Genetics and Diabetes

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1 Genetics and Diabetes Background Diabetes m ia. ellitus is a heterogeneous group of disord ers characterized by persistent hyperglycem on form The two m s of diabetes are type ost comm 1 diabetes (T1D, previously known as insulin- type 2 diabetes (T2D, previously known as non-insulin-dependent dependent diabetes or IDDM) and sed by a co diabetes or NIDDM). Both are cau tion of genetic and envir onm ental risk factors. mbina ar However, there are other rare form ectly inh erited. These inc lude m aturity s of diabetes that e dir es due to m utations in m itochondrial DNA. onset diabetes in the young (MODY), and diabet s of diabetes have very se rious effects on health. In additi on to the consequences of abnorm al All form of glucose (e.g., hyperlipidem metabolism tion of proteins, etc.), there are a num ber of ia, glycosyla com plications associated with the dise long-term ase. These include cardiovascular, peripheral which are responsible for m orbidity, disability and alities, vascular, ocular, neurologic and renal abnorm ature death in young adults. Furtherm ore, the disease is associat ed with reproductive prem plications causing problem s for both m others com proved glycem ic and their children. Although im control m developing these com plications, di abetes rem ains a very significan ay decrease the risk of t cause of social, psychologi cal and financial burdens in populations worldwide. Type 1 Diabetes Epidem iology . T1D is caused by the autoimm une destruction of the beta cells of the pancreas, and represents approxim ately 10% of all cases with diabetes. At present, lifelong insulin therapy is the only iseas ithout exogenous in sulin injections, indiv iduals with T1 D will not s urvive. ent for the d e. W treatm Although the prevalence of T1D is <1% in m ost popul ations, the geographic variation in incidence is ous, ranging from <1/100,000 per year in China to approxim ately 40/100,000 per year in Finland enorm (Figure 1) (Karvonen et al., 1993). The only chronic childhood disorder more prevalent than T1D is a. It has been es tim ated that a pproxim ately 20 m illion people worldwide, m ostly children a nd asthm young adults, have T1D (Holt, 2004). orldw ide Figure 1. T1D Incidence Rates W 40 35 30 25 20 /100,000/yr 15 10 5 0 SAR SWE ITA ISR JAP CHI FIN NOR US-WI US-PA FIN = Finland, SAR = Sardinia, SWE = Sweden, NOR = Nor way, US- WI = US- Wisconsin, US-PA = US-Pennsylvania, ITA = Italy, ISR = Israel, JA P = Japan, CHI = China ce of T1D is increasing worldwide at a rate of about 3% per y ear (Onkamo et al., 1999). The inciden This trend appears to be most dram atic in the you ngest age groups, and is com pletely unrelated to the current increase in T2D in children. More children with beta cell autoanti bodies, a hallm ark of T1D,

2 are being diagnosed with the T1D around the world ea ch year. Although the peak age at onset is at iologic studies have revealed no significant gender puberty, T1D can also develop in adults. Epidem d before age 15 (Kyvik et al., 2004). However, differences in incidence am ong individuals diagnose male incidence ratio is approxim after age 25, the m ale to fe ately 1.5. There is also a notable seasonal summer m ont , with lower rates in the warm any countries variation in the incidence of T1D in m hs, and higher rates during the cold winter (Dor man et al., 2003). . The epidem iological patterns describe d above suggest th at environmental Environm ental Risk Factors tribute to the etio logy of the T1D. In e recen t tem poral increase in T1D factors con particular, th ent rather than variati l environm on in the gene pool, which require incidence points to a changing globa multiple genera tions . Twin studies also p the passag evidenc e for the im portanc e of e of rovide ental risk factors for T1D. T1D concor dance rates for m onozygous environm twins are higher than those for dizygous twins (approxim 10%, respectively) (Hirschhorn, 2003). However, ately 30% vs. monozygous twin pairs rem ain discordant. most Thus, T1D cannot be completely genetically ined. determ ental risk factors are thoug ht to act as either ‘initiators’ or ‘accelerator s’ of beta cell Environm autoimm itators ’ of overt sym ptom s in individuals w ho already have evidence of beta unity, or ‘pre cip ay func tion by m cell destruction. They also m s that are directly harm ful to the pancreas, or echanism by indirect m abnorm al immune response to prot eins norm ally present in cells. ethods that produce an ental risk factors on are viruses and infant nutrition. ost attenti The T1D environm that have received m Enteroviruses, especially Coxsack e focus of num erous ecologic and ie virus B (CVB), have been th case-control studies (Dahlquist et al., 1998). CVB infections ar e frequent during childhood and are known to have system ic effects on th e pancreas. Recen t prospectiv e stud ies are h elpin g to elucidate the role of viruses to the etiology of T1D. For exam infections occurring as early as in ple, enteroviral appear to increase a child’s subsequent risk of developing the diseas utero e (Dahlquist et al., 1995, (Hyoty et al., 1993), cytom umps egalovirus (Pak et al., Hyoty et al., 1995). Other viruses, including m , (McIntosh and Menser, 1992) have also been 1988), rotavirus (Honeym an et al., 2000) and rubella e disease. ith th associated w subject of considerable interest relates to early exposure to cow’s Another hypothesis that has been the ent of T1 D. The fi rst epidem iologic observation of such a milk protein and the subsequent developm that T1D children were breast-fed for shorter relationship was by Borch-Johnsen et al., who found e than their non-diabetic siblings or children from the general population (Borsh-Johnsen periods of tim d that the lack of i mmunol et al., 1984). The authors postulate otection from insufficient breast- ogic pr feeding m ay increase risk for T1D later during chil dhood. It was also postulate d that shorter duration of breast feeding m ay indirectly reflect early exposu re to dietary proteins th at stim ulate an abnorm al immune response in newborns. Most recently it ha s been hypothesized that the protective effect of ay be due, in part, to its role in aturation (Kolb and Po zzilli, 1999; Harrison and breast-feeding m gut m an, 1999; Vaarala, 1999). B reast m ilk contains growth factors, cytokine s, and other substances Honeym ry f or the m aturation of the in testinal m ucosa. Breast-feeding also protects against enteric necessa infections during infancy, and promotes proper col onization of the gut. Interestingly, enteroviral infections can also interf ere with gut immunoregulation, which may explain the epidem iologic association l infections and T1D. s between vira The role of hygiene in the etiology of T1D is also currently being explored (McKinney et al., 1997; Marshall et al., 2004). It has been hypothesized that delayed exposure to m icroorganism s due to im prove ments in standard of living hinders the devel opm ent of the immune system , such that it is more 2

