Diabetologia 9 Springer-Verlag 1992

Transcription

1 Diabetlgia (1992) 35: Diabetlgia 9 Springer-Verlag 1992 The influence f human C-peptide n renal functin and glucse utilizatin in Type 1 (insulin-dependent) diabetic patients B.-L. Jhanssn 1' 3, S. Sj 6berg 2 and J. Wahren 1' 3 Departments f 1 Clinical Physilgy and 2 Medicine, Karlinska Institute, Huddinge Hspital, and Department f 3 Clinical Physilgy, Karlinska Hspital, Stckhlm, Sweden Summary. The pssible influence f C-peptide administratin n renal functin and whle bdy glucse utilizatin was examined in 11 patients (Grup 1) with Type 1 (insulin-dependent) diabetes mellitus. They were given an i. v. insulin infusin during the night befre the study and were euglycaemic at the time f examinatin. The glmerular filtratin rate and effective renal plasma flw were measured by clearance techniques using cnstant-rate infusins f inulin and sdium para-aminhippurate. After baseline measurements C-peptide was infused during tw perids f 60 min at rates f 5 and 30 pml. kg 1. min- 1. In a cntrl study 0.9 % NaC1 was infused during tw 60 min perids in ten Type 1 diabetic patients (Grup 2). Glmerular filtratin rate decreased by 7 % (p < 0.001), effective renal plasma flw increased by 3 %, (p < 0.05) and whle-bdy glucse utilizatin rse by apprximately 25 % (p < 0.05) abve basal during lw-dse C- peptide infusin. Grup 2 shwed an unaltered glmerular filtratin rate, effective renal plasma flw and glucse utilizatin during 60 min f NaC1 infusin. The differences between Grup 1 and Grup 2 in glmerular filtratin rate and glucse utilizatin were statistically significant. It is cncluded that shrt-term administratin f C-peptide in physilgical amunts t patients with Type i diabetes may reduce the gtmerular filtratin rate and increase whle-bdy glucse utilizatin. The results suggest the pssibility that shrt-term C-peptide administratin may exert a regulatry influence n renal functin and stimulate glucse utilizatin in Type i diabetic patients. Key wrds: Glmerular filtratin rate, filtratin fractin, renal bld flw, glmerular permeability. Insulin is synthesized by the Beta cells in the pancreatic islets as a single-chain precursr, prinsulin. The A and B chains f prinsulin are jined by a cnnecting peptide (Cpeptide). Prinsulin is stred in the Glgi regin and it is cleaved by membrane-bund prteases int equimlar amunts f insulin and C-peptide [1]. These prducts are subsequently transprted in secretry granules and released int the circulatin by excytsis [1]. C-peptide is nt knwn t exert bilgical actin in the mammalian rganism. Specifically, n circulatry, metablic r hrmnal effects have been ascribed t this peptide [1]. In patients with Type 1 (insulin-dependent) diabetes mellitus secretin f insulin is insuffient r entirely lacking. This is reflected in a reductin r absence f C-peptide levels in the plasma and urine in Type i diabetic patients [2]. Since C-peptide is eliminated frm the bdy primarily by the kidney [1], the urinary excretin f C- peptide is fequently used as an index f remaining insulin secretin in Type i diabetic patients [3]. An elevated glmerular filtratin rate (GFR) [4-10] and glmerular hypertrphy [11, 12] are frequent findings in Type i diabetic patients particulary during the early phase f the disease. The rise in GFR may persist fr several years - pssibly until the develpment f prteinuria and diabetic nephrpathy [7]. Insulin therapy appears t decrease the renal hyperfiltratin in untreated newly di agnsed Type i diabetic patients but nt t the nrmal levels f GFR seen in nn-diabetic subjects [8, 9]. Since the Type 1 diabetic patients with augmented GFR are likely t have lw r unmeasurable levels f C-peptide in plasma, and this peptide is mainly handled by the kidney, the pssibility that C-peptide exerts a regulatry influence n GFR may be cnsidered. This hypthesis is in line with the fact that Type 2 (nn-insulin-dependent) diabetic patients, wh retain endgenus insulin and C-peptide prductin, usually d nt develp glmerular hyperfiltratin [13] r glmerular hypertrphy [14]. N infrmatin is available regarding the pssible direct effects f C-peptide n renal functin in either Type 1 diabetic patients r healthy subjects. Cnsequently, the present study examined the influence f C-peptide administratin n renal functin in a grup f Type i diabetic

