Diabetologia 9 by Springer-Verlag 1977

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1 Diabetlgia 13, (1977) Diabetlgia 9 by Springer-Verlag 1977 Is a Lag-Strage Curve an Early Sign f Diabetes? Early Insulin Respnses t i.v. Glucse in Nrmal Subjects, Mild Maturity-Onset Diabetics and Patients with Lag-Strage Curves* E. de Nbel, A. van 't Laar and Th. J. Benraad Department f Internal Medicine, Radbud Ziekenhuis, University f Nijmegen, Nijmegen, The Netherlands Summary. Early insulin respnses were measured after a high dse (50 g/1.73 m 2) f rapidly injected glucse in 31 subjects wh had repeatedly shwn "lagstrage" curves in the OGTF, in 24 cntrls and in 19 mild maturity-nset diabetics. Divisin between cntrls and diabetics was virtually cmplete, when the insulin respnses were expressed as "insulin6genic index,,d_ A insulin~ ~ ~ }. Twenty ut f 31 patients with lag curves shwed nrmal early insulin respnses and 11 patients shwed diabetic respnses. In patients with lag curves, presence f besity, and absence f family histry f diabetes were assciated with nrmal insulin respnses. It is cncluded that the finding f a lag curve is f little cnsequence in bese persns but, when in cnjunctin with a genetic backgrund f diabetes, is suggestive f diabetes. Key wrds: Initial glucse-induced insulin secretin, ral glucse tlerance test, intravenus glucse tlerance test, brderline glucse tlerance, maturity-nset diabetes, insulingenic index, xyhyperglycaemic curve, lag-strage curve. The ral glucse tlerance test in patients with hyperthyridism r partial gastrectmy frequently shws a pattern in which the bld glucse cncentratin rapidly rises t an abnrmally high peak but falls t abut the fasting level within tw hurs. This s-called "lag-strage" curve r "xyhyperglycaemia" als ccurs in healthy peple. The prevalence in the nrmal * Part f this material was presented at the 8th meeting f the EASD in Madrid, 1972 (24) ppulatin is estimated at apprximately 9% [3]. The significance f this "idipathic" lag-strage curve (r lag curve) remains bscure. Sme investigatrs [22, 23] regard the lag curve as a trivial abnrmality; thers [1, 9, 16, 20] hwever, have bserved frequent prgressin t asymptmatic r symptmatic diabetes in patients exhibiting such curves and therefre regard the lag curve as an early sign f diabetes. Insulin release in patients shwing lag curves is claimed t be delayed during ral glucse tlerance tests, when the release is cmpared t that bserved in nrmals [11, 15] r in subjects with partial gastrectmy [19]. The insulingenic index during the initial stage f the ral test in these patients is lw as cmpared t nrmals [30]. Patients with lag curves have this phenmenn in cmmn with mild diabetics. Furthermre a minrity f them als have an intravenus glucse tlerance in the diabetic range [16, 19]. S there are several arguments indicating a lag curve as a diabetic feature. Definite evidence supprting such a view is still lacking, hwever. In nrmal subjects intravenus administratin f glucse is fllwed by a biphasic secretin f insulin [5, 26]. The initial insulin respnse t intravenus glucse is blunted r absent in patients with mild maturity-nset diabetes [10, 27] and als in grups f subjects with prediabetes [4, 5, 28]. Diminished initial insulin secretin is therefre regarded as the earliest detectable sign f diabetes, r even as its "genetic marker" [6]. T examine the questin whether patients with lag curves must be cnsidered diabetics, early insulin respnses t intravenus glucse were studied in patients with lag curves. Fr cmparisn results f similar investigatins in a grup f nrmal cntrls and a grup f mild maturity-nset diabetics are als presented.

