Exp. Clin. Endocrino!. 99 (1992) 164-168
Experimental and Clinical Endocrinology © 1992 Johann Ambrosius Barth
E. Chantelau and P. Wichmann Medical Department of Nutrition and Metabolic Diseases (WHO-Collaborating Centre for Diabetes Prevention and Treatment; Director: Prof. Dr. M. Berger), Heinrich-Heine-University, Düsseldorf/Germany
Key words: Insulin-dependent diabetes mellitus - Complications-Insulin therapy - Insulin pumps
proteinuria was 3/21, 5/21, and 15/21 in group A, B, and C, respectively; 22.0 (95% confidence interval: 19.5 to 24.5) years, 22.1 (19.9 to 24.3) years, and 22.6 (20.2 to 25.0) years after onset of IDDM in group A, B, and C. The prevalence of
Summary: A matched case-control study was performed to assess the prevalence of pathological proteinuria (>50 mg/l)
pathological proteinuria differed significantly between group A and B vs. group C (x2 = 16.2, p 8 years after onset of IDDM: group A changed from traditional insulin therapy to continuous subcutaneous insulin infusion (CSII), and patients of group B changed from traditional insulin treatment ( 130 .Lmol/l. Conclusion: Intensive insulin therapy either by CSII or by multiple injections initiated 8 years after onset of IDDM was associated with reduced prevalence of pathological proteinuria 18 years after onset of IDDM.
IDDM therapy affects the quality of diabetes control that is maintained on the long run (Mühlhauser et al., 1987), we have investigated the prevalence rates of pathological proteinuria in IDDM-patients in relation to different treatment regimens, and different degrees of long-term glycaemic control, respectively.
Material and Methods
evidence that some unknown individual predisposition
Study design
Presented in parts at the 26th Annual Meeting of the European Association for the Study of Diabetes, Copenhagen 1990
A matched case-control study was performed with 3 groups of patients, i.e. case-group A, and 2 control groups (group B, and group C), respectively.
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Pathological Proteinuria in Patients with Insulin-Dependent Diabetes Mellitus: Relation to Intensive Insulin Therapy'
E. Chantelau and P. Wichmann, Proteinuria and intensive Insulin Therapy in 1DDM
165
Patient selection
Modes of therapy
Patients were eligible for groups A and B, when meeting the
Prior to recruitment, all patients had performed traditional
following criteria:
IDDM therapy according to contemporary textbooks (Mehnert and Schöffling, 1984); in brief, traditional insulin therapy for
1990)) for > 8 years before changing to intensive insulin
IDDM is characterised by a strict diet with set timing and number of meals, planned food exchange, omission of
therapy (Nathan et al., 1982; Schade et al., 1983); 2) Having adopted intensive insulin therapy (group A: continuous subcutaneous insulin infusion CSII; group B: multiple insulin
metabolic self-monitoring (Hauner et al., 1990), and
injection therapy MITT) voluntarily in our department in 1980,
had been under care of their family physicians until being referred to our centre; neither data on long-term metabolic control as achieved with this mode of therapy, nor any other
and having been followed by our centre until 1990. Another control group (group C) was selected from patients with IDDM
having practised traditional insulin therapy (Mehnert and
Schöffling, 1984; Hauner et aI., 1990) under care of their family physicians during the past >10 years (1980-1989). All patients studied had been referred to our department because of unsatisfactory diabetes control. Group A (case group) comprised of all of the 21 patients (13 men and 8 women) who chosed to start CSII in 1980 in our centre. Group B (control group B) comprised of 21 patients, pair-matched for sex, age (± 2 years), and duration of diabetes
(± 2 years) with patients of group A; group B patients had started MITT in 1980 in our centre. Group C (control group C) comprised of 21 patients, pair-matched for sex, age (± 2 years), and duration of diabetes (± 2 years) with patients of group A; group C patients had been on traditional insulin therapy con-
tinuously, until being referred for improving their treatment
in 1989. Clinical details of all patients are summarised in Table 1.
2 injec-
tions per day of intermediate acting insulin (or of a fixed mixture of regular plus intermediate acting insulin). All patients
data (e.g. on blood pressure and renal function) were available from the family physicians. Patients of groups A and B participated in a 5-day diabetes teaching and treatment programme before starting with intensive insulin therapy; details of these programmes have been published elsewhere (Mühlhauser et al., 1987; Sonnenberg et al., 1983). In brief, these programmes introduced blood glucose self-monitoring, insulin-dosage adjustment, and a certain liberalisation of the diet (Chantelau et al., 1982; Chantelau et al., 1987) to the patients.
