Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of Type 1 (insulin-dependent) diabetes mellitus

Diabetologia, Jan 1990

An increased proinsulin to C-peptide molar ratio at the onset of Type 1 (insulin-dependent) diabetes mellitus has been suggested. We studied fasting proinsulin levels and proinsulin/C-peptide ratios in the newly diagnosed diabetic subjects participating in the Canadian/European placebo controlled cyclosporin study at entry, during the one year treatment period and six months of follow-up. Available entry data from 176 out of the 188 allocated patients were compared to 60 age and weight matched control subjects. Fasting proinsulin was significantly elevated in male patients compared to male control subjects (p<0.01), whereas the levels only tended to be elevated in female patients. The proinsulin/C-peptide ratio was three to fourfold elevated in the diabetic groups of both sexes, (p<0.001). Further, proinsulin and C-peptide were studied in 83 cyclosporin and 86 placebo-treated subjects during the trial and follow-up. An additional increase of proinsulin/C-peptide ratio was observed during the first three months of placebo treatment. It remained constantly high for nine months and then declined to entry level. This pattern was not seen in the cyclosporintreated group, where the ratio was unchanged during the 12 months trial and follow-up. The effect of cyclosporin on the induction of non-insulin requiring remission was unrelated to fasting and glucagon stimulated C-peptide levels at entry, whereas 64% of the cyclosporin-treated against 28% of the placebo-treated subjects (p<0.01) went into remission if the proinsulin/C-peptide ratio at entry was above 0.024. If the ratio was below 0.024 at entry, 42% and 33% went into non-insulin requiring remission, respectively (NS). We conclude that fasting proinsulin to C-peptide molar ratio is elevated at the onset of Type 1 diabetes mellitus. A further plateaushape elevation lasting nine months was seen during the remission period. Cyclosporin seems to inhibit or delay this development. The proinsulin/C-peptide ratio at diagnosis may show to be of value in the prediction of remission during cyclosporin treatment.

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Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of Type 1 (insulin-dependent) diabetes mellitus

Diabetologia Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of Type 1 (insulin-dependent) diabetes mellitus* O. Snorgaard S. G. H a r t l i n g C. B i n d e r Steno Memorial Hospital Gentofte Denmark Smnmary. An increased proinsulin to C-peptide molar ratio at the onset of Type i (insulin-dependent) diabetes mellitus has been suggested. We studied fasting proinsulin levels and proinsulin/C-peptide ratios in the newly diagnosed diabetic subjects participating in the Canadian/European placebo controlled cyclosporin study at entry, during the one year treatment period and six months of follow-up. Available entry data from 176 out of the 188 allocated patients were compared to 60 age and weight matched control subjects. Fasting proinsulin was significantly elevated in male patients compared to male control subjects (p < 0.01), whereas the levels only tended to be elevated in female patients. The proinsulin/C-peptide ratio was three to fourfold elevated in the diabetic groups of both sexes, (p < 0.001). Further, proinsulin and C-peptide were studied in 83 cyclosporin and 86 placebo-treated subjects during the trial and follow-up. An additional increase of proinsulin/C-peptide ratio was observed during the first three months of placebo treatment. It remained constantly high for nine months and then declined to entry level. This pattern was not seen in the cyclosporin* Prepared by the authors for The Canadian/European Diabetes Study Group. Type i (insulin-dependent) diabetes mellitus; recent-onset; proinsulin; C-peptide; cyclosporin; remission 9 Springer-Verlag1990 Characteristic quantitative changes of B-cell function are seen at onset and during the first year of remission and relapse of Type i (insulin-dependent) diabetes