Insulin Secretory Response of Diabetics during the Period of Improvement of Glucose Tolerance to Normal Range

Transcription

1 Diabetlgia 10, (1974) 9 by Springer-Verlag 1974 Insulin Secretry Respnse f Diabetics during the Perid f Imprvement f Glucse Tlerance t Nrmal Range K. Ksaka 1, R. Hagura 2, T. Kuzuya 3, and N. Kuzuya 2 1 Third Dept. f Internal Medicine, Faculty f Medicine, University f Tky, ttng, Tky, ~ The Institute fr Adult Diseases, Asahi Life Fundatin Nishishinjuku, Tky, 3 Dept. f Medicine, Jichi Medical Schl, Minamikchimachi, Tchigi-ken, Japan Received: January 3, 1974, and in revised frm: August 5, 1974 Summary. Serum insulin respnses t 100 g ral glucse, intravenus tlbutamide, and ral glucse plus intravenus glucagn and tlbutamide, were studied in patients wh were definitely diabetic but subsequently imprved t have nrmal glucse tlerance fllwing treatment. "Definite diabetes" was diagnsed when the patient had had fasting bld sugar higher than 150 nag/ 100 ml r had clear diabetic retinpathy plus glucse intlerance. This imprved grup, whether nnbese r bese, had significantly decreased insulin respnses during glucse tlerance test and glucse-glucagn-tlbutamide test, but the insulin respnse t intravenus tlbutamide was nt significantly different frm the cntrl. In cntrast, in the secndary diabetes grup, whse glucse intlerance might be attributable t ther diseases than diabetes, insulin respnse t glucse was enhanced, and was nrmalized when glucse tlerance became nrmal. The insulin respnse t glucse f the prediabetes grup (i.e. with bth parents diabetic) with nrmal glucse tlerance was intermediate between thse f the ]healthy and diabetes grups. It seems that the lw insulin respnse t glucse is a less easily crrigible feature than glucse intlerance and prbably cnstitutes ne f the mst fundamental abnrmalities in primary diabetes. Key wrds: Insulin respnse, ral GTT, tlbutamide test, glucse-glucagn-tlbutamide test, definite diabetes, prediabetes, secndary diabetes, retinpathy. A number f previus studies have demnstrated that insulin secretry respnses t glucse r ther stimuli are generally diminished in mderately r severely diabetic patients. In cases f mild diabetes r s-called chemical diabetes, althugh plasma insulin ften reaches a higher than nrmal level fllwing a glucse lad, the respnse is, in general,, delayed and if the influence f besity [1] and the increment f bld sugar [2, 3] are taken int cnsideratin, it is als regarded as subnrmal. Sme cntradictry results have als been reprted, hwever [4]. Decreased insulin respnse t glucse is cnsidered t be characteristic by sme investigatrs nt nly fr diabetic patients but als fr prediabetic subjects wh have a hereditary dispsitin t diabetes [5, 6]. Cerasi and Luft [6] prpsed a hypthesis that a lw insulin respnse t glucse infusin culd serve as a genetic marker f diabetes, and that true diabetes may develp nly in "lw insulin-respnders'. The insulin respnse f a diabetic patient can vary cnsiderably with the change f metablic state [7]. The aim f the present study was t investigate the insulin respnse f diabetic patients during the perid f best imprvement f their diabetic state. It is rather uncmmn fr a definitely diabetic patient t imprve t cmpletely nrmal glucse tlerance. We have had the pprtunity t study the insulin respnse f 23 such cases and fund that their insulin respnses remained significantly lwer than nrmal despite nrmal glucse tlerance at the time f examinatin. Materials and Methds The principal subjects f this study were the patients with definite diabetes, and subsequently with nrmal glucse tlerance. Amng abut 2000 patients attending the diabetes utpatient clinics f Tky Wmen's Medical Cllege and f University f Tky Hspitals, 23 such patients were fund. They are called "imprved grup". Amng them, 3 were initially treated with insulin, 6 with sulfnylureas, and 14 nly n diet. Nne f them hwever, needed any drugs at the time f examinatin. During imprvement, 8 patients lst weight by 5 kg r mre. In the present paper, definite diabetes is defined when we have cnfirmed that the patient has had a fasting bld sugar (FBS) higher than 150 rag/100 ml during the perid f bservatin, r when the patient has clear diabetic retinpathy with micraneurysms plus diabetic glucse tlerance. This "imprved" grup was cmpared with the fllwing grups fr their insulin respnses. 