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Paper text:
the insulin - like growth factor ( igf ) system and its binding proteins play important roles in a number of biological processes , including growth and development as well as energy homeostasis .
there is increasing evidence that the igf system is a contributing factor in the pathogenesis of diabetes . with multiple ligands , binding proteins , and receptors , the igf system is complex ; the biological effects are the results of the interactions among the components in the system .
it is of note that rather than mediating intracellular signaling transduction elicited by igf2 , the igf type 2 receptor ( igf2r ) acts as a igf2 scavenger .
igf2r is implicated in diverse biological processes including carcinogenesis , glucose homeostasis , and hiv replication . with regard to glucose homeostasis
, genetic variants in the igf2r gene have been shown to be associated with both type 1   and type 2 diabetes ( t2 dm ) .
furthermore , a soluble form of igf2r exists in the circulation and has been found to be related to body size in term infants . taken together , this suggests the importance of igf2r in the pathogenesis of disorders related to glucose and energy metabolism . however , whether circulating igf2r is determined by igf2r gene variants and how soluble igr2r is related to diabetes in adults are currently unknown .
it is therefore the purpose of the present study to investigate the igf2r gene and circulating soluble igf2r in relation to t2 dm in adults .
subjects consisted of 654 women and men without known history of diabetes who were invited for a screening of diabetes . a 75  gm oral glucose tolerance test ( ogtt ) was performed in the morning after an overnight fast . according to american diabetes association criteria
, subjects were divided into three groups : subjects with normal glucose tolerance , ifg / igt ( impaired fasting glucose / impaired glucose tolerance ) , and subjects with diabetes ( 297 , 260 , and 97 , resp . ) .
in addition , 145 subjects with known diabetes were recruited from a local diabetes clinic .
the study was approved by the ethical review board of ramathibodi hospital , and volunteers signed informed consent prior to the study .
dna samples were diluted in te buffer ( 0.1  mm edta , 10  mm tris hcl , and ph 8.0 ) and quantified using fluorometry ( hoefer dyna quant 200 ; hoechst dye ) to a target concentration of 100  ng/l and then to 50  ng/l .
dna pools were constructed separately for subjects with and without diabetes by combining the 50  ng/l dna in equal volume .
subjects were divided into four groups : ( 1 ) diabetes subjects with body mass index ( bmi ) of less than 25  kg / m ; ( 2 ) diabetes subjects with bmi of more than or equal to 25  kg / m ; ( 3 ) normal subjects with bmi of less than 25 
kg / m ; ( 4 ) normal subjects with bmi of more than or equal to 25  kg / m .
four pooled dna samples were then genotyped in triplicate using genechip mapping 500  k arrays ( affymetrix , santa clara , ca , usa ) following the manufacturer 's protocol .
briefly , 250  ng of dna sample from each pool was restricted by nsp i or sty i restriction endonuclease before ligation .
estimated allele frequencies and odds ratios for each snp were calculated by averaging hybridization intensity signals from the arrays .
data from pooled dna snp screening revealed that allele frequency of an intronic c / t snp rs416572 in the igf2r gene is different between subjects with and without diabetes .
individual genotyping of all subjects was performed using real - time pcr ( taqman mgb probes ) ; 20  ng of dna was added into the pcr reaction , consisting of taqman universal master mix ( 1x ) and taqman mgb probes for intronic c / t snp rs416572 ( 1x ) in a total volume of 20  l . the real - time pcr reaction protocol was 10  min at 95c , 40 cycles of 15  sec at 95c , and 1  min at 60c using applied biosystems 7500 real - time pcr system ( life technologies , carlsbad , ca , usa ) . circulating igf2r levels were measured by elisa method ( cusabio , wuhan , china ) .
data were expressed as mean  sd . the differences of variables were determined by anova and student 's t - test .
screening of 654 subjects with no previous history of diabetes revealed diabetes and ifg / igt in 97 and 260 , respectively . across the glucose tolerance status in subjects without previous diabetes , there were differences in weight , bmi , fasting plasma glucose , and 2  h plasma glucose , as shown in table 1 .
screening for snp in igf2r with pooled dna samples revealed that rs416572 is likely to have different allele frequency between diabetic and nondiabetic subjects .
individual genotyping was then performed and the genotype distribution was 69.2% cc , 27.8% ct , and 3.0% tt .
when comparing the genotype distributions according to the presence or absence of diabetes , it was found that the distributions were significantly different with the c allele more commonly found in subjects with diabetes ( p < 0.01 ) , as shown in table 2 .
logistic regression was then performed to control for other confounding factors for diabetes including age , gender , and bmi .
as shown in table 3 , each c allele of the igf2r polymorphism was associated with increasing risk of t2 dm independently of age , gender , and bmi . to explore potential mechanisms underlying the association between igf2r genotype and diabetes , analyses of circulating igf2r levels
were performed . in order to exclude the potential confounding effect of longstanding diabetes and diabetes treatments on circulating igf2r , only subjects with
newly diagnosed diabetes ( n = 97 ) were studied together with subjects having normal glucose tolerance and ifg / igt . as shown in table 4 , in the presence of the t allele ( genotypes ct and tt ) ,
there was no significant difference in other potential confounders including age , sex , and bmi . in a multiple regression model ,
the effect of bmi did not reach statistical significance ( p = 0.98 ) while that of the igf2r allele almost reached statistical significance ( p = 0.09 ) .