mellitus [ 1-6 ]. Further, a five to tenfold increase of the molar ratio between proinsulin and C-peptide suggests a qualitatively altered function of the B cells at the time of diagnosis [ 7, 8 ]. This elevated ratio seems to persist throughout the remission period [8]. The mechanisms behind, and significance of, this alteration of B-cell function is unknown. In recent years clinical trials of cyclosporin in newly diagnosed Type i diabetes, including the present study, have shown a beneficial effect of cyclosporin on the treated group, where the ratio was unchanged during the 12 months trial and follow-up. The effect of cyclosporin on the induction of non-insulin requiring remission was unrelated to fasting and glucagon stimulated C-peptide levels at entry, whereas 64% of the cyclosporin-treated against 28% of the placebo-treated subjects (p < 0.01) went into remission if the proinsulin/C-peptide ratio at entry was above 0.024. If the ratio was below 0.024 at entry, 42% and 33% went into noninsulin requiring remission, respectively (NS). We conclude that fasting proinsulin to C-peptide molar ratio is elevated at the onset of Type i diabetes mellitus. A further plateaushape elevation lasting nine months was seen during the remission period. Cyclosporin seems to inhibit or delay this development. The proinsulin/C-peptide ratio at diagnosis may show to be of value in the prediction of remission during cyclosporin treatment. frequency of non-insulin requiring remission and on C-peptide levels [ 9, 10 ]. The effect of cyclosporin on proinsulin levels is unknown. Ludvigsson [ 8 ] found a weak correlation between a long remission and a low proinsulin/C-peptide ratio at onset, suggesting a possible value of the ratio as a predictor of remission. Old age, high C-peptide levels and low islet cell antibody titres at diagnosis are suggested as having predictive value on the rate of fall of C-peptide levels and the frequency of remission [3-6[. We studied fasting proinsulin and C-peptide levels of the recent onset insulin-treated Type 1 diabetic subjects participating in the Canadian/European randomized placebo controlled trial of cyclosporin [ 9 ]. Primarily, we analysed the quantitative and qualitative changes of B-cell function at entry of the study. Secondly we studied the further changes of the molar ratio of proinsulin to C - p e p t i d e during the following remission t o g e t h e r with the effect of cyclosporin o n the ratio. Thirdly, the possible value of the p r o i n s u l i n / C - p e p t i d e ratio in the prediction of remission was considered. Subjects and methods A group of 188 newly diagnosed ketosis-prone Type i diabetic patients were consecutively admitted to 12 diabetic centers in Canada and Europe for a randomized placebo controlled trial of cyclosporin. Insulin treatment was started prior to allocation. Patients were included within 14 weeks of the onset of symptoms and 6 weeks of insulin treatment. Obesity, a strong family history of Type 2 (non-insulin-dependent) diabetes or conditions excluding cyclosporin treatment were exclusion criteria. The intention was to treat for 12 months, but placebo was substituted for cyclosporiu, if two consecutive fasting C-peptide measurements were less than 0.1 nmol/1, after the third month. Proinsulin and C-peptide were measured in the fasting state and 6 min after i. v. injection of I mg of glucagon at entry of the study and at 1, 3, 6, 9,12, 15 and 18 months. H L A - D R type was determined in all subjects. Islet cell and insulin antibodies were measured at entry, 3, 6, 9 and 12 months. Fasting blood glucose (fBG) and HbAic were measured at all time points, but were only available for us at entry. For further details consult the principal report of the trial [ 9 ]. C-peptide in plasma was analysed in two different laboratories using the same RIA techniques according to Heding [11] and Faber [ 12 ] with a good correlation (r = 0.96). Proinsulin was analysed with an enzyme linked immunoassay [ 13 ].Detection limit was 1.2 pmol/1. Below that, the figure 1.1 pmol/1was