364 Review Fetl progrmming of coronry hert disese Dvid J.P. Brker People who develop coronry hert disese grow differently from other people both in utero nd during childhood. Slow growth during fetl life nd infncy is followed by ccelerted weight gin in childhood. Two disorders tht predispose to coronry hert disese, type 2 dibetes nd hypertension, re preceded by similr pths of growth. Mechnisms underlying this re thought to include the development of insulin resistnce in utero, reduced numbers of nephrons ssocited with smll body size t birth nd ltered progrmming of the micro-rchitecture nd function of the liver. Slow fetl growth might lso heighten the body s stress responses nd increse vulnerbility to poor living conditions in lter life. Coronry hert disese Dvid J.P. Brker MRC Environmentl Epidemiology Unit, University of Southmpton, Southmpton Generl Hospitl, Southmpton, UK SO16 6YD. e-mil: djpb@ mrc.soton.c.uk The serch for the cuses of coronry hert disese hs hitherto been guided by destructive model. The cuses to be identified were thought to ct in dult life nd to ccelerte destructive processes, such s the formtion of therom, rise in blood pressure nd loss of glucose tolernce. However, it hs recently been shown tht the growth of people who develop coronry hert disese differs from tht of other people during fetl life, infncy nd childhood. This hs led to new developmentl model for the disese [1 3]. Figure 1 shows the growth of 357 boys who in lter life were either dmitted to hospitl with coronry hert disese or died from it [1]. They belong to cohort of 4630 men who were born in Helsinki during 1934 1944, nd their growth is expressed s stndrd devition or Z-scores. The Z-score for the cohort is set t zero, nd boy mintining stedy position s lrge or smll in reltion to other boys would follow horizontl pth on the figure. However, boys who lter developed coronry hert disese were smll t birth, remined smll in infncy, but hd ccelerted gin in weight nd body mss index (BMI) therefter. By contrst, their heights remined below verge, which is consistent with the known ssocition between coronry hert disese nd short dult stture [4]. Findings in girls re similr but mong those who lter developed coronry hert disese ccelerted weight gin begn round the ge of four yers. Tble 1 shows hzrd rtios for coronry hert disese ccording to size t birth [1]. The hzrd rtios fll with incresing birthweight nd, more strongly, with incresing ponderl index (birthweight/length 3 ), mesure of thinness t birth. These trends were found in bbies born t term or Stndrd devition (Z)-score 0.05 0 0.05 0.10 0.15 0.20 Cohort 0.25 0 1 2 3 4 5 6 7 8 9 10 11 12 Age (yers) BMI Weight Height TRENDS in Endocrinology & Metbolism Fig. 1. Growth of 357 boys who lter developed coronry hert disese in cohort of 4630 boys born in Helsinki. Abbrevition: BMI, body mss index. premturely nd therefore reflect slow intruterine growth. Tble 2 shows tht the hzrd rtios lso fell with incresing weight, height nd BMI t ge one yer. Low weight gin during infncy predicts coronry hert disese independently of size t birth. In simultneous nlysis with birthweight the hzrd rtio ssocited with ech unit decrese in Z-score for weight between birth nd one yer ws 1.21 (95% CI, 1.08 1.36, P = 0.001). The ssocition between coronry hert disese nd smll size t birth hs been shown in studies in Europe, North Americ nd Indi [5 9]. The ssocition with poor weight gin in infncy ws first shown in study of 5654 men born in Hertfordshire during 1911 1930 [5], nd confirmed in Helsinki [1], the strength of the ssocition being similr in the two studies. Tble 3, bsed on the sme dt used in Fig. 1, shows the combined effects of ponderl index t birth nd chnge in BMI between one nd 11 yers of ge [1]. The tble uses BMI t ge 11 yers, but the BMI t ges round this gives similr results. Boys who hd low ponderl index t birth incresed their risk of coronry hert disese if their body mss rose in childhood. The interction between ponderl index t birth nd BMI in childhood is highly sttisticlly significnt. Findings mong girls re similr. In both sexes the risk of coronry hert disese is determined more by the tempo of weight gin thn the body size ttined [10]. 