1. Cntrl grup : 75 subjects (50 nn-bese and 25 bese) wh had nrmal glucse tlerance and were withut a family histry f diabetes, and withut any acute r c:hrnic metablic diseases. 2. Diabetes grups : 139 cases with definite diabetes, wh had either FBS higher than 150 rag/100 ml initially r diabetic retinpathy, but with unspecified FBS at the time f GTT. They were either untreated, r, if treated n ral antidiabetic drugs, drugs were withheld at least fr a week befre the GTT. 3. ]?redia-

2 776 K. Ksaka el at. : Insulin Respnse during Imprvement f Diabetes betes grup: 16 subjects, bth parents diabetic, wh had nrmal glucse tlerance. 4. Secndary diabetes grup : 2 cases n erticsterid treatment fr systemic lupus erythematsus r hepatitis, 3 cases f hyperthyridism and 3 cases f acute hepatitis, wh all had diabetic glucse tlerance, but wh eventually came t have nrmal glucse tlerance. All the tests were carried ut after an vernight fast. The glucse tlerance test was perfrmed using 300 ml Trclan G 50 (Simizu Seiyaku C.) t. It has been reprted that plasma glucse and insulin respnses fllwing administratin f this slutin are essentially the same as thse after a standard 100 g glucse lad [8--10]. Bld sugar determinatin was made with bld samples taken frm a cut n the ear lbe befre and 30, 60, 90, 120 and 180 min after the ingestin f the test slutin. Samples fr serum insulin assay were withdrawn at the same time frm an arm vein int glass tubes. Bld sugar was measured by Hagedrn- Jensen's methd [11], which gave values rag/ 100 ml higher than the glucse-xidase methd in ur labratry. Serum insulin was assayed by a dubleantibdy technique [12]. The criteria fr the evaluatin f glucse tlerance curve were based n the recmmendatin f the Japan Diabetic Sciety [13]; the glucse tlerance curve in which 60 rain and 120 rain values were higher than 200 and 180 rag/100 ml, respectively, was defined as diabetic, and the glucse tlerance curve in which 60 rain and 120 rain values were less than 180 and 140 rag/ 100 ml respectively, was defined as nrmal. Intermediate curves were defined as brderline. The intravenus tlbutamide test was carried ut by injecting 0.5 g tlbutamide intravenusly in 1 min. Bld samples were cllected befre and 1, 5, 10, 20, 30, 40, 50, 60 and 90 min after the injectin. Gluese-glucagn-tlbutamide test was perfrmed accrding t the methd f Ryan and thers [14]. After a fasting bld sample was withdrawn, 300 ml f Trelan G was given rally. Anther bld sample was taken at 30 rain and then 1 mg glueagn and 0.5 g tlbutamide were quickly injected intravenusly. Bld samples were taken 1, 5, 10, 30, 60 and 120 rain after the injectin. Results Insulin Respnses During GTT Insulin respnses fllwing an ral glucse lad (mean SD) f cntrl, prediabetes, imprved grups and diabetic grups are shwn in Fig. 1. Because f the well-knwn effect f besity n serum insulin, nn-bese subjects (less than 110% ideal ml Trelan G cntains carbnated and flavured hydrlysates f carbhydrate crrespnding t 100 g glucse. The cmpsitin f sugars are as fllws: glucse 35.5~ maltse 19.5~, malttrise 12.5% and higher saccharides 32.5 ~. standard bdy weight s ) and bese subjects (.mre than 110% standard bdy weight) are shwn separately. Althugh the glucse tlerance curves f the first three grups all fell within the nrmal range, the imprved grup had slightly higher mean bld sugar values than the cntrl grup after ral glucse lad. The diabetic