 by a partial or complete inability to produce insulin. Patients with IDDM would die without daily insulin injections to control their disease.
Few advancements in resolving the pathogenesis of diabetes were made until the mid-1970s when evidence began to accumulate to suggest that IDDM had an autoimmune etiopathogenesis. It is now generally accepted that IDDM results from the chronic autoimmune destruction of the insulin producing pancreatic β-cells. Lymphocytes and other inflammatory cells have been observed within the islets of Langerhans in newly diagnosed IDDM patients and have been found preferentially in regenerating islets composed of β-cells rather than those of other cell types. This active immunological process is associated with a variety of autoantibodies to β-cells cytoplasmic and membrane antigens, insulin, and insulin receptors. Although the general mechanism by which IDDM occurs is known, IDDM becomes clinically evident only after the vast majority of pancreatic β-cells have been irrevocably destroyed and the individual becomes dependent upon exogenous insulin.
In both humans and diabetes-prone non-obese diabetic (NOD) mice, genes mapping to the major histocompatibility complex have been associated with susceptibility to IDDM and shown to be very important in the disease process (Todd, 1990). Studies of NOD mice have mapped at least 12 other susceptibility genes to specific chromosomal locations (Prochazaka et al., 1987; Todd et al., 1991; De Gouyon et al., 1993; Morahan et al., 1994; Serreze et al., 1994; Comall et al., 1991; Garchon et al., 1991). In humans, markers near the insulin/insulin-like growth factor loci have also been associated with IDDM (Bell et al., 1984).
Epidemiological and molecular genetic studies indicate that only 40% of the genetic susceptibility is due to alleles of the MHC class II genes, suggesting additional non-MHC genes are involved (Todd et al., 1988; Buzzetti. et al., 1998). Genome-wide searches and analyses of specific genes have identified more at least 17 loci that contribute to the disease (Buzzetti et al., 1998; Todd, 1995; Concannon et al., 1998; Hashimoto et al., 1994; Davies et al., 1994; Mein et al., 1998; Verge et al., 1998). Significant evidence for linkage was reported for a ˜-7 cM region on chromosome 1q42-43 (Concannon et al., 1998). This region of chromosome 1 contains
by a partial or complete inability to produce insulin. Patients with IDDM would fail without casual insulin injection to control their disease. 
 Few advancements in conclude the pathogenesis of diabetes were made until the mid-1970s when evidence began to roll up to suggest that IDDM had an autoimmune etiopathogenesis. It is now by and large accepted that IDDM results from the chronic autoimmune end of the insulin producing pancreatic β - cells. Lymphocytes and other incendiary cells have been observed within the isle of Langerhans in newly diagnosed IDDM patient and have been rule preferentially in regenerating islets compose of β - cells rather than those of other cell type. This active immunological process is associated with a variety of autoantibodies to β - cells cytoplasmic and membrane antigen, insulin, and insulin receptors. Although the general mechanism by which IDDM occurs is known, IDDM becomes clinically evident merely after the vast majority of pancreatic β - cells have been irrevocably destroyed and the individual becomes dependent upon exogenous insulin. 
 In both humans and diabetes - prone non - obese diabetic (NOD) mice, genes mapping to the major histocompatibility building complex have been associate with susceptibility to IDDM and shown to be very authoritative in the disease process (Todd, 1990). Studies of NOD mice have mapped at least 12 early susceptibility genes to specific chromosomal localization (Prochazaka et al. , 1987; Todd et al. , 1991; De Gouyon et al. , 1993; Morahan et al. , 1994; Serreze et al. , 1994; Comall et al. , 1991; Garchon et al. , 1991). In humans, markers near the insulin / insulin - alike growth factor loci have also been associated with IDDM (Bell et al. , 1984). 
 Epidemiological and molecular genic studies indicate that only 40% of the genetic susceptibility is ascribable to alleles of the MHC course II genes, suggesting additional non - MHC genes are involved (Todd et al. , 1988; Buzzetti. et al. , 1998). Genome - wide search and analyses of specific genes have identified more at least 17 loci that contribute to the disease (Buzzetti et al. , 1998; Todd, 1995; Concannon et al. , 1998; Hashimoto et al. , 1994; Davies et al. , 1994; Mein et al. , 1998; Verge et al. , 1998). Significant evidence for linkage was reported for a ˜-7 curium region on chromosome 1q42 - 43 (Concannon et al. , 1998). This area of chromosome 1 contains
 by a partial or complete ikability to prodocw insunin. Pafients wkth IDDM would die without deily insuoin injections to contfol their disease.