1043-2760/02/$ see front mtter 2002 Elsevier Science Ltd. All rights reserved. PII: S1043-2760(02)00689-6
Review 365 Tble 1. Hzrd rtios for coronry hert disese ccording to body size t birth Hzrd rtio (95% CI) No. of cses/ No. of men Birthweight (g) <2500 3.63 (2.02 6.51) 24/160 3000 1.83 (1.09 3.07) 45/599 3500 1.99 (1.26 3.15) 144/1775 4000 2.08 (1.31 3.31) 123/1558 >4000 1.00 21/538 P for trend 0.006 Ponderl index (kg m 3 ) <25 1.66 (1.11 2.48) 104/1093 27 1.44 (0.97 2.13) 135/1643 29 1.18 (0.78 1.78) 84/1260 >29 1.00 31/578 P for trend 0.0006 Dt tken from Ref. [1]. index t birth nd BMI in childhood is highly sttisticlly significnt. Findings mong girls re similr. In both sexes the risk of coronry hert disese is determined more by the tempo of weight gin thn the body size ttined [10]. Growth nd hypertension nd type 2 dibetes There is now substntil body of evidence showing tht people who were smll t birth remin biologiclly different to people who were lrger. The differences include n incresed susceptibility to hypertension nd type 2 dibetes mellitus (T2DM), two disorders tht re closely linked to coronry hert disese [11 15] nd which re ssocited with the Tble 2. Hzrd rtios for coronry hert disese ccording to body size t one yer of ge Hzrd rtio (95% CI) No. of cses/ No. of men Weight (kg) 9 1.82 (1.25 2.64) 96/781 10 1.17 (0.80 1.71) 85/1126 11 1.12 (0.77 1.64) 89/1243 12 0.94 (0.62 1.44) 49/852 >12 1.00 38/619 P for trend <0.0001 Height (cm) 73 1.55 (1.11 2.18) 79/636 75 0.90 (0.63 1.27) 68/962 77 0.94 (0.68 1.31) 87/1210 79 0.83 (0.58 1.18) 64/1011 >79 1.00 59/802 P for trend 0.007 Body mss index (kg m 2 ) 16 1.83 (1.28 2.60) 72/654 17 1.61 (1.15 2.25) 89/936 18 1.29 (0.91 1.81) 83/1136 19 1.12 (0.77 1.62) 59/941 >19 1.00 54/954 P for trend 0.0004 Dt tken from Ref. [1]. Tble 3. Hzrd rtios (95% CI) for coronry hert disese ccording to ponderl index t birth nd chnge in body mss index between one nd 11 yers of ge Ponderl index Chnge in body mss index (kg m 2 ) (kg m 2 ) Fll Rise 25 1.3 (0.7 2.3) 2.5 (1.4 4.4) 27 1.3 (0.8 2.3) 2.2 (1.3 4.0) 29 1.3 (0.7 2.2) 1.3 (0.7 2.6) >29 1.0 1.1 (0.4 2.9) sme generl pttern of growth s coronry hert disese. The risks for ech disese fll with incresing birthweight nd rise with incresing childhood BMI. Similr to coronry hert disese, risk is not determined only by the bsolute vlue of BMI in childhood but by the combintion of body size t birth nd during childhood [11,13]. It is the tempo of growth in ddition to the ttined body size tht determines risk. There is lso substntil literture showing tht birthweight is ssocited with differences in blood pressure nd insulin secretion within the norml rnge [14,15]. These differences re found in children nd dults but they tend to be smll. For exmple, 1-kg difference in birthweight is ssocited with ~1 2 mm Hg difference in systolic pressure [15]. This contrsts with the lrge effects of birthweight on hypertension. In the Helsinki cohort born 1934 1944, the cumultive incidence of hypertension requiring mediction fell from 20.2% in men nd women weighing <3000 g t birth to 12.3% in those weighing >4000 g [16]. Biologicl mechnisms The ssocition between ltered growth nd