grups were subdivided accrding t the FBS at the time f GTT. Serum insulin respnses in the cntrl, prediabetes and imprved grups were markedly different despite similar, nrmal glucse tlerances. In the cntrl grup, mean levels f serum insulin reached a peak f 86 ~U/ml (nn-bese) r 127 ~U/ml (bese) at 30 rain. The insulin respnse was markedly depressed in the imprved grup. The insulin respnse f the prediabetes grup was intermediate. In the diabetes grups, the insulin respnses were generally lw and prgressively decreased with increasing FBS. When the FBS levels were lwer than 160 mg/100 ml, the peak insulin levels were nt necessarily lw, but the 30 rain values were dearly subnrmal. In mst grups, bese subjects had higher insulin levels than nn-bese subjeers in the same grup. The individual data f bld sugar and serum insulin cncentratins f the imprved grup are presented in Table 1. Cases N and N were diagnsed as definite diabetes because their initial FBS were higher than 150 mg/100 ml, and cases N and N. 23 had diabetic retinpathy. With a few exceptins, their insulin values rain after the glucse lad were less than the range f crrespnding values in the cntrl grup. This was true bth fr nn-bese and bese eases. The decrease in insulin respnse in the imprved grup is mre dearly demnstrated when the ratis (AIRI/ABS) f the increments f insulin (~U/ml) t bld sugar (rag/100 ml) 30 min after glucse lad were calculated (Fig. 2). The AIRI/ABS values f the imprved grup and the diabetic grups were markedly lwer and thse f the prediabetes grup were mderately lwer than the cntrl values. As an index f verall insulin respnse, the sums f 6 insulin values (ZIRI) btained during GTT are shwn in ~'ig. 3 tgether with the sum f 6 bld sugar values (ZBS). The general pattern is similar t that f Fig. 2, in that the insulin respnse was decreased mderately in the prediabetes grup and markedly in the imprved grup. In the diabetes grups, ZIRI was mderately r markedly decreased. In the imprved grup, cases were examined twice fr their insulin respnse, befre and after nrmalizatin f their GTT. As shwn in t~ig. 4, there was a pr respnse f serum insulin in bth tests. The insulin levels after imprvement were nt significantly different frm thse befre. Fig. 4 als shws the data f "secndary diabetics", wh had had a diabetic glucse tlerance initially, pssibly due t causes ther than 2 Ideal bdy weight was calculated frm the bdy height accrding t the fllwing equatin (15). Ideal bdy weight (Kg) = [bdy height (era) ] 0.9.

3 K. Ksaka et al. : Insulin l~espnse dttring Imprvement f Diabetes 777 primary diabetes, and later had nrmal glucse tlerance. In this secndary diabetes grup, the insulin respnse was markedly higher than the cntrl when the glucse tlerance was diabetic, but decreased t the nrmal range after the nrmalizatin f glucse tlerance. The values f AIRI/ABS remained within the nrmal range in the secndary diabetes grup whether the results f GTT were diabetic r nrmal. Insulin Respnses t Intravenus Administratin f 0.5 g Tlbutamide As shwn in Table 2, serum insulin began t increase within ne minute and reached the maximum 5 rain after the injectin f tlbutamide, except fr the diabetic grup with FBS higher than 160 rag/100 ml, which had a mre sluggish insulin respnse. In the imprved grup, the peak insulin level was smewhat lwer, but was nt significantly different frm that in the healthy cntrl grup. The peak insulin level was lwer in the diabetes grups, and especially when FBS was higher than 160 rag/100 ml. The fall f bld sugar was mst prmpt and marked in the cntrl grup, and tended t be delayed and less marked in ther grups. Insulin Respnses t the Glucse. Glucagn-Tlbutamide Test In the cntrl grup, serum insulin increased prmptly t a peak f 605 =~ 343 ~U/ml 5 min after intravenus injectin f glucagn and tlbutamide 500, 400, Nn-bese grup --i-- Obese grup "-'~... *" i-,,! E. E 300.,e. J- 'lj m : A,:'. 