Diabetlgia 17, 213-22 (1979) Diabetlgia 9 by Springer-Verlag 1979 Originals Tempral Relatinship f Glycsylated Haemglbin Cncentratins t Glucse Cntrl in Diabetics P. J. Dunn, R. A. Cle, J. S. Seldner, R. E. Gleasn, E. Kwa, H. Firzabadi, D. Yunger, and C. A. Graham E. P. Jslin Research Labratry and Jslin Clinic Divisin f the Jslin Diabetes Fundatin, Inc., Bstn, MA, New England Deacness Hspital, and Department f Medicine, Peter Bent Brigham Hspital and Harvard Medical Schl, Bstn, MA, USA Summary. T examine the tempral relatinship between Hb Aic values and varius indices f bld glucse cntrl, 38 diabetic and 28 nndiabetic yuth cunsellrs emplyed at tw summer camps fr diabetic children tk part in an eight-week study. Each week fasting determinatins were made f Hb AI, Hb Al~, serum chlesterl, triglyceride and grwth hrmne and plasma glucse. Ttal daily urine glucse excretin was measured apprximately tw times per week, capillary glucse values were measured fasting and at 11 a. m. and 3 p. m. n tw days per week, and urine glucse was measured semiquantitatively fur times per day. As Hb AI was crrelated highly with Hb AI (r =.997), it was used as the primary index f glycsylated haemglbin. The mean values f Hb AI, serum chlesterl and triglycerides and fasting plasma glucse were all significantly elevated in the diabetic grup but nly Hb AI values prvided ttal separatin f the tw grups. Within the diabetic grup the Week 8 Hb A I values shwed a significant crrelatin with the Week 8 mean capillary glucse cncentratins, the prprtin f urine tests shwing 2% and % glycsuria, and mean serum triglycerides. Crrelatins f Week 8 Hb A~ with the mean values f these glycaemic parameters fr each week f the study demnstrated lw rder crrelatins with the glycaemie measures f Week 1, and a prgressive increase in the degree f crrelatin reaching a plateau with the glycaernic measures f Week 4 t 8. Similar crrelatin analysis using the Hb Ai values frm Week 4 cnfirmed these findings. Therefre, while Hb AI prvides an index f the cntrl f diabetes, it appears t be mre acutely respnsive t bld glucse alteratin than generally recgnized. Key wrds: Glycsylated haemglbin, juvenile diabetics, mean capillary bld glucse, fasting plasma glucse, twenty-fur hur urine glucse, chlesterl, triglycerides, camps, weekly. Fllwing the initial bservatin that the minr haemglbin, haemglbin (Hb) Aic, is increased in diabetic subjects [1, 2] it has been established that Hb Aic is a glycsylated derivative f the majr adult haemglbin, Hb A H [3, 4, 5, 6]. Hexse mlecules attach t the N-terminals f the tw B chains f the Hb An mlecule, initially in a reversible Schiff base linkage but subsequently they rearrange spntaneusly t frm a mre stable ketamine linkage [3]. Tw further minr haemglbin cmpnents Hb Aia and Hb At are cmmnly measured as a single entity, Hb Aia+b, which is als increased in the diabetic [7, 8]. All three minr haemglbin cmpnents are frmed pstsynthetically, their cncentratins increasing slwly and apparently linearly ver the life-span f a chrt f red cells [6]. On the basis f these bservatins, and the knwn cnstancy f red bld cell survival [9] it has been prpsed that the cncentratin f Hb Arc shuld prvide a measure f the average bld glucse cncentratins prevailing ver the life-span f the red cells sampled [6, 1]. Gabbay et al. [7] bserved that Hb A I crrelated significantly with 24- h urine glucse excretin determined at mnthly intervals ver a three-mnth perid prir t the Hb A t sample in a large grup f juvenile diabetics. The highest crrelatin was between the Hb A I level and the 24-hur urine glucse btained tw mnths prir t Hb A I determinatin. In additin, Ditzel et al. [11] nted that Hb Aic values fell ver a perid f weeks t mnths fllwing initiatin f insulin therapy in a grup f newly diagnsed diabetics. On the ther hand, the rate f decline f Hb Aic values fllwing impsitin f rigrus diabetic cntrl in a grup f five diabetics described by Kenig et al. [12] appeared incnsistent with a reductin in rate f synthesis alne. Furthermre, high crrelatins have been reprted between Hb Aic values and virtually simultaneus bld glucse cncentratins [13, 14]. Finally, shrt-term changes in bld glucse cncen- O12-186X/79/17/213/$1.6