coronry hert disese hs led to the suggestion tht the disese might originte in two phenomen ssocited with development developmentl, or phenotypic plsticity nd compenstory growth. Phenotypic plsticity is the phenomenon whereby one genotype gives rise to rnge of different physiologicl or morphologicl sttes in response to different environmentl conditions during development [17]. Such gene environment interctions re ubiquitous in development. Their existence is demonstrted by the numerous experiments showing tht minor ltertions to the diets of pregnnt nimls, which my not even chnge their offspring s body size t birth, cn produce lsting chnges in their physiology nd metbolism including ltered blood pressure nd glucose/insulin nd lipid metbolism [18,19]. Evidence of gene nutrient interctions in the genesis of type 2 dibetes is beginning to pper [20]. The effects of polymorphism of the gene encoding peroxisome prolifertor-ctivted receptor γ2 (PPARG2) depends on birthweight, which serves s mrker for intruterine nutrition. It hs been suggested tht the Pro12Al polymorphism of the gene increses tissue sensitivity to insulin nd
366 Review Tble 4. Men fsting insulin concentrtion nd HOMA-IR index ccording to PPAR-γ gene polymorphism nd birthweight,b Birthweight (g) 3000 3500 >3500 P b Fsting insulin (pmol l 1 ) Pro12Pro (n) 84 (56) 71 (161) 65 (107) 0.003 Pro12Al/Al12Al (n) 60 (37) 60 (67) 65 (48) 0.31 P c 0.008 0.02 0.99 Abbrevitions: HOMA-IR, homeostsis model ssessment-insulin resistnce; PPAR-γ, peroxisome prolifertor-ctivted protein-γ. b Numbers of subjects in ech cell re shown within prentheses. b For the difference mong birthweight groups. c For the difference between the Pro12Pro nd Pro12Al/Al12Al genotypes. thereby protects ginst T2DM. Tble 4 is bsed on study of 476 elderly people in Helsinki. The Pro12Al polymorphism only influenced fsting plsm insulin concentrtions in men nd women who hd low birthweight. As hs been shown mny times, low birthweight ws ssocited with rised plsm insulin concentrtions, indicting insulin resistnce. This, however, ws confined to people with the Pro12Pro polymorphism: the Pro 12Al polymorphism protected ginst the effect. The interction between the effects of the gene nd of birthweight ws sttisticlly significnt (P = 0.03). When undernutrition during development is followed by improved nutrition, mny nimls stge ccelerted or compenstory growth in weight or length. This restores the niml s body size but might hve long-term costs, which include reduced lifespn [21]. There re severl possible mechnisms by which reduced fetl nd infnt growth followed by ccelerted weight gin in childhood might led to coronry hert disese. Bbies who re thin t birth lck muscle, deficiency tht will persist becuse the crucil period for muscle growth is ~30 weeks in utero, nd there is little cell repliction fter birth [22]. If they gin weight rpidly in childhood, they re lible to put on ft rther thn muscle, leding to disproportiontely high ft mss in lter life. This might be ssocited with the development of insulin resistnce becuse children nd dults who hd low birthweight but re currently hevy re insulin resistnt [14,23,24]. Another mechnism linking retrded erly growth followed by compenstory growth with lter disese is through the effect of growth on the kidney. Smll Tble 5. Hzrd rtios (95% CI) for coronry hert disese ccording to ponderl index t birth nd txble income in dult life Household income 1000 mrks (pounds sterling) per yer Ponderl index (kg m 3 ) <26.0 (n = 1475) >26.0 (n = 2154) >140 (15 700) 1.00 1.19 (0.65 to 2.19) 111 140 (15 700) 1.54 (0.83 to 2.87) 1.42 (0.78 to 2.57) 96 110 (12 400) 1.07 (0.51 to 2.22) 1.66 (0.90 to 3.07) 76 95 (10 