200 &" " J. 1", '.,. [ Nn-bese (50) (7) (1S) (6) (16) (12) [Obese (25) (9) (8).,, (9) (17)..,, ( ' 1 i,-, -r T (2~) (12) (17) (12) --, 100.c_ -5 u~ E 50. J u}, " ' T I, 9 T, i T -:' ' " " t t I i i 9,, ~ '." $... ", "r : ", ~,.,, ", -r, ', T;,, "1" ~, I,~fl I "~t T,- :,, T :.~ ~0 1i0 1800" ~ go ~} {)" ~0 rain. Healthy Prediabetes Imprved GTT:brderline F'BS <120 FBS: F'BS: F'BS >200 Diabetes Fig. l. Changes in bld sugar and serum insulin cncentratins (mean=lsd) during 100 g GTT in the h,aalthy cntrl, prediabetes, imprved and diabetes grups. The number f nn-bese r bese subjects in each grup is shwn in parentheses

4 - Interval after withrawal a Tw hur bld sugar level after 100 g glucse lad. b The degree f retinpathy is based n Sctt's classificatin (Sctt: Brit. J. Ophth. 37, 705, 1953). c The time in the parentheses means the duratin f each treatment. "Nne" means that the patient was treated n diet nly. (d = days, m = mnths, y = years). O0 O Table 1. Individual bld sugar and serum insulin data during 100 g GTT f patients in the imprved grup Befre Treatmerit 100 Glucse Tlerance Test Bld Sugar Serum Insulin cprevius medicatins O tv H ~ O F M M Ia F O VI M F M 2i0 265 II M M M Ia M II F I F II IV[ Ia rain rain f medicatin ~ Nne Nne Insulin (21d), SU(6m) 8Y8M Insulin (21d) 1M SU(llm) 20d Nne ~" Nne SU(6m) 3M SU(4m) 1Y1M Nne r SU(ly) 5M Nne Nne ~" Nne I6 9 Nne 4 i6 66 F II M IIIa F III M M ~ VI ~r M Ia Z Insulin (39d), SU (ly3m) Nne 1Y SU(4y6m) 1M Nne Nne Nne SU (4ylm) 1Y5M Nne ~

5 Table 2. Changes in bld sugar and serum insulin cncentratins (mean 4- SD) fllwing the intravenus injectin f 0.5 g tlbutamide in the healthy, imprved and diabetes grups Table 3. Changes in bld sugar and serum insulin cncentratins (mean 4- SD) during the gtucse-glueagn-tlbutamids test in the healthy, imprved and diabetes grups ~O. f Cases 0 ~ 30 $ $ min. ~.~ Healthy ~ Imprved :[: :k ~ 39, i K: ~ * ~- p. Diabetes (I~BS<160) "* ** ** 285.3~ 23.5** "* "* ** ** ~ Diabetes ~ (FBS>160) ** ** "* "* 370.4=[= 58.6** "* 420.8~79.4"* 365.3=[=100.2"* Healthy i ~'~ Imprved :i: " " ~ Diabetes ~ (FBS<160) * 24.0:I:12.7"* ** * * ~ Diabetes ~" (~BS>160) =]= =h10.9"* ** ** 61.7={= 32.3** 32.8~ 14.6"* "* Arrws 1, 2 and 3 indicate the ingestin f 1O0 g glucse, intravenus injectins f ling Glueagn and 0.5 g tlbutamide, respectively. Asterisks mean significant diffcrences frm healthy cntrl (*: p <0.05, **: p<0.01) ~176 5~ g 9 g g Healthy 6 ~ 5 ~ Diabetes N t:~ ~(FBS>16O) 4 Imprved 6 ~: ~ ~ ~ Healthy 6 ~H-~ ~ Diabetes Imprved 6 N. Time in Minutes f Cases : K:18.6"* "* "* "* "* "* "* "* "* "* ** ** ** ** ** ** ** :j= =[= ={= =[: ={=11.5"* * Asterisks mean significant differences frm healthy cntrl (*: p <: 0.05, **: p <: 0.01)

6 780 K. Ksaka et al. : Insulin Respnse during Imprvement f Diabetes (Table 3). The insulin respnses in the imprved grup and the diabetic grups were bth much smaller than cntrl. Discussin Althugh diabetes mellitus is ften diagnsed n the basis f glucse intlerance, it is bvius that simple glucse intlerance is inadequate fr the diagnsis f true primary diabetes, in view f the diversity f the factrs which can impair glucse tlerance. As ur attentin was particularly fcussed upn the insulin respnse after nrmalizatin f glucse tlerance, chemical diabetes and withut retinpathy, were excluded frm ur study. In cnfrmity with mst previus reprts, definitely diabetic patients thus selected were all lw insulin respnders t ral glucse, if their bld sugar values were taken int cnsideratin t evaluate insulin respnses. Insulin respnses were markedly de. pressed in patients wh had definite diabetes, but with nrmal glucse tlerance at the time f GTT. Luft and assciates [16] reprted that the lw insulin respnse f diabetics with acrmegaly remained lw after imprvement f glucse tlerance by hypphysectmy. Our results seem t indicate that the persistence f a 5.0 Diabetes (a) FB$ >160 (b)'~ Retinpathy Secndary Diabetes ,~! 