2 36 E. de Nbel et al.: Lag-Strage Curves Table 1. Subjects Grup n Age mean (range) Cntrls (24-69) Patients with lag curves (21-68) Diabetics (18-63) PLASMA retl/i ! GLUCOSE ORAL GT T m -+ sem i i i i i % f ideal bdyweight (mean + SD) 109 -! _ DIAB nffi19 LAG n =31 NORM n ffi minutes rag/t Fig. 1. Mean ral glucse tlerance curves f 19 mild maturity-nset diabetics, 31 patients with lag curves and 24 nrmal cntrls. Plasma glucse cncentratins can be read in mml/l r mg/100 ml. The dashed lines represent the criteria f Fajans and Cnn (14). The asterix dentes the mean peak value in the lag curve grup, irrespective f time f ccurrence Materials and Methds Subjects The distributin f age and relative bdy weight in the three grups f subjects investigated is presented in Table 1. Selectin f subjects was based n the re- 50 m I suits in a standard 100 g ral glucse tlerance test (OGTT). The glucse curves btained in the ral tests in the three grups are represented in Figure 1. The 24 nrmal cntrls were selected because f their nrmal glucse tlerance as judged by the criteria f Fajans and Crm, adapted t the determinatin f glucse in plasma [14], and absence f family histry f diabetes. Rutine histry and physical and bichemical examinatin revealed n abnrmalities. Obesity was n reasn fr exclusin, but as a grup the cntrls were nt verweight. In seven subjects the bdy weight was mre than 15% abve the calculated ideal value [29]. An OGTr respnse was cnsidered a lag curve when the plasma glucse peak at either 30 r 60 rain after the 100 g lad reached r was abve 200 rag/100 ml (11 retl/l) and the 2=hur-level was belw 130 rag/100 ml (7.2 mml/1). Only thse persns wh had shwn lag curves n at least tw ccasins within ne mnth and had never shwn ther respnses were selected. Patients with peptic ulcers, signs f hyperthyridism r with partial gastrectmy were excluded. Screening f apprximately 2100 OGTT's, perfrmed in ut-patients, resulted in the selectin f 31 patients fulfilling these criteria and able and willing t underg an IVGTr. Thirteen f these 31 subjects were bese, i. e. mre than 115% f ideal weight [29]. First degree relatives with diabetes were knwn in 14 cases. Fr the purpse f this study, diabetes was diagnsed if the 2 h glucse level in the OGTT was ver 180 mg/100 ml (10 mml/1) and the K-value in a high dse intravenus glucse tlerance test [8] was belw 1.3, the critical value in this test being 1.5. Thus cases f brderline glucse tlerance were excluded. Only untreated maturity-nset diabetics withut a histry f ketsis were included. Nne f them needed insulin later n. Of the 19 diabetic patients selected, 7 had vert disease as evidenced by fasting plasma glucse values f 8 mml/1 r mre, the remaining 12 exhibiting merely "chemical" diabetes. Obesity as defined earlier was present in 10 individuals, 3 with vert and 8 with "chemical" diabetes. Differences in age between the three grups were nt significant. Methds The standard OGTTwas started at 8 a.m. after an vernight fast. When the patient was n a restricted diet, he was primed with a diet cntaining at least 200 g f carbhydrate during 3 preceding days. The 100 g glucse lad was cnsumed as a 25% slutin within 5 rain. Venus bld samples were taken befre and every 30 min up t tw hurs after the lad. The subject was seated all the time. Samples were centrifuged immediately. Determinatins f glucse