214 P. J. Dunn et al.: Serial Glycsylated Haemglbin in Juvenile Diabetics tratins have been reprted t influence Hb A~c values [15]. In view f the clinical imprtance f the relatinship between bld glucse cncentratins and the related Hb Aic cncentratins, and in particular, the respnse f the latter t bld glucse changes, we have examined this relatinship in a grup f thirtyeight juvenile nset diabetics studied fr an eightweek perid. Methdlgy Subjects Thirty-eight diabetic and 28 nndiabetic cunsellrs at the E. P. Jslin and Clara Bartn Diabetic Camps vlunteered fr the study. The diabetic grup cmprised 2 male subjects, mean age 19.1+_.5 years (_+ SEM), mean % f Ideal Bdy Weight (% IBW) 18+2, and 18 female subjects, mean age 19.4+1.1 years and mean % IBW 111 _+4. All were n insulin therapy and had n majr diabetic cmplicatins. The nndiabetic grup cmprised 6 male subjects, mean age 2_+l.3 years, mean % IBW 16_+5, and 22 female subjects, mean age 2.9+.6 years and mean % IBW 14_+3. Infrmed written cnsent was btained frm all subjects prir t the study and cuntersigned by a parent r guardian in the case f minrs. Prcedures The study was perfrmed during the curse f a summer camp sessin f eight-weeks duratin. Each Mnday fllwing an vernight fast, a bld sample was drawn fr determinatin f plasma glucse, serum triglycerides, serum grwth hrmne, and glycsylated haemglbin in bth the diabetic and nndiabetic subjects. The diabetic subjects tested their urine semiquantitatively fur times a day fr glucse cncentratin, prvided tw r mre 24-h urine cllectins per week fr glucse determinatin and n tw r mre days per week had capillary glucse cncentratins determined fasting, at 11 a.m. and at 3 p.m. Methds Hb Aic% and Hb AI% were determined with a high perfrmance liquid chrmatgraphy technique [16]. Aliquts f a pled haemlysate were kept in liquid nitrgen and run at the beginning and end f each day's samples. The inter- and intra-run ceffidents f variatin f the quality cntrl sample were bth apprximately 3% [16]. Serum chlesterl and serum triglycerides were measured with an autmated clrimetric methd [ 17], and serum grwth hrmne by radiimmunassay [18]. The fasting plasma glucse levels were determined with a glucse xidase methd [19], the capillary glucse levels with Dextrstix and the Eyetne Reflectance Meter (Ames Cmpany, Elkhart, Indiana). Twentyfur h urine glucse excretin was measured with Sumner's technique [2]. T assess the adequacy f the 24-h urine cllectins, the ttal creatinine excretin was determined frm tw cllectins fr each subject. The mean ttal creatinine excretin ( SEM) was 1.2_+.5 g/day. The daily semiquantitative urine glucse tests were determined with Benedict's slutin, the results being expressed in g/1 ml ranging frm % t 2%. Fr purpses f analysis the ttal number f % and 2% urine tests recrded by each subject fr each week f the study were calculated as the prprtin f the ttal number f tests fr the week. Statistical Analyses The data fr all the subjects were prcessed by an IBM Mdel 37/168 cmputer using the Data Text prgram package [2 l]. The statistical analyses invlved the cmputatin f cnventinal crrelatin cefficients and regressin equatins; differences between tw grup means were determined by Student's t-test, either paired r unpaired where apprpriate. All data are expressed as mean + SEM. Results Relatinship f lib A1% t Hb A~c% The relatinship f Hb AI% with Hb Axe% values recrded in the diabetic and nndiabetic subjects in Week 1 f the study was calculated. The crrelatin cefficient was clse t 1 (r =.996, p <.1), and the regressin equatin was: 9 Hb A I = 1.2 + 1.14 Hb Aic. Repeated analysis f this relatinship fr Weeks 2-8 f the study prduced crrelatin cefficients f a similarly high magnitude, and the regressin equatins were virtually identical. Diabetic Cmpared t Nndiabetic Values The diabetic and nndiabetic fasting plasma glucse, serum chlesterl, serum triglyceride and Hb A I values recrded in Week 1 f the study are depicted in Figure 1. The mean values f all fur variables were significantly greater in the diabetic grup (p <.1, with chlesterl, p <.5). There was n verlap f the diabetic and nndiabetic Hb AI% values (with ne exceptin), but marked verlap f the ther three variables. Mean levels f Hb AI, fasting plasma glucse, serum chlesterl and serum triglyceride cncentratins fr bth diabetics and nndiabetics in each week f the study are listed in Table 1. The significant differences nted between the tw grups in the first week were maintained ver the eight weeks althugh nt cnsistently fr chlesterl. The mean serum grwth hrmne cncentratins did nt differ significantly between the tw grups fr any f the eight weeks (data nt shwn). The mean values in the diabetics ver the eight weeks ranged frm 3.6 t 2. ng/ml; in the nndiabetics the range was frm 3.6 t 2.1 ng/ml. T assess the relative stability f Hb A I in the diabetic cmpared t the nndiabetic subjects, the mean, standard deviatin and cefficient f variatin f Hb AI were calculated fr each diabetic and nndiabetic subject frm the eight values determined ver the study perid. The mean cefficient f variatin in the diabetic and nndiabetic grups respectively were 9.1+.7% vs 6.6+.5% (p <.1).
P. J. Dunn et al,: Serial Glycsylated Haemglbin in Juvenile Diabetics 215 Hb A 1% FASTI N G PLASMA GLUCOSE SERUM CHOLESTEROL SERUM TRIGLYCERIDES (rng/looml) (mg/looml) (mg/looml) 15 8 8 3 Z,..J (..9 ILl -t- _J,< I.-- IO-. @.. Q t J: $ 9O $ 2 9 ~ Fig. 1. Week 1 Hb A b fasting plasma glucse, fasting serum chlesterl and fasting serum triglyceride cncentratins in 38 diabetic and 28 nndiabetic subjects, = Nndiabetics, 9 = Diabetics Table 1. Mean (+ SEM) f weekly fasting metablic values in 28 nn-diabetic and 38 diabetic subjects Weeks ] 2 3 4 5 6 7 8 Hb A I (%) 6.2+.1 6.1+_.2 6.1+.1 6.2+_.1 6.3+.1 6.5+.2 6.2+_.1 6.3+_.1 Nn-diabetic 11.4_+.4 11.1+_.4 1.9+.4 1.7+.4 1.9_+.4 11.3_+.4 11.1+.3 1.7-+.4 Diabetic p <.1 <.1 <.1 <.1 <.1 <.1 <.1 <.1 Fasting plasma 62-+ 2 57 + _ 1 66+_ 2 63+- 2 75-+ 3 82+ 2 8_ + 2 63+_1 Nn-diabetic glucse 137_+13 168_+16 187+14 166_+13 18+16 212+19 154_+16 155_+2 Diabetic (mg/1 ml) p <.1 <.1 <.1 <.1 <.1 <.1 <.1 <.1 Serum 164-+5 147+_5 158 +_6 159 _+6 159 -+6 167 -+6 166 _+7 164 +-6 Nn-diabetic chlesterl 178-+4 159_+5 179.5_+5.6 168.9+-4.3 17._+4.9 182.2+6.1 184.4_+5.5 171.9_+4.6 Diabetic (mg/1 ml) p <.5 NS <.2 NS NS NS <.5 NS Triglycerides 68_+5 63+-2 79_+ 6 73_+3 75_+1 74+- 5 71+-4 72_+ 7 Nn-diabetic (mg/1 ml) 12-+7 84+6 133+23 94-+6 16-+7 95_+1 89+_6 13_+12 Diabetic p <.1 <.1 <.5 <.1 <.1 NS <.2 <.5 Weekly Mean Glycaemia in the Diabetic Grup The weekly mean values in the diabetic grup fr capillary glucse, 24-hur urine glucse excretin, prprtin f 2% and % urine tests are listed in Table 2. A statistically significant increase in mean capillary glucse values was bserved in Weeks 5, 6 and 8 cmpared with Week i n paired t-test analysis, als in 24-h urinary glucse in Week 6 and a significant decrease in the prprtin f % urine tests in Weeks 2, 3, 4, 5, 6 and 8. Crrelatin f Week 8 Hb A I Values with Mean Glycaemia in the Antecedent Eight Weeks f the Study The mean values fr capillary glucse, prprtin f 2% and % urine tests, 24-h urine glucse excretin, serum chlesterl and serum triglyceride cncentratins ver the eight weeks f the study were calculated fr each diabetic subject and crrelated with the Hb A I values frm Week 8 (Figure 2). The highest crrelatin was nted with the mean capillary glucse (r =.78; p <.1). Smewhat lwer, but still