700) 2.07 (1.13 to 3.79) 1.44 (0.79 to 2.62) 75 (8 400) 2.58 (1.45 to 4.60) 1.37 (0.75 to 2.51) P for trend <0.001 0.75 bbies hve reduced numbers of nephrons [25,26]. It hs been suggested tht this leds to hyperperfusion of ech nephron nd consequent glomerulr sclerosis. Rpid childhood growth is thought to increse the hyperperfusion. Aging brings nephron loss, nephron deth nd cycle of incresing blood pressure, glomerulr sclerosis nd nephron deth is initited, leding to the development of hypertension. This frmework fits with the hypothesis tht essentil hypertension is disorder of growth with two seprte mechnisms, growth-promoting process in childhood nd self-perpetuting mechnism, which might be initited erly but cts in dult life [27]. The existence of such self-perpetuting cycles, initited in utero, but triggered by ging or other influences in lter life, would explin the smll effects of birth size on blood pressure levels in the norml popultion, but its lrge effects on the risk of hypertension [16]. Findings in Hertfordshire suggest tht one of the mechnisms linking poor weight gin in infncy with coronry hert disese is ltered liver function, reflected in rised serum concentrtions of totl nd low density lipoprotein cholesterol, nd rised plsm fibrinogen concentrtions [28,29]. Unlike orgns such s the kidney, the liver remins plstic during its development until the ge of round five yers. Its function might be permnently chnged by influences tht ffect its erly growth [30 32]. Support for n importnt role for liver development in the erly pthogenesis of coronry hert disese comes from findings in Sheffield [33]. Among men nd women reduced bdominl circumference t birth, mesure tht reflects reduced liver size, gve stronger predictions of lter serum cholesterol nd plsm fibrinogen thn ny other mesure of body size t birth. Responses to dult living stndrds Observtions on nimls show tht the environment during development permnently chnges not only the body s structure nd function but lso its responses to environmentl influences encountered in lter life [34]. Tble 5 shows the effect of low income in dult life on coronry hert disese mong men in Helsinki [35]. As expected, men who hd low txble income hd higher rtes of the disese [36,37]. There is no greed explntion for this nd it is mjor component of the socil inequlities in helth in Western countries. However, the effect of low income is confined to men who hd slow fetl growth nd were thin t birth, defined by ponderl index <26 kg m 3. Men who were not thin t birth were resilient to the effects of low income on coronry hert disese, so tht there ws sttisticlly significnt interction between the effects of fetl growth nd dult income (P = 0.005). One explntion of these findings emphsizes the psychosocil consequences of low position in the socil hierrchy, s indicted by low income nd socil clss, nd suggests tht perceptions of low socil sttus nd lck of success led to chnges in
Review 367 neuroendocrine pthwys nd hence to disese [38]. The findings in Helsinki seem consistent with this. People who re smll t birth re known to hve persisting ltertions in responses to stress, including rised serum cortisol concentrtions [39]. It is suggested tht persisting smll elevtions of cortisol concentrtions over mny yers might hve effects similr to those seen when tumours led to more sudden, lrge increses in glucocorticoid concentrtions. People with Cushing s syndrome re insulin resistnt nd hve rised blood pressure. Interctions New studies, especilly those of the two exceptionlly well-documented cohorts in Helsinki, incresingly suggest tht coronry hert disese nd the disorders relted to it develop through series of interctions. The