we further explored the influence of both igf2r gene polymorphism and igf2r levels on insulin resistance as assessed by the homeostatic model assessment ( homa ) model .
as shown in a linear regression model with age , sex , bmi , igf2r gene polymorphism , and circulating igf2r as independent variables , only circulating igf2r , age , and bmi were independently associated with the degree of insulin resistance . in a similar model for homa - b
it was found that age , sex , and bmi were associated with beta cell function , while the igf2r gene and circulating igf2r had no effect ( table 5 ) .
a number of genome - wide association studies have implicated variants of a number of genes in the pathogenesis of t2 dm [ 9 , 10 ] .
most of these genes encode proteins involved in the proliferation and function of pancreatic beta cells . with regard to the igf system , only insulin - like growth factor - binding protein 2 ( igfbp2 ) [ 1113 ] has been implicated in genome - wide association studies in various populations so far , although not without discrepant results .
the genetic variant in igf2bp2 affects first - phase insulin secretion   and may be the underlying basis for the influence of igf2bp2 polymorphism on the susceptibility to t2 dm . in the present study ,
we have identified a genetic variant in igf2r , another protein in the igf system , as being associated with t2 dm in thais .
a previous study of igf2r as a susceptibility gene for t2 dm has similarly implicated an insertion / deletion variant in the 3utr region of igf2r .
the insertion / deletion polymorphism is likely to result in the change in igf2r expression .
although the previously reported insertion / deletion polymorphism was not genotyped , the snp investigated in the present study is located in more than 50,000 nucleotides from the 3utr , so the possibility of its being in linkage disequilibrium with the 3utr insertion / deletion polymorphism is small . not unlike igf1 , igf2r is expressed ubiquitously . rather than mediating the effect of igf2 , igf2r modulates the abundance of igf1 by leading igf1 through lysosomal degradation after its binding to igf2r .
although igf2r is mainly a membrane receptor , its soluble form exists in the circulation .
however , the physiologic role of soluble igf2r is not entirely clear . in a recent study
, it was suggested that soluble igf2r may play a role in angiogenesis by blocking plasminogen activation . in the present study we demonstrated that soluble igf2r levels were associated with igf2r genotype , and it is likely that igf2r gene polymorphism may influence diabetes - related phenotypes partly through its association with the availability of soluble igf2r .
indeed , the association between igf2r genotype and diabetes - related phenotypes including age , gender , and bmi became less apparent or disappeared after controlling for circulatory igf2r .
our finding , however , is in keeping with a recent study showing similar relationships between soluble igf2r and glucose homeostasis and serum lipids .
soluble igf2r could directly affect susceptibility to type 2 diabetes , or indirectly through growth hormone ( gh ) and igf1 .
the gh / igf1 system is very complex , and the influence of each single component in the system on biological processes of interest can not be easily teased out .
the major effect of igf2r is to act as a scavenger receptor for igf2 and igf1 by the internalization of igfs to lysosomes .
it is unknown at present how soluble igf2r is related to membrane - bound igf2r and what the biological function of soluble igf2r is .
igf1 , however , is believed to be the predominant effector of the gh / igf1 system , although a number of igf - binding proteins have recently been established to have direct biological functions of their own .
again , there has been no study on the relationship between soluble igf2r and these well - established players in the igf system .
however , a more recent meta - analysis of gwas for type 2 diabetes studies in african americans has found a novel type 2 dm locus near the insulin and igf2 genes .
moreover , igf2 overexpression in transgenic mice leads to islet hyperplasia   and igf2 deficiency in the goto - kakizaki rat leads to beta cell mass anomaly . taken together with the association of igf2r gene polymorphism and soluble igf2r to diabetes in the present study , further investigation to elucidate how soluble igf2r fits in the complex system of igf and how igf2 together with igf2r influence the susceptibility to type 2 dm is warranted .
the aim of this study is to investigate the insulin - like growth factor type 2 ( igf2r ) gene and circulating soluble igf2r in relation to type 2 diabetes ( t2 dm ) . 
 six hundred fifty - four subjects without history of diabetes were screened for diabetes by oral glucose tolerance test . 
 in addition , 145 subjects with known diabetes were recruited from a local diabetes clinic . 
 circulating igf2r levels were measured by elisa method ; plasma glucose was measured by colorimetric method ; insulin levels were determined by chemiluminescent method ; igf2r gene rs416572 was genotyped using real - time pcr . 
 the distributions of igf2r genotypes were 69.2% cc , 27.8% ct , and 3.0% tt . 
 the c allele was more commonly found in diabetes subjects , with a significant difference ( p < 0.01 ) . in the presence of the t allele , 
 circulating igf2r levels were significantly lower ( p < 0.05 ) . 
 there was no significant difference in other potential confounders including age , sex , and bmi . only circulating igf2r , age , and bmi 
 were independently associated with the degree of insulin resistance , as assessed by the homa model . 
 it was found that age , sex , and bmi were associated with beta cell function . in conclusion , 
 igf2r gene polymorphism and circulating igf2r are associated with t2 dm .