3 E. de Nbel et al.: Lag-Strage Curves 37 in plasma were perfrmed with the aut-analyser (Hffman's ferricyanide methd, 12). The intravenus challenge was given under the same cnditins (except fr a supine psitin f the patient) and cnsisted f 50 g f glucse per 1.73 m 2 bdy surface. This high dse [8] was injected as a 50% slutin in exactly 3 rain. The start f the injectin was called zer time. Bld samples were taken frm an indwelling catheter in the ppsite arm, prvided with a heparin lck. Three samples were taken prir t the glucse injectin and subsequently 1, 2, 3, 4, 6, 8, 10, 12, 15, 20, 30, 40, 50, 60, 90 and 120 min after the start f the injectin. Centrifuged aliquts f plasma fr determinatin f insulin were stred at -20~ until radiimmunassay. Separatin f the "free" and "bund" fractins was perfrmed with a "duble antibdy slid phase" technique [13]. Glucse disappearance rates (K-values) were calculated frm semilgarithmic plts f abslute plasma glucse values, accrd.ing t the frmula f Lundbaek [16]: K = Fr each experiment, an insulingenic tl/2 index [27] was calculated by dividing the fasting-tpeak insulin rise (~U/ml) by the cncmitant change in plasma glucse (retl/i): A insulin. The insulin peak was invariably reached at A glucse three r fur minutes after the start f the injectin. Fr statistical analysis Wilcxn's test (fr unpaired and fr paired bservatins) was used, and Spearman's crrelatin cefficient, as results did nt represent nrmal distributins. Results Plasma Glucse The mean plasma glucse cncentratin in the fasting state was slightly but significantly higher in patients with lag curves than in cntrls (p < 0.02). This was nt due t the presence within this grup f subjects with significant hyperglycaemia: the highest fasting value encuntered (in ne extremely bese patient) was 7.05 mml/1. Fasting glucse levels were substantially higher in the diabetic grup. The glucse peaks reached in the intravenus tests were nt significantly different in the three grups: retl/1 (M + S.D.) in nrmals, in patients with lag curves and 32.4 _+ 4.1 in diabetics. The mean fasting-t-peak change f the plasma glucse in the i. v. test (A glucse) was 25.0 retl/1 fr cntrls, 26.2 mml/1 fr patients with lag curves and 25.2 mml/1 fr diabetics. This insulingenic stimulus was nt statistically different in the three grups. INSULIN UU/ml 110 to0 9O O SO 40 3O 20 ~0 --1 glucse ,73 rn 2 r "''" ~ NORM n= 24, i ~,. i i i t rnin n= 31 DIAB n=lg Fig. 2. Early insulin respnses (mean _+ SEM) fllwing a large intravenus glucse lad rapidly injected in nrmal cntrls (NORM), patients with lag curves (LAG) and mild maturity-nset diabetics (DIAB). Differences are significant with p < 0.05 (NORM : LAG) and p < (LAG : DIAB) K- Values The glucse disappearance rates (K-values) in the nrmal cntrls all were greater than 1.5, with a mean f 2.45 _ 0.96 (S.D.). These values were unduly influenced by a few individuals with very high K- values, causing skewness f the distributin t the right. By definitin, K-values in diabetics were less than 1.3. In the lag-strage grup, K-values were nrmal i. e. greater than 1.5, in 16 cases, diabetic (less than 1.3) in 9 cases and equivcal (between 1.3 and 1.5) in the remaining 6. The mean + SD fr all lag curve patients was 1.58 _+ 0.42, the difference frm the cntrl grup being highly significant (p < 0.005). Insulin Respnses Mean insulin levels in the fasting state were nt significantly different in the three grups: ,uU/ml (S.D.) in the nrmals, in the patients with lag curves and in the diabetics. Early insulin respnses (mean + SEM) t the intravenus glucse challenge are shwn in Figure 2. During the 15 rain f the test depicted here, the mean respnse f the lag-strage grup is less than that f the cntrl grup. As such, this is a significant phenmenn (p < 0.05 in the sign test fr 7 differences). When each time-pint is cnsidered separate-

4 38 E. de Nbel et al.: Lag-Strage Curves INSULIN i glucse 5 0 9/1,73 m2 PU/m I ~INSULIN,~GLUCOSE t 80 "70 p<002s ~-, 6O \ NORM n = P< 0,005 ~ ~ -~ LAG ~am - n:17 LAG ram + n:14 9 bese nn bese 30 t i I p DIAB n =lg 2O i/ 10 i rnin i Fig. 3. Early insulin respnses in the same subjects as represented in Fig. 2. Hwever, the lag curve grup has been divided int tw subgrups: ne with psitive family histry f diabetes (LAG ram + ),and a grup withut such family histry (LAG ram -). P-values dente significance f differences between the peaks f the adjacent curves 2 e9 ee9 :~ ~ Table 2. Insulin release, expressed as mean insulingenic index, in the nrmal and the lag-strage grups, each divided accrding t besity. The difference between the grups is cnfined t the nnbese categries 1.5 e 9 Nrmals Nn-bese Obese P n 16 8 Insulingenic index (M + SEM) n Lag curves 0.05 Insulingenic index (M + SEM) P < 0.01 NS NS ~ ** Q9 9 nrm lag ramlag fam+ diab n=24 n=17 n=14 n=19 A insulin in ~tu/ml Fig; 4. Insu!ingenic indices \)~ -glu~ese in m~m0~l/!