Methods of evaluation In all patients, the prevalence rates of pathological proteinuria, of serum-creatinine level > 130 mol/l, and of hypertension/or antihypertensive medication were assessed. Furthermore, the
degree of diabetes control was recorded as displayed by the
Plan of the study (Fig. 1) Patients of group A (cases) were recruited after 12.0 (95 % confidence interval 9.5 to 14.5) years of traditional IDDM therapy, and were followed-up after 10 years of subsequent CSII. Patients of control group B were recruited after 12.1 (95 % Ci 9.9 to 14.3) years of traditional IDDM therapy, and were followed-up after 10 years of subsequent MITT. Patients of control group C were recruited after 22.6 (95 % CI 20.2 to 25.0) years of traditional IDDM therapy.
Statistical evaluation MIIT
ID
0
2
4
6
8
10
12
14
16
18 20 22 24
years after onsef of IDDM ''I'll'' traditional therapy assessments
intensive therapy Fig. 1
Diagram of the study plan
Mean values are given with 95 % confidence intervals (in parentheses). Frequencies were compared using chi-squared test and relative risk ratios (Morris and Gardner, 1988). A p < 0.05 was considered statistically significant.
ulIlulIlulIlIllIuuhIIulIIOII'l
DMD
with standard laboratory techniques, and glycosylated haemoglobin Ale (HbAlc) was determined by HPLC (Little et al., 1988). The normal ± 2 SD range of HbAlc in our laboratory is 4.4 to 5.6% of total haemoglobin. Blood pressure was measured according to international standards (Mühlhauser et al., 1988), using a sphygmomanometer. The prevalence of antihypertensive medication was assessed from clinic records (groups A and B), and from the patients' reports (group C). Data on the frequency of visits to the diabetes care providers were obtained
CSII Cs!'
group B group C
normal proteinuria was 500 mg/l (Borch-Johnsen et al., 1985). Serumcreatinine was measured
similarly.
I
group A
glycosylated haemoglobin Ale. Proteinuria was measured by a laser turbidimetric method (Sawicki et al., 1989). The measurements were carried out in spot urine at least twice per year in patients of groups A, and B, respectively; in group C patients during hospitalisation, spot urines and 24-hour collections were studied. The definition of
Results The results are summarised in Table 1. In group A, 17/21 patients had carried on with CSII during the 10 years from recruitment until follow-up, and
4/21 patients had changed back to MuT. All patients
Downloaded by: Collections and Technical Services Department. Copyrighted material.
1) Having IDDM (WHO Study Group, 1985) and traditional insulin therapy (Mehnert and Schöffling, 1984; Hauner et al.,
Exp. Clin. Endocrinol. 99 (1992) 3
166
Group A, starting CSII 10 years ago
Group B, starting MIIT lO years ago
Group C, unchanged traditional therapy
Number of patients Gender, rn/f Age, years Duration of IDDM, years Actual HbAlc, % Prevalence of
21
21
21
13/8
13/8
13/8
35.8(95% CI 33.1 to 38.5) 22.0(95% Cl 19.5 to 24.5) 7.5 (95% CI 6.9 to 8.1)
33.7 (96% CI 30.8 to 36.6) 22.1 (95% CI 19.9 to 24.3) 7.6 (95% CI 6.9 to 8.3)
35.5 (95% CI 31.8 to 39.2) 22.6 (95% CI 20.2 to 25.0) 8.9 (95% CI 8.2 to 9.6)*
proteinuria 500 mg/i
18/21 3/21 0/21 0/21
16/2 1
6/21 **
3/21 2/21 2/21
7/21 8/21* 0/21
4/21
4/21
11/21*
- serum-creatinine > 130 .tmol/i - hypertension/antihypertensives
significantly different from group A, and group B, respectively (chi-squared, p < 0.05) ** = significantly different from group A, and group B, respectively (chi-squared, p < 0.001) *
were analysed according to their original therapy. They had been visiting the diabetes outpatient clinic on the
21 at recruitment, and 4/21 at the final examination after 10 years of MuT.
average 5.4 (95 % CI 3.2-7.6) times per year; their
In group C, patients had been in contact with their family physicians because of diabetes problems on the average 4.6 (95 % CI 2.2-7.0) times annually. On refer-
annual mean HbA 1 c, as calculated from 1 to 5 determina-
tions per year, was 6.9 (95% CI 6.5-7.3)% during the past decade. At the initial examination, the HbAlc had been 7.95 (95%CT 7.35-8.55)%, as compared to 7.5 (95% CI 6.9-8.1) % at the final examination. Microproteinuria (range 185 to 205 mg/i) was present in 2/21 patients of group A upon changing from injections to
ral to our department, group C patients had HbA 1 c of 8.9
(95 0/ CI 8.2_9.6)0/; previous HbAlc values were not available. Microproteinuria (range 70 to 160 mg/l) was present in 7/21 patients, and macroproteinuria (range 840
to 4500 mg/I) was found in 8/21 patients. However,
CSII treatment; at follow-up 10 years later, micro-
none of the patients had serum-creatinine > 130 l.Lmol/
proteinuria (range 63 to 308 mg/i) was present in 3/21 patients. The prevalence of hypertension/antihyperten-
1.