216 P.J. Dunn et al.: Serial Glycsylated Haemglbin in Juvenile Diabetics Table 2. Mean (_+ SEM) glycaemic index values fr weeks ne t eight Weeks 1 2 3 4 5 6 7 8 Mean capillary glucse mg/1ml 14 _+6 158 _+1 148 +8 162 _+1 184 ~ _+1 174 a _+11 159 +1 29 c _+18 24 hur urine glucse g/day 16 _+3 14 _+2 2 _+3 22 _+4 2 _+3 33 b _+4 18 _+2 23 _+4 Prprtin 2% urine tests.22_+.3,26_+.3.22_+.3.28-+.4.29-+.4.24-+.4.19+.3.22-+.22 Prprtin % urine tests.4_+.4.32~-+.4.33"-+.4.28b-+.4.21c--+.3.31a-+.4.36_+.4.28~_+.4 p<.5; Up<.1; ~p<.1 Paired t-test analysis f changes in glycaemic parameters between week 1 and the later weeks f the study SOOFA 275~ r = '78 l.a 7O _B r :.5 D 25" ~ 2~. " <~ g 2 "... 9 9 d%,75." "" ~ 15 " " " "" 125 m I %" 75: E# 2~.4 ~ 13_.2 c r =.67 9 9 w" 5 zcn -~ 4 Zg ~E 3 ~= 2 Z~ a_ z~ g.6 A.2 p 9 9 9,_D i i r : -.66 i I I I i t i d (.9 26 E "~ -- 24 r =.3 22 2 9 14 9 I 2Q 7 8 9 IO I I 12 13 14 15 16 Hb A 1% 35 5 25 2 15 IO 5Q _v r :.59 i,, ~, n,, n 8 9 I I1 12 15 14 15 16 Hb A 1% Fig. 2. Relatinship in the diabetics f Hb AI% n Week 8 with the mean values f the capillary glucse determinatins, 24-hur urinary glucse excretin, prprtin f 2% and % urine tests, and fasting serum chlesterl and fasting serum triglyceride cncentratins ver the eight week study perid. Significance f r and n fr panel A is p<.1 and 35, panel B is p<.1 and 35, panel C is p<.1 and 34, panel D is p<.1 and 34, panel E is p = ns and 34 and panel F is p<.25 and 34 highly significant crrelatins were bserved with the mean 24-h urine glucse excretin (r =.5; p <.1), the prprtin f 2% tests (r =.67; p <.1), and the prprtin f % tests (r = -.66; p <.1). A significant crrelatin was nted with mean triglycerides (r --.39; p <.25) but nt with mean chlesterl (r =.3; p <.1). Crrelatin f Hb A 1 with Mean Weekly Glycaemia T examine the influence f degree f cntrl in each week n the Hb Ax values determined at the end f the study, the weekly mean capillary glucse, fasting plasma glucse, 24-h urine glucse excretin and prprtin f 2% and % urine test values were calculated fr each diabetic subject. These weekly indices f glycaemia were then crrelated with the Week 8 Hb Ai values (Figure 3 - upper panel). Lw magnitude statistically significant crrelatins were nted between Hb A I values and mst f the indices f glycaemia in Week 1 f the study but the degree f crrelatin imprved prgressively frm Week I t a plateau frm Week 4 t 8. Similar crrelatin analysis f Week 4 Hb A 1 values illustrated that Hb AI crrelated maximally with the degree f glycaemia in the immediately preceding Week 3 (Figure 3 - lwer
P. J. Dunn et al.: Serial Glycsylated Haemglbin in Juvenile Diabetics 217 panel). In additin, it was apparent that the change f glucse cntrl frm week t week within the subjects was such that the predictive value f the Week 4 Hb AI fr subsequent glycaemia was restricted t apprximately ne week (Figure 3 - lwer panel). Fr cntrl purpses, the mean 24-h urine glucse excretin in Week 8 f the study was crrelated fr each subject with their mean weekly indices f glycaemia, as shwn in Figure 4. It was apparent that the Week 8 mean 24-h urine glucse excretin crrelated highly significantly with fur f the five indices f glycaemia in the last five weeks f the study. Thus, the stability f glucse cntrl in the latter half f the study undubtedly influenced the perid f time fr which the Week 8 Hb A I was useful as an index f prir glucse cntrl. Crrelatin f Hb Az with Antecedent Weekly Serum Fasting Lipids The crrelatin cefficients f Week 8 Hb A I values with the weekly serum chlesterl and serum triglyceride cncentratins f the diabetic subjects are listed in Table 3. The Week 8 Hb A~ values crrelated significantly with bth these serum lipids fr Weeks 3 and 4 and with triglycerides in Week 7 (Table 3). Discussin T date, the lack f