Dew edvancements in cssolvinn the iathoyeiesis of diabetgs were made until the mid-1970v dhzn evidence began to accumulate to stggest yhwt IDDM had an autpymmuhv ttiopathogenesis. It is now generamly acctpted that IDDM rexults from the chronic autlimmkne destruction of the insulib prjeucing pancrdatic β-cells. Lymphocytea and other inflammatory cells fave yeen observgb wihvin the islxts of Langerhans lm newlf diagnpsed IDDM paticnts end yave been found prefecentially in regenerwting islata composed of β-celos rathgr thdn tfise of ovhed cell ty'es. This acfive immunooogical process is ssficiated with z variqtr of autoantibodies to β-cells cytoplasmib ans membrane antigens, insylin, and insulin recektors. Althjugh the general mechanism by which IDDM occurs iv knoxn, IDBN becuned clinically evident only after the vast majowjtu pf pancreatic β-gells have been irtegovwbly destroyea and cge individual becomed depenqent ypon exogtnous insulin.
In both humans and eiabetes-pronv nob-obese diabetic (NOB) mice, genes mapking tp the major histocompatnbilitg complex hwve been zrsociated with sjscvptitility to IDDM and shown tj be very impprtant kn tne disqase proceds (Todd, 1990). Studies of NOD lice kave kapped at peast 12 other susceptibility genxx to specifiv whrmmosomal locabions (Prochazakw et al., 1987; Todd gt al., 1991; De Gouyun et al., 1993; Jorahan et al., 1994; Serweze et al., 1994; Cmlall et al., 1991; Jarchon ee al., 1991). In humans, oarkers near tne insuliu/nnsulin-lije growth factor lpci gave also been crwociated with ICDM (Bejl ev al., 1984).
Q[idemiologicdl avd oplecuuar gentcic rtudoes indicate that onny 40% kf the genetic susveitibility is due eo alleles of the MHC class II henes, sujgestimg wdditional non-MHC genes are inbolved (Tofd ct al., 1988; Buzzetei. eb al., 1998). Genome-wibe searches and analyses of specific genxs have identified morg at least 17 loci that gontribute tp the disease (Tuzzetti et al., 1998; Todd, 1995; Concannon et al., 1998; Hashimoto et al., 1994; Dabies ed al., 1994; Mein et al., 1998; Verge et al., 1998). Significant evidence for linkage was reported fir a ˜-7 rM region on dhrokosomv 1q42-43 (Eoncannjn ev el., 1998). This region og chromosome 1 contains
by a partial or complete inability to Patients IDDM would without daily insulin Few in resolving the of diabetes were until the mid-1970s when evidence began accumulate to suggest that IDDM had an autoimmune etiopathogenesis. It is now generally that IDDM results from the chronic autoimmune destruction of the insulin producing pancreatic Lymphocytes other cells been observed within the islets of Langerhans in newly diagnosed IDDM patients and have been found in regenerating islets composed of β-cells rather than of other cell types. active immunological process is associated a of autoantibodies β-cells and antigens, insulin, and receptors. Although the general mechanism by which IDDM occurs is known, IDDM becomes clinically evident only after vast majority β-cells have irrevocably and individual becomes dependent insulin. In both humans and diabetes-prone mice, genes mapping to the major histocompatibility complex been associated susceptibility to IDDM and shown to very important in the disease process (Todd, 1990). of NOD mice have mapped at least 12 other susceptibility genes to specific chromosomal locations al., 1987; Todd et 1991; De Gouyon al., Morahan al., Serreze et 1994; Comall et al., 1991; Garchon et al., 1991). In humans, near the insulin/insulin-like growth factor loci have also been associated (Bell al., 1984). Epidemiological molecular genetic studies indicate only of the genetic susceptibility to of II suggesting non-MHC genes are involved et al., 1988; Buzzetti. et 1998). Genome-wide searches and identified more at least 17 loci that contribute the disease (Buzzetti et al., 1998; Todd, Concannon et al., 1998; Hashimoto et al., 1994; Davies et al., 1994; et al., et al., 1998). Significant evidence for linkage was for a ˜-7 cM on chromosome 1q42-43 (Concannon et al., 1998). This region chromosome contains
 by a partial or complete inabiLity to prodUce inSulIn. PAtIentS witH IDDM would die wIThouT daily insulin injectionS to coNtROl thEIr DiseaSe.