2 122 Table 1. Clinical individual data in the tw grups studied Subject Sex Age Dura- HbA~0 Insulin n. (years) tin f (%) dsage diabetes (IU. kg- ~. (years) 24 h- 1) Grup i 1 M (C-pep- 2 M tide) 3 M M F F M M M M F Grup 2 1 M (0.9% 2 M NaC1) 3 M M M M M M M M patients with increased GFR. At the same time the pssible effect f C-peptide n whle-bdy glucse utilizatin was studied. Subjects and methds Subjects Tw grups were examined. Grup 1 cnsisted f 11 Type 1 diabetic patients (8 male, 3 female) between years f age with a histry f diabetes mellitus f between 3-20 years (mean, 11 years). Clinical data are given in Table 1. The mean HbAlc was 7.0 _+ 0.3 % (nrmal value at ur labratry is < 5.0 %). Nine f the patients had n detectable plasma C-peptide levels in the fasting state ( < 0.05 nml/1) while tw retained lw cncentratins (0.12 and 0.14 nml/1, respectively). The mean insulin dse was 0.82 _ IU. kg h- 1. Ten patients were treated with shrt-acting insulin, three t fur dses during the day and ne dse f medium-acting insulin at bedtime, and in ne patient insulin was given by cntinuus subcutaneus insulin pump therapy. All patients were nrmtensive and nne f them shwed clinical evidence f retinpathy, neurpathy r nephrpathy. Only ne case f mild backgrund retinpathy was fund n eye-grund examinatin by an experienced phthalmlgist. Nephrpathy was excluded n the basis f nrmal serum creatinine levels and n detectable prteinuria was bserved. Grup 2 served as a cntrl grup and cnsisted f ten male Type I diabetic patients between years f age and with a histry f diabetes mellitus f 3-21 years (mean, 9 years). Fur f them had participated in the C-peptide infusin study (Grup 1) 3-12 mnths earlier and their insulin regimen was nt changed. Their mean HbAI~ was % and their mean insulin dse was 0.77 _ IU. kg h - 1. All were nrmtensive and they had n detectable C-peptide levels in plasma r urine and did nt shw clinical evidence f retinpathy, neurpathy r nephrpathy. Clinical data are given in Table 1. All patients were infrmed f the nature, purpse and pssible risks invlved in the study prir t giving their cnsent t participate. B.-L. Jhanssn et al.: C-peptide, renal functin and glucse utilizatin The study prtcl was reviewed and apprved by the thics Cmmittee f Karlinska Institute. Prcedure All subjects came t the labratry the mrning after an vernight fast. During the night they had been given an i. v. infusin f insulin, regulated s that their bld glucse cncentratins were clse t euglycaemic levels prir t the study. The investigatins were made with the patients in the supine psitin. Three catheters were inserted percutaneusly during lcal anaesthesia. One was placed in the femral vein and advanced under flurscpic cntrl t a renal vein and the ther tw were inserted int a brachial artery and an antecubital vein. ffective renal plasma flw (RPF) and GFR were then measured in the basal state and during infusin f C-peptide at tw different dse levels r during infusin f 0,9 % NaC1. Water was given rally t ensure an adequate diuresis during the study; apprximately 20 ml/kg was ingested during the first hur and apprximately 10 ml-kg- 1. h- ~ during the next 5h. Insulin was given via i.v. infusin (0.5mU-kg-i.min -1) thrughut the