a simple and rapid analytical methd has greatly restricted the clinical evaluatin f Hb A I and Hb A~c measurements. In the present study, a high perfrmance liquid chrmatgraphy methd was used that permitted bth variables t be determined with a cnsiderable degree f accuracy in a large number f samples. The high degree f crrelatin nted by Gabbay et al. [7] between Hb AI and Hb A~c was cnfirmed in this study, and in additin, it was demnstrated that this relatinship (as evidenced by regressin analysis) remained cnstant n repetitive determinatins ver an eight-week perid. Therefre, fr clinical purpses, it seems reasnable t use the simpler measurement f Hb A I alne in place f the mre lengthy determinatin f Hb AI~. The ne prvis t this is the need fr greater care in sample handling fr there is a prgressive increase in the Hb AI~+b fractin with time [22] unless this is bviated by strage at -8 ~ r prmpt analysis f the samples. With present technlgy, hwever, Hb A~ can be determined in apprximately ten minutes per sample [16] and accrdingly this methd is feasible fr rutine clinical applicatin. The Hb A I values nted in this study in the diabe- w~z.2.7,../..a~ 9.7 J t i r.5 -A... p <.1.4... ~----p <. i.3... ~--p <.5 / -;i/ \/ \ 2 5 4 5 6 7 8 WEEKS Fig. 3. Crrelatin cefficients between Hb AI% values frm Weeks 8 (tp panel) and 4 (bttm panel) and the mean weekly metablic parameters fr Weeks 1-8 fr the 38 diabetic subjects. The vertical dtted lines indicate the Week f the study fr which the Hb A I was selected fr crrelatin with the varius weekly metablic parameters. 9 = Fasting bld glucse; 9 = Mean capillary glucse; ~ = Mean 24 hur urinary glucse; A = Prprtin 2% urine tests; 9 = Prprtin % urine tests,7.6.5,4,3,2 O.I......................... p <O.OOI........................................................ 2 3 4 5 6 7 8 WEEKS Fig. 4. Crrelatin cefficients between Week 8 mean 24-hur urinary glucse excretin and the mean weekly metablic parameters fr Weeks 1-8 fr the 38 diabetic patients. The vertical dtted line indicates the Week f study fr which the mean 24-hur urinary glucse excretin was selected fr crrelatin with the varius weekly metablic parameters
218 P.J. Dunn et al.: Serial Glycsylated Haemglbin in Juvenile Diabetics Table 3. Crrelatin cefficients f week eight Hb A I with weekly fasting serum lipid measurements Weeks 1 2 3 4 5 6 7 8 Chlesterl mg%.27.19.42 a.55 b.24.23.21.22 Triglycerides mg%.14.35.46 b.41 a.33.13.47 b.2 a p<.5; b p<.1 tic grup were cnsistently greater than the highest values recrded in the nndiabetic subjects. In cntrast the diabetic serum chlesterl, serum triglyceride and plasma glucse cncentratins verlapped the nrmal range f values cnsiderably althugh the mean values were significantly elevated in the diabetic grup. These findings are cnsistent with the generally accepted mechanism f frmatin f glycsylated haemglbin in that it is an integral related t the average glucse level t which the haemglbin is expsed. Cnsequently, this shuld prvide a better discriminant f diabetic frm the nndiabetic than a rapidly fluctuating variable such as the fasting bld sugar. Similarly, the bservatin that the cefficient f variatin f Hb A I fr diabetic subjects was nly abut 5% greater than that fr nndiabetics is in keeping with the ntin that Hb A~ is a relatively stable parameter. Smewhat surprisingly, the mean serum grwth hrmne cncentratins did nt differ significantly between the diabetic and the nndiabetic grups. Serum grwth hrmne cncentratins have been previusly reprted t be elevated in juvenile diabetic subjects in basal and ambulant cnditins and als in respnse t prvcative stimuli [23, 24, 25]. In the present study, hwever, it is ntewrthy that the grwth hrmne samples were all drawn under fasting cnditins and this restricted sampling may accunt fr the discrepant findings. It has been previusly reprted that significant