The Genetic Basis of Type 2 Diabetes Mellitus: Impaired Insulin Secretion versus Impaired Insulin Sensitivity

Transcription

1 X/98/$03.00/0 Endorine Reviews 19(4): Copyright 1998 y The Endorine Soiety Printed in U.S.A. The Geneti Bsis of Type 2 Dietes Mellitus: Impired Insulin Seretion versus Impired Insulin Sensitivity JOHN E. GERICH University of Rohester, Shool of Mediine nd Dentistry, Deprtments of Mediine, Physiology, nd Phrmology, Rohester, New York I. Introdution A. Generl onsidertions B. Dietogeni vs. dietes-relted genes C. Seondry impirment of insulin seretion nd insulin sensitivity D. Insulin defiieny vs. impired insulin seretion E. Misinterprettion of the Orl Gluose Tolerne Test (OGTT) II. Strtegy III. Studies in Genetilly Predisposed Individuls with NGT A. First-degree reltives (exluding twins) B. Identil twins disordnt for type 2 dietes IV. Prospetive Studies of Individuls Before Development of Type 2 Dietes V. Studies of Norml Gluose-Tolernt Women with History of Gesttionl Dietes VI. Reversiility of Insulin Resistne nd Impired Insulin Seretion y Therpeuti Interventions VII. Are ll Type 2 Dietis Insulin Resistnt? VIII. Hypothesis for Pthogenesis of Type 2 Dietes IX. Summry nd Conlusion I. Introdution A. Generl onsidertions TYPE 2 dietes mellitus ounts for 80 90% of ll dietes in most ountries (1). It is, however, n extremely heterogeneous disorder: 5 10% of ptients my hve mturity-onset dietes of youth (MODY) (2); nother 5 10% my hve ltent dult-onset utoimmune dietes (3); nd nother 5 10% my hve dietes seondry to rre geneti disorders (4 6). The etiology of dietes in the remining 70 85% of ptients, the typil ptient, remins poorly defined nd mtter of gret ontroversy. Ethni nd geogrphi differenes in the inidene of this grden-vriety type type 2 dietes indite tht it too is heterogeneous (1). Indeed, two dietes suseptiility genes for type 2 dietes hve reently een identified: the one found in Mexin Amerins [NIDDM 1 (7)] is different from the one found in Finnish fmilies (NIDDM 2) (8). Address reprint requests to: John E. Gerih, M.D., Deprtment of Mediine, Physiology, nd Phrmology, University of Rohester Shool of Mediine nd Dentistry, 601 Elmwood Avenue, Rohester, New York USA. Although the pthogenesis of grden-vriety type type 2 dietes is ontroversil, it is generlly greed tht: 1) the disese hs strong geneti nd environmentl (quired) omponents (9 13); 2) its inheritne is polygeni (14 17), mening tht the simultneous presene of severl norml genes or polymorphisms is neessry for development of the disese; 3) impirment of insulin sensitivity nd insulin seretion, eh of whih is under geneti ontrol (18 20), re oth importnt elements in its pthogenesis (12, 16, 21 23); 4) most ptients re oese; nd 5) oesity, espeilly intrdominl oesity (24 27), uses insulin resistne nd is under geneti ontrol (11). Wht is disputed re: 1) the quntittive ontriution of insulin resistne nd impired insulin seretion; 2) their role s geneti ftors; 3) the mjor sites of insulin resistne (liver vs. musle vs. dipose tissue vs. kidney); nd 4) the steps tht led to the development of type 2 dietes (28 34). The fous of this dete is whether the primry geneti determinnts for type 2 dietes re norml genes or polymorphisms relted to insulin resistne or impired insulin seretion, not whether insulin resistne or impired insulin seretion is more importnt in the pthogenesis of type 2 dietes. Clerly, oth re importnt nd whether or not their sis is geneti does not diminish their importne. The overwhelmingly predominnt view t the present time, s refleted in textooks nd review rtiles (35 37), is tht genes ffeting insulin sensitivity re the primry geneti ftors. Consequently, sustntil effort is underwy to determine its moleulr sis. As will eome pprent, however, there is lso onsiderle ody of evidene suggesting tht genes ffeting insulin seretion my e the primry geneti ftors. Beuse insulin resistne lmost universlly is regrded s the primry geneti ftor in type 2 dietes, I hve tken pins to point out potentil shortomings in studies supporting this point of view. Clerly, mny of the studies supporting geneti defet in the -ell hve similr shortomings. Although not pointing these out with equl emphsis my e viewed s is on my prt, this pproh ws tken to demonstrte tht the evidene supporting insulin resistne s the primry geneti defet is not s strong s is generlly pereived. It is not expeted tht this dete will resolve the question of whether impired insulin seretion or insulin resistne is the primry genetilly determined ftor for development of type 2 dietes, ut rther it is hoped tht this dete will led to ressessment of urrent dogm nd perhps more equitle rellotion of efforts to determine the moleulr sis for the geneti 491 Downloded from

2 492 GERICH Vol. 19, No. 4 omponents of type 2 dietes onsistent with ville evidene. B. Dietogeni vs. dietes-relted genes A mjor prolem limiting our understnding of the geneti sis of type 2 dietes is tht mny environmentl nd genetilly sed ftors influene insulin sensitivity nd insulin seretion: these inlude ge, gender, ethniity, physil fitness, diet, smoking (38), oesity, nd ft distriution (12). Although mny of these my e under geneti ontrol (11), it is importnt to emphsize tht the genes my not neessrily represent speifi dietes genes. For exmple, let us suppose tht the insulin resistne in type 2 dietis ws minly due to intrdominl ft umultion nd tht this were minly under geneti ontrol. One ould onlude tht the insulin resistne found in type 2 dietis ws geneti, ut it would not represent speifi dietes gene sine most insulin-resistnt oese people do not develop dietes (39). On the other hnd, muttion in the insulin reeptor gene using insulin resistne ould e onsidered dietesspeifi gene sine, if severe enough, most people with the geneti defet would develop dietes nd most people without dietes would not hve this gene. It is importnt, therefore, to distinguish etween dietogeni genes, with whih this rtile is onerned, nd dietes-relted genes (e.g., those regulting ppetite, energy expenditure, nd intrdominl ft umultion) (10). The ltter lss of genes my e defined s not eing speifi (i.e., not eing minly limited to people with dietes), s y themselves not eing suffiient to use dietes nd not neessrily eing essentil. These genes re est onsidered s genetilly determined risk ftors. An exmple