3 likely to respond inappropriately when introduced to such agents at older (com pared to younger) ages. ation is cons isten indicating that facto rs s uch as day care attendan ce This explan t with recent reports with a sibling, an d contact with pets (McKinney et al. 2000), sharing a be droom are protective against ine if improved hygiene can explain her studies are needed to determ T1D (Marshall et al., 2004). Furt the tem poral increase in the incidence of T1D worldwide. Type 2 Diabetes . T2D is the m ost common for m of the dis ease, accounting for approxim ately 90% of all Epidem iology ade if a fasting pl asm a glucose concentration is > 7.0 affected individuals. A diagnosis of T2D is m mmol/L ( 126 m a glucose 2 hours af ter a standard glucose challenge is > 11.1 mmol/L > g/dl) or plasm ( > g/dl) (W HO, 1999) T2D is caused by relati ve im paired insulin se cretion and peripheral 200 m insulin resistance. Typically, T2D is m th diet, exercise, oral hypoglycem ic agents and anaged wi som ated with the sam e long- term complications as etimes exogenous insulin. However, it is associ T1D. cans, particularly the Pim a Indians who reside The highest rates of T2D are found among Native Am eri uru (W Pacific islands, such as Na in Arizona in the US, and in natives of the South ild et al., 2004). T2D is also known to be m ore predom inant in Hi spanic and African Americ an populations than in estim ated th at 171 m illio n people (2. 8% of the worlds population) h Caucasians. In 2000, it is ad diabetes and 0 this num ber will be 36 6 million (4. 4% of the world' s population ). The vast that by 203 en a this inc e will occu r in m majority of nd wom en aged 45 to 64 year s living in d eveloping reas countries. According to W ild et al .(2004), the ‘top’ three countries in term s of the number of T2D individu als with diabetes are Ind illion in 2000; 79. 4 m illion in 2030), China (20.8 m illion in ia (31.7 m illion in 2 030) and the US (17.7 million 0; 30.3 m illion in 2030). Clearly, T2 D has 2000; 42.3 m in 200 st ic in the 21 e an epidem becom century. In addition to the burden of T2D there is an even la rger num ber of people with raised levels of blood orld Health Organization defines im paired fasting glucose but below the level for diabetes. The W -1 -1 glucose as a fasting plasm a glucose level of oll 6.1 mm , and im paired > and less than 7 mmoll -1 t glucose challenge, of glucose tolerance as 2 hour plasm oll a glucose, pos 7.8 to less than 11.1 mm (WHO, 1999). The prevalence of T2D increases with age of populat ion (W ild et al., 2004). In developing countries, the largest num ber of people with diabetes are in the age g roup 45 to 64 years, while in developed the largest number is found in those aged 65 years and over. These differenc es largely reflected differences developed and developing countri ilar in population age structure between es. Worldwide rates are sim en and wom en, although they are slightly higher in m en < 60 years of age and in wom en > age 65 in m years. Of great con cern is the recent in crease in T2D in child ren (Bloom garden, 2004). A report based o n the Pim a Indians in Arizona noted that between 1967 -76 and 1987-96, the prevalence of T 2D increased 6- fold in adolescents (Fagot-Cam In the US, the incidence of T2D increased from pagna et al., 2000). 0.3-1.2/100, 000/yr before 1992 to 2. 4/100,000/y r in 1994 (Weill et al., 2004). Mos t T2D children diagnosed during this period were fem ales from m inority populations, with a m ean age of onset at around puberty. They were also likely to have a p ositiv e fam ily history of the dis ease, particularly maternal diabetes. 3

4 Environm ental Risk Factors that T2D represen ted a ‘thrifty . As early as 1962, Neel hypothesized vantage (Neel , 1962). H itive tim es, genotype’, which had a selective ad e postulated that in prim thrifty ’ an re a hi gh proportion of energy as fat when individuals who were ‘m etabolically d able to sto mine. However, in recent years, m es of fa food was plentiful were more likely to survive tim ost populations experience a continuous s upply of calorie-dense processed fo ods, as well as a decrease in physical activity. This likely explains the rise in T2D prevalence worldwide. ajor environm The m ental risk factors for T2D are obesity ( 120% ideal body weight or a body mass > 2 index > 30 k/m ) and a sedentary lifestyle (van Dam , 2003; Shaw and Chisholm , 2003). Thus, the endous increase in the rates of T2D in recen t y ears has b een attribu trem arily, to the d ramatic ted, prim rise in obesity worldwide (Zimm ated that approxim ately 80% of all et et al., 2001). It has been estim ean, 2000). This is true f a new T2D cases are due to obesity (L or adults and children. In the Pim (Fagot-Cam were either overweight or obese Indians, 85% of the T2D children pagna et al., 2000). Another study in the US reported that IGT was dete cted in 25% of obese children age 4-10 years, and in 21% of obese adolescents (Sinha et al., 2002). Undiagnosed T2D was detected in 4% of the adolescents. In addition to general obesity, th ated by the ratio of waist-to-hip e distribution of body fat, estim ference (W sk. WHR is a reflection of abdom inal (central) circum HR), also has an impact on T2D ri ore strongly associated with T obesity, which is m easures of obesity, such as 2D than the standard m those based on body m ass index. The other m ajor T2D risk factor is physical inacti vity. In addition to cont rolling weight, exercise im proves glucose and lipid m , which decrease s T2D risk. Physical activity, such as daily etabolism inutes, has b een shown to significantly reduce the risk of T2D walking or cycling for more than 30 m ted to body m ass index and IGT. (Hu et al., 2003). Physical activ ity has also been inversely rela Recently, intervention studies in China (Pan et al land (Tuom ilehto J et al., 2001) and the ., 1997), Fin St udy Group, 2002) have shown that lifestyle interventions targeting US (Diabetes Prevention Program diet and exercise d ecreased the IGT to T2D by approxim ately 60% . In risk of progression from ic m progression by about 30%. contrast, oral hypoglycem edication only reduced the risk of ce suggesting that the intrauteri There is also considerable eviden ent is an im portant ne environm predictor of T2D risk (Hales and Barker, 2001; S obngwi et al., 2003), Num erous studies have shown that low birth weight, which is an indicator of fetal m alnutrition, is associated with IGT and T2D later in life. However, it is unclear whether low birth weight is causal or rela ted to potential confounding h poor fetal growth and T2D (F factors that contribute to bot rayling and Hattersley, 2001). etics in the Development of Diabetes Role of Gen Type 1 Diabetes First degree relatives have a higher risk of developi ng T1D than unrelated indi viduals from the general population (approxim ately 6% vs. <1%, respectively ) (Dorm an and Bunker, 2000). These data suggest that genetic factors are involved with ent of the disease. At present, there is evidence that the developm more than 20 regions of the genom e m ay be involved in genetic susceptibility to T1D. However, none of the candidates identified have a greater influen ce on T1D risk than that conferred by genes in the HLA region of chrom osom e 6. This region contains several hundred genes known to be involved in 4