sive medication had increased from 1/21 at recruitment to 4/21 patients at the final examination 10 years later. In group B, 15/21 patients had performed MuT during
lent in group C, as compared to groups A and B,
Pathological proteinuria was significantly more preva-
annual mean HbA Ic, as calculated from 1 to 5 determina-
respectively (X2 = 16.2; df2; p < 0.001); the same holds true for the prevalence of hypertension/antihypertensive medication (C > A, B; x2 = 7.4; df2; p < 0.01). The risk of having pathological proteinuria >22 years after onset of IDDM differed significantly between patients on CSII (group A, odds ratio 1.0), or patients with MITT (group B, odds ratio 1.87 (95% CI 0.39-9.12)), versus patients on traditional therapy (group C, odds ratio 15 (95% CI 3.19-70.28)), respectively.
lions per year, was 7.5 (95 % CI 7.0-8.0)% during the past decade. At the initial examination, the HbAlc had
HbAlc at the final examination was significantly higher in group C (8.9 (95%CT 8.2-9.6)%), as com-
been 8.2 (95% CI 7.6-8.9) %, as compared to 7.6
pared to group A (7.5(95% CI 6.9-8. l)%), and group B
(95 % CI 6.9-8.3) % at the final examination 10 years later. Microproteinuria (range 60 to 200 mg/I) was present in 7/21 patients upon changing from traditional to MITT therapy, at follow-up 10 years later, microproteinuria (range 54 to 61 mg/l) was present in 3/21 patients. However, another 2/21 patients had progressed
(7,6(95%C1 6.9-8.3)%), respectively (p 130 ltmol/l, during the follow-up period. The prevalence of hypertension/antihypertensive medication was 0/
Discussion
The results of this study indicate that the prevalence of pathological proteinuria in IDDM patients approx. 22 years after onset of the disease is related to the mode of treatment as applied during the preceding decade; patients who had intensified their insulin therapy
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Table 1 Clinical data of all study participants, according to the final assessment. (CSII = continuous subcutaneous insulin infusion; MuT = multiple insulin injection therapy)
E. Chantelau and P. Wichmann, Proteinuria and Intensive Insulin Therapy in IDDM
167
10 years ago (either by CSII or by MITT) exhibited 8-15 times less frequently pathological proteinuria as compared to patients, who never had discontinued with traditional insulin therapy since onset of their diabetes. Thus, our study demonstrates the failure of traditional IDDM therapy to establish sufficient diabetes control for a majority of patients, as could be expected from previous crosssectional (Chase et al., 1989) and longitudinal observa-
IDDM patients with glycosylated haemoglobin permanently >1.6 times the mean normal value will exhibit nephropathy in 29% of cases, as compared to O% of patients with glycosylated haemoglobin permanently 1.6 times the mean normal value (Hauner et al., 1990);
had glycosylated haemoglobin > 1.6 times the mean normal value. Like other authors (Chase et al., 1989; Dahl-Jorgensen
et al., 1990) we found a certain threshold of HbAlc of 7% (representing an average glycaemia around 8 mmol/ 1), above which the risk of getting diabetic nephropathy becomes really dangerous. According to their reports,
seven years results from the Oslo Study. (Abstract). Diabetes 39, Suppl. 1 (1990) 16 A Hauner, H.; Schubert, J.; Pfeiffer, E. F.: Die Prävalenz von Sekundärkomplikationen bei Patienten mit Typ- 1 Diabetes mellitus. Ergebnisse einer retrospektiven Analyse an 549 Typ- 1 Diabetikern der Universitätsklinik Ulm. Med. Klin. 85 (1990) 690-695
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Patients of group C (traditional treatment) had a mean HbAlc of 8.9 o/e, representative of an average glycaemia around 12 mmolf 1 (Nathan et al., 1984). Intensively treated patients, however, maintained a HbA 1 c around
in order to prevent diabetic nephropathy; aiming at glyco-
Exp. Clin. Endocrinol. 99 (1992) 3
168
lated hemoglobin predicts the incidence of proteinuria. (Abstract). Diabetes 39, Suppi. 1 (1990) 39 A Krolewski, A. S.; Canessa, M.; Warram, J. H.; Laffel, L. M. B.; Christlieb, R.; Knowler, W. C.; Rand, L. I.: Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N. EngI. J. Med. 318 (1988) 140--145 Little,
R. R.; England, J. D.; Wiedmeyer, H. M.;
[201 Nathan, D. M.; Lou, P.; Avrouch, J.: Intensive conventional and insulin pump therapy in adult type-1 diabetes. Ann. Intern. Med. 97 (1982) 31-36 Nathan, D. M.; Singer, S. E.; Hurxthal, K.; Goodson, J. D.: The clinical information value of the glycosylated hemoglobin
assay.