/fr early peaks after intravenus glucse, in nrmal cntrls (NORM), mild maturity-nset diabetics (DIAB) and patients with lag curves (LAG), with and withut a family histry f diabetes. Each pint represents the index fr ne subject. Open circles stand fr lean patients, dts fr bese patients. The dashed line gives the best separatin between nrmals and diabetics ee ly, differences between these tw grups d nt reach statistical significance, but the difference between the means f the peaks (irrespective f their ccurrence at 3 r 4 min) is significant at the 5% level. The mean insulin curve f all patients with lag curves resembles that f the nrmal grup in exhibiting a steep early rise and is at all pints significantly separated frm the curve f the diabetics. Influence f Family Histry Figure 3 gives early insulin respnses divided n the basis f negative r psitive family histry fr dia- betes. The mean insulin curve f the 17 patients with lag curves and n diabetes in their families is at all pints lwer than that f the cntrl grup, but the mean initial peaks d nt differ significantly. Hwever, the difference between the respnses f the subgrups with and withut a family histry fr diabetes is significant at 3, 4, 6 and 8 min. The grup with family histry released significantly mre insulin than did the diabetic grup (p < fr peaks). Insulin Respnses f Individuals Hw individuals respnded can be derived frm Figure 4, where the insulingenic indices are shwn fr all

5 E. de Nbel et al.: Lag-Strage Curves 39 subjects tested. There is nearly cmplete divisin between nrmals and mild maturity-nset diabetics at the value f 1.5. The mean values (+ SEM) f the indices fr the grups were fr cntrls, 2.45 _ fr all patients with lag curves and 0.55 _ fr diabetics. Statistically the differences between the means f the three grups were clearly significant (p < 0.01). Of the 31 patients with lag curves, 20 shwed nrmal respnses whereas 11 had blunted, diabeticlike, early insulin secretin (insulingenic index < 1.5). Out f 17 patients shwing lag curves withut diabetes amng their first degree relatives, nly 3 exhibited lw insulin respnses (index < 1.5). Relatin f Insulin Respnse t K- Value Within the lag-strage grup, glucse disappearance rates were nt significantly crrelated with the height f the early insulin peaks (r = 0.15). Insulingenic indices were nrmal in 10 ut f 16 patients with nrmal K-values, in 7 ut f 9 with lw and in 3 ut f 6 with brderline K-values. When the 9 subjects with lag curves and subnrmal, diabetic K-values are discarded, the mean insulin peak f the remaining lag-patients is still lwer than that f the cntrls, but with marginal significance (0.05 < p < 0.10). The mean insulingenic index, hwever, remains definitely diminished in this grup (p < 0.02). There was n difference in relative bdyweight between bth subgrups f patients with lag curves: (118% + 18 S.D. fr the lw-k-grup and fr the grup f patients with nrmal K-value). Relatin f Insulin Respnse t Obesity Within the lag-strage grup, but nt within the ther grups, there was a significant crrelatin between insulin respnse and degree f besity (r = 0.38; p < 0.05). When all cases with besity (115% r mre f ideal bdyweight) are rejected, 18 patients with lag curves (105% + 7 S.D.), 16 cntrls (102 _+ 5) and 9 diabetics (109 _+ 4) remain t be cnsidered. The relatinships between these three grups are exactly the same as have been described fr the whle grups, as far as mean insulin curves, mean insulin peaks and mean insulingenic indices are cncerned. Significance