differences in diurnal grwth hrmne cncentratins may nt be apparent frm fasting values alne [26]. T examine the relatinship between Hb AI and time averaged bld glucse cncentratins, the Fib A I values frm the last week f the study were initially crrelated with the average degree f glycaemia present in the antecedent eight weeks f the study. Highly significant crrelatins were achieved with the varius measures f diabetic cntrl, the highest crrelatins being nted with the mean f the multiple capillary glucse determinatins. These findings culd be taken t cnfirm the general premise that Hb A~ values prvide a reflectin f average bld glucse cncentratins present fr a substantial perid f time, in this case, tw mnths. Further analysis, hwever, f the relative influence f the degree f glycaemia in each week f the study n the subsequent Hb A I values did nt cnfirm this finding. Thus, it was apparent that the Hb A~ values frm Week 8 crrelated mst strngly with the degree f glycaemia present in the fur t five weeks prir t the samples. Furthermre, crrelatin f the Hb Ar values frm Week 4 f the study cnfirmed that the highest crrelatins were thse between the Hb A~ and the events f the immediately antecedent few weeks. Therefre, it appeared that Hb AI was representative f the average degree f glycaemia present in the fur t five weeks prir t the sample and maximally predictive f the degree f glycaemia fr the week immediately prir t the sample. Similar crrelatin analyses f Week 8 mean 24-h urine glucse excretin with these same weekly indices f glycaemia clearly demnstrated that stability f glucse cntrl in the latter half f the study undubtedly cntributed t the high crrelatins with the Week 8 Ub A I values. Under cnditins f acute change in bld glucse cntrl therefre, it is pssible that the perid f time fr which Hb A I is useful as an index f glucse cntrl may be further abbreviated. These bservatins are at variance with the view that glycsylated haemglbin is synthesized slwly and essentially irreversibly ver the life span f the red cell, fr such a mechanism precludes any abrupt changes in Hb A~ cncentratins. On the ther hand, the published data supprting this cncept in the diabetic subject are relatively scant, as mentined earlier, and als incnclusive. Therefre, while the bservatins f Gabbay et al. [7] may be taken t indicate that a single Hb A~ value is representative f glucse cntrl fr a three-mnth perid, it is alternatively pssible that the findings f this study were due slely t stability f glucse cntrl in the grup studied. The decline in Hb AIc values nted by Ditzel et al. [11] in a grup f diabetics cmmenced n insulin therapy prvides strnger evidence f a relatively rapid decrease in Hb AI, but unfrtunately the assciated glucse cncentratins that are needed t interpret the rate f decline f the Hb Aic cncentratins are nt dcumented. The present study and that f Karamans et al. [15] prvide evidence that Hb AI, r Hb Aic, may be relatively acutely respnsive t changes in bld glu-
P. J. Dunn et al.: Serial Glycsylated Haemglbin in Juvenile Diabetics 219 cse cncentratins. While the minimum perid f time ver which a change in bld glucse cncentratin must be sustained t prduce a respnse in Hb A~ is nt clear, it may be f the rder f a week r less [15] assuming reasnable accuracy f the methd. The mechanism by which these relatively rapid changes in Hb A I are prduced is nt knwn. Reduced red cell survival in the diabetic is virtually excluded by the study f Petersn et al. [27], fr the bserved reductin in life span was nt adequate t explain the present bservatins. Dissciatin f glycsylated haemglbin in the stable ketamine frm als seems unlikely [13], but the pssibility f a disprprtinate increase in the reversible Schiff base miety in the diabetic has nt been excluded. A third theretical pssibility is a disprprtinately accelerated synthesis f glycsylated