N.
Engl. J.
Med.
310
(1984)
341 346 Nyberg, G.; Blohme, G.; Norden, G.: Impact of metabolic control on progression of clinical diabetic nep-
McKenzie, E. M.; Pettitt, D. J.; Knowler, W. C.; Goldstein, D. E.: Relationship of glycosylated hemoglobin to oral glucose tolerance. Diabetes 37 (1988) 60-64
hropathy. Diabetologia 30 (1987) 82-86
Mathiesen, E. R.; Ronn, B.; Jensen, T.; Storm, B.;
3 1-43 Sawicki, P.; Heinemann, L.; Berger, M.: Comparison of methods for determination of microalbuminuria in diabetic patients. Diabetic Med. 6 (1989) 412-415 Schade, D. A.; Santiago, J. V.; Skyler, J. S.; Rizza, R. A.: Intensive insulin therapy. Excerpta Medica, Princeton NJ, 1983
Deckert, T: Relationship between blood pressure and urinary albumin excretion in development of microalbuminuria. Diabetes 39 (1990) 245-249 McNally, P. G.; Burden, A. C.; Swift, P. G. F.; Walls, J.; Hearnshaw, J. R.: The prevalence and risk factors
associated with the onset of diabetic nephropathy in
Reddi, A. S.; Camerini-Davalos, R. A.: Diabetic nephropathy - an update. Arch. Intern. Med. 150 (1990)
juvenile-onset (insulin-dependent) diabetics diagnosed
Selby, J. V.; Fritz-Simmons, S. C.; Newman, J. M.;
under the age of 17 years in Leicestershire 1930-1985. Quarterl. J. Med. 280 (1990) 831-844 Mehnert, H.; Schöffling, K. (Eds.): Diabetologie in Klinik und Praxis. 2nd Edition. Stuttgart/New York:
Katz, P. P.; Sepe, S.; Showstack, J.: The natural history and epidemiology of diabetic nephropathy. J. Amer. Med. Ass. 263 (1990) 1954-1960 Sonnenberg, G. E.; Chantelau, E.; Berger, M.: Educa-
Thieme Verlag 1984 Mogensen, C. E.: Management of diabetic renal involvement and disease. Lancet j (1988) 867-869
tional aspects of insulin pump treatment in type-1 diabetic patients. In: Handbook of diabetes education. Eds. Assal, J. P.; Berger, M.; Canivet, J.; Gay, N., Amsterdam:
Mogensen, C. E.: Prediction of clinical diabetic nephropathy in IDDM patients. Diabetes 39 (1990) 761-767 Morris, J. A.; Gardner, M. J.: Calculating confidence
Excerpta Medica 1983, pp. 70-77
intervals for reltive risks (odds ratios) and standardised ratios and rates. Br. Med. J. 296 (1988) 1313-1316
Mühihauser, I.; Bruckner, I.; Berger, M.; Cheta, D.; Jörgens, V.; Ionescu-Tirgoviste, C.; Scholz, V.; Mincu,
I.: Evaluation of an intensified insulin treatment and teaching programme as routine management of type-1 (insulin-dependent) diabetes: the Bucharest-Düsseldorf
study. Diabetologia 30 (1987) 681-690 Mühlhauser, I.; Sawicki, P.; Didjurgeit, U.; Jörgens, V.; Berger, M.: Uncontrolled hypertension in type-1 diabetes: assessment of patients desires about treatment and improvement of blood pressure control by a structured treatment and teaching programme. Diabetic Med. 5 (1988) 693-698
Steffes, M. W.; Sutherland, D. E. R.; Goetz, F. C.; Rich, S. S.; Mauer, S. M.: Studies of kidney and muscle biopsy specimen from identical twins discordant for type1
diabetes mellitus.
N. Engi.
J.