f the differences regarding the subgrups with nrmal and subnrmal K-values and with different family histries is lst hwever. In Table 2 mean insulingenic indices are given fr bese and nn-bese subjects separately. It is bvius frm this table that the difference in insulin release between the nrmal and the lag-strage grup is cnfined t the nn-bese categry. Twenty patients with lag curves culd be matched, with regard t degree f besity, with 20 f the cntrls. The matching prcedure was perfrmed withut knwledge f K-values r insulin secretin patterns, but age was knwn and taken int accunt whenever mre than ne pssibility fr matching ccurred. Mean relative weights were identical in the tw grups s frmed: 110% f ideal _+ 14 S.D.; 7 pairs were bese. The difference, within pairs, f relative weight never exceeded 3% and was zer in 10 f them; the calculated duplicate variatin was 1%. K-values were definitely subnrmal in 7 ut f 20 patients and marginal in 2. The mean K fr cntrls was S.D., fr patients 1.54 _ (p < 0.01). The mean insulin curve f the patients was at all timepints situated belw that f the cntrls. The mean peaks (+ S.D.) were 99 ~tu/ml (+ 50) and 75 (+ 50) respectively (0.05 < p < 0.10). The means f the insulingenic indices were: S.D. and 2.30 _ The grups differed significantly in this respect (p < 0.02). When pairs with a subnrmal K-value in the patient-partner are discarded, the significance f the difference between the indices f the grups becmes marginal (0.05 < p < 0.10). When the 20 pairs are divided in tw subgrups as t relative bdyweight ver r belw 115%, it appears that nly in nn-bese pairs is there a significant difference in insulingenic index between nrmals and patients with lag curves (p < 0.05). This difference is insignificantly small in bese pairs (mean difference 0.33 _+ 0.72). Discussin The present methd f measuring early insulin respnses t i.v. glucse lading is in sme respects different frm thse used by mst ther investigatrs. Rapid injectin f a high dse f glucse was used, as described by Dyck and Mrhuse [8]. These investigatrs have clearly shwn [21] that high dses permit better distinctin between glucse disappearance rates (K-values) f nrmals and diabetics. Rapid glucse injectin yields higher insulin respnses; even small differences in injectin time cause striking differences in insulin respnse [10]. Phlebitis was seen nly in three cases ut f the nearly 150 tests perfrmed s far. The necessity f early sampling is well established, bth fr i.v. tlbutamide [17] and i.v. glucse [4, 25] lading tests. Frm Figure 4 it is bvius that this methd nt nly permits gd distinctin between nrmal and diabetic grups, but als allws classificatin, with minimal verlap, f individuals as nrmal r diabetictype insulin secretrs.

6 40 E. de Nbel et al.: Lag-Strage Curves Cerasi and cwrkers [7] have demnstrated a dse-related insulin respnse t i.v. glucse: their "lw-respnders" apprximated nrmal insulin secretin when the glucse challenge was very high. It culd therefre be argued that the high dse we used lessened the discriminative pwer f ur test. Hwever, Cerasi and cwrkers take the first bld sample 10 rain after the start f the injectin, whereas, as is again demnstrated in this study, insulin peaks ccur earlier. Pfeiffer [25], using early sampling, did nt find a dse-respnse relatinship within the range described by Cerasi. Mrever, even in the highest bld-glucse range achieved by Cerasi, distinctin between his lw- and high-respnders remains fairly gd and the range btained in the present investigatin was substantially lwer. And, finally, individuals with nrmal glucse tlerance and decreased early insulin secretin, deemed prediabetics by Luft and Cerasi, als appear t be detectable with the present methd. The finding f glucse disappearance rates (Kvalues) in the definitely diabetic range in 9 ut f 31 patients with lag curves is in accrdance with the 3 ut f 11 reprted by Lundbaek [16] and