given. C-peptide did not crossreact up to a concentration of 10,000 pmol/1and insulin not up to 400 pmol/1 at 50% dilution. Both intact proinsulin and major split products were measured. The islet cell antibody titres were measured using workshop methodology as recently described in detail [ 14 ]. A group of 60 normal subjects were selected from a pool of 176 healthy non-diabetic subjects. All were without first degree Type 1 diabetic relatives. Selection criteria was an age range of 9 to 35 years and a body mass index below 25 kg/mz. Statistical analysis C-peptide and proinsulin results are indicated as median, 25th and 75th percentile. Between-group comparisons were made with Mann-Whitney Rank Sum Test, and within-group with Wilcoxon Test for Pair Differences. Log~(proinsulin) and 1Oge(proinsulin/Cpeptide ratio) were used as dependent variables in the analyses of variance and in the regression analyses. Only complete records were entered in the former, n=113 (proinsulin) and n= 112 (prohlsulin/C-peptide ratio). BMDP software programmes (version 1987, Los Angeles, Calif., USA) were used for the statistical analyses. Results Prior to cyclosporin treatment P l a s m a f r o m the t i m e of entry to the study w e r e available f r o m 176 of the 188 diabetic subjects for proinsulin and Cp e p t i d e m e a s u r e m e n t s . T h e characteristics of these patients and the 60 n o r m a l subjects are indicated in Table 1. T h e two groups w e r e m a t c h e d with r e g a r d to age and weight w h e n considering the two sexes separately. Fasting proinsulin was a p p r o x i m a t e l y d o u b l e d (p < 0.01) and fasting C - p e p t i d e a p p r o x i m a t e l y halved (p < 0.001) in the m a l e insulin-treated p a t i e n t s at e n t r y c o m p a r e d to the n o r m a l m a l e subjects (Table 1), leading to a m a r k e d l y e l e v a t e d p r o i n s u l i n / C - p e p t i d e ratio, p < 0.001. Fasting proinsulin was not significantly e l e v a t e d in the f e m a l e g r o u p but C - p e p t i d e was h a l v e d (p < 0.001) leading to the s a m e level of increased proinsulin/C-peptide ratio (p < 0.001) as in m a l e subjects (Table 1). C o m paring the two sexes r e v e a l e d n o significant differences in proinsulin, C-peptide, p r o i n s u l i n / C - p e p t i d e ratio or any o t h e r of the available p a r a m e t e r s at entry o r at any t i m e point during the study, except for the higher weight and a significantly higher HbAIr a m o n g m a l e diabetic p a t i e n t s (Table 1, p < 0.05). I n spite of these m i n o r differences bet w e e n sexes, the d a t a o f b o t h sexes are p o o l e d in Figures 1 and 2 and in the s u b s e q u e n t results. A s is a p p a r e n t f r o m Figures 1 and 2, the fasting proinsulin and proinsulin/C-peptide ratio c a n n o t b e approxim a t e d to a n o r m a l distribution. H o w e v e r , the loge values s h o w e d n o r m a l distributions with similar shapes in T y p e 1 diabetic and n o r m a l subjects. N e i t h e r fasting proinsulin n o r p r o i n s u l i n / C - p e p t i d e ratio at e n t r y of the study w e r e r e l a t e d to age, weight, U b A l c , f B G concentration, insulin dose p e r kg or insulin antibodies. Islet cell a n t i b o d y titres w e r e not c o r r e l a t e d to O. Snorgaard et al.:Proinsulin and C-peptide at onset of Type I diabetes mellitus proinsulin or proinsulin/C-peptide ratio at any time. Furthermore, there were no significant differences in proinsulin and proinsulin/C-peptide ratio, when dividing the population according to the H L A - D R types, DR3/4, DR4/X, DR3/X and DRX/X. Diabetic patients on insulin therapy _<14 days prior to allocation had significantly lower proinsulin levels and proinsulin/C-peptide ratio at entry. Excluding subjects with > 6 weeks of symptoms according to the definition used in the principal report [ 9 ], these differences disappeared. Fasting proinsulin was correlated to fasting C-peptide (r = 0.41, p < 0.001), to glucagon-stimulated C-peptide (r = 0.41, p < 0.001) and very closely to glucagon-stimulated