investigatin and glucse was given i.v. at rates adjusted t maintain bld glucse levels at 5.6 mml/1 _+ 10 %, as indicated by plasma glucse levels measured at 5 min intervals. Inulin and sdium para-aminhippurate (PAH) infusins were given fr 90 min fr baseline measurements befre the infusin f C-peptide (Grup 1) r NaC1 (Grup 2) was begun. Recmbinant human C- peptide, generusly supplied by li Lilly C. (Indianaplis, Ind., USA) was used. In Grup 1, C-peptide was given i.v. fr 1 h (lw dse, blus f 25pml.kg-l-min -1 fr 1.5min fllwed by Table 2. Insulin, glucse and C-peptide levels in arterial bld and glucse utilizatin within each perid (basal, lw- and high-dse C- peptide and tw 60 min 0.9 % NaC1 infusin perids) in the grups studied. Mean -+ SM is given Insulin Glucse C-peptide Glucse (gu/ml) (mmvl) (nml/1) utilizatin (mg. min- 1. kg -1) Grupl Basal 21+_1 5.8_+0.2 < _+0.24 (n = 11) Lw-dse _ _ ~'b C-peptide (n = 11) High-dse _ c C-peptide (n =7) Grup2 Basal 21_ < (n = 10) 60 min 22 _ < % NaC1 (n = 10) 120 min _+ 0.1 < % NaC1 (n = lo) a Indicates significant difference (p < 0.05) between basal state and lw-dse C-peptide infusin. u Indicates significant difference (p < 0.01) between the grups cncerning the percental change frm basal state t lw-dse C-peptide infusin and frm basal t 60 rain 0.9 % NaC1 infusin. c Indicates significant difference (p < 0.02) between basal state and high-dse C-peptide infusin. d Indicates significant difference (p < 0.05) between basal state and 120 min 0.9 % NaC1 infusin.

3 B.-L. Jhanssn et al.: C-peptide, renal functin and glucse utilizatin 10pml-kg-l.min -1 fr 6.5min and ending with 5pml.kg -1- min- z fr 52 min) and then fr an additinal hur using a blus and infusin rates six times thse f the first infusin perid (high dse). Instead f C-peptide, a 0.9 % NaC1 infusin was given fr 2 h in Grup 2. Urine (spntaneus viding) and bld samples were cllected at timed intervals thrughut the study perid fr analyses f inulin, PAH and C-peptide. Renal vein catheterisatin was nt perfrmed in fur patients (tw in each grup). GFR and RPF were measured by the clearances f inulin (Inutest, 25 %, Laevsan-Gesellschaft, Linz, Austria) and PAH (Aminhippurate sdium, 20%, Merck Sharp & Dhme, Westpint, PA, USA) respectively. The inulin and PAH were mixed in a rati 17: 3. After a prime dse f 0.3 ml/kg a cntinuus infusin (0.375 ml/min) f the mixed slutin was given fr 3.5 h. Bdy surface area was calculated accrding t Haycck et al. [15]. ~3- v g2 "O _ 6 T T----~-- Lw-ds~ C-peptide TTT ~igh-d~ C-peptide Fig.1. Steady-state levels f arterial plasma C-peptide cncentratin during the last 10 min f lw- and high-dse C-peptide infusin perids (Mean + SM are given) 123 Analyses The cncentratin f C-peptide in plasma was measured in duplicate samples by a radiimmunlgical technique [16] using antibdy M1230. The detectin limit in the assay is 0.05 nml/1. The prcedure has been described in detail elsewhere [17]. Inulin was analysed in bld by using the anthrne methd [18] and PAH by a mdified Smith technique [19]. Plasma glucse was measured by a glucse xidase methd (Glucse analyser 2, Beckman, Brea, CA, USA). HbAlc was determined by a specific in-exchange chrmatgraphy technique, using a cmmercial kit (Mn S HR 5/5, Pharmacia AB, Uppsala, Sweden). Calculatins Whle-bdy glucse utilizatin was calculated as described by De Frnz et al. [20] during the last 40 rain f each perid (basal state, lw- and high-dse C-peptide and tw 60 min NaC1 infusin perids). Despite high water intake, mst f the subjects had prblems with spntaneus viding f urine in the supine psitin which resulted in a smewhat unstable diuresis. Hwever, since a cnstant rate infusin f PAH and inulin was given, resulting in steady-state plasma cncentratins f these substances, RPF and GFR culd be determined accrding t fllwing frmulas. 