effects of genes re conditioned by fetl growth [20]: the effects of smll body size t birth re conditioned by growth during childhood [1], nd by living conditions in childhood [16] nd dult life [35]. Any one influence, such s low income, does not hve single quntifible risk ssocited with it. Its risk to n individul is conditioned by events t erlier crucil stges of development. This embodies the concept of development switches triggered by the environment. Sttements such s low birthweight explins only smll proportion of dibetes [40] re incorrect. The results in Tbles 1 5 show tht the lrge effects [41] of smll body size t birth extend cross the rnge of birthweight nd re not confined to those conventionlly described s hving low birthweight, <2.5 kg (5.5 lb). The effects of birthweight cnnot be quntified s smll proportion or lrge proportion. Fetl life is n importnt phse in brnching pth of development. The brnchings re triggered by the environment nd determine the vulnerbility of ech individul to wht lies hed. Birthweight, lthough convenient mrker in epidemiologicl studies, is n indequte description of the phenotypic chrcteristics of bby tht determine its long-term helth. The wrtime fmine in Hollnd produced lifelong insulin resistnce in bbies who were in utero t the time, with little ltertion in birthweight [42]. In bbies, s in children, slowing of growth is response to poor environment, but it does not describe the morphologicl nd physiologicl consequences [43]. The sme birthweight cn be ttined by mny different pths of fetl growth nd ech is probbly ccompnied by different gene environment interctions. Conclusion The ssocitions between slow fetl, infnt nd childhood growth nd lter coronry hert disese re strong nd grded. Boys who t birth hd ponderl index bove 26 kg m 3 nd who t one yer of ge were bove the cohort verge for BMI (17.7 kg m 3 ) nd height (76.2 cm) were t hlf the risk of developing coronry hert disese before the ge of 65 yers [1]. Such findings confirm the strong effects of erly growth on lter disese [41]. The principl determinnt of growth rtes in erly life is the vilbility of nutrition [43]. As yet, we do not know the impct of mternl nutrition on fetl nutrition. However, it is becoming cler tht the concept of mternl nutrition must be extended beyond the mother s diet in pregnncy to include her body composition nd metbolism both during pregnncy nd t the time of conception [44]. Moreover, birthweight is n indequte summry mesure of fetl experience, nd we need more sophisticted view of optiml fetl development, which tkes ccount of the long-term sequele of fetl responses to undernutrition. References 1 Eriksson, J.G. et l. (2001) Erly growth nd coronry hert disese in lter life: longitudinl study. Br. Med. J. 322, 949 953 2 Brker, D.J.P. (1995) Fetl origins of coronry hert disese. Br. Med. J. 311, 171 174 3 Brker, D.J.P. (1998) Mothers, Bbies nd Helth in Lter Life (2nd edn), Churchill Livingstone 4 Mrmot, M.G. et l. (1984) Inequlities in deth specific explntions of generl pttern? Lncet 1, 1003 1006 5 Brker, D.J.P. et l. (1989) Weight in infncy nd deth from ischemic hert disese. Lncet 2, 577 580 6 Leon, D. et l. (1998) Reduced fetl growth rte nd incresed risk of deth from ischemic hert disese: cohort study of 15 000 Swedish men nd women born 1915 29. Br. Med. J. 317, 241 245 7 Frnkel, S. et l. (1996) Birthweight, body-mss index in middle ge, nd incident coronry hert disese. Lncet 348, 1478 1480 8 Rich-Edwrds, J.W. et l. (1997) Birthweight nd risk of crdiovsculr disese in cohort of women followed up since 1976. Br. Med. J. 315, 396 400 9 Stein, C.E. et l. (1996) Fetl growth nd coronry hert disese in South Indi. Lncet 348, 1269 1273 