron burden increases , sensitivity to insulin decreases , even in the face of chelation therapy . at this stage , a compensatory increase in insulin secretion serves to maintain the carbohydrate homeostasis near normal , implying that impairment of insulin action precedes the defects in insulin secretion . statistical significance in beta cell function between cases and controls was observed in our study . beta cell function is observed to deteriorate with age , unlike in the present study , where we found that it increased with age followed by a decline . there was a linear relation with age and ferritin levels , showing an increasing trend with an increase in the number of units transfused . however , when compared with fasting insulin , there was an increasing trend with the number of units transfused , which was then followed by a decline with a further increase in the number of units transfused . a similar relation was observed with the beta cell function and the insulin resistance index also . our results showed a similar finding , where with increasing age and total number of transfusions , the insulin resistance increased , and to compensate , the beta cell activity also increased thereby producing more insulin up to a certain limit of maximum and then started declining when it could not keep up with the demand . hence , persistent insulin resistance with progressive reduction in insulin secretion may lead to glucose intolerance and diabetes , which have a higher prevalence in thalassemia major . in recent times it leads to inability of the pancreas to secrete sufficient amounts of insulin in response to glucose stimulation . diabetic ketoacidosis might be the initial presentation of diabetes in 31% of thalassemia major patients . hence , all of them should be periodically screened , at least after 10 years of age , to prevent this life - threatening complication . after the diagnosis of abnormal glucose tolerance or diabetes , they should be given intensive chelation therapy , as it improves glucose tolerance and prevents the development of overt diabetes . in conclusion , igt and insulin resistance precede the onset of insulin - dependent diabetes mellitus , and hence , children with thalassemia major on long - term transfusion should be periodically monitored with glycemic indices and serum ferritin levels after the age of 10 years .
background : diabetes mellitus is a major complication of iron overload in patients with beta thalassemia major.design:this is a descriptive study conducted in a tertiary care teaching hospital to analyze beta cell function and insulin resistance , and their relation to iron overload status in beta thalassemia major . 
 fasting glucose , two - hour post load glucose , fasting insulin , alanine amino transaminase ( alt ) , and ferritin were used as outcome measures . the homeostatic model assessment ( homa model ) 
 was used to calculate the beta cell function and insulin resistance index.results:of the 30 cases , 20% had impaired fasting glucose , 3.3% had impaired glucose tolerance , and none had diabetes . 
 fasting glucose was not significant between the cases and controls ( p = 0.113 ) . 
 fasting insulin ( p = 0.001 ) , ferritin ( p = 0.001 ) , and alt ( p = 0.001 ) levels were significantly high in the cases . 
 insulin resistance index was significantly higher in the cases ( p = 0.001 ) as also the beta cell function ( p = 0.001 ) . 
 with increase in age and the number of units transfused there is a decline in beta cell function , fasting insulin , and insulin resistance after attaining the maximum level . 
 this suggests that initial insulin resistance is followed by insulin depletion due to loss of beta cell function , leading to diabetes mellitus.conclusion:impaired glucose tolerance ( igt ) and insulin resistance precede the onset of insulin - dependent diabetes and adequate chelation therapy is essential for delaying the onset or for prevention of diabetes .