1. RPF = PAH Infusin Rate x A (PAH) - RV (PAH). A (PAH) - RV (PAH) A (PAH) PAH Infusin Rate 2. RPF = A (PAH) where A (PAH) and RV (PAH) represent the cncentratins f PAH in arterial and renal venus (RV) plasma. InulinInfusinRate A (IN) - RV (IN). 3. GFR - x A (IN) - RV (IN) A (IN) ' 4. GFR = Inulin Infusin Rate. A (IN) where A (IN) and RV (IN) indicate the arterial and renal venus cncentratins f inulin. Renal extractin f PAH is calculated as the rati between the renal venus-arterial cncentratins difference f PAH and the arterial cncentratin f PAH. A (IN and PAH) and RV (IN and PAH) represent the mean value f fur determinatins taken every 5 min during the last 15 min within each perid (basal state, lw- and high dse C-peptide and tw 60 min NaC1 infusin perids). ~20 c 18-8 ~14- S -'r 2- ~ ----s...._~ i I I i ~ i I I -600 '~ -500.~_ -400 " - g.i 0 8~ min Fig.2. Steady-state cncentratins f inulin (A---A) and sdium para-aminhippurate (PAH) (H) in the brachial artery and PAH (m---l) in the renal vein during the last 10 min f the 90-min basal study perid. Mean + SM are given Statistical analysis Standard statistical methds were emplyed using the paired t-test, Wilcxn's signed-rank test, and analyses f variance (repeated measurements) when applicable. Data in the text, tables and figures are presented as mean + SM. Results Nne f the patients in Grup i reprted any adverse reactins during the C-peptide infusins. Hwever, in fur f the patients the study was discntinued after the first C- peptide infusin because f prblems with viding in the supine psitin. Bth grups shwed stable and unchanged insulin and bld glucse cncentratins thrughut the study and the levels did nt differ between the grups (Table 2). C-peptide: Steady-state levels f C-peptide were reached during bth the lw- and high-dse infusin (Fig. 1). As seen frm Figure 1 and Table 2 a six-fld increase in the C- peptide infusin rate frm lw t high dse was accmpanied by a three-fld rise in the bld levels f C-peptide [ nml/1 and nml/1, respectively]. Nne f the patients in Grup 2 had detectable C-peptide levels in plasma r urine during the study. g

4 124 B.-L. Jhanssn et al.: C-peptide, renal functin and glucse utilizatin Table 3. Mean values + SM fr glmerular filtratin rate (GFR), effective renal plasma flw (RPF), filtratin fractin (FF, GFR/RPF) and sdium para-aminhippurate (PAH) extractin during basal state and C-peptide infusin (lw and high dse) in Grup t and during basal state and 0.9 % NaC1 infusin (60 and 120 min) in Grup 2 GFR RPF FF PAH extractin (ml.min-~. 1.73m -2) (ml.min m -2) (%) (%) Grup i Basal _ (n = 11) Lw-dse ~'~ b ~'~ C-peptide (n = 11) High-dse ~ g f, J C-peptide (n = 7) Grup 2 Basal (n = 10) t _ min _ _+ 0.4r % NaC1 (n = 10) 120 min 127 _+ 3 k 725 _ ~ 91 _ % NaC1 (n = 10) a,b Indicate significant differences (p < and p < 0.05, respectively) between basal and lw-dse C-peptide infusin9 ~. a Indicate significant differences (p < 0.01 andp < 0.05, respectively) between the grups cncerning the percental change frm basal state t lw-dse C-peptide infusin and frm basal t 60 min 0.9 % NaC1 infusin. e, f. g Indicate significant differences (p < 0.001,p < 0.01 and p < 0.05, respectively) between basal state and high-dse C-peptide infusin. h,~ Indicate significant difference (p < 0.05 and p < 0.01, respectively) between the grups cncerning the percental change frm basal state t high-dse C-peptide infusin and frm basal state t 120 rain 0.9 % NaC1 infusin. J Indicates significant difference (p < 0.05) between basal and 60 rain 0.9 % NaC1 infusin. k,j Indicate significant difference (p < 0.05 and p < 0.0!, respectively) between basal state and 120 min 0.9 % NaC1 infusin Renal functin: Infusin f inulin and PAH resulted in steady-state levels f