5 immune response. Those m ost strongly associated with the disease are the HLA class II genes (i.e., HLA-DR, DQ, DP). The HLA class II genes, als o referred to as IDDM1 , contribute approxim ately 40-50% of the IDDM1. hen evaluated as haplotypes, DQA1*0501- heritable risk for T1D (Hirschhorn et al., 2003 ). W *0302 are most str and DQA1* ongly associated T1D in Caucasian 0301-DQB1 DQB1*0201 populations. rium with DRB1*03 and DRB1*04, respectively. Specific They are in linkage d isequilib odify the risk associ ated with the DQA1*0301-DQB 1*0302 haplotype. DRB1*04 al leles also m Other include DRB1*07-DQA1*0301-DQB1*0201 a reported high risk haplotypes for T1D mong African am nese, and DRB1*04-DQA1*0401- ericans, DRB1*09-DQA1*0301-DQB1*0303 ong Japa Am ong Chinese. DRB1 DQB1*0302 0602-DQB1 *0102 is protective and associated with a am *15-DQA1* ons. Recent reports suggest that reduced risk of T1D in most populati other genes in the central, class I and extended class I regions m 1D ri sk independent of HLA class II genes (Nejentsev ay also increase T et al., 1997; Lie et al., 1999). Individuals with two high risk DRB1-DQA1-DQB1 ha plotypes have a significantly higher T1D risk e T1D risk among those with only one susceptibility than individuals with no high risk haplotype. Th 10 – 45 and odest. Relati haplotype is also increase range from d, but effect is m ore m ve risk estimates epending on race (Dorman and Bunker, 2000). In term s of 3-7, respectively, for these groups, d als with two sus ceptib ility h absolute risk, Caucasian individu ypes have an approxim ately 6% aplot chance of developing T1D through age 35 years. Ho substantially lower in wever, this figure is re (i.e., < 1% am , two other genes are ns). In addition to IDDM1 populations where T1D is ra ong Asia now known to influence T1D risk (Anjos INS and CTLA-4. and Polychronakos, 2004). These include Table 1. Several T1D Susceptibility Genes Gene Locus Estimated Variant † RR 6p21.3 *0201 & *0302 3 – 45 HLA-DQB1 Class I 11p15. 5 1 – 2 INS Thr17Ala 1 – 2 2q31-35 CTLA4 † RR = rela tive risk (insulin). INS INS gene, located on chrom osom e 11p15.5, has been designated as IDDM2 . The Positive ass erved with a non-tran scribed variable num ber of tandem repeat ociations have been obs 1997; Pugliese et al., 1997) . There are two common (VNTR) in the 5’ flanking region (Bennett et al., variants. The shorter class I vari ant predispos es to T1D (rela tive incr ease: 1 – 2), whereas the longer class III v ariant appea rs to be dom inantly pro tective. The biological p laus ibility of thes e associatio ns may relate to the expression of insulin mRNA in the thym us. Class III variants appear to generate class I variants. Such differen higher levels of insulin mRNA than ces could contribute to a better immune tolerance for class III pos itive individuals by increasing the likelihood of negative selection for INS autoreactive T-cell clones. The effect of with less er ef fects in no n- appears to vary by ethnicity, Caucasian populations (Undlien et al. 1994). CTLA-4 (cytotoxic T lymphocyte-associated 4) . The CTLA-4 gene is located on chromosom e 2q31-35 (Anjos and Polychronak ultiple T1D genes m ay be located. CTLA-4 varian ts have os, 2004), where m been associated with T1 D, as we ll as other autoimmune disease. CTLA-4 negatively regulates T-cell 5

6 function. However, impaired activity, which has b een associated with the Thr17Ala variant, may e in risk for the CTLA-4 Ala17 variant has been increase T1D risk. Overall, the relative increas estimated as ~ 1.5. Type 2 Diabetes It has long been known that T2D is, in have revealed that first degree part, inherited. Family studies relatives of individuals with T2D ar e about 3 times more likely to de velop the disease than individuals lores et al., 2003; Hansen 2003; Gloyn 2003). It has without a positive family history of the disease (F ce rates for monozygotic twins, also been shown that concordan which have ranged from 60-90%, are dizygotic twins. Thus, it is cl significantly higher than those for ear that T2D has a strong genetic component. One approach that is used to identify disease su d on the identification of sceptibility genes is base candidate genes (Barroso et al., 2003; Stumvoll, 2004). Candidate genes are selected because they are thought to be involved in pancreatic β cell function, insulin action / glucose metabolism, or other metabolic conditions that increase T2D risk (e.g., energy intake / e xpenditure, lipid metabolism). To been studied in various date, more than 50 candidate genes for T2D have populations worldwide. s have been conflicting. Possible explanations for However, results for essentially all candidate gene the divergent findings include sm all sample sizes, differences in T2D susceptibility across ethnic groups, variation in environmental exposures, and gene -environmental interacti ons. Because of current controversy, this review will focus only on a few of the most promising candidate genes. These include PPAR γ , ABCC8 , KCNJ11 , and CALPN10 . Table 2. Several T2D Susceptibility Genes † P Gene Locus Variant Estimated RR P 3p25 Pro12Ala 1 – 3 PPAR γ 11p15.1 Ser1369Ala 2 – 4 ABCC8 11p15.1 Glu23Lys 1 – 2 KCNJ11 2q37.3 A43G 1 - 4 CALPN10 † P P RR = relative risk PPAR γ U γ ) U . This gene has been widely studied because it is (peroxisome proliferator-activated receptor- important in adipocyte and lipid metabolism. In addition, it is a target for the hypoglycemic drugs known as thiazolidinedione s. One form of the γ gene (Pro) decreases insulin sensitivity and PPAR portantly is that this variant is very common in increases T2D risk by several fold. Perhaps more im rry at least one copy of the Pro allele. Thus, it most populations. Approximately 98% of Europeans ca likely contributes to a consider able proportion (~25%) of T2D that occurs, particularly among Caucasians. U ABCC8 (ATP binding cassette, s ubfamily C, member 8) U . This gene encodes the high-affinity , U KCNJ11 U also coupled to the Kir6.2 subunit (encoded by sulfonylurea receptor (SUR1) subunit that is known as the potassium channel, inwardly rectifying s ubfamily J, member 11). Both genes are part of the ATP-sensitive potassium channel, which plays a key role in regulating the release of hormones, tations in either gene can affect the potassium such as insulin and glucagon, in the beta cell. Mu 6

