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The significance of the prepubertal diabetes duration for the development of retinopathy and nephropathy in patients with type 1 diabetes
Journal of Diabetes and Its Complications 18 (2004) 160 – 164
The significance of the prepubertal diabetes duration for the development of retinopathy and nephropathy in patients with type 1 diabetes Birthe S. Olsen a,*, Anne Katrin Sjølie b, Philip Hougaard c, Jesper Johannesen d, Karin Marinelli a, Bent Brock Jacobsen e, Henrik B. Mortensen a and the Danish Study Group of Diabetes in Childhood1 a
Department of Paediatrics, Glostrup University Hospital, DK-2600 Glostrup, Denmark b Department of Ophthalmology, A˚rhus University Hospital, Denmark c Novo Research Institute, Bagsvaerd, Denmark d Steno Diabetes Center, Gentofte, Denmark e Department of Paediatrics, Odense University Hospital, DK-2600 Glostrup, Denmark Received 24 September 2002; accepted 9 June 2003
Abstract Objective: A Danish nationwide prospective cohort of children and adolescents with type 1 diabetes was followed for 8 years to study the effect of the prepubertal duration of diabetes on early retinopathy and elevated albumin excretion rate (AER) ( > 20 Ag/min). Research Design and Methods: In 1989, blood glucose control (HbA1c) and AER was investigated in approximately 80% of all Danish children and adolescents with type 1 diabetes. A cohort of 339 young patients were restudied in 1995 including physical examination, demographic data, HbA1c, AER, and fundus photography with central reading. Among the patients, a number of 304 had a prepubertal onset of diabetes defined as an onset age less than 11.7 years in girls and 12.9 years in boys. Microalbuminuria was defined as an AER of 20 – 150 Ag min 1 and macroalbuminuria as AER >150 Ag min 1 in two out of three timed overnight urine samples. Results: At the follow-up in 1995 – 1996, no patients were younger than 12 years of age. The prevalence of any level of retinopathy was 17.7% in the age group 12 – 15 years, 45.4% from 16 to 20 years, and increased to 67.6% in patients more than 20 years of age. Diabetic retinopathy was significantly associated to poor longterm metabolic control (HbA1c) ( P < .0001) and to diabetes duration both in patients with a prepubertal onset of disease as well as patients with a pubertal ( P < .001) onset of disease. However, the pubertal diabetes duration contributed two times more than the prepubertal diabetes duration. Mean postpubertal diabetes duration to any retinopathy was significantly shorter (9.4 years) in patients with prepubertal onset of the disease compared to patients with postpubertal onset (11.8 years) ( P = .0004). In total, the prevalence of elevated AER (>20 Ag/min) increased from 4% in 1989 to 13% in 1995. None of the patients younger than 15 years of age had elevated AER, while the prevalence of elevated AER was about 14% from 15 years of age and onwards. Elevated AER in 1995 was significantly related to long-term metabolic control ( P < .001) and elevated AER in the preceding years ( P < .001) but was not correlated to diabetes duration neither before nor after the age of 12 years. Conclusion: The prepubertal diabetes duration is significantly associated with the development of diabetic retinopathy. The period, however, contributes less compared to the years after puberty. In concert with other studies, we found no association between raised AER and diabetes duration. This may be explained by the fact that other factors are more significant and dilute the significance of diabetes duration. Nonetheless, it seems prudent to optimise blood glucose control irrespective of age. D 2004 Elsevier Inc. All rights reserved. Keywords: Type 1 diabetes; Pre-pubertal diabetes duration; Glycosylated haemoglobin; Diabetic retinopathy; Diabetic nephropathy; Adolescents
* Corresponding author. Tel.: +45-43233020; fax: +45-43233964. E-mail address: [email protected] (B.S. Olsen). 1 Members of the Danish Study group of Diabetes in Childhood: Managing Committee: HB Mortensen, S. Krabbe, B. Brock Jacobsen, T. Mandrup. ˚ rhus), J. Haar (Viborg), L.P. Hansen (Sønderborg), K. Henriksen (Nykøbing Falster), Participating Departments: O. Andersen (Hillerød), N. Birkebæk (A B. Brock Jacobsen (Odense), T. Klinge (Holbæk), S. Krabbe (Næstved), J. Kreutzfeldt (Kolding), H.T. Lund (Randers), J. Løchte (Bornholm), B. Marner (Sundby), H.B. Mortensen (Glostrup), M. Muff (Hjørring), I. Leer Pedersen (Herning), Jørn Nerup (Steno Diabetes Center), I.M. Nielsen (Hvidovre), ˚ lborg), H. Sardemann (Roskilde). C. Pedersen (Esbjerg), M. Rix (A 1056-8727/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/S1056-8727(03)00073-4