these substances during each study perid (Fig.2) as is required fr the calculatin f GFR and RPF. In Grupl, GFR was 143+_3mt.min -~ m -2 in the basal state and decreased n the average by 7% during the lw-dse C-peptide infusin t ml. min m- 2 (p < 0.001). A fall in GFR was seen in each f the 11 patients studied (Fig.3). GFR tended t decrease further in the seven patients in whm high-dse infusin culd be carried ut (frm t 132_+4ml.min-~.1.73 m -2, p <0.1, Table3, Figure 3). N changes in GFR were fund in the cntrl subjects after i h f NaC1 infusin but a slight decrease (4 %, p < 0.01) was bserved frm basal t 2 h infusin f NaC1. The fall in GFR was greater in Grup 1 bth frm basal t lw-dse and frm basal t high-dse C-peptide than A "7 e ~D B ~k --.I. p<0.001 ~ ~ ~, -- A, p<0.05 ~ ~ p<~.01 - " I I I I I I Basal Lw-dse High-dse Basal 60 min 120 min I C-peptide infusin ~ I 0.9%NCI infusin Fig. 3. Individual values fr glmerular filtratin rate in the basal state and during lw- and high-dse C-peptide infusin in Grup 1 (lefipanel) and in basal state and during 60- and 120-min infusins f 0.9 % NaC1 in Grup 2 (rightpanel)

5 B.-L, Jhanssn et al.: C-peptide, renal functin and glucse utilizatin 125 ') 160 "T._c i_ c- O i_ " p<0.05 I I I I Basal Lw-dse Basal 60 min I C-peptide infusin I NaCI infusin,,. r n.s. Fi8.4. Individual values fr glmerular filtratin rate in the fur patients wh participated in bth Grup I and Grup 2. Lefipanelrepresents the values received at the basal state and during lwdse C-peptide infusin (Grup 1) and rightpanel represents the values received at basal state and during 60-min infusins f 0.9 % NaC1 (Grup 2) during crrespnding perids in Grup 2 ( % vs %, p < and % vs %, p < 0.05). In additin, the fur patients wh participated in bth Grup I and Grup 2 (Fig. 4) all had a greater fall in GFR frm basal t lw-dse C-peptide infusin than frm basal t 60 min NaC1 administratin ( % vs %,p < 0.05). RPF in Grup1 was in the basal state ml-min m -2 with a slight increase (3 %, p < 0.05) t 760 _+ 35 ml. min m -2 during lw-dse C-peptide infusin. At the end f the high-dse infusin RPF had risen by 6% in relatin t the basal value (p < 0.05). N significant change in RPF was fund between lw- and high-dse administratin (Table 3, Fig. 5). '% 1000 = "T c.2." 800 1, Q. c L_ 0J > 600 v kl.l p<o Im, p<0.05' I I I I I I Basal Lw-dse High-dse Basal 60 min 120 min I C-peptide infusin,~ I 0.9NC[ infusin Fig.& Individual values fr effective renal plasma flw in the basal state and during lw- and high-dse C-peptide infusin in Grup 1 (left panel) and in basal state and during 60 and 120-min infusins f 0.9 % NaC1 in Grup 2 (right panel)

6 126 B.-L. Jhanssn et al.: C-peptide, renal functin and glucse utilizatin 6 "7 0~ 2~ "7.c /, c-. O.N s D p<0.01 -~ p<0.01 ~- -~ p<0.05 ~- I I I I I I Basal Lw-dse High-dse Basal 60 rnin 120 min I C-peptide infusin ~-- I 0.gNaCI infusin ~- Fig. 6. Individual values fr glucse utilizatin in the basal state and during lw- and high-dse C-peptide infusin in Grup 1 (left panel) and in basal state and during 60- and 120-min infusins f 0.9 % NaC1 in Grup 2 (right panel) In the cntrl subjects RPF did nt change frm the basal t 60 r 120 min infusin f NaC1 (Table 3, Fig. 5). Filtratin fractin calculated as the rati between GFR and RPF decreased frm % in the basal state t % (p < 0.001) during lw-dse C-peptide in Grup 1 with a further reductin frm lw-t high-dse infusin (t %, p < 0.05, Table 3). Filtratin fractin was als reduced in Grup 2 during 60 min (p < 0.05) and 120 min (p < 0.01) NaC1 infusin in cmparisn with basal value. Hwever, Grup 1 shwed a mre marked reductin than did Grup 2 during crrespnding perids (p < 0.01,bth frmbasaltlwrbasal t high-dse). The renal PAH extractin was stable and cnstant (90-92 % ) in bth grups thrughut the