the 2 ut f 6 fund by McKiddie et al. [19]. As the intravenus test generally is regarded as less sensitive than the ral G.T.T. [18], these results can be explained as evidence that a lag curve indicates decreased glucse tlerance. Within the lag-strage grup, n crrelatin culd be fund between ral glucse tlerance (the sum f the 5 values taken as a parameter) r intravenus glucse tlerance (K-value) and the insulingenic index. This latter finding is at variance with the wrk f Prte and Pup [26] with small dses. An bservatin similar t urs hwever, was made by Alfrd and cwrkers [2] in a grup f patients with mildly abnrmal ral glucse tlerance, als challenged with a high intravenus glucse dse. Apparently, decreased early insulin secretin des nt simply reflect the decrease in glucse tlerance. This underscres the hypthesis f Cerasi and Luft [6] n the specific meaning f blunted early insulin secretin as a sign f prediabetes. A lwer than nrmal mean insulin respnse t intravenus glucse in patients with lag curves has briefly been reprted by McKiddie and cwrkers [19]. The individual results f their 9 subjects are nt given and the finding is nt discussed. In the present study, the ccurrence f a lag curve was, in abut ne third f cases, accmpanied by sluggish early insulin secretin as a marker f impending r incipient diabetes. Even when we remved thse individuals wh appeared t be diabetic because f their subnrmal K-values, this prcedure did nt substantially alter the rati (9 ut f 22). The results cannt be attributed t the differences between grups in degree f besity. On the cntrary, ne wuld expect a pssibly decreased insulin secretin in the grup f patients with lag curves t be bscured rather than caused by their higher mean weight. Table 2 illustrates this pint. Prcedures meant t rule ut the influence f besity (i. e. discarding f all verweight persns, r matching fr relative weight) d nt change the results, but they reduce the number f subjects under investigatin, With the wide variatin f insulin respnses, the decreased statistical significance btained shuld be explained this way. The insulin respnse separates patients with lag curves, but withut first degree relatives with diabetes, mre clearly frm thse with such family histry, than frm nrmal cntrls (Figs. 3 and 4). This culd mean that a lag curve in cnjunctin with a psitive family histry is indicative f diabetes. When nt accmpanied by a strng family histry f diabetes, a lag curve is indicative f early diabetes nly in a small minrity f cases. Obesity seems even further t decrease a pssible specific significance f the lag curve: e.g. 10 bese persns with lag curves had nrmal early insulin secretin, whereas the 3 bese "lw-respnders" all had psitive family histries. The results presented here suggest that a lagstrage curve has a significance cmparable t that f brderline r slightly diminished glucse tlerance. As such, the finding f a lag curve is f little cnsequence in bese persns. Hwever, when assciated with a genetic backgrund f diabetes either in lean r bese patients, a lag curve is suggestive f diabetes. Rderences 1. Ackerman, I. P., Fajans, S. S., Cnn, J.W.: The develpment f diabetes rnellitus in patients with nndiabetic glycsuria. Clin. Res. Prc. 6, (Abstr.) 251 (1958) 2. Alfrd, F.P., Martin, F.I.R., Pearsn, M.J.: The significance and interpretatin f mildly abnrmal ral glucse tlerance. Diabetlgia 7, (1971) 3. Birmingham Survey Wrking Party: Glucse tlerance and glycsuria in the general ppulatin. Brit. reed. J Ill, Bden, G., Seldner, J. S., Gleasn, R. E., Marble, A.: Elevated serum human grwth hrmne and decreased sermn insulin in prediabetic males after intravenus tlbutamide and glucse. J. clin. Invest. 47, (1968) 5. Cerasi, E., Luft, R.: Plasma-insulin respnse t sustained hyperglycaemia induced by glucse infusin in human subjects. Lancet 1967 II, Cerasi, E., Luft, R.: "What is inherited - what is added" hypthesis fr the pathgenesis f diabetes mellitus. Diabetes 16, (1967) 7. Cerasi, E., Luft, R., Efendic, S.: Decreased sensitivity f the pancreatic beta cells t glucse in prediabetic and diabetic subjects. A glucse dse-respnse study. Diabetes 21, (1972)