Med. 312 (1985)
1282 1287 Viberti, G. C.; Hill, R. D.; Jarrett, R. J.; Argyropoulos, A.; Mahmud, U.; Keen, H.: Microalbuminuria as a predictor
of clinical nephropathy
ïn
insulin-dependent
diabetes mellitus. Lancet j (1982) 1430-1432 WHO study group. Diabetes mellitus. Technical Report Series 727. Geneva (Switzerland) 1985 Accepted: 27 June 1991
Author's address: Dr. E. Chantelau, Diabetesambulanz MNRKlinik, Heinrich-Heine-Universität Düsseldorf, Moorenstraße 5, W-4000 Düsseldorf (FRG)
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Klein, R.; Moss, S. E.; Klein, B. E. K.: Glycosy-
Experimental and Clinical Endocrinology © 1992 Johann Ambrosius Barth
E. Chantelau and P. Wichmann Medical Department of Nutrition and Metabolic Diseases (WHO-Collaborating Centre for Diabetes Prevention and Treatment; Director: Prof. Dr. M. Berger), Heinrich-Heine-University, Düsseldorf/Germany
Key words: Insulin-dependent diabetes mellitus - Complications-Insulin therapy - Insulin pumps
proteinuria was 3/21, 5/21, and 15/21 in group A, B, and C, respectively; 22.0 (95% confidence interval: 19.5 to 24.5) years, 22.1 (19.9 to 24.3) years, and 22.6 (20.2 to 25.0) years after onset of IDDM in group A, B, and C. The prevalence of
Summary: A matched case-control study was performed to assess the prevalence of pathological proteinuria (>50 mg/l)
pathological proteinuria differed significantly between group A and B vs. group C (x2 = 16.2, p 8 years after onset of IDDM: group A changed from traditional insulin therapy to continuous subcutaneous insulin infusion (CSII), and patients of group B changed from traditional insulin treatment ( 130 .Lmol/l. Conclusion: Intensive insulin therapy either by CSII or by multiple injections initiated 8 years after onset of IDDM was associated with reduced prevalence of pathological proteinuria 18 years after onset of IDDM.
IDDM therapy affects the quality of diabetes control that is maintained on the long run (Mühlhauser et al., 1987), we have investigated the prevalence rates of pathological proteinuria in IDDM-patients in relation to different treatment regimens, and different degrees of long-term glycaemic control, respectively.
Material and Methods
evidence that some unknown individual predisposition
Study design
Presented in parts at the 26th Annual Meeting of the European Association for the Study of Diabetes, Copenhagen 1990
A matched case-control study was performed with 3 groups of patients, i.e. case-group A, and 2 control groups (group B, and group C), respectively.
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Pathological Proteinuria in Patients with Insulin-Dependent Diabetes Mellitus: Relation to Intensive Insulin Therapy'
E. Chantelau and P. Wichmann, Proteinuria and intensive Insulin Therapy in 1DDM
165
Patient selection
Modes of therapy
Patients were eligible for groups A and B, when meeting the
Prior to recruitment, all patients had performed traditional
following criteria:
IDDM therapy according to contemporary textbooks (Mehnert and Schöffling, 1984); in brief, traditional insulin therapy for
1990)) for > 8 years before changing to intensive insulin
IDDM is characterised by a strict diet with set timing and number of meals, planned food exchange, omission of
therapy (Nathan et al., 1982; Schade et al., 1983); 2) Having adopted intensive insulin therapy (group A: continuous subcutaneous insulin infusion CSII; group B: multiple insulin
metabolic self-monitoring (Hauner et al., 1990), and
injection therapy MITT) voluntarily in our department in 1980,
had been under care of their family physicians until being referred to our centre; neither data on long-term metabolic control as achieved with this mode of therapy, nor any other
and having been followed by our centre until 1990. Another control group (group C) was selected from patients with IDDM
having practised traditional insulin therapy (Mehnert and
Schöffling, 1984; Hauner et aI., 1990) under care of their family physicians during the past >10 years (1980-1989). All patients studied had been referred to our department because of unsatisfactory diabetes control. Group A (case group) comprised of all of the 21 patients (13 men and 8 women) who chosed to start CSII in 1980 in our centre. Group B (control group B) comprised of 21 patients, pair-matched for sex, age (± 2 years), and duration of diabetes
(± 2 years) with patients of group A; group B patients had started MITT in 1980 in our centre. Group C (control group C) comprised of 21 patients, pair-matched for sex, age (± 2 years), and duration of diabetes (± 2 years) with patients of group A; group C patients had been on traditional insulin therapy con-
tinuously, until being referred for improving their treatment
in 1989. Clinical details of all patients are summarised in Table 1.
2 injec-
tions per day of intermediate acting insulin (or of a fixed mixture of regular plus intermediate acting insulin). All patients
data (e.g. on blood pressure and renal function) were available from the family physicians. Patients of groups A and B participated in a 5-day diabetes teaching and treatment programme before starting with intensive insulin therapy; details of these programmes have been published elsewhere (Mühlhauser et al., 1987; Sonnenberg et al., 1983). In brief, these programmes introduced blood glucose self-monitoring, insulin-dosage adjustment, and a certain liberalisation of the diet (Chantelau et al., 1982; Chantelau et al., 1987) to the patients.