study (Table 3). Glucse utilizatin: Whle-bdy glucse utilizatin was mg.min-t-kg -1 in the basal state and increased by apprximately 25 % frm the basal level t lw-dse C-peptide infusin (p < 0.01, Table 2, Fig. 6). A further increase frm t mg. min- 1. kg -1 (15 %, p < 0.05) was bserved during the high-dse infusin in the seven patients wh participated in bth lw- and high-dse C-peptide administratin. There was a significant difference in the glucse utilizatin change frm basal t lw-dse (25 + 6%) and frm basal t 60 min NaC1 infusin (6 + 7 %) between the tw grups < 0.02). In Grup 2 n significant change in glucse utilizatin was seen during the first 60 rain f NaC1 infusin but a small rise was bserved after 120 min (p < 0.05, Table 2, Fig. 6). Discussin The present study grup was made up f yung Type 1 diabetes patients withut signs f clinical late diabetic cmplicatins and in a state f gd metablic cntrl, as indicated by HbAlc values clse t the nrmal range. Mst f the patients had an increased GFR in the basal state (138+3 fr Grup1 and 2 as cmpared t ml. rain m-2, p < 0.001, fund in 16 healthy subjects, aged years, studied at this department) and n significant residual C-peptide prductin at the time f the study. Previus wrk has suggested that hyperglycaemia per se might induce renal hyperfiltratin [10]. Cnsequently, all patients were studied in the euglycaemic state in rder t minimize the pssible influence f hyperglycaemia n renal functin. During lw-dse C-peptide infusin the patients shwed a small but significant decrease in GFR ( - 7 %) a finding which is supprted by the fact that all patients shwed a similar respnse. An influence f C-peptide n RPF was als bserved during this perid but in the ppsite directin and f lesser magnitude (3 %), leading t a mre marked reductin in filtratin fractin than in GFR. It is ntewrthy that the influence f C-peptide n renal functin ccurred already with the lw-dse infusin, which had been estimated t restre basal physilgical cncentratins f C-peptide. Only a small further decrease in GFR tk place when the C-peptide infusin rate was increased six-fld. Thus, a dse-respnse relatinship culd nt be established between GFR and plasma C-peptide cncentratins. The pssibility shuld be cnsidered that the experimental prcedure itself, by virtue f the prlnged

7 B.-L. Jhanssn et al.: C-peptide, renal functin and glucse utilizatin study perid (5 h) during which the subjects rested in the supine psitin withut ingestin f fd, and/r the slw rate insulin infusin (0.5 mu- kg- 1. min- 1) may have influenced renal functin. Hwever, in the ten patients wh received 0.9 % NaC1 rather than C-peptide under therwise identical cnditins, n change in GFR culd be bserved during the first 60 min. In additin, all fur patients wh participated in bth study grups had a greater fall in GFR during lw-dse C-peptide infusin cmpared with 60 min 0.9 % NaC1 infusin (p < 0.05). These bservatins supprt the hypthesis that C-peptide des in fact exert a direct effect n renal functin in Type 1 diabetic patients. A dse-respnse relatinship culd nt be seen fr C- peptide infusin rate and steady-state plasma levels f C- peptide. A six-fld increase f C-peptide infusin resulted in n mre than a three-fld increase in plasma C-peptide levels. Thus, ur findings suggest that whle bdy metablism f C-peptide increases with augmented rates f C- peptide infusin. This finding cntrasts with that f Plnsky et al. [21], wh bserved that the metablic clearance rate fr C-peptide remained unchanged in Type 1 diabetic patients regardless f the rate f C-peptide administratin. The differences may be due t variatins in study design. In the present study cnstant insulin and variable glucse infusins were adjusted s as t maintain plasma glucse in the nrmglycaemic range. This resulted