proinsulin (r = 0.94, p < 0.001). Thus, the latter has not been considered further in the present study. Data obtained during cyclosporin or placebo treatment Of the 93 patients allocated to cyclosporin and the 95 to placebo, only data from 83 and 86 were included in the present part of the study. The others were either excluded from the original trial or no plasma for proinsulin measurements were available. Fasting proinsulin, fasting C-peptide, proinsulin/Cpeptide ratio and insulin dose per kg during the 12 months cyclosporin or placebo treatment are given in Table 2, together with data from the subsequent six months, when no immunotherapy was given. Proinsulin increased in the placebo group from entry to one m o n t h (p < 0.01) and from one m o n t h to three months (p < 0.001). It remained elevated the following nine months and then declined significantly to entry levels (p < 0.01). The proinsulin/C-peptide ratio displayed a similar development in this group. A smaller but significant increase of fasting proinsulin was seen during the first three months of cyclosporin (p < 0.01), followed by unchanged levels. The ratio did not change from baseline in this group. Proinsulin/C-peptide ratio was significantly lower during cyclosporin treatment at 3, 6, 9 (p < 0.01) and 12 months (p<0.05) and fasting proinsulin lower at 3 (p < 0.05) and 9 months (p < 0.05) (Table 2). The one-way analyses of variance showed a significant treatment effect on proinsulin/C-peptide ratio (p < 0.01), but not on proinsulin. An inverse correlation was found between the mean values of insulin dose per kg at each time point and the respective loge (proinsulin) values in both treatment groups, cyclosporin: r = - 0 . 9 4 , p < 0 . 0 1 and placebo: r = - 0.88, p < 0.05. The individual correlations expressed as the median r-values were - 0.45 ( - 0.70 to - 0.01) and - 0 . 4 3 ( - 0.77 to -0.11), respectively. However, insulin dose was only correlated to the m e a n C-peptide values during cyclosporin (r = - 0.97, p < 0.01), and not during placebo ( r = -0.49, NS). The individual coefficients of correlation were - 0.55 ( - 0.70 to - 0.25) and - 0.34 ( - 0 . 6 7 to -0.08), respectively. Insulin dose and loge (proinsulin/C-peptide ratio) seem to be better related in the placebo-treated group ( r = - 0 . 6 2 , individual rvalues: - 0 . 4 0 ( - 0.66 to -0.07)) compared to the cy00 9 e e 9 o9~ 9 e~ r 20 c 'O c l o s p o r i n g r o u p ( r = - 0 . 1 5 , i n d i v i d u a l r-values: - 0 . 2 4 ( - 0.56 t o 0.20) ). Similar i n v e r s e c o r r e l a t i o n s c o u l d b e d e m o n s t r a t e d b e t w e e n m e a n HbA1c at entry, 3, 6, 9 a n d 12 m o n t h s [ 9 ] a n d t h e r e s p e c t i v e m e a n 1oge ( p r o i n s u l i n ) v a l u e s in b o t h A o .= e~ |O. 6 ~eB ql .E O el 6F i f t y - f o u r p e r c e n t o f t h e c y c l o s p o r i n - t r e a t e d subjects p a r t i c i p a t i n g in t h e p r e s e n t s t u d y a c q u i r e d a n o n - i n s u l i n r e q u i r i n g s t a t e d u r i n g t h e first y e a r against 31% in t h e p l a c e b o g r o u p (p < 0.01). P r o i n s u l i n / C - p e p t i d e r a t i o s a t e a c h t i m e p o i n t in t h e t w o g r o u p s with o r w i t h o u t N I R , a r e i n d i c a t e d in F i g u r e 3. C y c l o s p o r i n h a d t h e s a m e i m p a c t o n t h e r a t i o as e a r l i e r d e s c r i b e d , i n d e p e n d e n t o f N I R . T h e p o s s i b l e v a l u e o f the r a t i o at o n s e t in the p r e d i c tion of r e m i s s i o n is i l l u s t r a t e d in T a b l e 3. A p r o i n s u l i n / C p e p t i d e r a t i o a b o v e 0.024 ( m e d i a n v a l u e o f all d i a b e t i c subjects) at e n t r y to t h e trial f o l l o w e d b y c y c l o s p o r i n t r e a t merit w a s a s s o c i a t e d with a f r e q u e n c y o f N I R o f 64% a g a i n s t 4 2 % if t h e r a t i o w a s b e l o w 0.024 (p = 0.077). T h i s t e n d e n c y w a s n o t s e e n in the p l a c e b o g r o u p . F u r t h e r m o r e , a significant effect o f c y c l o s p o r i n w a s o n l y