might e gene or group of genes using oesity. These genes would not e limited to individuls destined to eome dieti (e.g., not speifi), would not e suffiient sine most oese individuls do not eome dieti, nd would not e essentil sine, depending on the popultion, onsiderle numer of len individuls develop type 2 dietes. A dietogeni gene my e defined s eing essentil nd reltively speifi ut, given the polygeni nture of type 2 dietes, my not e suffiient in itself to use dietes. For exmple, mild ltertion in the tivity of gluokinse, suh s is found in some MODY ptients (32), whih redues insulin seretion, is reltively speifi, eing minly limited to fmilies with this type of dietes; it my not e suffiient to use dietes in most individuls unless there re inresed requirements for insulin suh s tht due to superimposition of quired insulin resistne (e.g., oesity, physil intivity, or pregnny) ut it my e onsidered to e essentil sine without this defet, dietes would not otherwise our. Thus, depending on the severity of the expression of the genes in given individul nd on the ompnying environmentl (quired) ftors, omintion of severl dietes-relted genes nd severl dieti genes my e neessry to use dietes. Indeed, in the GK rt there ppers to e t lest six geneti loi involved (40), nd in humns two different suseptiility genes hve een reently identified, one in Mexin-Amerins (NIDDM 1) (7) nd one in Finnish fmilies (NIDDM 2) (8). C. Seondry impirment of insulin seretion nd insulin sensitivity Another onfounding ftor is tht hyperglyemi nd hyperinsulinemi in themselves n impir insulin seretion nd insulin sensitivity (41 43). Thus, people with impired gluose tolerne (IGT) nd overt type 2 dietes n e expeted to hve insulin resistne nd impired insulin seretion independent of geneti uses merely euse they re hyperglyemi. Beuse of this, ross-setionl studies inluding individuls with IGT nd type 2 dietes hve not proven to e prtiulrly informtive in delineting etween geneti nd quired ltertions in insulin seretion nd tion. D. Insulin defiieny vs. impired insulin seretion Another ftor tht hs led to onfusion regrding our understnding of the geneti sis of type 2 dietes is tht the literture hs een ofusted y estlishment of dihotomy of insulin defiieny vs. insulin resistne. For exmple, it hs een rgued tht individuls with type 2 dietes or IGT re hyperinsulinemi, nd therefore the min prolem must e insulin resistne rther thn insulin defiieny (21, 28, 29). Although this my e true, it is misleding nlysis. It ssumes tht hyperinsulinemi, even if inpproprite for the previling hyperglyemi, indites norml pnreti -ell funtion. In other words, insulin defiieny, rther thn impired -ell funtion, hs een ontrsted with insulin resistne. Stritly speking, solute insulin defiieny rrely ours exept in ptients with insulin-dependent type 1 dietes of severl yers durtion. Mny type 1 dieti ptients in ketoidosis hve een reported to hve plsm insulin levels in the norml rnge (44). These insulin levels re of ourse grossly inpproprite for the degree of hyperglyemi. The dihotomy estlished etween insulin defiieny nd insulin resistne hs led to generl underemphsis of the issue of the ppropriteness of -ell funtion. Aording to the dihotomy, person hving plsm gluose level of 200 mg/dl nd plsm insulin of 20 U/ml would e hyperinsulinemi ompred with person with plsm gluose of 100 mg/dl with plsm insulin of 10 U/ml. Suh person would e onsidered not to hve impired -ell funtion, ut to e insulin resistnt euse of the hyperinsulinemi. However, person with norml gluose tolerne whose plsm gluose level is rised 200 mg/dl would serete 2 4 times more insulin thn type 2 dieti ptient with plsm gluose of 200 mg/dl (45, 46). Thus, lthough hyperinsulinemi my signify the presene of insulin resistne, this my not neessrily e the se, nd inresed plsm insulin levels do not neessrily indite norml -ell funtion. It is importnt to reognize tht nother determinnt of insulin seretion, in ddition to the mient plsm gluose levels, is insulin sensitivity. Oese insulin-resistnt individuls serete more insulin thn len insulin-sensitive individuls t omprle plsm glu- Downloded from

3 August, 1998 GENETIC BASIS FOR TYPE 2 DIABETES 493 ose levels (45). Few studies hve nlyzed insulin seretion in reltion to insulin sensitivity (47). As reently pointed out y Reven (48), euse of the feedk etween plsm gluose onentrtion (the mjor stimulus for insulin relese) nd -ell insulin seretion, it is virtully impossile to develop dietes due to the severity of insulin resistne found in most type 2 dieti ptients unless the pity to serete dditionl mounts of insulin to ompenste for the insulin resistne is impired. Thus, hyperglyemi my e onsidered prim fi evidene for impired insulin seretion. The question of ourse is whether this inility to ompenste for insulin resistne is the result of n underlying geneti defet or merely seondry to -ell exhustion. E. Misinterprettion of the Orl Gluose Tolerne Test (OGTT) The misleding dihotomy etween insulin defiieny (vs. impired insulin relese) nd insulin resistne hs een reinfored y questionle interprettion of ross-setionl studies exmining plsm insulin responses during OGTTs (21, 49). Virtully ll studies exmining the reltionship etween the 2-h plsm gluose level ( generlly reognized index of gluose tolerne) nd the 2-h plsm insulin level hve found n inverted U reltionship (Fig. 1) with plsm insulin levels inresing to pek round 200 mg/dl followed y progressive derese. This pttern hs een interpreted to indite tht erly on, s gluose tolerne dereses, there is inresed insulin seretion nd, therefore, tht insulin resistne, rther thn insulin defiieny, is responsile for the development of IGT; lter on, dietes develops when the -ell n no longer ompenste for this insulin resistne (21, 49, 50). This interprettion my e questioned. First of ll, it is inomptile with the results of numerous studies (32, 47, 51 62) demonstrting tht individuls with IGT lredy hve impired insulin seretion. Seond, it does not tke into onsidertion the importne of the kinetis of insulin relese nd the dependene of insulin seretion upon the previling plsm gluose onentrtion. As shown in Fig. 1, if one exmines the erly (30 min) plsm insulin response during the OGTT, one finds tht there is progressive derese in this erly plsm insulin response s gluose tolerne deteriortes. This derese is