7 channel’s activity and insulin secretion, ultimately l eading to the development of T2D. Interestingly, KCNJ11 are only 4.5 kb apart, and not far from the gene. Variant forms of KCNJ11 and ABCC8 INS genes have been associated with T2D, as well as other diabetes-related traits. ABCC8 (Lys) and (Ala) Because of the close proximity of these genes, cu rrent studies are evaluating whether they work in independent effect on T2D susceptibility. concert with each other, or rather have an inely in the treatment of T2D, γ and KCNJ11 Since , ABCC8 PPAR are the targets of drugs used rout cations for maintaining good gly cemic control. Response to there are pharmacogenetic impli notype. Thus, genetic te sting may not only help hypoglycemic therapy may actually be related one’s ge determine who is at high risk for developing T2 D, but may also be useful in guiding treatment regimens for T2D. (calpain 10) U . CAPN10 CAPN10 ndent cysteine protease that is U encodes an intracellular calcium-depe 2004). A haplotype that was init ially linked to T2D included an ubiquitously expressed (Cox et al., 43, which appears to be involved in intronic A to G mutation at position transcription. Two CAPN10 amino acid polymorphisms (Thr504Ala and Phe200Thr) ha ve also been associated with T2D risk. ng and noncoding polymorphisms do not independently However, it has been suggested that the codi influence T2D risk, but instead cont ribute to an earlier age at diagnos is. Physiological studies suggest that variations in calpain 10 activity effects insuli n secretion, and therefore, susceptibility to T2D. Studies from different ethni c groups indicate that the contribution of this locus to increased T2D risk may be much larger in Mexican-A merican than Caucasian populations. Maturity-Onset Diabetes of the Young An uncommon form of T2D (accounting for <5% of a ll T2D cases) that generally occurs before age 25 years is MODY. MODY is characterized by a slow onset of symptoms, the absence of obesity, no ketosis, and no evidence of beta cel l autoimmunity. It is most of ten managed without the need for e, generally spanning exogenous insulin. MODY displays an autosomal dom inant pattern inheritanc of advances in molecular genetics, it is now three generations (Stride and Hattersley, 2002). Because known that there are at least six forms of MODY, each of which caused by a mutation in a different 2003). Table 3 lists the MODY genes gene that is directly involved with beta cell function (Winter, ry mutations in one of of MODY patients do not car that have been identified to date. Because ~15% these genes, it is anticipated that other genes that cause MODY will be discovered in the near future al., 2003; Kim et al., 2004). (Demenais et al., 2003; Frayling et Table 3. MODY Genes Locus # Mutations % Type Gene U (glucokinase) GCK U . The MODY GCK gene is currently the 20q12-q13.1 12 ~5% MODY1 HNF4A only MODY gene that does not 7p15-p13 ~200 ~15% MODY2 GCK regulate the expression of 12q24.2 >100 ~65% MODY3 HNF1A other genes. Rather, the MODY4 13q12.1 Few IPF1 GCK gene plays a key role MODY5 17cen-q21.3 Few <3% HNF1B glucose metabolism and in 2q32 Few MODY6 NEUROD1 insulin secretion. Thus, the ciated with other types of MODY. 2 patients differs from the prognosis asso clinical course of MODY at is present from birth, and generally stable MODY2 patients have a mild fasting hyperglycemia th with age, but patients with ld deterioration of normoglycemia throughout life. There may be a mi 7

8 MODY2 mutations are usually asymptomatic. Most are detected during rou tine medical screening. ing pregnancy. However, the outcome of the Women with MODY2 mutations are often diagnosed dur pregnancy can be influenced by whether the moth er and / or fetus carry the mutation. When both ight. However, MODY2 rally no effect on birth we mother and fetus are MODY2 positive, there is gene negative fetuses are carried by MODY2 positive mothers gestational age due to are typically large for maternal hyperglycemia. In contrast, if the fetu s, but not the mother, ca rries the MODY2 mutation, 500g due to reduced fetal insulin secretion, which their birth weight will be reduced by approximately inhibits growth. HNF4A HNF4A α ) U . Mutations in promoter U (hepatocyte nuclear factor 4- gene and coding regions of the cause MODY1. HNF4A is expressed in many tissues, including the liver and pancreas. It regulates hepatic gene expression, and influences th e expression of other MODY genes such as HNF1A, which causes MODY3. In the beta cell of the pancreas, it dire ctly activates insulin gene expression. HNF4A with T2D (Silander et al., 2004). Mutations in the gene also have been associated HNF1A U α ) U . MODY3, the most frequent cause of the disease, results from (hepatocyte nucleara factor 1- mutations in the HNF1A gene. HNF1A is expressed in the liver and pa ncreas. It can also influence HNF4A MODY1 and MODY3. This suggests that the expression, indicating a connection between MODY transcription factors form a regulatory network that maintains glucose homeostasis. In addition to causing MODY3, HNF1A mutations have been associated w ith T1D (Moller et al., 1998; Lehto et al., 1999) and T2D (Pearson et al., 2004). (insulin promoter factor-1) U IPF1 . MODY4, which is a rare form of th U e disease, is due to mutations in the IPF1 been associated with newborn pancreatic gene. Homozygosity for such mutations has s who carry MODY4 mutations tend to be small for agenesis and neonatal diabetes. Therefore, infant s with MODY4 may also develop T2D (Cockburn et al., 2004). IPF1 gestational age. Individual regulates expression of glucokina se, insulin and other genes invol ved in glucose metabolism. HNF1B (hepatocyte nucleara factor 1- β ) U . MODY5, another rare form of MODY, has also been linked U with MODY1 because β regulates HNF4 α HNF1 . However, unlike MODY1, MODY5 is also associated with renal cysts, proteinuria and renal failure. U NEUROD1 (neurogenic differentiation factor 1) U . Mutations in NEUROD1 are responsible for MODY6. MODY6 is also rare. Together, MODY4, MODY5 and MODY6 comprise less then 3% of NERUOD1 e pancreas, the intest ine and the brain. all MODY cases. is expressed in the beta cells of th In the pancreas, it contributes to the regulation of the expression of insulin. To summarize, all MODY genes are expressed in the is let cells of the pancreas, and play a role in the metabolism of glucose, the regulation of insulin or other genes involved in glucose transport, and/or the development of the fetal pancreas. Because MODY phenotypes vary depending which gene is involved (Table 4), genetic te sting may also assist in th e treatment of the disease. Table 4. MODY Phenotypes Type Disease Complications Treatment Onset MODY1 Severe Frequent Diet, oral agents, insulin Diet Rare MODY2 Mild 8