B.S. Olsen et al. / Journal of Diabetes and Its Complications 18 (2004) 160–164
1. Introduction Unsatisfactory blood glucose control is a common finding in young patients with type 1 diabetes. Noncompliance, psychological problems, and decreased insulin sensitivity contribute to poor control and may lead to impaired quality of life and the development of microvascular complications in kidneys and eyes (Dahlquist & Rudberg, 1987; Diabetes Control and Complications Trial (DCCT) Research Group, 1993a, 1993b; Hoey et al., for the Hvidøre Study Group on Childhood Diabetes, 2001; Mortensen, Hartling, Petersen, & Danish Study Group Diabetes in Childhood, 1998; Mortensen, Houggard, Ibsen, Parving, & the Danish Study Group of Diabetes in Childhood, 1994; Olsen et al., 1999; Olsen et al., 2000; Rogers et al., 1987). The fact that early microvascular complications rarely are present before puberty (Danne, Kordonouri, Ho¨vener, & Weber, 1997; Mortensen et al., 1998) led to the hypothesis that the prepubertal period had minor impact on the development of complications. Recent papers, however, have established that even young patients with diabetes are vulnerable to microvascular complications of diabetes (Dahlquist & Rudberg, 1987; DCCT Research Group, 1993b; Olsen et al., 1999; Olsen et al., 2000). A Danish nationwide cohort of children and adolescents with type 1 diabetes was followed for 8 years with assessment of metabolic control and development of microvascular complications (Olsen et al., 1999; Olsen et al., in press). Approximately 60% of the young patients developed abnormalities in the eyes and 15% elevated albumin excretion rate (AER). Here we report on the significance of the preand postpubertal diabetes duration in relation to the development of retinopathy and increased AER in this cohort of children and adolescents.
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childhood and adolescence was chosen as 11.7 years in girls and 12.9 years in boys corresponding to the mean age for Tanner Stage 2 in Danish girls and boys (Juul et al., 1994). Using this classification, 304 had a prepubertal onset of diabetes. For further demographic data, see Table 1. Clinical information and HbA1c, analysed centrally at Glostrup, were registered in all patients in 1987, 1989, and 1995. Likewise timed, overnight AER was centrally determined in 1989 and 1995, while fundus photography was assessed by the same ophthalmologist in 1995. During the observation period 1989 – 1995, the method for HbA1c determination changed from an isoelectric focusing method (Ampholine PAG plate, cat. no. 1804-131; LKB-Products, Bromma Sweden), normal range 4.0 –6.5 (mean 5.3%), to a high pressure liquid chromatographic method Hi-Auto A1c (Type 8121, Kyoto Daiichi Kagaku, Kyoto, Japan), normal range 4.3 – 5.8 (mean 5.3%). The adjusted reference interval for HbA1c determined by calibration of Hi-Auto A1c(x) to isoelectric focusing values ( y) was 4.5 – 5.7, mean 5.1% (mean F 2 S.D.), calculated from the regression equation y = 0.877x + 1.47, obtained by comparison of the two assays. The relationship of HbA1c analysed at our department and in the American DCCT was established by direct sample exchange. For the Glostrup centre, the mean HbA1c was 7.70 (S.E. = 0.28) and for the DCCT reference laboratory 7.52 (S.E = 0.29). The average difference was 0.18% (S.E. = 0.03), implying that the Glostrup centre gave a higher value (95% confidence interval for the difference: 0.12 – 0.24%). The albumin concentration in two out of three consecutive overnight timed urine samples were analysed by an immunoturbidimetric method with an interassay CV of 7% and a detection limit of 1 mg 1. Microalbuminuria was defined as an AER of 20 –150 Ag min 1 and macroalbuminuria as AER >150 Ag min 1 in two out of three overnight urine samples. Systolic and diastolic blood