lerly evident efore the dignosis of IGT would e mde (e.g., 2 h plsm gluose exeeding 140 mg/dl). Moreover, experimentl redution in erly insulin relese in norml humn volunteers hs een shown to produe gluose intolerne nd lte (2 h) hyperinsulinemi (63). These oservtions provide evidene tht there is impired pnreti -ell funtion efore the onset of IGT nd tht lte hyperinsulinemi my tully e the result of n indequte -ell response to the hyperglyemi due to impired erly insulin relese nd my not neessrily indite the presene of insulin resistne. II. Strtegy Beuse IGT nd type 2 dietes n e ssoited seondrily with impired insulin seretion nd insulin resistne due to gluose toxiity, this review will rely primrily on the nlysis of dt derived from study of individuls with norml gluose tolerne (NGT) who re t high risk to develop type 2 dietes, presumly on geneti sis. These individuls inlude 1) NGT first-degree reltives of people with type 2 dietes; 2) NGT women with history of gesttionl dietes; nd 3) NGT individuls who susequently developed IGT or type 2 dietes. In ddition, the reversiility of defets in insulin sensitivity nd insulin seretion y weight loss will e exmined. The rtionle for this is tht if insulin resistne or impired insulin seretion were purely geneti in origin, these normlities should not e ompletely reversed y suh n intervention. On the other hnd, it is possile tht geneti ftors my use given degree of oesity to hve exggerted effets on insulin sensitivity nd -ell funtion. This possiility will e onsidered in detil lter. Although, s indited erlier, it is generlly greed tht development of type 2 dietes nnot our without impired insulin seretion, evidene will e presented tht type 2 dietes n our without insulin resistne. Finlly, sed on this review of the literture, shem will e proposed for the pthogenesis of type 2 dietes inorporting the onept of intertions etween dietes-relted genes, dietogeni genes, nd environmentl ftors. III. Studies in Genetilly Predisposed Individuls with NGT A. First-degree reltives (exluding twins) FIG. 1. Reltionship etween 2 h plsm gluose, 30 min plsm insulin, nd 2 h plsm insulin levels during OGTTs. 1. Insulin seretion. Over the pst 30 yr, there hve een more thn 60 studies of insulin seretion nd/or insulin sensitivity in norml gluose-tolernt individuls who were the firstdegree reltive of someone with type 2 dietes (30, 31, 39, 47, 53, 56, 60, 61, ) (Tles 1, 2, nd 3). Unfortuntely, in most of these studies insulin seretion nd insulin resistne were not simultneously ssessed. Furthermore, in Downloded from

4 494 GERICH Vol. 19, No. 4 TABLE 1. -Cell funtion in NGT individuls with first-degree type 2 dieti reltive Author (Ref.) Sujets -Cell funtion Comments 1. Grodsky et l. (64) 8C, 24FM Norml (OGTT) 2. Welorn et l. (65) 46C, 4FM Norml (OGTT) 3. Riketts et l. (156) 24C, 21FM Norml (OGTT) 4. Colwell nd Lein (66) 7C, 6FM Redued (OGTT) 5. Siperstein et l. (67) 15C, 27FM Norml (OGTT) 6. Simpson et l. (68) 10C, 10FM Redued (IVGTT) 7. Boden et l. (69) 13C, 13FM Redued (IVGTT) 8. Dweke et l. (70) 58C, 21FM Redued (OGTT) 9. Pulsen et l. (71) 16C, 11FM Inresed (OGTT) 10. Soeldner et l. (72) 11C, 5FM Redued (OGTT) 11. Rojs et l. (73) 25C, 14FM Redued (IVGTT) Norml (TTT) 12. Serrno-Ris et l. (74) 34C, 22FM Redued (IVGTT) Norml (OGTT, TTT) 13. Rull et l. (75) 31C, 67FM Redued (OGTT) 14. Lowrie et l. (76) 10C, 12FM Norml (IVGTT) 15. Jkson et l. (77) 17C, 28FM Inresed (OGTT) 16. Sonksen et l. (78) 26C, 24FM Redued (OGTT, IVGTT) 17. Pozefsky et l. (79) 7C, 9FM Redued (OGTT) 18. Boerg et l. (80) 93C, 116FM Redued (IVGTT) 19. Aronoff et l. (81) 26C, 32FM Norml (OGTT, IVGTT) 20. Ohlsen et l. (82) 33FM Redued (GIT) 21. Bonor et l. (83) 55C, 55FM Redued (OGTT) d 22. Berntorp nd Lindgrde (84) 51C, 22FM Redued (OGTT) 23. O Rhilly et l. (60) 64C, 75FM Norml (GIT) 24. Leslie et l. (85) 18C, 32FM Inresed (OGTT) de 25. Hffner et l. (86) 1013C, 584FM Inresed (OGTT) d 26. O Rhilly et l. (53) 10C, 10FM Redued pulstility e 27. Lws et l. (87) 16C, 19FM Redued (OGTT) 28. Ho et l. (88) 25C, 25FM Norml (OGTT) 29. Eriksson et l. (56) 14C, 13FM Norml (OGTT, lmp) 30. Wrrm et l. (39) 186C, 155FM Norml (IVGT) f 31. Rmhndrn et l. (89) 15C, 24FM Inresed (OGTT) f 32. Johnston et l. (90) 12C, 12FM Norml (MM, lmp) 33. Osei et l. (91) 10C, 10FM Inresed (IVGTT) f 34. Elein et l. (92) 35C, 171FM Redued (OGTT) 35. Henriksen et l. (93) 29C, 20FM Redued (OGTT) Norml (MM) 36. Lemieux et l. (94) 28C, 11FM Norml (OGTT) d 37. Gulli et l. (95) 10C, 11FM Inresed (OGTT, lmp) e 38. Gelding et l. (96) 12C, 12FM Norml (OGTT) 39. Byrne et l. (47) 11C, 10FM Norml vrious tests 40. Piment et l. (30) 50C, 50FM Norml (OGTT) Redued (lmp) 41. Armstrong et l. (97) 90C, 93FM Norml (HOMA) 42. Tylor et l. (98) 29C, 19FM Redued (OGTT) 43. Cersi nd Luft (99) 6C, 2FM Redued (GIT) 44. Clrk et l. (100) 28C, 8FM Redued (GIT) 45. Vg nd Henriksen (101) 20C, 20FM Inresed (OGTT) 46. Roder et l. (102) 14C, 11FM Norml (lmp) 47. Birkelnd et l. (103) 30C, 26FM Norml (OGTT) 48. Migdlis et l. (106) 31C, 96FM Norml (OGTT) 49. Fernndez-Cstner et l. (107) 49C, 86FM Redued (HOMA) 50. Shmitz et l. (105) 13C, 15FM Redued (GIT) f 51. Vuhkonen et l. (117) 14C, 38FM Redued (IVGTT) f 52. Henriksen et l. (118) 20C, 20FM Redued (IVGTT) 53. Vn Heften et l. (119) 21C, 21FM Redued (lmp) OGTT, Orl gluose tolerne test; IVGTT, intrvenous gluose tolerne test; TTT, tolutmide tolerne test; GIT, gluose infusion test; MM, miniml model; Clmp, hyperglyemi lmp; HOMA, homeostsis model; C, ontrol sujet; FM, sujet with type 2 dieti reltive. Questionle mthing. Blood gluose levels different. All nonoese. d Did not evlute erly insulin responses. e Inluded IGT. f FM more oese. most of the erly studies, the methods used to evlute insulin seretion or insulin sensitivity would not e onsidered to e stte of the rt y present stndrds. Finlly nd most importntly, in mny studies sujets were usully not well mthed for quired ftors suh s ge, gender, nd oesity tht re known to influene insulin seretion nd insulin sensitivity. Downloded from