9 MODY3 Severe Diet, oral agents, Frequent insulin MODY4 Oral agents, insulin Moderate Little data Renal cysts Oral agents, insulin MODY5 Severe Little data MODY6 Diet, oral agents, Severe insulin etes etics in the Treatme Role of Gen nt and Prevention of Diab Type 1 Diabetes e, there is no way to prevent T1D. ons are the only available At the present tim Lifelong insulin injecti t currently play a role in the m ent or ent for the disease. Thus, genetics does no treatm anagem prevention of T1D. tly unavailable, seve ral large m ulti-national investigations h ave been Although a cure for T1 D is curren prim designed to evaluate a variety of rventions (Devendr a et al., 2004). ary and secondary disease inte The tested interventions have included prophylactic ediction and Prevention nasal insulin (Diabetes Pr P) in Finland), oral a nd injected insu tion Trial – 1 (DPT -1) in th e US), Project (DIP lin (Diabetes Preven Nicotinam ide Diabete s Interven tion Trial - ENDIT), as well as high doses of nicotinam ide (European ilk exposure during th e first six m onths of lif e (Trial to Reduce in and the avoidance of cow’s m Genetically At-Risk (TRIGR) in Finland, US and ot her countries). These investigations focus on iabetes. DIPP individu ied f rom families with at leas ‘prediabetic’ als identif and t one child with type 1 d TRIGR use HLA-DQB1 screening a nd recruit only individuals at increased geneti c risk. The rem aining tr ials rec ruit r elatives with evidence of be ta cell au toimmunity as a pre-clinical m arker for disease. To date, none of these interventions have prevented or delayed the onset of T1D (Diabetes Group, 2002; NIDDK, 2003; The ENDI Prevention Trial-Type 1 Study T Group, 2003; Paronen, et al., Type 1 Diabetes TrialNet (www.trialnet.com) mation of , a collaborative 2000). However, with the for network of clinical centers and experts in diabet es and imm unology, new interv ention strategies are currently being planned. It is ul sting, individuals at high risk for tim ately hoped that through genetic te e onset of the disease – at a tim e when prim ary prevention strategies T1D could be identified prior to th could be saf inistered. It is m ost likely that such predictive genetic testing would be offered to ely adm families with an affected individu it was m ade available to the g eneral population. al before Type 2 Diabetes aintaining an age-appropriate body weight and Unlike T1D, T2D can generally be prevented by m m essages that em phasi ze a nutritious diet and engaging in physical activity. Although public health regular physical activity are now commonplace, they have n ot been effective in terms of disease prevention. Given the recent obesity ent intervention strategies are ic, it is obvious that curr epidem being ignored by a m ajority of indi viduals in the general population. the Hum an Genom e Project have p redicte d that g enetic tes ts will b ecom e availab le f or Leaders of st during th e first d ecade o f the 21 many common disorders ce itting p erson s “to learn their ntury, perm individual susceptibilities and to tak e steps to reduce those risks” by applying interventions based on “m edical surveillance, lif estyle m odifications, diet or drug therapy” (Collins and McKusick, 2001). In 9

10 fact, several com panies are now offering genetic sus ceptibility testing, which can be ordered online by ch as cardiovascular disease and obesity (Khoury et al., 2004). any individual, for conditions su professionals share this optim istic Although many scientists and health perspective regarding genetics a variety of reasons. Fi istic for and disease prevention, others are m rst, the predictive value ore pessim ates do not account for well-known of m ost genetic tests is low (Haga et al., 2003) ; and risk estim is unclear whether knowledge of one’s genetic risk inants of disease. Secondly, it environm ental determ otiva tion to engage in d isease in terventi ons. Thirdly, genetic test incre ases m ing presents educational ation-dissem outlined in detail by the Secretary’s Advisory and inform ination challenges that were Society (Holtzm These include being able to ittee on Genetics, Health and an and Watson, 1998). Comm ts, as well as the potential risks and b enefits communicate the validity and utility of proposed genetic tes an genetics. Fourthly, m ost tle knowledge of hum of being tested, to individuals who may have lit health care professionals are curren tly unqualified to interpret the result s of genetic tests; and there are no standards for the use of m diagnostics in clinical practice. Fifthly, genetic testing m ay lead olecular to significan e magnitude of which is likely to vary as a function of ac tual test resu lts, t distress, th perception, optim ism, health beliefs depression or coping skills and resources, risk and pre-existing anxiety. These factors directly relate to other concerns such as insurance and em ent discrim ination, ploym confidentiality and stigmatization ba sed on knowing that one is at high ge netic risk. In the near future, ting f or T2D and other ch ronic d iseas es w genetic tes ost certainly b ecom e available. Althou gh it is ill m unclea lly con tribu te to the prevention of T2D, it may be beneficial in term s of r whether this will actua anagem ent. Many of the current T2D suscep tibility genes of intere st are dr ug t argets. disease m Evidence for the role of pharm acogene tics in diabetes is already appare nt in treatm ent approaches for MODY. nset Diabetes of the You ng Maturity-O mmon causes of MO utations in MODY3, MODY2 an d MODY1 ost co DY are related to m The m ild for genes. Although individuals who carry MODY2 mutations have a very m m of the disease, those d MODY3 v ariants have a m uch mo re severe expression that is associated with who carry MODY1 an co mplications. In addition, there has long-term cause of been a link between MODY3 and MODY5 be their interaction in term wever, it is now becom ing clear that the m etabolic s of gene expression. Ho ms o rent (Pearson et al., phenotype of individuals with these two for f MODY is actually quite diffe other than its association with renal cysts. 2004). To date, little has been known about MODY5 ore st However, it now appears that MODY5 is m ia and rongly associated with hyperinsulinem dyslipidem ia (and m ore closely rela ted to insulin resistance and T2 D) than MODY3. Thus, knowledge about the underlying MODY de fect is likely to lead to better m anagem ent and an im proved prognosis for individuals with the disease. al dom itance of all for ms of M ODY, indi viduals with a diabetic parent Given the autosom inant inher gnosis MO DY m ay also help reduce the likelihood of may also wish to have genetic testing. Early dia com plications. In addition, psychological and family adjustm ents to diabetes m ay also be long-term im proved when the specific form of the disease is known. Approxim ately one-third of individuals with MODY3 and MODY1 are each treate d by diet, oral agents and insulin. So ve been previously classified as having T1D because of me individuals with MODY3 ha the severity of the diseas e (Moller et al., 1998; Leht o et al., 1999). It is now known that individuals with MODY3 m utations are extrem ely sensitive to the hypoglycem ic effe cts of sulfonylureas. Thus, these oral ag ents are likely to be the treatm ent of choice of individuals with MODY3. Recently, there 10