p r e s e n t if t h e "Cy and pla together;bAll Cyvs all pla ratio was above 0.024 (p < 0.01). Considering the H L A subgroups separately revealed that this association originated from the H L A - D R 3,4 4,X and X,X groups, whereas a low rather than high ratio at entry tended to be related to a higher frequency of remission among H L A - D R 3,X subjects (Table 3). Neither fasting nor glucagon-stimulated C-peptide at entry could predict NIR in either of the treatment groups or in any of the H L A subgroups. Discussion The Canadian/European study of cyclosporin was designed to test the possible effect of the drug on the frequency of remission and C-peptide levels as a measure of B-cell function [ 9 ]. No hypothesis concerning proinsulin levels or the proinsulin/C-peptide ratio was suggested beforehand. This must be kept in mind in the evaluation of the present results. Another problem is the large amount of missing values especially during the follow-up period (Table 2). Mainly because of the descriptive nature of the results, we included all patients with available plasma for proinsulin measurements not excluded from the original study. In the choice of statistical methods we have tried to take this into account. The present study had given evidence for the Presence of an altered B-cell function, with a three to fourfold elevation of the molar ratio between fasting proinsulin and C-peptide in recent onset insulin-treated Type 1 diabetic subjects. Thereby, we have substantiated the findings of Ludvigsson [ 8 ] and Heding [ 7 ]. Furthermore, we have described further changes of [3-cell function during rex mission and relapse of Type 1 diabetes (placebo group). A plateau-shaped nine months long further elevation of the proinsulin/C-peptide ratio at entry was demonstrated (Fig.3). O.Snorgaardet al.:Proinsulinand C-peptideat onsetofType 1diabetesmellitus This pattern and the inverse correlation between mean HbAlc at each time point and the respective loge (proinsulin) and log~ (proinsulin/C-peptide ratio) values together with the lack of a "cross sectional" correlation at entry between these parameters, speak against a metabolic "drive" on a reduced number of B ceils as the only explanation for the elevated proinsulin/C-peptide ratio in Type 1 diabetes [ 15 ]. The finding of elevated proinsulin levels in non-diabetic siblings of Type 1 diabetic subjects further oppose this explanation [ 16 ]. The hypothesis, however, is a likely explanation for the observed elevation in poorly controlled Type 2 diabetes [ 15, 17, 18 ]. The inverse correlations between proinsulin and both HbA~o and insulin dose in the placebo group suggest that proinsulin may be a better indicator of B-cell function than C-peptide. This is supported by the finding of a significantly lower insulin dose during late remission (6 months) compared to shortly after the onset, in spite of similar fasting C-peptide levels (Table 2). The released proinsulin could have some metabolic effects during the late remission. Changes in insulin resistance may, however, be the primary determinant of this phenomenon [ 19 ]. Another explanation for the inverse correlation between proinsulin and insulin dose could be a negative feedback control of insulin on proinsulin release, probably through a inhibition of glucagon. A feedback control has been demonstrated in non-diabetic subjects [ 20 ], but remains to be studied in Type 1 diabetes. There is no evidence of a changed metabolic clearance rate of either proinsulin or C-peptide in diabetic subjects [ 21-23 ]. Thus, apart from the possible modulating effect of insulin, it seems justified that the plateau-shaped further elevation of proinsutin/C-peptide ratio in the placebo group reflects alterations of B-cell function during remission and relapse. One could speculate that the relief of the hyperglycaemic drive on the islets makes a partial regeneration of the B cells possible. The ratio between primitive high proinsulin releasing and mature lower proinsulin releasing cells may then increase. The finding of an increased proinsulin to insulin