300 ~00 n=3 n=8 Acute hepatitis 3 Hyperthyridism 3 Prednislne treatment 2 " " to rn <3 \2.5 < ;~. ".! 2 ". ** ~176, ~ 9 e nn-bese bese : ~ 9 = T T.,_, ~. ~ (~.. 0 :~ ~ I_.Q V "" A (/) (,~ to U} "~ 9. )._ m m m m a _e ~ u_,,,, u_ Diabetes Fig. 2. The ratis (AIRI/ABS) f the increment f insulin (~U/ml) t the increment f bld sugar (rag/100 ml) 30 rain after 100 g glucse lad in the healthy cntrl, prediabetes, imprved and diabetes grups. Asterisks mean the sigrdfieance f difference frm crrespnding cntrls (* P<0.05, ** P<0.01) we attempted t select patients wh had unequivcal r definite diabetes by either f tw criteria. Our criteria f FBS higher than 150 rag/100 ml befre treatment, r the presence f definite diabetic retinpathy plus impaired GTT are rather arbitrary. Cases wh might have true primary diabetes, but at the stage f J._c _c E U'} t~ m \ 100 I D 150 loo Mean SD ~ i j i 0 I 2 3 befre after 'i'i befre after 0" i" ; ;h,,. befre after 0] Fig. 3. Changes in bld sugar, serum insulin cncentratins (meanisd) and AIRI/ABS (30 rain) during 100 g GTT in the imprved and secndary diabetes grups befre and after nrmalizatin f their glucse tlerance lw insulin respnse after imprvement f GTT is a general phenmenn in diabetics in whm there is n specific diabetgenic factr. The prediabetes grup als had lwer insulin respnses than the cntrl, in keeping with the data f previus reprts [5, 6]. The decrease ill insulin respnse in prediabetes, hwever, was less marked than that f the imprved grup.

7 K. Ksaka et al. : Insulin Respnse during Imprvement f Diabetes 781 These data suggest that the impaired insulin release by glucse is a less easily crrigible defect in primary diabetes than is glucse intlerance. It prbably cnstitutes ne f the mst inherent and fundamental abnrmalities in the pathphysilgy f diabetes during the phases f prediabetes and f imprvement. In cntrast, in the secndary diabetes patients whse glucse intlerance might be attributable t ther diseases than diabetes, insulin respnses were enhanced when the GTT was diabetic and nrmalized when GTT became nrmal. As AIt~I/ABS ratis were within the nrmal range in these patients, it may be that the B-cells respnded nrmally t the changes in bld sugar during the curse f their primary dis- eases. It has been suggested that impairment f insulin respnse in prediabetes r mild diabetes is a selective defect t glucse stimulatin. Insulin respnses in mild diabetics may be nearly nrmal after tlbutamide [17] r isprterenl [18], but severely impaired fllwing intravenus glucse. Sme investigatrs [5, 19] reprted a subnrmal insulin release after tlbntamide in prediabetic subjects. Hwever, ur data shwed that tlbutamide induced smaller insulin respnses in the imprved and diabetes grups than nrmal, but the decreases in insulin respnses were nt s marked after tlbutamide as thse fllwing glucse stimulatin. Selective impairment f insulin release t glucse may exist t sme extent in these cases. The marked decrease in insulin respnse t the glucse-glueagntlbutamide test in the imprved and diabetes grups may be explained by their insensitivity t glucse stimulatin. Several questins emerge frm the subnrmal insulin respnse t glucse in the imprved and pr. diabetes grups. Nrmal glucse tlerance despite lw insulin release might mean sme cmpensatry adaptatin in the bdy. It is nt knwn whether lw insulin respnse means lack f insulin in the bdy. It is pssible that glucse tlerance is a t insensitive index t be affected by a very minr lack f insulin. The pssibility exists that such a small deficiency f insulin might be relevant t diabetic micrangipathy, which may appear even in the stage f prediabetes [20] and prgresses even with the best means f treatment f diabetes. Anther questin is whether the decreased in. sulin release in prediabetes exists frm birth r whether it appears and prgresses during grwth. That the pre. diabetes grup had intermediate insulin respnses between the cntrl and diabetes grup might supprt the latter view r simply indicate that nt all the subjects with bth parents diabetic have a genetic dispsitin t diabetes. A lng-term fllw up study f the same prediabetic cases is necessary t clarify this prblem. References i. Bagdade, J.D., Bierman, E.L., Prte, D. Jr.: The significance f basal insulin levels in the ewduatin f the insulin respnse t glucse in diabetic and nndiabetic subjects. J. lin. Invest. 