11 have been a nu mber of reports of MODY3 individuals ent regim ens fro m being able to change treatm considerable im provem ic control insulin injections to oral sulphonylurea agents, with ent in glycem (Shepherd, 2003a; Shepherd and Hattersley, 2004)). This is frequently associated with a positive im lity of stopping insulin. pact on lifestyle and self im and anxiety about the possibi age, as well as fear complicati hose who have long-term e individuals, particularly t Som ons, have become angry because they were previously m isdiagnosed and/or treated in appropriately. These reac tions have im plications hological consequences for health professionals who need to be knowledgeab le about the potential psyc ent regim ens (Shepherd, 2003b). of changing treatm Future Role of Genetics in Diabetes at inc rease ris k of developing all form Within the next decad diabetes will likely b e e, the genes th s of that scientists, health professi onals, and m embers of population at known. It is, therefore, important ize the advantages, a nd m inimize the disadvantage s of predic tive g enetic large consider how to maxim testing for diabetes. ber 2004, the Office of Ge no the Centers for Disease Control In Septem mics and Disease Prevention at eeting entitled “Pu lth Assessm ent of Genetic Tests f or Scre ening and ld a m in the US he blic Hea Prevention”. One of the objectives of this session was to discuss issues related to the evaluation and phasis was placed on three m ajor barriers: 1) the lack o f available utilization o f genetic tests. Em population data regarding the contribution of genetic vari ants to disease susceptibi lity, 2) the lack of an evidence-based process for the integr ics into practice and, 3) the lack of readiness of the ation of genom health care and public health system ting for disease prevention. At the end of the s to utilize genetic tes a society, are a long way from practice of ‘genom ic m edicine’. meeting it was apparent that we, as the the f irst bar With regards to diabetes, addressing ost critica l at the present tim e. This barr ier rier is m pertains to the lack of consistent results across populations with rega rds to the genetic determ inants of the disease. Failure to replicate study results m ay be due to a variety of factors, the m ost im portant of which m ay be that different gene-environm ctions operate different populations to increase ent intera considerab ly more epidem earch will b e needed bef ore we risk of developing diabetes. Thus, iologic res also likely m particular genetic variants. This eans that we will not know the actual risk associated with odel when it com es to the gene be able to apply a ‘one size fits a ms of ll’ m tic testing for any of the for diabetes. ise of the Hum an Genom e Project, se veral is sues that warrant careful consideration. To fulfill the prom tory to the ultid lina ry team s will be requir ed to tran slate gen etic d iscove ries f rom the labora iscip First, m community. This is, perhaps, best exem e deve lopm ent of new initiativ plified by th es such as the NIH Roadm ap in the US. Scientists will no longer be able to work in isolation, w ithout input of individuals from other professions, if they are to m aximize th e im pact of their research in term s of im proving health. In particular, issues such as quality assurance, health risk ics need to s and benefits, and econom ed. This will requir rtis e f rom persons who have typically worked outside the be address e expe the ethical, legal and social issu es associated with wid espread profession of science. Finally, availability and use of predictiv e g ts must been add ressed. These include confidentiality, enetic tes discrim ed c onsent, keepi ng up with genetic discove ries and uncertainty. ination, diversity, inform Ideally, cons idera tion of such issu es will lead to the develop ment of practice gu idelin es f or diabe tes, or other com which will h ully ser ve as a m odel f or genetic tes ting f opef plex diseas es. 11

12 Acknowledg ement e acknowledge the contribution of Dr Janice S. Dorm an, Ph.D., University of : W rgh, School of Nursing, 350 Victoria Buil ding, Pittsb aper. Pittsbu urgh, PA, USA, to this p References ett, P. ellitus Definition, diagnosis and classification of diabetes m 1. Alberti, K.G.M.M., Zimm and its complications part 1: diagnosis and clas sification of diabetes mellitus provisional report of a WHO consultation. Diabet Med, 1998. 15 : 539-553. Mechanisms of genetic susceptib ility to type 1 diabetes: beyond Anjos, S., Polychronakos, C. 2. 81 HLA. Mol Genet Metab, 2004. : 187-195. Barroso, I., Luan, J., Middelberg, R.P.S., et al. 3. Candidate gene association study in type 2 ctio icate for genes in volved in B- Cell func s ind n as well as insulin a s a role n. PLoS diabete tio 1 : 41-55. Biol, 2003. Bennett, S.T ., W ilson, A.J., Esposito, L. Insulin V NTR allele- 4. ffect in type 1 d iabetes specific e depends on identity of untr Nat Genet, 1997. 17 : 350-352. ansmitted paternal allele. garden, Z.T. Diabetes Care, 2004. 5. Bloom Type 2 diabetes in the young: the evolving epidemic. : 998-1010. 27 Borch-Johnsen, K., Joner, G ., Mandrup-Poulsen, T., et al. Relation between breast-feeding and 6. ce ra tes of insulin -dependen t diabete s mellitus. A h ypothesis. Lancet, 1984. 2 : 1083- inciden 1086. 7. mano, G., Boodram , L.-L.G., et al. Insulin promoter factor-1 mutation and Cockburn, B.N., Ber ation of a novel diabetes-asso diabetes in Trinidad: identific ciated mutation (E224K) in an J Clin Endocrinol Metab, 2004. 89 : 971-978. Indo-Trinidadian family. Collins, F.S. 8. V.A. Implications of the Human Geno me Project for medical science. , McKusick, JAMA, 2001. 285 : 540-544. 9. Cox, N.J., Hayes, M.G., Roe, C.A., e t al. Linkage of calpain 10 to type 2 diabetes: the biological rationale. Diabetes, 2004. : S19-S25. 53 G. The aetiology of type 1 diabetes: epidemiolo gical pe rspe ctive. Acta P aedia tr 10. Dahlquist, an 425 : 5-10. Suppl, 1998. ., Frisk, G., Ivarsson, S.A., et al. Indications that maternal coxsackie B Virus 11. Dahlquist, G infection during pregnancy is a ri Diabetologia, 1995. 38 : sk factor for childhood-onset IDDM. 1371-1373. 12. De A meta-analysis of four European genome manais, F., Kanninen, T., Lindgren, C.M., et al. shows e ce for a novel region on chromosome 17p11.2-q22 screens (GIFT Consortium) viden linked to type 2 diabetes. Hum Mol Genet, 2003. 12 : 1865-1873. Devendra, D., Liu, E., Eisenbarth, G.S. 13. BMJ, 2004. Type 1 diabetes: recent developments. 328 : 750-754. 14. Dor man, J.S., Bunker, C.H. HLA-DQ locus of the human leukocyt e antigen complex and type 1 diabete s mellitus : a HuGE review. Epidem iol Rev, 2000. 22 : 218-227. 15. Dor .E., Songer, T.J. Epidemiology of Type 1 Diabetes , in Type 1 Diabetes: man, J.S., LaPorte, R , Mark A. Sperling, Editor. 2003, Hum Etiology and Treatment ana Press: Totowa, NJ. p. 3-22. Fagot-Cam pagna, A., Pettitt, D.J., Engelgau, M.M., et al. Type 2 diabetes among North 16. American children and adolescents and a public health perspective. J : an epidemiologic review Pediatr, 2000. 136 : 664-672. 17. Flores, J.C., Hirsc hhorn, J., Altshuler, D. The inherited basis of diabetes m ellitus: implications for the genetic analysis of complex traits. ics Hum Gene t, 2003. 4 : 257-291. Annu Rev Genom 18. Frayling, T.M., Hattersley, A.T. The role of g enetic sus ceptib ility in the association of low birth weight with type 2 diabetes. Br Med Bull, 2001. 60 : 89-101. 12