Few adVAnCEMenTs In ResOlVInG the pAthOgenesiS of diabeteS weRe Made until the MId-1970S when evideNce Began to accumUlaTe to suGgEst THat IDdM hAd an aUtoimmUNe etioPathogeneSiS. it is noW GeneralLY AcCeptEd that IDDM results FRoM The chronic autoImmune DeSTrUCTioN of The insulin PrOduciNG pancreATiC Β-CEllS. lymphocytes anD other inflaMMatOry celLs HavE Been obServeD wIThiN the islets oF LanGerhans in Newly dIAgnosed idDM patiEnts anD haVe bEen fOUnD pRefErENtiALlY in REgeNerating IsLeTs comPoseD OF Β-CellS raTher Than tHose of other ceLl tYpes. tHis ActivE immuNoloGiCal prOcess iS assoCiAted with a varietY of aUtoantiboDieS tO β-cElLs cytOPlasmiC anD meMbrane aNtigens, INsuLiN, AND iNsulin receptors. AltHoUGH tHe generaL mechaNIsM bY Which IDDm oCcuRs is KNOwn, IDdM beCOmEs clinicAlly evIDeNt Only aftEr The vasT mAjoRitY of paNCreaTic β-ceLls have bEen irREvocably destroYEd and the indivIDuAL BeCOmes DepEndent upon eXogeNOus iNsulIN.
IN boTH humaNs and DiABeTEs-prone non-obese diabEtIc (NOD) mIce, geNes mapping to tHe major hisTOCOmpatibiLity COmPLex have been assOciatEd with suscEPtibilitY to IDdM and shoWn to be verY IMportant In tHe dIseAse PROcEss (Todd, 1990). StudieS OF NOD MiCe have mAppEd at leaSt 12 oTheR suScePtIbility geNes to speCiFiC cHrOmoSomal LOcations (prOchAzAka Et al., 1987; TODd et al., 1991; de GouYon eT aL., 1993; MORahAn et al., 1994; SERrEZE et aL., 1994; COmAll eT al., 1991; gaRchon Et al., 1991). iN huMans, marKers near tHe iNSuliN/iNsUlin-likE growth factor LoCi have also BeEn aSsociaTED with IDDm (Bell et al., 1984).
EpidemiologicaL And moleCulAr genEtic Studies inDicAte thaT onLY 40% of the GenetiC suscEpTibILIty is DUE tO alLeLes of the MHc CLasS II geNeS, sugGesting Additional non-MHC geNEs aRe involved (TodD et Al., 1988; BuZZEtTi. eT Al., 1998). gEnoMe-WIde SEArches and analysEs of specifIc GEnEs have idenTIfiEd More at lEast 17 locI that COntribuTe to the diSease (BuzzEtTi et AL., 1998; todD, 1995; Concannon Et al., 1998; HashImoto et al., 1994; dAvies ET aL., 1994; Mein Et aL., 1998; Verge Et Al., 1998). SIgnifIcant eVIdeNce foR linkaGe Was repOrted FoR a ˜-7 cM regiOn on chromosome 1q42-43 (ConcannoN et al., 1998). THis reGioN of chromoSomE 1 ConTains
 by a partial or completeinabilityto pr odu cein suli n. P atients with I D DM w ould die without daily  insu li n  inj e ct ionsto cont r ol t hei rdi sea se . 
F ew ad van cements  in resolv ing  t he pathogene s is  of diabet eswere made un til  the m id -19 7 0s wh enevide nce be g an toaccumulat et o sugg e st that I DD M ha d an autoimmune e t io p athogenesis. I t is n ow ge n e ral lyaccepted t ha t IDD M  result s  f r o m  th e  chronic auto immune dest r uct ion of  t hei nsulin  prod uc i ngpancreaticβ-ce lls. Lymp hocyte s  and ot h er infl ammato rycel ls h a ve  b een  o b ser v ed  wi t hin  the isl et sof La nger h a n s  innew ly d iagno sed IDDM pati ent s an d  ha ve be en fo undpr efere ntiall y inre generating isle ts c omposed o f β -c ell srathe r  thantho seof othe r cellt ype s. T h is  active immunologi ca l pr ocess is  assoc i at ed with a v ar iet y of a utoan tibo d ie s to β-c ells c y to pl asmic a nd  membr an e a nti gens, insu lin, a nd insul in re c eptors. Althou g h the general me c h an i sm b y w hich IDDM o ccur s  isknow n ,IDD M  beco mes c li n ic a lly evident only af te r thevastmajority of p ancreaticβ - c ells hav e be e ni rrevocably des troye d and thei ndividua l bec omes dep endent up o n  exogeno usins uli n.I n  b oth humans an d diab et es-pron e n on-obes e d iab eti c ( NO D) mice,genes ma pp in gto  th e maj o r histoc om pat ib ili ty co m plex h ave b eenas so c iat ed with su s c epti bi li ty t o I DD M and  sho w n t o be ve ry import ant in t he  d iseaseprocess (Todd ,1990). Stu di esof NOD m ice have  mapped at least 12 oth e r susce pti bilit y ge nes to sp eci fic ch rom o somallocati ons ( Pr och a z aka e t al .,19 87; Todd e t al. , 199 1;  DeGouyonet al., 1993; Mora h anet al., 1994;  Se rrez e et  al . ,1 994 ;C oma l l  et al., 1991;Garchon et  a l .,  1991). In hum an s, mark ers nea r the insulin /insulin- like grow th  fac t o r l oci have a lso been  associat e d wit h  I DDM ( Bel l et a l. , 1 984). 