Methods of evaluation In all patients, the prevalence rates of pathological proteinuria, of serum-creatinine level > 130 mol/l, and of hypertension/or antihypertensive medication were assessed. Furthermore, the
degree of diabetes control was recorded as displayed by the
Plan of the study (Fig. 1) Patients of group A (cases) were recruited after 12.0 (95 % confidence interval 9.5 to 14.5) years of traditional IDDM therapy, and were followed-up after 10 years of subsequent CSII. Patients of control group B were recruited after 12.1 (95 % Ci 9.9 to 14.3) years of traditional IDDM therapy, and were followed-up after 10 years of subsequent MITT. Patients of control group C were recruited after 22.6 (95 % CI 20.2 to 25.0) years of traditional IDDM therapy.
Statistical evaluation MIIT
ID
0
2
4
6
8
10
12
14
16
18 20 22 24
years after onsef of IDDM ''I'll'' traditional therapy assessments
intensive therapy Fig. 1
Diagram of the study plan
Mean values are given with 95 % confidence intervals (in parentheses). Frequencies were compared using chi-squared test and relative risk ratios (Morris and Gardner, 1988). A p < 0.05 was considered statistically significant.
ulIlulIlulIlIllIuuhIIulIIOII'l
DMD
with standard laboratory techniques, and glycosylated haemoglobin Ale (HbAlc) was determined by HPLC (Little et al., 1988). The normal ± 2 SD range of HbAlc in our laboratory is 4.4 to 5.6% of total haemoglobin. Blood pressure was measured according to international standards (Mühlhauser et al., 1988), using a sphygmomanometer. The prevalence of antihypertensive medication was assessed from clinic records (groups A and B), and from the patients' reports (group C). Data on the frequency of visits to the diabetes care providers were obtained
CSII Cs!'
group B group C
normal proteinuria was 500 mg/l (Borch-Johnsen et al., 1985). Serumcreatinine was measured
similarly.
I
group A
glycosylated haemoglobin Ale. Proteinuria was measured by a laser turbidimetric method (Sawicki et al., 1989). The measurements were carried out in spot urine at least twice per year in patients of groups A, and B, respectively; in group C patients during hospitalisation, spot urines and 24-hour collections were studied. The definition of
Results The results are summarised in Table 1. In group A, 17/21 patients had carried on with CSII during the 10 years from recruitment until follow-up, and
4/21 patients had changed back to MuT. All patients
Downloaded by: Collections and Technical Services Department. Copyrighted material.
1) Having IDDM (WHO Study Group, 1985) and traditional insulin therapy (Mehnert and Schöffling, 1984; Hauner et al.,
Exp. Clin. Endocrinol. 99 (1992) 3
166
Group A, starting CSII 10 years ago
Group B, starting MIIT lO years ago
Group C, unchanged traditional therapy
Number of patients Gender, rn/f Age, years Duration of IDDM, years Actual HbAlc, % Prevalence of
21
21
21
13/8
13/8
13/8
35.8(95% CI 33.1 to 38.5) 22.0(95% Cl 19.5 to 24.5) 7.5 (95% CI 6.9 to 8.1)
33.7 (96% CI 30.8 to 36.6) 22.1 (95% CI 19.9 to 24.3) 7.6 (95% CI 6.9 to 8.3)
35.5 (95% CI 31.8 to 39.2) 22.6 (95% CI 20.2 to 25.0) 8.9 (95% CI 8.2 to 9.6)*
proteinuria 500 mg/i
18/21 3/21 0/21 0/21
16/2 1
6/21 **
3/21 2/21 2/21
7/21 8/21* 0/21
4/21
4/21
11/21*
- serum-creatinine > 130 .tmol/i - hypertension/antihypertensives
significantly different from group A, and group B, respectively (chi-squared, p < 0.05) ** = significantly different from group A, and group B, respectively (chi-squared, p < 0.001) *
were analysed according to their original therapy. They had been visiting the diabetes outpatient clinic on the
21 at recruitment, and 4/21 at the final examination after 10 years of MuT.
average 5.4 (95 % CI 3.2-7.6) times per year; their
In group C, patients had been in contact with their family physicians because of diabetes problems on the average 4.6 (95 % CI 2.2-7.0) times annually. On refer-
annual mean HbA 1 c, as calculated from 1 to 5 determina-
tions per year, was 6.9 (95% CI 6.5-7.3)% during the past decade. At the initial examination, the HbAlc had been 7.95 (95%CT 7.35-8.55)%, as compared to 7.5 (95% CI 6.9-8.1) % at the final examination. Microproteinuria (range 185 to 205 mg/i) was present in 2/21 patients of group A upon changing from injections to
ral to our department, group C patients had HbA 1 c of 8.9
(95 0/ CI 8.2_9.6)0/; previous HbAlc values were not available. Microproteinuria (range 70 to 160 mg/l) was present in 7/21 patients, and macroproteinuria (range 840
to 4500 mg/I) was found in 8/21 patients. However,
CSII treatment; at follow-up 10 years later, micro-
none of the patients had serum-creatinine > 130 l.Lmol/
proteinuria (range 63 to 308 mg/i) was present in 3/21 patients. The prevalence of hypertension/antihyperten-
1.