ratio in newborn babies compared to adults supports this theory [ 24 ]. Another possibility is the existence of a pool of primitive high proinsulin releasing cells more resistant to destruction. In the cyclosporin-treated group no elevation of the proinsulin/C-peptide ratio was seen during the remission period, indicating that cyclosporin in some way prevents or delays the further alteration of B-cell function observed in the placebo group during remission. There is evidence suggesting a supressive action of cyclosporin on interleukin-1, which may be an important mediator of B-cell destruction in Type 1 diabetes [ 25, 26 ]. Interleukin-1 induces hypoglycaemiain rodents by increasing insulin levels and probably through other, at the moment, unknown mechanisms [27]. A significant part of the measured insulin in this study could have been proinsulin. Thus, a suppression of interleukin-1 may explain why no further increase of proinsulin/C-peptide ratio is observed in the cyclosporin-treated group. The level of the ratio may in O. Snorgaard et al.: Proinsulin and C-peptide at onset of Type i diabetes mellitus s o m e w a y b e r e l a t e d to t h e c y t o t o x i c activity against t h e B cells. T h e a s s o c i a t i o n b e t w e e n a p r o i n s u l i n / C - p e p t i d e ratio a b o v e 0.024 a n d t h e effect o f c y c l o s p o r i n gives, in o u r o p i n i o n n o f i r m guideline f o r a f u t u r e t h e r a p y , b u t a v o cates testing t h e possible p r e d i c t i v e v a l u e o f t h e p r o i n s u l i n / C - p e p t i d e ratio in n e w r a n d o m i z e d c o n t r o l l e d trials o f c y c l o s p o r i n o r o t h e r drugs w i t h a possible effect o n t h e f r e q u e n c y o f remission. R e n a l failure is a s s o c i a t e d with a decline in c l e a r a n c e a n d increasing s e r u m levels o f C - p e p t i d e a n d proinsulin [ 28 ]. C y c l o s p o r i n t r e a t m e n t w a s in t h e p r e s e n t s t u d y a s s o c i a t e d w i t h a significant decline o f c a l c u l a t e d c r e a t i n i n e c l e a r a n c e [ 9 ], w h e r e a s n o c h a n g e was o b s e r v e d in t h e p l a c e b o g r o u p . T h u s , a c y c l o s p o r i n i n d u c e d c h a n g e o f p r o i n s u l i n c l e a r a n c e c a n n o t explain t h e effect o f c y c l o s p o r i n o n t h e p r o i n s u l i n / C - p e p t i d e ratio. Thus, w e h a v e c o n f i r m e d t h a t t h e proinsulin to C - p e p tide m o l a r ratio is e l e v a t e d in r e c e n t o n s e t T y p e 1 d i a b e t i c subjects a n d identified f u r t h e r alterations o f B-cell funct i o n d u r i n g r e m i s s i o n a n d relapse w i t h a 9 m o n t h l o n g furt h e r e l e v a t i o n o f t h e ratio. This p a t t e r n is discussed in detail a n d v a r i o u s h y p o t h e s e s are p r o p o s e d . A n association b e t w e e n a relatively h i g h p r o i n s u l i n / C - p e p t i d e ratio at e n t r y to t h e s t u d y a n d a significant effect o f c y c l o s p o r i n o n t h e i n d u c t i o n o f remission, suggest a possible v a l u e o f t h e ratio in t h e p r e d i c t i o n o f r e m i s s i o n o f T y p e 1 d i a b e t e s t r e a t e d with cyclosporin. Acknowledgements. We thank the management committee for giving us the opportunity to measure proinsulin and for giving us access to a major part of the collected data. We thank Ms. S.Kjellberg and Ms. J. Falk for skillful technical assistance. The primary study was supported by Sandoz Pharmaceuticals. The following comprises the Canadian/European Diabetes Study Group: Management Committee C.R.Stiller, H. Kolb, B. yon Graffenried, M. Gent, J.Dupr6, J. Nerup and G. Murphy. Data Centre (not used in the present part of the study) Robarts Research Institute, London, Ontario, Canada. M. Gent, A. Donner and N. 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O. Snorgaard, S. G. Hartling, C. Binder. Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of Type 1 (insulin-dependent) diabetes mellitus, Diabetologia, 1990, 36-42, DOI: 10.1007/BF00586459