haemglbin at elevated bld glucse cncentratins, but this als is purely cnjectural. Irrespective f the mechanism, it is clear that the kinetic relatinship between Hb A I and bld glucse cncentratins will need t be carefully defined befre glycsylated haemglbin cncentratins can be accurately interpreted as a measure f diabetic cntrl. Nevertheless, it is imprtant t emphasize that an integral f bld glucse cncentratins, if nly fr a perid f weeks rather than mnths, is still clearly superir in simplicity and bjectivity t the cnventinal measures f cntrl. Mrever, the ptimum frequency f Hb A1 determinatins required t mnitr diabetic cntrl fr a prtracted perid f time will need t be based nt slely n kinetic cnsideratins, but als n the actual variability f Hb AI bserved in diabetic subjects under daily life cnditins. Data n this latter pint are currently nt available. There are cnflicting reprts n the crrelatin f Hb A I with the fasting cncentratins f serum chlesterl and triglycerides [7, 13, 14, 28]. In the present study, the Hb Ax values frm Week 8 did crrelate significantly with the mean serum triglyceride values fr Week 3, 4 and 7 and with the serum chlesterl at Weeks 3 and 4 but these crrelatins were f a lw magnitude. A high crrelatin has been nted by Petersn et al. [28] between Hb AIc and serum triglycerides, but this study differs frm thers in that the serum level f triglycerides were cnsiderably elevated prir t institutin f rigrus diabetic cntrl. In cntrast, in the present study ver half the serum triglyceride cncentratins f the diabetic subjects were in the nrmal range and the remainder were nt greatly elevated. Therefre, it seems prbable that under the mre rutinely encuntered cnditins f diabetic cntrl the influence f the degree f glycaemia, as manifested by Hb A1 values, n fast- ing chlesterl and triglyceride cncentratins is slight. In summary, this study prvides further evidence f the clse crrelatin between Hb AI values and bld glucse cncentratins, but additinally it prvides evidence that the Hb A I values are relatively mre influenced by the degree f glycaemia present in the weeks immediately preceding the test date. Acknwledgements. We wuld like t gratefully acknwledge the help and c-peratin f the staff and members f the Clara Bartn and the E. P. Jslin Diabetic Summer Camps and the technical assistance f Mr. F. McGuire, L. Markwitz, A. Usala and Miss E. Hayes. This wrk was presented in part at the 38th Annual Meeting f the American Diabetes Assciatin held in Bstn, 1978 (Diabetes 27: 434, 1978). The prject was supprted by NIH research grants AM-9748, EY-1421, AM-2 53, the Massachusetts Lins Eye Research Fund, Bstn, Mass., and the Upjhn Cmpany, Kalamaz, Michigan. P. J. Dunn was supprted by Fgarty Internatinal Fellwship 1 F5-TWO-2533-1 and by the New Zealand Diabetes Assciatin. R. A. Cle was supprted by NIH training grant AM-7 26. References 1. Rahbar, S.: An abnrmal hemglbin in the red cells f diabetics. Clin. Chim. Acta 22, 296-298 (1968) 2. Rahbar, S., Blumenfield, O., Ranney, H.M.: Studies f an unusual hemglbin in patients with diabetes mellitus. Bichem. Biphys. Res. Cmmun. 36, 838-843 (1969) 3. Bunn, H.F., Haney, D.N., Gabbay, K.H., Gallp, P.M.: Further identificatin f the nature and linkage f the carbhydrate in hemglbin Aic. Bichem. Biphys. Res. Cmmun. 67, 13-19 (1975) 4. Bkchin, R. M., Gallp, P. M.: Structure f hemglbin A k. Nature f the N-terminal B-chain blcmng grup. Bichem. Biphys. Res. Cmmun. 32, 86-93 (1968) 5. Kenig, R.J., Blbstein, S.H., Cerami, A.: Structure f carbhydrate n hemglbin AIc. J. Bil. Chem. 252, 2992-2997 (1977) 6. Bunn, H. F., Haney, D. M., Kamin, S., Gabbay, K. H., Gallp, P.M.: The bisynthesis f human hemglbin Ak: Slw glycsylatin f hemglbin in viv. J. Clin. Invest. 5"/, 1652-1659 (1976) 7. Gabbay, K. H., Hasty, K., Breslw, J. 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