sive medication had increased from 1/21 at recruitment to 4/21 patients at the final examination 10 years later. In group B, 15/21 patients had performed MuT during
lent in group C, as compared to groups A and B,
Pathological proteinuria was significantly more preva-
annual mean HbA Ic, as calculated from 1 to 5 determina-
respectively (X2 = 16.2; df2; p < 0.001); the same holds true for the prevalence of hypertension/antihypertensive medication (C > A, B; x2 = 7.4; df2; p < 0.01). The risk of having pathological proteinuria >22 years after onset of IDDM differed significantly between patients on CSII (group A, odds ratio 1.0), or patients with MITT (group B, odds ratio 1.87 (95% CI 0.39-9.12)), versus patients on traditional therapy (group C, odds ratio 15 (95% CI 3.19-70.28)), respectively.
lions per year, was 7.5 (95 % CI 7.0-8.0)% during the past decade. At the initial examination, the HbAlc had
HbAlc at the final examination was significantly higher in group C (8.9 (95%CT 8.2-9.6)%), as com-
been 8.2 (95% CI 7.6-8.9) %, as compared to 7.6
pared to group A (7.5(95% CI 6.9-8. l)%), and group B
(95 % CI 6.9-8.3) % at the final examination 10 years later. Microproteinuria (range 60 to 200 mg/I) was present in 7/21 patients upon changing from traditional to MITT therapy, at follow-up 10 years later, microproteinuria (range 54 to 61 mg/l) was present in 3/21 patients. However, another 2/21 patients had progressed
(7,6(95%C1 6.9-8.3)%), respectively (p 130 ltmol/l, during the follow-up period. The prevalence of hypertension/antihypertensive medication was 0/
Discussion
The results of this study indicate that the prevalence of pathological proteinuria in IDDM patients approx. 22 years after onset of the disease is related to the mode of treatment as applied during the preceding decade; patients who had intensified their insulin therapy
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Table 1 Clinical data of all study participants, according to the final assessment. (CSII = continuous subcutaneous insulin infusion; MuT = multiple insulin injection therapy)
E. Chantelau and P. Wichmann, Proteinuria and Intensive Insulin Therapy in IDDM
167
10 years ago (either by CSII or by MITT) exhibited 8-15 times less frequently pathological proteinuria as compared to patients, who never had discontinued with traditional insulin therapy since onset of their diabetes. Thus, our study demonstrates the failure of traditional IDDM therapy to establish sufficient diabetes control for a majority of patients, as could be expected from previous crosssectional (Chase et al., 1989) and longitudinal observa-
IDDM patients with glycosylated haemoglobin permanently >1.6 times the mean normal value will exhibit nephropathy in 29% of cases, as compared to O% of patients with glycosylated haemoglobin permanently 1.6 times the mean normal value (Hauner et al., 1990);
had glycosylated haemoglobin > 1.6 times the mean normal value. Like other authors (Chase et al., 1989; Dahl-Jorgensen
et al., 1990) we found a certain threshold of HbAlc of 7% (representing an average glycaemia around 8 mmol/ 1), above which the risk of getting diabetic nephropathy becomes really dangerous. According to their reports,
seven years results from the Oslo Study. (Abstract). Diabetes 39, Suppl. 1 (1990) 16 A Hauner, H.; Schubert, J.; Pfeiffer, E. F.: Die Prävalenz von Sekundärkomplikationen bei Patienten mit Typ- 1 Diabetes mellitus. Ergebnisse einer retrospektiven Analyse an 549 Typ- 1 Diabetikern der Universitätsklinik Ulm. Med. Klin. 85 (1990) 690-695
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Patients of group C (traditional treatment) had a mean HbAlc of 8.9 o/e, representative of an average glycaemia around 12 mmolf 1 (Nathan et al., 1984). Intensively treated patients, however, maintained a HbA 1 c around
in order to prevent diabetic nephropathy; aiming at glyco-
Exp. Clin. Endocrinol. 99 (1992) 3
168
lated hemoglobin predicts the incidence of proteinuria. (Abstract). Diabetes 39, Suppi. 1 (1990) 39 A Krolewski, A. S.; Canessa, M.; Warram, J. H.; Laffel, L. M. B.; Christlieb, R.; Knowler, W. C.; Rand, L. I.: Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N. EngI. J. Med. 318 (1988) 140--145 Little,
R. R.; England, J. D.; Wiedmeyer, H. M.;
[201 Nathan, D. M.; Lou, P.; Avrouch, J.: Intensive conventional and insulin pump therapy in adult type-1 diabetes. Ann. Intern. Med. 97 (1982) 31-36 Nathan, D. M.; Singer, S. E.; Hurxthal, K.; Goodson, J. D.: The clinical information value of the glycosylated hemoglobin
assay.