10 Forsen, T. et l. (1999) Growth in utero nd during childhood mong women who develop coronry hert disese: longitudinl study. Br. Med. J. 319, 1403 1407 11 Eriksson, J.G. et l. (2000) Fetl nd childhood growth nd hypertension in dult life. Hypertension 36, 790 794 12 Curhn, G.C. et l. (1996) Birthweight nd dult hypertension nd obesity in women. Circultion 94, 1310 1315 13 Forsen, T. et l. (2000) The fetl nd childhood growth of persons who develop type 2 dibetes. Ann. Intern. Med. 133, 176 182 14 Lithell, H.O. et l. (1996) Reltion of size t birth to non-insulin dependent dibetes nd insulin concentrtions in men ged 50 60 yers. Br. Med. J. 312, 406 410 15 Huxley, R.R. et l. (2000) The role of size t birth nd postntl ctch-up growth in determining systolic blood pressure: systemtic review of the literture. J. Hypertens. 18, 815 831 16 Brker, D.J.P. et l. Growth nd living conditions in childhood nd hypertension in dult life: longitudinl study. J. Hypertens. (in press) 17 West-Eberhrd, M.J. (1989) Phenotypic plsticity nd the origins of diversity. Annu. Rev. Ecol. Syst. 20, 249 278 18 Kwong, W.Y. et l. (2000) Mternl undernutrition during the preimplnttion period of rt development cuses blstocyst bnormlities nd progrmming of postntl hypertension. Development 127, 4195 4202 19 Desi, M. nd Hles, C.N. (1997) Role of fetl nd infnt growth in progrmming metbolism in lter life. Biol. Rev. Cmb. Philos. Soc. 72, 329 348 20 Eriksson, J.G. et l. (2002) The effects of the Pro12Al polymorphism of the peroxisome prolifertor-ctivted receptor-γ2 gene on insulin sensitivity nd insulin metbolism interct with size t birth. Dibetes 51, 2321 2324 21 Metclfe, N.B. nd Monghn, P. (2001) Compenstion for bd strt: grow now, py lter? Trends. Ecol. Evol. 16, 254 260
368 Review 22 Widdowson, E.M. et l. (1972) Cellulr development of some humn orgns before birth. Arch. Dis. Child. 47, 652 655 23 Brker, D.J.P. et l. (1993) Type 2 (non-insulindependent) dibetes mellitus, hypertension nd hyperlipidemi (syndrome X): reltion to reduced fetl growth. Dibetologi 36, 62 67 24 Bvdekr, A. et l. (1999) Insulin resistnce syndrome in 8-yer-old Indin children. Smll t birth, big t 8 yers, or both? Dibetes 48, 2422 2429 25 Brenner, B.M. nd Chertow, G.M. (1994) Congenitl oligonephropthy nd the etiology of dult hypertension nd progressive renl injury. Am. J. Kidney Dis. 23, 171 175 26 Merlet-Bénichou, C. et l. (1993) Retrd de croissnce intr-utérin et déficit en néphrons. (Intruterine growth retrdtion nd inborn nephron deficit). Médecine/Sciences 9, 777 780 27 Lever, A.F. nd Hrrp, S.B. (1992) Essentil hypertension: disorder of growth with origins in childhood? J. Hypertens. 10, 101 120 28 Fll, C.H.D. et l. (1992) Reltion of infnt feeding to dult serum cholesterol concentrtion nd deth from ischemic hert disese. Br. Med. J. 304, 801 805 29 Brker, D.J.P. et l. (1992) Reltion of fetl nd infnt growth to plsm fibrinogen nd fctor VII concentrtions in dult life. Br. Med. J. 304, 148 152 30 Gebhrdt, R. (1992) Metbolic zontion of the liver: regultion nd implictions for liver function. Phrmcol. Ther. 53, 275 354 31 Desi, M. et l. (1995) Adult glucose nd lipid metbolism my be progrmmed during fetl life. Biochem. Soc. Trns. 23, 331 335 32 Kind, K.L. et l. (1999) Restricted fetl growth nd the response to dietry cholesterol in the guine pig. Am. J. Physiol. 