5 August, 1998 GENETIC BASIS FOR TYPE 2 DIABETES 495 TABLE 2. Insulin sensitivity in norml gluose tolernt individuls with first degree type 2 dieti reltive Author (Ref.) Sujets Insulin sensitivity Comments 1. Pozefsky et l. (79) 7C, 9FM Norml (FGU) 2. O Rhilly et l. (60) 64C, 75FM Norml (GIT) 3. Leslie et l. (108) 10C, 10FM Redued (GIIT) 4. Lws et l. (87) 16C, 19FM Redued (GIIT) 5. Ho et l. (88) 25C, 25FM Redued (GIIT) 6. Eriksson et l. (56) 14C, 13FM Redued (lmp) 7. Rmhndrn et l. (89) 15C, 24FM Redued (ITT) 8. Johnston et l. (90) 12C, 12FM Norml (MM) 9. Osei et l. (91) 10C, 10FM Redued (MM) 10. Henriksen et l. (93) 20C, 20FM Redued (MM) 11. Hnderg et l. (109) 8C, 10FM Norml (lmp) 12. Gulli et l. (95) 10C, 11FM Redued (lmp) 13. Shlin-Jntti et l. (110) 16C, 18FM Redued (lmp) 14. Gelding et l. (96) 12C, 22FM Norml (ITT) 15. Gelding et l. (111) 9C, 8FM Norml (ITT) 16. Byrne et l. (47) 11C, 10FM Norml (MM) 17. Piment et l. (30) 50C, 50FM Norml (lmp) 18. Armstrong et l. (97) 90C, 93FM Norml (ITT, HOMA) 19. Vg nd Henriksen (101) 20C, 20FM Redued (lmp) 20. Eriksson et l. (112) 12C, 10FM Redued (lmp) 21. Migdlis et l. (106) 31C, 96FM Norml (HOMA) 22. Nyholm et l. (104) 22C, 21FM Norml (lmp) 23. Wrrm et l. (39) 188C, 155FM Redued (MM) 24. Fernndez-Cstner et l. (107) 49C, 86FM Norml (HOMA) 25. Shmitz et l. (105) 13C, 15FM Redued (lmp) 26. Vuhkonen et l. (117) 14C, 38FM Norml 27. Henriksen et l. (118) 20C, 20FM Norml (MM) 28. Vn Heften et l. (119) 21C, 21FM Norml (lmp) Clmp, Euglyemi hyperinsulinemi or hyperglyemi lmp; ITT, insulin tolerne test; MM, miniml model; HOMA, homeostsis model; C, ontrol sujet; FM, sujet with type 2 dieti reltive; FGU, forerm gluose uptke; GIT, gluose infusion test. Questionle mthing. FM more oese. Inluded IGT. TABLE 3. -Cell funtion nd insulin sensitivity in monozygoti twins disordnt for type 2 dietes Author (Ref.) Sujets -Cell funtion Insulin sensitivity 1. Cersi nd Luft (113) 85C, 5M Redued (GIT) NS 2. Gottlie et l. (114) 24C, 12M Norml (OGTT) NS 3. Pyke nd Tylor (116) 24C, 9M Redued (OGTT) NS 4. Brnett et l. (115) 5C, 5M Redued (OGTT) NS 5. Vg et l. (61) 13C, 5M Redued (H-Clmp) Norml (E-lmp) GIT, Gluose infusion test; OGTT, orl gluose tolerne test; H-Clmp, hyperglyemi lmp; E-Clmp, euglyemi hyperinsulinemi lmp; M, monozygoti disordnt twin; C, ontrol sujet; NS, not studied. Proly inluded twins of type 1 dieti ptients. My hve inluded 3 twins of type 1 dieti ptients. Tle 1 provides the oservtions of -ell funtion of NGT first-degree type 2 dieti reltives exluding those of monozygoti twins. Of the 53 studies, 26 (49%) indite impired -ell funtion, 20 (38%) indite norml -ell funtion, nd only 7 ( 13%) indite -ell hyperseretion. Thus, the preponderne of experimentl evidene fvors impired, rther thn exessive, insulin seretion eing present in these individuls efore the development of IGT nd thus provide support for the onept tht the initil (? geneti) lesion in type 2 dietes my involve impired insulin seretion rther thn insulin resistne. It is importnt to point out tht the studies using more sophistited tehniques or more rigorous tests to evlute -ell funtion (e.g., hyperglyemi lmps nd stndrdized gluose infusion tests) were more likely to detet normlities. For exmple, Piment et l. (30) nd Vn Heften et l. (119) found solutely norml plsm insulin responses to OGTTs in first-degree reltives with NGT ut during hyperglyemi lmp studies found redued responses. These results suggest tht, in some individuls with NGT, the OGTT my not e suffiient stress to eliit sutle defets in -ell funtion. Certin widely ited reports deserve dditionl omment. In one of the erliest studies, Rojs et l. (73) exmined plsm insulin responses to intrvenous gluose in ontrol volunteers nd NGT offspring of two dieti prents who were refully mthed for ge, gender, nd oesity. It ws found tht gluose-stimulted insulin relese ws deresed in the NGT offspring. Wrrm et l. (39) susequently nlyzed the dt of these nd dditionl offspring of two dieti prents using the miniml model pproh of Bergmn et l. (120, 121). Initil results of those who susequently either hd or hd not developed dietes were ompred. In this popultion, lredy demonstrted to hve redued -ell funtion, Downloded from

6 496 GERICH Vol. 19, No. 4 presumly on geneti sis, it ws found tht those who susequently developed dietes hd een insulin resistnt when they were still NGT, wheres those who did not develop dietes hd not een insulin resistnt. It ws onluded tht insulin resistne ws risk ftor for development of type 2 dietes. This study is often ited in the literture s providing evidene tht insulin resistne is the min geneti ftor for type 2 dietes. However, sine the group who susequently developed dietes were mrkedly oese ompred with the group tht did not develop dietes (i.e., 140 vs. 106% idel ody weight), it is possile tht the insulin resistne ws simply the result of oesity. Indeed, omprison of the miniml model prmeters of insulin seretion nd insulin sensitivity in this group with those of similrly oese individuls hving no fmily history of dietes reported y Bergmn et l. (120, 121) (Tle 4) provides evidene tht the sujets studied y Wrrm et l. (39) were no more insulin resistnt thn these individuls ut hd redued first-phse insulin relese. Thus, the study of Wrrm et l. (39) n e interpreted s showing tht people with geneti predisposition to impired insulin seretion develop dietes when quired insulin resistne (due to oesity) is superimposed nd exeeds the ility of the -ell to ompenste for it. The study of Gulli et l. (95), whih exmined plsm insulin responses during hyperglyemi lmp experiments in nondieti offspring of two type 2 dieti prents with other nondieti Mexin-Amerin sujets, is lso often ited s finding insulin resistne without impired insulin seretion. However, the study hd two limittions: first, sujets with IGT were inluded in the group with dieti prents, nd seond, sujets were not lmped t identil plsm gluose levels. During the lmps, plsm gluose levels were inresed y ertin inrement. Sine it is likely tht the sujets inluded with IGT hd higher fsting plsm gluose levels, they would hve een lmped t higher plsm gluose levels, thus providing greter stimulus for insulin relese. Consequently, it is diffiult to interpret the results of this study. The study of Eriksson et l. (56) is lso ited frequently s demonstrting inresed insulin relese in offspring of people with type 2 dietes. However, in this study reltives of type 2 dieti nd ontrol sujets were not well mthed for gender nd oesity. Furthermore, during the hyperglyemi lmps, plsm gluose levels were inresed y ertin inrement so tht the groups were not neessrily studied t identil plsm gluose levels. These limittions mke the results of the study diffiult to interpret. Indeed, in susequent study (102), whih proly inluded some of the sme sujets ut with etter mthing, insulin responses during hyperglyemi lmps were similr in the ontrol group nd first-degree NGT reltives of type 2 dietis. In summry, ontrry to the urrent prevlent view, the preponderne of the dt from studies exmining -ell funtion of individuls with NGT nd presumed geneti predisposition to develop type 2 dietes, euse they hd first-degree type 2 dieti reltive, provides evidene for n underlying impirment in insulin seretion. 