N.
Engl. J.
Med.
310
(1984)
341 346 Nyberg, G.; Blohme, G.; Norden, G.: Impact of metabolic control on progression of clinical diabetic nep-
McKenzie, E. M.; Pettitt, D. J.; Knowler, W. C.; Goldstein, D. E.: Relationship of glycosylated hemoglobin to oral glucose tolerance. Diabetes 37 (1988) 60-64
hropathy. Diabetologia 30 (1987) 82-86
Mathiesen, E. R.; Ronn, B.; Jensen, T.; Storm, B.;
3 1-43 Sawicki, P.; Heinemann, L.; Berger, M.: Comparison of methods for determination of microalbuminuria in diabetic patients. Diabetic Med. 6 (1989) 412-415 Schade, D. A.; Santiago, J. V.; Skyler, J. S.; Rizza, R. A.: Intensive insulin therapy. Excerpta Medica, Princeton NJ, 1983
Deckert, T: Relationship between blood pressure and urinary albumin excretion in development of microalbuminuria. Diabetes 39 (1990) 245-249 McNally, P. G.; Burden, A. C.; Swift, P. G. F.; Walls, J.; Hearnshaw, J. R.: The prevalence and risk factors
associated with the onset of diabetic nephropathy in
Reddi, A. S.; Camerini-Davalos, R. A.: Diabetic nephropathy - an update. Arch. Intern. Med. 150 (1990)
juvenile-onset (insulin-dependent) diabetics diagnosed
Selby, J. V.; Fritz-Simmons, S. C.; Newman, J. M.;
under the age of 17 years in Leicestershire 1930-1985. Quarterl. J. Med. 280 (1990) 831-844 Mehnert, H.; Schöffling, K. (Eds.): Diabetologie in Klinik und Praxis. 2nd Edition. Stuttgart/New York:
Katz, P. P.; Sepe, S.; Showstack, J.: The natural history and epidemiology of diabetic nephropathy. J. Amer. Med. Ass. 263 (1990) 1954-1960 Sonnenberg, G. E.; Chantelau, E.; Berger, M.: Educa-
Thieme Verlag 1984 Mogensen, C. E.: Management of diabetic renal involvement and disease. Lancet j (1988) 867-869
tional aspects of insulin pump treatment in type-1 diabetic patients. In: Handbook of diabetes education. Eds. Assal, J. P.; Berger, M.; Canivet, J.; Gay, N., Amsterdam:
Mogensen, C. E.: Prediction of clinical diabetic nephropathy in IDDM patients. Diabetes 39 (1990) 761-767 Morris, J. A.; Gardner, M. J.: Calculating confidence
Excerpta Medica 1983, pp. 70-77
intervals for reltive risks (odds ratios) and standardised ratios and rates. Br. Med. J. 296 (1988) 1313-1316
Mühihauser, I.; Bruckner, I.; Berger, M.; Cheta, D.; Jörgens, V.; Ionescu-Tirgoviste, C.; Scholz, V.; Mincu,
I.: Evaluation of an intensified insulin treatment and teaching programme as routine management of type-1 (insulin-dependent) diabetes: the Bucharest-Düsseldorf
study. Diabetologia 30 (1987) 681-690 Mühlhauser, I.; Sawicki, P.; Didjurgeit, U.; Jörgens, V.; Berger, M.: Uncontrolled hypertension in type-1 diabetes: assessment of patients desires about treatment and improvement of blood pressure control by a structured treatment and teaching programme. Diabetic Med. 5 (1988) 693-698
Steffes, M. W.; Sutherland, D. E. R.; Goetz, F. C.; Rich, S. S.; Mauer, S. M.: Studies of kidney and muscle biopsy specimen from identical twins discordant for type1
diabetes mellitus.
N. Engi.
J.
Med. 312 (1985)
1282 1287 Viberti, G. C.; Hill, R. D.; Jarrett, R. J.; Argyropoulos, A.; Mahmud, U.; Keen, H.: Microalbuminuria as a predictor
of clinical nephropathy
ïn
insulin-dependent
diabetes mellitus. Lancet j (1982) 1430-1432 WHO study group. Diabetes mellitus. Technical Report Series 727. Geneva (Switzerland) 1985 Accepted: 27 June 1991
Author's address: Dr. E. Chantelau, Diabetesambulanz MNRKlinik, Heinrich-Heine-Universität Düsseldorf, Moorenstraße 5, W-4000 Düsseldorf (FRG)
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Klein, R.; Moss, S. E.; Klein, B. E. K.: Glycosy-