277, R1675 R1682 33 Brker, D.J.P. et l. (1993) Growth in utero nd serum cholesterol concentrtions in dult life. Br. Med. J. 307, 1524 1527 34 Bteson, P. nd Mrtin, P. (1999) Design for Life: How Behviour Develops, Jonthn Cpe 35 Brker, D.J.P. et l. (2001) Size t birth nd resilience to the effects of poor living conditions in dult life: longitudinl study. Br. Med. J. 323, 1273 1276 36 Mrmot, M. nd McDowell, M.E. (1986) Mortlity decline nd widening socil inequlities. Lncet 2, 274 276 37 Mcintyre, K. et l. (2001) Reltion between socio-economic deprivtion nd deth from first myocrdil infrction in Scotlnd: popultion bsed nlysis. Br. Med. J. 322, 1152 1153 38 Mrmot, M. nd Wilkinson, R.G. (2001) Psychosocil nd mteril pthwys in the reltion between income nd helth: response to Lynch et l. Br. Med. J. 322, 1233 1236 39 Phillips, D.I.W. et l. (2000) Low birthweight predicts elevted plsm cortisol concentrtions in dults from three popultions. Hypertension 35, 1301 1306 40 Zimmet, P. et l. (2001) Globl nd societl implictions of the dibetes epidemic. Nture 414, 782 787 41 Brker D.J.P. et l. (2002) Fetl origins of dult Erly progrmming of glucose insulin metbolism Susn E. Oznne nd C. Nichols Hles Epidemiologicl studies hve reveled strong inverse reltionships between birthweight nd the risk of developing type 2 dibetes mellitus (T2DM) nd the metbolic syndrome. The mechnistic bsis of these reltionships remins the subject of reserch nd debte. Evidence for the importnce of the fetl environment hs been obtined from both humn nd rodent studies. Studies of monozygotic twins hve shown tht genetic effects cnnot explin these reltionships entirely, if t ll. Fetl nd erly postntl growth restriction produced by feeding reduced protein diet to rt dms leds to T2DM in old mle offspring nd, if combined with n obesity-inducing diet fter wening, to ll the fetures of the metbolic syndrome. Published online: 12 September 2002 Susn E. Oznne C. Nichols Hles* Dept of Clinicl Biochemistry, Level 4, Addenbrooke s Hospitl, Hills Rod, Cmbridge, UK CB2 2QR. *e-mil: cnh1000@ cm.c.uk As mny s 70 yers go, it ws recognized tht the erly environment in which child grows could hve long-term effects on its helth [1]. This ws bsed on observtions in the UK nd Sweden tht deth rtes in specific ge groups depended more upon the dte of birth of individuls thn upon the yer under considertion [1]. Further evidence for the importnce of the erly environment cme from study by Forsdhl et l. [2], who looked t geogrphicl vritions in current deth rtes from rteriosclerotic hert disese in Norwy. This showed tht there ws significnt positive correltion between these current deth rtes nd geogrphicl vrition in pst infnt mortlity rtes. No such reltionship ws observed with current infnt mortlity rtes [2]. Similrly, it ws subsequently shown tht the geogrphicl pttern of mortlity from crdiovsculr disese (CVD) in Englnd nd Wles ws relted to mternl nd neontl mortlity erlier in the century [3]. The hypothesis tht this pttern could be explined by reltionship between poor nutrition in fetl nd erly life nd CVD ws supported by study of men in Englnd for whom birthweight records were vilble: men of low birthweight nd low weight t one yer of ge experienced incresed deth rtes from ischemic hert disese lter in life [4]. An inverse reltionship hs lso been observed between birthweight nd systolic blood pressure [5]. Fetl nd neontl life re known to be crucil periods for pncretic β-cell development, becuse by one yer of ge, round hlf of the dult β mss is lredy present [6]. In light of this informtion nd the findings of epidemiologicl studies, reltionship between erly growth nd the subsequent development of glucose intolernce nd type 2 dibetes mellitus (T2DM) ws sought, initilly in group of men in Hertfordshire, UK. Glucose tolernce tests were performed on these 64-yer old men for whom birthweight records were vilble [7]. The proportion of men with impired glucose tolernce 1043-2760/02/$ see front mtter 2002 Elsevier Science Ltd. All rights reserved. PII: 10.1016/S1043-2760(02)00666-5