46, 154!) (1967) 2. Seltzer, H. S., Allen, E.W., I-Ierrn, A.L. Jr., 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) 3. Perley, M.J., Kipnis, D.M. : Plasma insulin respnses t ral and intravenus glucse -- Studies in nrmal and diabetic subjects. J. clin. Invest. 46, (1967) 4. Reaven, G.M., Shen, S.W., Silvers, A., Farquhar, J. W. : Is there a delay in the plasma insulin respnse f patients with chemical diabetes mellitus? Diabetes 20, (1971) 5. Bden, G., Seldner, J.S., Gleasn, R.E., Marble, A. : Elevated serum human grwth hrmne and decreased serum insulin in prediabetie males after intravenus tlbutamide and glucse. J. clin. Invest. 47, (1968) 6. Cerasi, E., Luft, R. : "What is inherited -- what is added" hypthesis fr the pathgenesis f diabetes mellitus. Diabetes 16, (1967) 7. Ksaka, K., Hagura, R., Sait, R., Tsukamt, F., Kuzuya, T. : Changes in plasma insulin and glucse tlerance in stable diabetes in a yung wman. Diabetes 18, (1969) 8. Ikeda, Y., Sait, It., Anzawa, R., Sane, T., Yaginuma, N., Shimizu, N. : A new carbhydrate slutin, SDT-25 fr testing ral glucse tlerance. J. Jap. Diab. See. ll, (1968) (in Japanese) 9. IIirata, Y., Nakamura, Y., Inuzuka, S., Katsuki, S. : Side effects during the standard glucse tlerance test and an imprved new slutin fr the test. J. Jap. Diab. Sc. 11, (1968) 10. Nakan, M., It, M., Sakn, J., Knd, S. : Changes f bld sugar, insulin and nn-esterified fatty acid after Trelan G50 and glucse lading. A cmparative study. J. Jap. Diab. Sc. 15, (1972) 11. tiagedrn, H. C., Jensen, 13. N. : Zur Mikrbestiramung des Blutzuckers mittels Ferricyanid. Bichem. Z. 1135, (1923) 12. Kanazawa, Y., Kuzuya, T., Id, T., Ksaka, K.: Plasma insulin respnses t glucse in femral, hepatic and pancreatic veins in dgs. Amer. J. Physil. 211, (1966) 13. Kuzuya, N. and thers: Reprt f the cmmittee n the diagnstic criteria f the ral glucse tlerance test fr diabetes mellitus. Recmmendatins n the evaluatin f the ral glucse tlerance test fr the diagnsis f diabetes mellitus. J. Jap. Diab. Sc. 13, 1--8 (1970) (in Japanese) 1~. Ryan, W.G., Schwartz, T.B., Nibbe, A.F.: Serum Immunreactive insulin levels during glucse tlerance and intensive islet stimulatin. Diabetes 20, 40d~--409 (1971) 15. Katsura, E.: In Iwatsuru, R. (ed.), Thery and Practice f diet therapy (in Japanese), ed. 4., Nanzand, Tky P. 483 (1955) 16. Luft, R., Cerasi, E., I-Iamberger, C.A. : Studies n the pathgenesis ~ diabetes in acrmegaly. Aeta Endcr. (khb.) 56, (1967) 17. Varsan-Aharn, N., Echemendia, E., Yalw, 1%.S., Bersn, S.A. : Early insulin respnses t glucse and

8 782 K. Ksaka et al. : Insulin Respnse during Imprvement f Diabetes t tlbutamide in maturity-nset diabetes. Metablism 19, (1970) 18. Rbertsn, R.P., Prte, D. Jr. : The glucse receptr. A defective mechanism in diabetes mellitus distinct frm the beta adrenergic receptr. J. elin. Invest. 52, (1973) 19. Cerasi, E., Luft, R.: Further studies n healthy subjects with lw and high insulin respnse t glucse infusin. Acta Endcr. (kbh.) 55, (1967) 20. Siperstein, M.D., Nrtn, W., Unger, R.H., Madisn, L. L. : Capillary basement membrane width in nrmal, diabetic and prediabetie patients. In ()stman, ft. (ed) Diabetes. Excerpta mediea. Internatinal Cngress Series Amsterdam 172, p (1969) Dr. ixl Kuzuya The Institute f Adult Diseases, Asahi Life Fundatin Nishishinjuku Shinjuku-ku Tky 160/Japan