2. Insulin sensitivity. Twenty-eight studies hve exmined the ppropriteness of insulin tion in NGT individuls with first-degree type 2 dieti reltive (Tle 2). Of these, 15 (54%) found norml insulin sensitivity while 13 (46%) found redued insulin sensitivity. If one exludes studies tht proly inluded some people with IGT or where there ws ovious poor mthing of groups for ftors known to ffet insulin sensitivity (e.g., ge, gender, oesity, VO 2 mx), or where it is not ler whether groups were well mthed (39, 56, 60, 88, 89, 91, 95, 108, 110, 112, 105, 117), we re left with 16 studies of whih 14 ( 88%) indite norml insulin sensitivity nd 3 ( 12%) indite redued insulin sensitivity. Grnted tht these exlusions my represent ertin is, it is sfe to sy, nevertheless, tht the preponderne of dt do not provide strong support for the onept tht NGT first-degree reltives of type 2 dieti ptients re insulin resistnt independent of ftors suh s ge, gender, oesity, physil fitness, nd ody ft distriution. Indeed, Nyholm et l. (104) reently reported tht pprent differenes in insulin sensitivity etween NGT sujets with nd without fmily history of dietes were no longer sttistilly signifint when dt were orreted for differenes in VO 2 mx, n index of physil fitness. B. Identil twins disordnt for type 2 dietes Studies of disordnt identil twins (Tle 3) hve provided more definitive piture of -ell funtion nd insulin sensitivity efore development of dietes thn those of firstdegree reltives of type 2 dieti ptients. Of the five studies, ll (61, 113, 115, 116) exept tht of Gottlie et l. (114) hve indited tht the NGT disordnt twin hd redued insulin seretion. Gottlie et l. (114) studied hildren nd thus proly inluded twins disordnt for type 1 dietes. As shown in Tle 3, the only study exmining oth insulin sensitivity nd et ell funtion (61) found impired insulin seretion without insulin resistne. This ltter study deserves more omment. Although the smll numer of sujets studied presents the possiility of type 1 nd type 2 sttistil errors, ertin oservtions re of interest. Disordnt twins with NGT nd IGT oth hd impired insulin relese. The degree of impirment ws omprle ut those with IGT lso hd redued insulin sensitivity. This ws ssoited with n inresed wist/hip rtio ( vs in NGT twins nd in norml ontrols), nd n inresed H A1C ( % vs % in NGT twins nd % in norml ontrols). Thus, one ould postulte from these dt tht gluose toxiity (41, 42) nd exess intrdominl ft in the IGT twins were responsile for the deresed insulin sensitivity. The twins with type 2 dietes were more oese thn those with IGT [ody mss index (BMI) kg/m 2 vs kg/m 2 ] nd hd modertely worse insulin sensitivity (M vlue vs mg/kg/min) nd mrkedly worse first-phse insulin seretion ( vs U/ml/min). Note tht the vlue for insulin seretion in the type 2 dieti twin is negtive. The oservtions of this study suggest tht the mjor ftor responsile for trnsition from NGT to IGT is superimposi- Downloded from

7 August, 1998 GENETIC BASIS FOR TYPE 2 DIABETES 497 tion of insulin resistne upon impired -ell funtion nd tht the mjor ftor responsile for trnsition from IGT to type 2 dietes is worsening of the lredy impired insulin seretion. The ltter ould represent progression of geneti -ell defiit nd/or toxi effets of hyperglyemi. The pperne in insulin resistne ould e redily explined y omintion of oesity nd gluose toxiity (i.e., not neessrily dietogeni gene). In summry, the dt from twin studies re onsistent with the onsensus of the dt from other fmily studies disussed ove inditing tht impired -ell funtion preedes insulin resistne in the pthogenesis of type 2 dietes when onfounding ftors suh s ge, gender, nd oesity re tken into onsidertion. IV. Prospetive Studies of Individuls Before Development of Type 2 Dietes There hve een numerous studies reporting seline dt on NGT individuls who susequently developed type 2 dietes (Tle 5). Mny of these hve een epidemiologil in tht they ompred, within ertin popultion, the seline hrteristis of individuls who did or did not susequently eome dieti. These studies hve provided evidene tht oth impired insulin seretion nd insulin resistne re risk ftors for development of type 2 dietes TABLE 4. Miniml model nlysis nd seline dt of mthed sujets who developed dietes with norml ontrols Controls (n 15) Future type 2 dietis (n 25) Age (yr) IBW (%) Insulin sensitivity (min 1 / U per ml) Insulin relese (10 3 pmol/min/mmol) Dt from Bergmn et l (120) nd 1981 (121). Dt from Wrrm et l. (39). (22, 23, ). However, they do not diretly ddress the issue of whih of these ftors preedes the other nd whih is geneti euse often those who susequently developed dietes were more oese or less physilly tive thn those who did not develop dietes (22, 122, 124). Moreover, in mny ses insulin sensitivity ws not diretly mesured, nd surrogte determintions suh s fsting or 2 h OGTT plsm insulin levels were used. Rell tht n inresed 2 h plsm insulin level my e the result of impired erly insulin relese euse this leds to greter hyperglyemi nd greter stimulus for insulin relese nd therefore my not neessrily indite insulin resistne. Finlly, individuls with IGT nd potentilly seondry hnges due to gluose toxiity were often inluded (122, 125). Severl of these studies deserve omment. There hve een two relevnt reports from the Pim Indin Study (49, 126). In one report, seline dt of sujets who developed type 2 dietes were ompred with group of NGT sujets (126). Unfortuntely, individuls with IGT were inluded nd no demogrphi dt were given to ssure the groups were well mthed. OGTT plsm insulin levels t 30 min were not signifintly different. However, if inrements in plsm insulin responses hd een evluted in reltion to inrements in plsm gluose, the group tht susequently