in a steady-state insulin plasma level f 21 gu/ml. In the studies by Plnsky et al. [21] a variable insulin infusin was given, adjusted t maintain the plasma glucse levels in the euglycaemic range. The plasma insulin levels fund in their healthy cntrl subjects were 6-7 gu/ml. The plasma insulin levels fund in the Type I diabetic patients were nt reprted but we assume that they had levels similar t thse f the healthy cntrl subjects. In that case, ur Type 1 diabetic patients had insulin levels at least twice as high as the patients in the study by Plnsky et al. [21]. In rder t maintain an unchanged bld glucse level during C-peptide infusin the rate f glucse infusin had t be increased by abut 25 % during lw-dse C-peptide infusin but culd be kept unchanged during the crrespnding time perid with NaC1 infusin. High-dse infusin resulted in a further small rise in glucse utilizatin as is evident frm the data in the seven patients wh received bth high- and lw-dse infusin. In the latter patients the rise amunted t 43 % abve basal after high-dse infusin as cmpared t n mre than 18% in NaC1 cntrl subjects. In view f these findings and the fact that arterial insulin levels remained unchanged during this perid, it is unlikely that the bserved rise in glucse utilizatin was an effect f insulin. This finding suggests that C-peptide exerts a stimulatry effect n glucse utilizatin in Type 1 diabetic patients althugh the pssibility f an inhibitin f hepatic glucse prductin by C-peptide cannt be excluded. There is, as far as we knw, nly ne human study, presented in abstract frm, in which the effect f C-peptide n carbhydrate metablism in Type i diabetic patients has been evaluated [22]. N significant changes in the cncentratins f glucse, lactate, alanine, [3-hydrxybuturate, glycerl r nn-esterified fatty acids during 2 h bservatin after an i. v. C-peptide injectin (24-36 nml) 127 in either diabetic (n =7) r healthy cntrl subjects (n = 4) culd be fund. Hwever, Wallberg-Henrikssn et al. [23] have recently reprted that human C-peptide in physilgical amunts increases glucse uptake in incubated skeletal muscle under in vitr cnditins in healthy persns. Anther study by Wallberg-Henrikssn et al. [24] demnstrates that glucse uptake in skeletal muscle frm Type i diabetic patients is stimulated by C-peptide t almst 100 % f the effect btained by equimlar amunts f insulin. Hgwerf et al. [25] fund in a recent study that C-peptide infusin in physilgical amunts t healthy persns might exert a suppresive effect n insulin and glucagn release. Wjcikwski et al. [26] fund that infusin f rat C-peptide in unphysilgicalty high dses increases and prlngs the hypglycaemic effect f exgenus insulin in allxan-diabetic rats. Thus, the abve studies supprt the ntin that C-peptide may stimulate glucse utilizatin. In cnclusin, the present study des nt cnfirm earlier suggestins that C-peptide is a bilgically inactive substance [1]. Instead, the results suggest the pssibility that shrt-term administratin f C-peptide may exert a regulatry influence n renal functin as well stimulate glucse utilizatin in Type i diabetic patients. Acknwledgements. This study was supprted by grants frm the Karlinska Institute and the Swedish Medical Research Cuncil (n. 3108). References 1. Steiner DF (1978) On the rle f the prinsulin C-peptide. Diabetes 27 [Suppl 1]: Heding LG (1978) Insulin, C-peptide, and prinsulin in nndiabetics and insulin-treated diabetics. Diabetes 27 [Suppl 1]: Blix PM, Bddie-Willis C, Landau RL, Rchman H, Rubenstein AH (1982) Urinary C-peptide: an indicatr f beta-cell secretin under different metablic cnditins. J Clin ndcrinl Metab 54: Stalder G, Schmid R (1959) Severe functinal disrders f glmerular capillaries and renal hemdynamics in treated diabetes mellitus during childhd. Ann