13 19. Frayling, T.M., Lindgren, C.M., Chevre, J.C., et al. ith A genome-wide scan in families w the young: evidence for further genetic heterogeneity. Diab maturity-onset diabetes of etes, : 872-881. 2003. 42 Ageing Res Rev, 2003. 2 : 111-127. 20. Gloyn, The search for type 2 diabetes genes. A.L. f in tensive treatmen t of diab etes on the d evelopment and D.C.a.C.T.R. 21. Group, The effect o ns in insu lin -dependen t diabetes mellitus. N Engl J Med, progression of long-term complicatio : 977-986. 329 1993. Effe in rela tives of patients w ith type 2 diabetes mellitus. N 22. Group, cts of insulin D.P.T.-T.S. : 1685-1691. Engl J Med, 2002. 346 Interven ing b efore the on set of type 1 diabetes: base line data from the T.E.N.D.I.T.E. 23. Group, Diabetologia, 2003. European Nicotinamide Diabetes Group. : 339-346. 46 24. . Genomic profiling to promot e a healthy lifesty le: not Haga, S.B., Khoury, M.J., Burke, W Nat Genet, 2003. 34 ready for prime time. : 347-350. The thrifty phenotype hypothesis. 60 : 5-20. Hales, C.N., Barker, D.J. Br Med Bull, 2001. 25. Candidate genes and late-onset 26. Hansen, Susceptibility genes or L. type 2 diabetes mellitus. Dan Med Bull, 2003. 50 : 320-346. common polymorphisms? Harrison, L.C., Honeyman, M.C. Cow's milk and type 1 diabetes. Diabetes, 1999. 27. : 1501- 48 1507. J.N. epidemiolo gy of type 1 diabetes. Pediatr Diabetes, 2003. 4 : 87-100. 28. Hirschhorn, Genetic 29. Holt, Diagnosis, epidemiology and pathogenesis of diabetes mellitus: an update for R.I.G. psychia tris ts. Br J Psychiatry, 2004. 184 : s55-s63. 30. Holztm an, N.A., W atson, M.S. eds. Promoting Safe and Effective Ge netic Testing in the United States . Johns Hopkins University Press, 1998. Honeym an, M.C., Coulson, B.S., Stone, N.L. 31. Association between rotavirrus infection and at risk of developing type 1 diabetes. munity i nchildren Diabetes, 2000. pancreatic islet autoim 49 . Sedentary lifestyle and risk of obesity and type 2 diabetes. Lipids, 2003. 38 32. Hu, F.B. : 103-108. Hyoty, H., Hiltunen, M ., Knip, M., et al. A prospective study of th e role of coxsackie B and 33. other enterovirus infections in the pat hogenesis of IDDM. Chil dhood Diabetes in Finland (DiMe Diabetes, 1995. 44 : 652-657. ) Study Group. 34. ., Reuranen, A. Decline of mumps antibodies in type 1 (insulin- Hyoty, H., Hiltunen, M diabetic children with nce of type 1 diabetes after dependent) a plateau in the rising incide s-rubella vaccine in Finland. Diabetologia, 1993. 41 : 40-46. introduction of the mumps-measle Karovonen, M., Tuom ilehto, J., Libman, I., et al. A review of the recen t ep idemiolog ical data on 35. the worldwide incidence of type 1 (insulin -dependent) diabetes mellitus. World Health Organization DiaMond Group. Diabetologia, 1993. : 883-892. 36 Khoury, M.J., Yang, Q., Gwinn, M., et al. idemiologic assessmen t of genomic profilling 36. An ep for measuring susceptibility to comm on diseases and targeting interventions. Genet Med, 2004. 6 : 38-47. Ki 37. erem owicz, S., et al. Identifica tion of a locus fo r maturity-onset diabetes m, S.-H., Ma, X., W of the young on chromosome 8p23. Diabetes, 2004. 53 : 1375-1384. 38. Kolb, H., Pozzilli, P. Cow's milk and type 1 di abetes: the gut immune sy stem deserves attention. Immunol Today, 1999. : 108-110. 20 39. Kyvik, K.O., Nystrom , L., Gorus, F., et al. The epidemiology of type 1 diabetes mellitus is not the same in young adults as in children. Diabetologia, 2004. 47 : 377-384. 40. Lean, M.E. Obesity: burdens of illness and strate gies for prevention or management. Drugs Today (Barc), 2000. 36 : 773-784. 13