developed type 2 dietes might hve een seen to hve redued plsm insulin response (0.39 vs U/mg per dl). Thus, it would e diffiult to onlude tht pnreti -ell funtion ws norml s hd een suggested. Insulin sensitivity ws not reported. In the other study of the Pim Indins (49), longitudinl dt were given for 24 individuls who developed IGT. Although not nlyzed, the seline ute insulin response of these individuls (IVGTT) ws less ( 190 vs. 220) thn tht of ontrol group while their gluose infusion rte ( 3.3 mg/kg/min) during hyperinsulinemi lmp ws omprle to tht of the ontrol group (3.8 mg/kg/min). Sine the sujets tht eme dieti were more oese (BMI 38 vs. 32 Kg/M 2 ), the smll redution in their gluose infusion rtes TABLE 5. -Cell funtion nd insulin sensitivity of norml gluose tolernt individuls who susequently developed type 2 dietes or IGT Author (Ref.) Sujets -Cell funtion Insulin sensitivity Comments 1. Dnowski et l. (157) 0C, 3FDM Redued (OGTT) NS 2. Struss nd Hles (158) 16C, 12FDM Redued (OGTT) NS 3. Cersi nd Luft (159) 134C, 16FDM Redued (GIT) NS 4. Svge et l. (126) 13C, 13FDM Norml (OGTT) NS 5. Chrles et l. (123) 4079, 23FDM Norml (OGTT) NS d 6. Lillioj et l. (49) 0C, 24FIGT NS NS 7. Sd et l. (160) 12C, 11FDM Inresed (OGTT) NS 8. Lundgren et l. (161) 221C, 8FDM Redued (IVGTT) NS 9. Skrfors et l. (153) 1262C, 46FDM Redued (IVGTT) NS 10. Mrtin et l. (127) 126C, 25FDM Norml (IVGTT) Redued (MM) 11. Lillioj et l. (22) 151C, 17FDM Redued (OGTT) Redued (Clmp) 12. Hffner et l. (23) 545C, 44FDM Redued (OGTT) NS 13. Eriksson nd Lindgrde (122) 4521C, 116FDM Redued (OGTT) NS 14. Chen et l. (125) 114C, 23FDM Redued (OGTT) NS 15. Siree et l. (124) 215C, 14FDM Inresed (OGTT) NS d OGTT, Orl gluose tolerne test; GIT, gluose infusion test; IVGTT, intrvenous gluose tolerne test; MM, miniml model; C, ontrol sujets; FDM, future dieti; FIGT, future impired gluose tolerne; NS, not studied. No ontrols. Inluded IGT. FDM more oese. d Did not evlute erly insulin responses. e Questionle mthing. Downloded from

8 498 GERICH Vol. 19, No. 4 ould e ttriutle to their greter oesity. Moreover the ft tht their ute insulin responses were not greter thn tht of the ontrol group, despite their greter oesity, suggests tht their -ell funtion my hve een impired. These two studies (49, 126) re widely ited s supporting genetilly determined insulin resistne s the initil ftor predisposing to type 2 dietes ut the evidene is equivol. The report of Mrtin et l. (127) represents the sme dt reported y Wrrm et l. (39), whih hs lredy een ommented on in detil. As explined erlier, the oservtions of this study tully re onsistent with the onept tht superimposition of the insulin resistne of oesity upon genetilly impired pity to seretion insulin is ommon sequene leding to type 2 dietes. Chen et l. (125) reported seline dt on 23 individuls who developed type 2 dietes nd ompred them to 144 individuls who remined nondieti. Those who developed type 2 dietes initilly hd impired erly insulin relese during n OGTT. Unfortuntely, out hlf of eh group hd IGT t seline. Thus, it is diffiult to use these dt to distinguish etween geneti use nd one due to gluose toxiity in explining the redued insulin seretion. Tken together, these prospetive studies indite tht oth impired insulin relese nd insulin resistne re risk ftors for development of type 2 dietes nd tht eh n, nd usully does, preede type 2 dietes. However, they do not provide unssille evidene tht either the impired insulin seretion or the insulin resistne neessrily hs geneti sis. V. Studies of Norml Gluose-Tolernt Women with History of Gesttionl Dietes Women who hve experiened trnsient dietes during pregnny (gesttionl dietes) re t high risk to susequently develop type 2 dietes (128), nd it hs een suggested tht gesttionl dietes nd type 2 dietes re the sme disorder (129). Current evidene suggests tht gesttionl dietes ours in women who nnot serete suffiient insulin to ompenste dequtely for the redution in insulin sensitivity tht normlly ours during the third trimester of pregnny (128, 130). This would e nlogous to the sitution wherein person with genetilly redued pity to ugment insulin seretion develops type 2 dietes fter eoming oese. Severl studies summrized in Tle 6 hve exmined insulin seretion nd insulin sensitivity in women with prior gesttionl dietes fter their gluose tolerne hd returned to norml. Of the eight studies ( ) exmining insulin seretion, ll ut one (136) found evidene for redued insulin seretion. On the other hnd, of the five studies (132, 135, ) exmining insulin sensitivity, only one (135) found it to e redued, nd in tht study there ws lso evidene of redued insulin seretion. Thus, if gesttionl dietes represents the forerunner of type 2 dietes, the results of these studies support the view tht defet (possily geneti) in insulin seretion preedes insulin resistne in the pthogenesis of type 2 dietes. It should e pointed out, however, tht gesttionl dietes represents heterogeneous disorder tht my inlude those destined to develop type 2 dietes s well s those with type 1 dietes, ltent dult-onset utoimmune dietes, nd MODY. VI. Reversiility of Insulin Resistne nd Impired Insulin Seretion y Therpeuti Interventions One my exmine the extent to whih insulin resistne or impired insulin seretion represents the underlying geneti predisposition for type 2 dietes y the reltive ility of therpeuti interventions to reverse these normlities. Geneti defets would not e expeted to e ompletely eliminted simply y weight loss unless, of ourse, geneti defets predisposed individuls to eome more insulin resistnt for given mount of weight gin. This possiility, however, seems unlikely sine, s indited erlier in Setion III.A.2, the preponderne of studies indite tht oese norml gluosetolernt individuls with first-degree type 2 dieti reltive re not more insulin resistnt thn omprly oese individuls with no first-degree type 2 dieti reltive. Three studies hve unequivolly demonstrted omplete reversl of insulin resistne with dietry intervention in type 2 dieti ptients ( ). Reversl to norml (143) or ner norml (144) insulin sensitivity hd lso een oserved fter insulin therpy in len nd oese type 2 dieti ptients. In ontrst, no study hs unequivolly demonstrted restitution of norml islet -funtion with therpeuti interventions. Bek-Nielsen et l. (141) studied oese type 2 dieti sujets efore nd