Paediatr 193:12% Mgensen C, Andersen MJF (1973) Increased kidney size and glmerular filtratin rate in early juvenile diabetes. Diabetes 22: Mgensen C (1972) Glmerular filtratin rate and renal plasma flw in lng-term juvenile diabetics withut prteinuria. Br Med J 4: Mgensen C, Christe'nsen CK, Beck Nielsen H, Vittinghus (1983) arly changes in kidney functin, bld pressure and the stages in diabetic nephrpathy. In: Keen H, Legrain M (eds) Preventin and treatment f diabetic nephrpathy. MTP press, Lancaster, pp 57~83 8. Mgensen C, Andersen MJF (1974) Increased kidney size and glmerular filtratin rate in untreated juvenile diabetes. Nrmalisatin by insulin treatment. Diabetlgia 11: Sandahl-Christiansen J, Gammelgaard J, Trnier B, Svendsen PA, Parring HH (1982) Kidney functin and size in diabetics befre and during initial insulin treatment. Kidney Int 21:683~ Sandahl-Christiansen J, Frandsen M, Parving HH (1981) The effect f intravenus insulin infusin n kidney functin in insulindependent diabetes mellitus. Diabetlgia 20:

8 Osterby R, Gundersen HJG (1975) Glmerular size and structure in diabetes mellitus. I. arly abnrmalities. Diabetlgia 11: Gundersen HJG, Osterby R (1977) Glmerular size and structure in diabetes mellitus. II. Late abnrmalities. Diabetlgia 13: Friedman A, Sheih S-D, Hirsch SR, Bshell BR (1981) N supranrmal glmerular filtratin (GFR) in type II (nn-insulin-dependent) diabetes. Am Sc Nephr114:102A (Abstract) 14. Schmitz A, Gundersen HJG, Osterby R (1988) Glmerular mrphlgy by light micrscpy in nn-insulin-dependent diabetes mellitus. Diabetes 37: Haycck GB, Schwartz GJ, Wistsky DH (1978) Gemetric methd fr measuring bdy surface area: a height-weight frmula validated in infants, children and adults. J Paediatr 93: Heding LG (1975) Radiimmunlgical determinatin f human C-peptide in serum. Diabetlgia 11: SjSberg S, Gunnarssn R, Gj/3tterberg M, Lefvert A-K, Persn A, CIstman J (1987) Residual insulin prductin, glycaemic cntrl and prevalence f micrvascular lesins and plyneurpathy in lng-term insulin-dependent diabetes. Diabetlgia 30: Hilger HH, Klumper JD, Ullrich KJ (1958) Wasserrfickresrptin und Inentransprt durch die Sammelrhrzellen der Sfiugetierniere. Pflugers Arch 267: Smith HW, Finkelstein N, Aliminsa L, Crawfrd B, Graber M (1945) The renal clearances f substituted hippuric acid derivatives and ther armatic acids in dg and man. J Clin Invest 24: DeFrnz RA, Tbin DT, Reubin R (1979) Glucse clamp technique: a methd fr quantifying insulin secretin and resistance. Am J Physi1237: B.-L. Jhanssn et al.: C-peptide, renal functin and glucse utilizatin 21. Plnsky KS, Licini-Paixa J, Given BD et al. (1986) Use f bisynthetic human C-peptide in the measurements f insulin secretin in nrmal vlunteers and type i diabetic patients. J Clin Invest 77: Hagen C, Faber OK, Binder C, Alberti KGMM (1977) Lack f metablic effects f C-peptide in nrmal and juvenile diabetic patients. Acta ndcrin185 [Supp1209]: 29A (Abstract) 23. Wallberg-Henrikssn H, Andr6assn K, Galuska D et al. (1989) C-peptide stimulates glucse transprt in incubated nrmal muscle but nt in muscles frm type II diabetic patients. Diabetlgia 32: 555A (Abstract) 24. Zierath JR, Th6rne A, Jhanssn B-L, Wallberg-Henrikssn H (1990) C-peptide stimulates glucse transprt in type 1 diabetic skeletal muscle. Diabetes 39: 564A (Abstract) 25. Hgwerf BJ, Bantle JR Gaenslen H et al, (1986) Infusin f synthetic human C-peptide des nt affect plasma glucse, serum insulin, r plasma glucagn in healthy subjects. Metablism 35: Wjcikwski Cz, Maier V, Dminiak K, Pfeiffer F (1985) ffects f synthetic rat C-peptide in nrmal and diabetic rats. Diabetlgia 25: Received: 11 March 1991 and in revised frm: 16 September 1991 Dr. B.-L. Jhanssn Department f Clinical Physilgy Karlinska Hspital Bx S Stckhlm Sweden