14 41. Lehto, M., W High frequency of mutations in MODY and ipemo, C., Ivarsson, S.A., et al. candinavian patien l ea rly-ons et d iabetes. Diabetologia, mitochondrial genes in S ts with familia : 1131-1137. 1999. 42 diabetes linked to the human Lie, B.A., Todd, J.A., Pociot, F., et al. 42. The predisposition to type 1 J Hum Genet, 1999. 64 leukocyte antigen complex include s at least one non-class II gene. Am : 793-800. Marshall, A.L., Chetwynd, A., Morris, J., et al. Type 1 diabetes mellitus in childhood: a 43. 21 : 1035-1040. matched case control study in Lancashire and Cumbria, UK. Diabet Med, 2004. .D.G., Menser, M. 44. -up of congenital rubella. Lancet, 1992. 340 : McIntosh, E A fifty-year follow 414-415. McKinney, P.A., Okasha, M., Parslow, R., et al. rs for childhood diabetes Ante-natal risk facto 45. cal record data in Yorkshire, UK. 40 : mellitus, a case-control study of medi Diabetologia, 1997. 933-939. Moller, A.M., Dalgaard, L.T., Pociot, F., et al. 46. yte nuclear factor-1a Mutations in the hepatoc gene in Caucasian families originally ing type 1 diabetes. Diabetologia, 1998. classified as hav : 1528-1531. 41 Dia betes mellitu s: a thr ifty g enotype r endered detr imental by "p J. Am J Hu m 47. Neel, rogress"? 14 : 353-362. Genet, 1962. Nejentsev, S ., Reijonen, H., Adojaan, B., et al. Th e effect o 48. llele on the IDDM risk f HLA-B a defined by DRB1*04 subtypes and D Diabetes, 1997. 46 : 1888-1892. QB1*0302. N.I.o.D.D.K. . Oral Insulin Does Not Prevent Typ e 1 Diabetes 49. (NIDDK), News Briefs (June D. 15, 2003): Available at: e/releases/6-15-03.htm March 8, 2004. www.niddk.nih.gov/welcom 50. Onka mo, P., Vaananen, S., Karvonen, M., et al. Worldwide increase in incidence of type 1 diabetes--the analysis of the dat a on published incidence trends. Diabetologia, 1999. 42 : 1395- 1403. 51. Association of cytomegal ovirus infec tion with Pak, C.Y., McArthur, R.G., Eun, H.M. Lancet, 1988. 2 autoimmune type 1 diabetes. : 1-4. ., Hu, Y.H., et al. iet and exercise in preven ting NIDDM in Pan, X.R., Li, G.W Effects of d 52. people with impaired gluc ose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care, 20 : 537-544. 1997. Paronen, J., Knip, M., Savilahti, E., et al. Effect of cow's milk expos ure and maternal type 1 53. unization to dietary insulin in diabetes on cellular and humoral imm infants at genetic risk for Diabetes, 2000. : 1657-1665. type 1 diabetes. 49 Pearson, E.R., Badm an, M.K., Lockwood, C., et al. Contrasting diabetes phenotypes associated 54. with hepatocyte nuclear fa Diabetes Care, 2004. 27 : 1102-1107. ctor-1a and -1B mutations. 55. Pugliese, A., Zeller, M., Ferndandez, J.A. The insulin gene is transcribed in human thymus and transcr iptio n leve ls corr elated with alle lic varia tion at the I NS VNTR-IDDM 2 susceptib ility locus for type 1 diabetes. Nat Genet, 1997. : 293-297. 15 Shaw, J., Chisholm Epidemiology and prevention of type 2 diabetes an d the metab olic 56. , D. MJA, 2003. 179 syndrome. : 379-383. 57. Shepherd, M. 'I'm amazed I've been able to come off in jections': Patients' perceptions of genetic testing in diabetes. Pract Diab Int, 2003. 20 : 338-342. 58. Shepherd, M. Genetic testing in maturity onset diabetes of the young (MODY) -practical guidelines for professionals. Pract Diab Int, 2003. : 108-110. 20 Shepherd, M., Hattersley, A.T. 'I don't feel like a diabetic an 59. y more': the impact of stopping insulin in patients with m aturity onset di abetes of the young follo wing genetic testing. Clin Med, 2004. 4 : 144-147. 60. Genetic variation near the hepatocyte nuclear Silander, K., Mohlke, K.L., Scott, L.J., et al. factor-4a gene predicts suscep tibility to type 2 diabetes. Diabetes, 2004. 53 : 1141-1149. 14

15 61. Sinha, R., Fisch, G., Teague, B., et al. Prevalence of impaired glucose tolerance among N Engl J Med, 2002. 346 children and adolescents with marked obesity. : 802-810. Effect of a diabetic en Sobngwi, E., Boudou, P., Mauvais-Jarvis, F., et al. vironment in utero on 62. predisposition to type 2 diabetes. Lancet, 2003. 361 : 1861-1865. Differen t genes, differ ent diabe 63. : lesson s fro m maturity- onset Stride, A., Hattersley, A.T. tes Ann Med, 2002. 34 : 207-216. diabetes of the young. voll, M. Control of glycaemia: from molecu 64. Stum les to men. Minkowski Lecture 2003. Diabetologia, 2004. : 770-781. 47 Tuom Preven tio n of type 2 d iabetes mellitus by 65. ilehto, J., Lindstrom, J., Eriksson, J.G., et al. g subjects with impaired glucose tolerance. N Engl J Med, 2001. 344 : changes in lifestyle amon 1343-1350. 66. maguchi, K., Kimura, A. Type 1 diabetes susceptibi lity Undlien, D.E., Ha associated with polymorphism in the insulin gene region: a study of blacks, Cauc asians, and orientals. Diabetologia, 1994. 37 : 745-749. 67. Vaarala, O. tolerance in type 1 diabetes. Diabetes M etab Res Gut and the induction of immune 15 Rev, 1999. : 353-361. 68. van Da m, R.M. The epidemiology of lifestyle and risk for type 2 diabetes. Eur J Epide miol, 18 : 1115-1125. 2003. Weill, J., Vanderbecken, S., Froguel, P. 69. e of type 2 diabetes in Understanding the rising incidenc Arch Dis Child, 2004. adolescence. : 502-504. 89 70. WHO, 1999. Definition, Diagnos is and Classification of Diabetes Mellitus and its Com plications. W HO/NCD/NCS/99.2. 71. Wild, S., Roglic, G., Green, A., et al. Diabetes Care, 2004. 27 : Global prevalence of diabetes. 1047-1053. inter, W.E. Newly defined genetic diabetes syndromes: maturity onset diabetes of the young. 72. W Rev Endocr Metab Disord, 2003. 4 : 43-51. 73. Global and societal implication of the diabetes Zimmett, P., Alberti, K.G.M.M., Shaw, J. epidemic. Nature, 2001. 414 : 782-787. 15

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