fter yer s tretment on weight-reduing diet nd ompred the results to ontrol group of nondieti sujets. Although the type 2 dieti sujets did not ttin norml weight, insulin sensitivity (ssessed y the TABLE 6. -Cell funtion nd insulin sensitivity in norml gluose tolernt women with prior gesttionl dietes Author (Ref.) Sujets -Cell funtion Insulin sensitivity 1. Dornhorst et l. (131) 44C, 44PGD Redued (OGTT) NS 2. Wrd et l. (132) 19C, 19PGD Redued (IVGTT) Norml (MM) 3. Chn et l. (133) 15C, 15PGD Redued (OGTT) NS 4. Dmm et l. (134) 30C, 23PGD Redued (OGTT) NS 5. Ryn et l. (135) 14C, 14PGD Redued (OGTT, IVGTT) Redued (MM) 6. Persson et l. (136) 39C, 108PGD Norml (OGTT) NS 7. Efendi et l. (137) 10C, 17PGD Redued (OGTT, GIT) Norml (SGIT) 8. Ctlno et l. (138) 5C, 5PGD NS Norml (lmp) 9. Dornhorst et l. (139) 7C, 7PGD Redued (OGTT) Norml (ITT) OGTT, Orl gluose tolerne test; IVGTT, intrvenous gluose tolerne test; GIT, gluose infusion test; ITT, insulin tolerne test; MM, miniml model; SGIT, somtosttin, gluose, insulin infusion test; Clmp, euglyemi hyperinsulinemi lmp; C, ontrol sujet; PGD, previous gesttionl dietes; NS, not studied. Downloded from

9 August, 1998 GENETIC BASIS FOR TYPE 2 DIABETES 499 perent derese in plsm gluose fter intrvenous insulin) improved to the point where it ws indistinguishle from tht of the norml ontrols. In ontrst, insulin seretion (evluted s the ute response to intrvenous gluose) remined mrkedly impired. Bk et l. (140) nd Freidenerg et l. (142) found similr resolution of insulin resistne using the euglyemi hyperinsulinemi lmp tehnique. These studies demonstrting the reversiility of insulin resistne ut not impired insulin relese therefore provide evidene tht, in type 2 dietes, insulin resistne my e n quired defet nd tht impired insulin seretion is the geneti ftor. VII. Are All Type 2 Dietis Insulin Resistnt? Although one would expet tht ll people with type 2 dietes should e insulin resistnt simply euse of gluose toxiity (41, 42), suh is tully not the se. Severl studies hve filed to find people with type 2 dietes to e insulin resistnt (27, ). Arner et l. (145), for exmple, hve reported tht newly dignosed len Swedish type 2 dietis re not insulin resistnt ut merely hve impired insulin seretion. Bnerji et l. (27) hve reported tht similr sitution exists mong nonoese lks. Byrne et l. (47) found norml insulin sensitivity in mixed popultion. Furthermore, it ppers tht insulin resistne, when present in this popultion (26, 27), my e lrgely explined on the sis of ody ft distriution. Finlly, two other studies hve found tht British nd Jpnese people with IGT hve impired insulin seretion without eing insulin resistnt (58, 60). Although there re no popultion-sed studies inditing wht perentge of people with type 2 dietes or IGT re insulin resistnt, one n nevertheless onlude tht not ll people with type 2 dietes re insulin resistnt. Thus, insulin resistne is not requirement for development of type 2 dietes. VIII. Hypothesis for Pthogenesis of Type 2 Dietes Bsed on the reviewed evidene, the following working hypothesis is proposed s n explntion for the intertion etween geneti nd environmentl ftors in the pthogenesis of most ses of type 2 dietes, relizing, of ourse, tht type 2 dietes is genetilly nd environmentlly heterogeneous (Fig. 2). This hypothesis is sed on the premise tht threshold exists whih, if exeeded y the umultive dverse effets of geneti nd quired ftors on insulin seretion nd insulin sensitivity, will led to either IGT or type 2 dietes. Another premise of this hypothesis, supported y the literture reviewed, is tht defets in -ell funtion re likely to e the most importnt geneti predisposing ftors. Aording to this shem, in some individuls, depending on the severity, omintion of severl geneti defets or polymorphisms ffeting insulin seretion would e suffiient to use dietes in onjuntion with norml dpttions to ging (e.g., hnges in ody omposition nd physil tivity). Exmples inlude MODY (2, 32), nonoese lks (99), nd Swedes (145) who develop type 2 dietes without eing insulin resistnt. FIG. 2. Hypothesis for intertion of geneti nd environmentl ftors in the pthogenesis of type 2 dietes. Four possile omintions re depited. Length of segments in eh r reflets severity of the dverse influene of the ftor on gluose tolerne. In most individuls, however, multiple geneti defets in insulin seretion my e neessry ut not suffiient to use dietes without quired ftors suh s superimposition of insulin resistne (e.g., pregnny, weight gin, gluose toxiity, physil intivity, et.) or without the simultneous presene of dietes-relted or dietogeni genes using or predisposing to insulin resistne. An experimentl exmple of suh sitution omes from the results of reent knokout studies in mie (152): mie with homozygous knokout of insulin reeptor sustrte 1 (IRS 1) hd insulin resistne nd hyperinsulinemi ut mintined NGT with ging. Mie heterozygous for knokout of the -ell gluokinse (GK) gene developed gluose intolerne with ging due to redued insulin seretion. Doule knokout mie (IRS 1 plus GK) developed overt dietes with ging. In different individuls, different omintions of geneti defets of insulin seretion nd insulin tion nd of environmentl ftors re expeted. This ould redily provide n explntion of the heterogeneity of type 2 dietes. For simpliity, if one ssumes 1) tht two defetive -ell genes re required nd four exist; nd 2) tht, in ddition, one environmentl ftor is needed nd four exist (e.g., overeting, redued physil tivity, toxins, gluose toxiity); nd 3) tht one geneti polymorphism in either ppetite or energy expenditure or ody ft distriution is needed, the unique omintion of these elements leding to dietes would exeed IX. Summry nd Conlusion Despite the ft tht it is the prevlent view tht insulin resistne is the min geneti ftor predisposing to development of type 2 dietes, review of severl lines of evidene in the literture indites lk of overwhelming support for this onept. In ft, the literture etter supports the se of impired insulin seretion eing the initil nd min geneti Downloded from