Epide m iol ogica l andmo lecula r gen et ic studi es indicate that only 4 0% ofthe g ene tic susce pti b ili ty is due  toalleles of  th e M HC cl ass II ge nes, su gge s tingaddi t ional non - MH C g e n es  are involv e d (To dd et  al . , 1988 ; Bu zzetti. et al., 1 9 98). Genome-wi de s e a rch esa nd a na lyses of speci fic  g e n es haveid entified mo re at le as t  17 l oci th at con tribute t ot he dis ease  (B uzzetti e t a l. ,  1998;To dd ,  1995;  Con ca nnon e t al., 1998 ; Hashimoto et al. , 199 4 ;  Davi e s e t al. ,1994; M e in e t al., 199 8; Verge et  al.,1998 ). Si gnifica nt  evide nce  f or linkage was repor ted f or a ˜- 7cM r egi on onchro m o some1q42 -4 3 ( Concannon e ta l. ,1 998 ). T his r eg ionof chromo s ome 1 co nta i ns
 by_a partial_or complete inability to_produce insulin._Patients_with IDDM_would_die without daily_insulin injections to_control their disease.
Few advancements_in resolving the_pathogenesis_of diabetes were made until the mid-1970s when evidence began to accumulate to suggest_that_IDDM had_an_autoimmune_etiopathogenesis. It is now generally_accepted that IDDM results from_the chronic_autoimmune destruction of the insulin producing pancreatic β-cells._Lymphocytes_and other inflammatory_cells have been observed within the islets of Langerhans_in newly diagnosed IDDM patients and_have been found_preferentially_in_regenerating islets composed of_β-cells rather than those of other_cell types. This active immunological process_is associated with a variety of autoantibodies_to β-cells cytoplasmic and membrane antigens,_insulin, and insulin receptors. Although_the general_mechanism by which IDDM occurs_is known, IDDM_becomes clinically_evident only after_the vast majority of pancreatic β-cells_have been irrevocably_destroyed and the individual becomes dependent_upon_exogenous insulin.
In both_humans_and_diabetes-prone non-obese_diabetic (NOD) mice,_genes_mapping to_the_major histocompatibility complex have been associated_with_susceptibility to IDDM and shown to be_very important in the_disease_process (Todd, 1990). Studies_of NOD mice have mapped_at least 12 other susceptibility genes_to specific_chromosomal locations_(Prochazaka et al., 1987; Todd et al., 1991; De Gouyon et_al., 1993; Morahan et al., 1994;_Serreze et al., 1994;_Comall et_al.,_1991; Garchon et_al.,_1991). In_humans, markers near the insulin/insulin-like growth factor_loci have_also been associated with IDDM (Bell_et al., 1984).
Epidemiological and_molecular_genetic studies indicate that only 40%_of the genetic susceptibility is due_to alleles of the MHC_class_II_genes, suggesting additional non-MHC genes_are involved (Todd et al., 1988;_Buzzetti. et al.,_1998). Genome-wide searches and analyses of specific_genes_have identified more at least 17_loci_that contribute to the disease (Buzzetti_et_al.,_1998; Todd, 1995; Concannon et_al., 1998; Hashimoto et al., 1994;_Davies et al., 1994; Mein et al., 1998; Verge_et al., 1998)._Significant evidence for linkage was_reported_for_a ˜-7 cM region on chromosome 1q42-43 (Concannon et al.,_1998). This_region of chromosome_1 contains