7 E. de Nbel et al.: Lag-Strage Curves Dyck, D.R., Mrhuse, J.A.: A high-dse intravenus glucse tlerance test. J. clin. Endcr. 26, (1966) 9. Fajans, S.S., Cnn, J.W.: The early recgnitin f diabetes mellitus. Ann. N.Y. Acad. Sci. 82, (1959) 10. Fujita, Y., Herrn, A.L., Seltzer, H.S.: Cnfirmatin f impaired early insulin respnse t glycemic stimulus in nn-bese mild diabetics. Diabetes 24, (1975) 11. Gt, Y., Sat, S.-I., Ohira, S., Maruhama, Y.: Plasma insulin and free fatty acids in yung peple with pstprandial glycsuria: plasma insulin respnse in the cases with brderline glucse tlerance test. Diabetlgia 9, (1973) 12. Hffman, W. S.: A Rapid phtelectric methd fr the determinatin f glucse in bld and urine. J. bil. Chem. 120, (1937) 13. Hllander, F.C. den, Schuurs, A.H.W.M., Hell, H. van: Radiimmunassays fr human gnadtrphins and insulin emplying a "duble-antibdy slid-phase" technique. J. Immunl. Methds 1, 247 (1972) 14. Klimt, C. R., Prut, T.E., Bradley, R. F., Dlger, H., Fisher, G., Gastineau, C. F., Marks, H., Meinert, C. L., Schumacher, O. P.: Standardizatin f the ral glucse tlerance test. Diabetes 18, (1969) 15. Krystn, L.J., Shaw, R.A., Mlines, M., Mills, L.C.: Atypical glucse and insulin respnses in prediabetes. Diabetes 20 (Suppl. I), (Abstr.) 364 (1971) 16. Lundbaek, K.: Intravenus glucse tlerance as a tl in definitin and diagnsis f diabetes mellitus. Brit. med. J II, Maingay, D., Tuber, J.L., Schpman, W., Ruyter, H.A. de, Crughs, R.J.M., Lequin, R.M.: Rapid rise f insulin cncentratin in the plasma after intravenus administratin f sdium tlbutamide. Lancet 1967 I, Marble, A., White, P., Bradley, R.F., Krall, L.P.: Jslin's diabetes mellitus, 1 lth Ed., p Philadelphia: Lea and Febiger McKiddie, M.T., Sctt, R.T.A., Buchanan, K.D.: Plasma insulin studies in patients with lag curves. Diabetlgia 6, (1970) 20. McKiddie, M.T., Sctt, R.T.A., Cle, R.: The insulin respnse t glucse in patients with nn-diabetic glycsuria. Pstgrad. reed. J. 47, (1971) 21. Mrhnse, J.A., Steinberg, J., Tessler, B. B.: Effect f glucse dse upn intravenus glucse tlerance in health and in diabetes. J. clin. Endcr. 23, (1963) 22. Msenthal, H.O., Barry, E.: Criteria fr and interpretatin f nrmal glucse tlerance tests. Ann. Intern. Med. 33, (1950) 23. Myer, J. H., Wmack, C.R.: Glucse tlerance: I. A cmparisn f 4 types f diagnstic tests in 103 cntrl subjects and 26 patients with diabetes. Amer. J. med. Sci. 219, (1950) 24. Nbel, E. de, Laar, A. van 't, Kene, R.A.P., Benraad, T.J.: Insulin respnse t intravenus glucse administratin in nrmal subjects, mild maturity-nset diabetics and subjects with a "Lag-strage" curve. Diabetlgia 9, (Abstr.) 65 (1973) 25. Pfeiffer, E.F.: Dynamics f insulin secretin in nrmal, bese and diabetic subjects fllwing beta-cell stimulatin. In: Tlbutamide... after ten years, pp Amsterdam: Excerpta Medica Internat. Cngr. Series Nr. 149, Prte, D., Pup, A.A.: Insulin respnses t glucse: evidence fr a tw pl system in man. J. clin. Invest. 48, (1969) 27. Seltzer, H.S., Alien, E.W., Herrn, A.L., Brennan, M.T.: Insulin secretin in respnse t glycemic stimulus: relatin f delayed initial release t carbhydrate intlerance in mild diabetes mellitus. J. clin. Invest. 46, (1967) 28. Simpsn, R.G., Benedetti, A., Grdsky, G.M., Karam, J.H., Frsham, P.H.: Early phase f insulin release. Diabetes 17, (1968) 29. Statist. Bull. Metrp. Life Insur. C. 40, 1-4 (1959) 30. Stephan, T., Nlan, S., Khurana, R. C., Mrgan, C. R., Wingert, J.P., Danwski, T.S.: Lag glucse tlerance curves. Amer. J. med. Sci. 264, (1972) Received." May 7, 1976, and in revised frm: Octber 14, 1976 Dr. E. de Nbel Dept. f Internal Medicine Radbud Ziekenhuis University f Nijmegen Geert Grte plein Zuid 16 Nijmegen The Netherlands