10 500 GERICH Vol. 19, No. 4 ftor predisposing to type 2 dietes, espeilly 1) the studies in people t high risk to susequently develop type 2 dietes (disordnt monozygoti twins nd women with previous gesttionl dietes), 2) the studies demonstrting ompete llevition of insulin resistne with weight loss, nd 3) the studies finding tht people with type 2 dietes or IGT n hve impired insulin seretion nd no insulin resistne ompred with well mthed NGT sujets. The ft tht insulin resistne my e lrgely n quired prolem in no wy lessens its importne in the pthogenesis of type 2 dietes. Life style hnges (exerise, weight redution) nd phrmologil gents (e.g., igunides nd thizolidendiones) tht redue insulin resistne or inrese insulin sensitivity lerly hve mjor enefiil effets (122, , ). Referenes 1. MCrty D, Zimmet P 1994 Dietes 1994 to 2010: glol estimtes nd projetions. Byer Pus ISBN Fjns S 1989 Mturity-onset dietes of the young (MODY). Dietes Met Rev 5: Nisknen L, Tuomi T, Krjlinen J, Groop L, Uusitup M 1995 GAD ntiodies in NIDDM: ten-yer follow-up from the dignosis. Dietes Cre 18: Geritz K, Gempel K, Brdizk D 1996 Mitohondri nd dietes: geneti, iohemil, nd linil implitions of the ellulr energy iruit. Dietes 45: Moller D, Flier J 1991 Insulin resistne mehnisms, syndromes, nd implitions. N Engl J Med 325: Tylor SI 1992 Moleulr mehnisms of insulin resistne. Lessons from ptients with muttions in the insulin-reeptor gene. Dietes 41: Hnis C, Boerwinkle E, Chkrorty R, Ellsworth D, Connnon P, Stirling B, Morrison V, Wopelhorst B, Spielmn R, Gogolin- Ewens K, Shephrd J, Willims S, Rish N, Hinids D, Iwski N, Ogt M, Omori Y, Petzold C, Rietzsh H, Shroder H, Shulze J, Cox N, Menzel S, Bourj V, Chen X, Lim L, Lindner T, Meren L, Wng Y, Xing K, Ymgot K, Bell G 1996 A genome-wide serh for humn non-insulin-dependent (type 2) dietes genes revels mjor suseptiility lous on hromosome 2. Nt Genet 13: Mhtni M, Widen E, Lehto M, Thoms J, MCrthy M, Bryer J, Brynt B, Chn G, Dly M, Forslom C, Knninen T, Kiry A, Kruglyk L, Munnelly K, Prkkonen M, Reev-Dly M, Wever A, Brettin T, Duyk G, Lnder E, Groop L 1996 Mpping of gene for type 2 dietes ssoited with n insulin seretion defet y genome sn in Finnish fmilies. Nt Genet 14: Hmmn R 1992 Geneti nd environmentl determinnts of noninsulin dependent dietes mellitus (NIDDM). Dietes Met Rev 8: Khn C 1994 Insulin tion, dietogenes, nd the use of type II dietes. Dietes 43: Bouhrd C 1995 Genetis nd the metoli syndrome. Int J Oesity 19[Suppl]:S52 S Yki-Järvinen H 1995 Role of insulin resistne in the pthogenesis of NIDDM. Dietologi 38: Hles C, Brker D 1992 Type 2 (non-insulin-dependent) dietes mellitus: the thrifty phenotype hypothesis. Dietologi 35: Hitmn G, Metlfe K 1993 The genetis of dietes n updte. Dietes Annu 7: Turner R, Httersley A, Shw J, Levy J 1995 Type II dietes: linil spets of moleulr iologil studies. Dietes 44: Grnner D, O Brien R 1992 Moleulr physiology nd genetis of NIDDM. Dietes Cre 15: Aitmn T, Todd J 1995 Moleulr genetis of dietes mellitus. Billieres Clin Endorinol Met 9: Iselius L, Lindsten J, Morton N, Efendi S, Cersi E, Hegermrk A, Luft R 1985 Geneti regultion of the kinetis of gluose-indued insulin relese in mn. Clin Genet 28: Bogrdus C, Lillioj S, Nyom B, Zurlo F, Swinurn B, Esposito- DelPuente A, Knowler W, Rvussin E, Bennett P 1989 Distriution of in vivo insulin tion in Pim Indins s mixture of three norml distriutions. Dietes 38: Mrtin B, Wrrm J, Rosner B, Rih S, Soeldner J, Krolewski A 1992 Fmilil lustering of insulin sensitivity. Dietes 41: DeFronzo R, Bondonn R, Ferrnnini E 1992 Pthogenesis of NIDDM lned overview. Dietes Cre 15: Lillioj S, Mott D, Sprul M, Ferrro R, Foley J, Rvussin E, Knowler W, Bennett P, Bogrdus C 1993 Insulin resistne nd insulin seretory dysfuntion s preursors of non-insulin-dependent dietes mellitus: prospetive studies of Pim Indins. N Engl J Med 329: Hffner S, Miettinen H, Gskill S, Stern M 1995 Deresed insulin seretion nd inresed insulin resistne re independently relted to the 7-yer risk of NIDDM in Mexin-Amerins. Dietes 44: Bjorntorp P 1988 Adominl oesity nd the development of noninsulin-dependent dietes mellitus. Dietes Met Rev 4: Kisseh A, Freedmn D, Peiris A 1989 Helth risk of oesity. Med Clin North Am 73: Crey D, Jenkins A, Cmpell L, Freund J, Chisholm D 1996 Adominl ft nd insulin resistne in norml nd overweight women: diret mesurements revel strong reltionship in sujets t oth low nd high risk of NIDDM. Dietes 45: Bnerji M, Chiken R, Gordon D, Krl J, Leovitz H 1995 Does intr-dominl dipose tissue in lk men determine whether NIDDM is insulin-resistnt or insulin-sensitive? Dietes 44: Olefsky J, Noln J 1995 Insulin resistne nd non-insulin-dependent dietes mellitus: ellulr nd moleulr mehnisms. Am J Clin Nutr 61:980S 986S 29. Bek-Nielsen H, Groop L 1994 Metoli nd geneti hrteriztion of predieti sttes. Sequene of events leding to noninsulin-dependent dietes mellitus. J Clin Invest 94: Piment W, Kortytkowski M, Mitrkou A, Jenssen T, Yki-Jrvinen H, Evron W, Diley G, Gerih J 1995 Pnreti et-ell dysfuntion s the primry geneti lesion in NIDDM. JAMA 273: Cersi E 1995 Insulin defiieny nd insulin resistne in the pthogenesis of NIDDM: is divore possile. Dietologi 38: Polonsky K, Sturis J, Bell G 1996 Noninsulin-dependent dietes mellitus genetilly progrmmed filure of the et ell to ompenste for insulin resistne. N Engl J Med 334: Tylor SI, Aili D, Imi Y 1994 Insulin resistne or insulin defiieny. Whih is the primry use of NIDDM? Dietes 43: Cersi E, Luft R 1967 Wht is inherited wht is dded hypothesis for the pthogenesis of dietes mellitus. Dietes 16: DeFronzo R, Bondonn R, Ferrnnini E 1997 Pthogenesis of NIDDM. In: Alerti K, Zimmet P, DeFronzo R (eds) Interntionl Textook of Dietes Mellitus. Wiley nd Sons, New York, pp Olefsky J 1995 Dietes mellitus (type II): etiology nd pthogenesis. In: DeGroot L, Besser M, Burger H, Jmeson J, Loriux D, Mrshll J, O Dell W, Potts J, Ruenstein A (eds) Endorinology. W. B. Sunders, Phildelphi, pp Grer A 1994 Dietes mellitus. In: Stein J, Hutton J, Kohler P, O Rourke R, Reynolds H, Smuels M, Snde M, Trier J, Zvrfler N (eds) Internl Mediine. C.V. Mosy, Boston, pp Trgher G, Alerihe M, Zenere M, Bondonn R, Muggeo M, Bonor E 1997 Cigrette smoking nd insulin resistne in ptients with noninsulin-dependent dietes mellitus. J Clin Endorinol Met 82: Wrrm J, Mrtin B, Krolewski A, Soeldener S, Khn C 1990 Slow gluose removl rte nd hyperinsulinemi preede the development of type II dietes in the offspring of dieti prents. Ann Intern Med 113: Guguier D, Froguel P, Prent V, Bernrd C, Bihoreu M, Porth B, Jmes M, Peniud L, Lthrop M, Ktorz A 1996 Chromosoml Downloded from