2. Patients and methods This prospective nationwide multicenter 8-year cohort study involved 19 pediatric departments and six departments of internal medicine. Blood and urine samples were collected from 339 patients (47% of the inception cohort) on three occasions, in 1987, 89, and 95. The original cohort from 1987 to 1989 has previously been described in detail; however, in brief, 720 young patients participated in the surveys of 1987 and 1989. In 1989, this accounted for approximately 60% of all young patients with diabetes in Denmark. All 720 patients were invited to participate in the follow-up study in 1995. Of these patients, 108 declined to participate, 152 did not respond, 11 had emigrated, 2 were not traceable, 2 were dead, and 106 had accepted to participate but failed to show up. Multiple regression analysis showed that those who did not participate in 1995 were significantly older and had significantly poorer metabolic control in 1989 compared to the participating patients (Olsen et al., 1999). In the present study, distinction between
Table 1 Demographic characteristics of diabetic subjects at the follow-up in 1995 – 1996 by pubertal status at onset of disease Onset of diabetes before Onset of the age of diabetes z12 years 12 (prepubertal) (pubertal/postpubertal) P Number of patients Sex (m/f ) Mean age (years) (mean F S.D.). Mean age at diabetes onset (years) (mean F S.D.). Mean diabetes duration (years) (mean F S.D.). Mean diabetes duration after puberty (z12 years of age) (years) (mean F S.D.).
304 156/148 20.4 (F3.2)
49 32/17 24.2 (F1.3)
< .0001
13.6 (F1.0)
< .0001
13.8 (F3.2)
10.7 (F1.3)
< .0001
8.4 (F3.2)
11.4 (F1.6)
< .0001
6.6 (F3.05)
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pressure were recorded locally under standardised conditions (Mortensen et al., 1994) for all patients with a semiautomatic apparatus (Digital blood pressure meter UA-751, Takeda Medical, Tokyo, Japan). Colour retinal photographs were taken using a 40j to 60j retinal camera and included two fields of each eye, macular – temporal field, and disc/nasal field, recording a retinal view of f80j horizontally by 45j vertically. Assessment of diabetic retinopathy was carried out centrally by a trained reader using the ‘‘EURODIAB-Hammersmith grading system’’ (Olsen et al., 1999). Retinopathy was classified into five levels: 0 = none, 1 = minimal, 2 = moderate, 3 = severe nonproliferative retinopathy, and 4 = proliferative retinopathy. For most evaluations, Levels 1 –4 were combined into ‘‘any retinopathy.’’ 2.1. Statistical analysis Summary statistics are given as mean F S.D. Comparison between groups was performed with unpaired t test and chi-square test. The prevalence of diabetic complications in kidneys and eyes was evaluated by a backward stepwise multiple logistic regression analysis where the dependent responses were AER z 20 Ag/min and any retinopathy (both 1995). Variables included in the model were sex, age, diabetes duration before and after the chronological age of 11.7 years in females and 12.9 years in males, HbA1c, insulin dose, log AER, BMI, systolic, and diastolic blood pressure. P values < .05 were considered significant. Only the final model is reported.
3. Results In 1995, diabetic retinopathy (all levels) was present in 57.6% of the patients. The prevalence of retinopathy increased with age from 17.7% in the age group 12 –15 years to 67.6% in patients more than 20 years of age. By multiple regression analysis, long-term metabolic control ( P < .0001) and diabetes duration before puberty (11.7 years for girls and 12.9 years for boys) ( P < .05), as well as diabetes duration after the onset of puberty ( P < .001), were significantly associated to the development of diabetic retinopathy. The regression coefficient for prepubertal and pubertal diabetes duration was 0.156 (S.E = 0.048) and 0.311 (S.E = 0.054) per year, respectively. This corresponds to odds ratios of 1.17 (1.06 –1.28) and 1.37 (1.23 – 1.52) per year and a two times greater contribution of the postpubertal diabetes duration. The significance of the pre- and postpubertal diabetes duration for the development of diabetic retinopathy according to the regression model is shown in Fig. 1. The logit transformed curve illustrates four different onset ages, 4, 8, 12, and 16 years and are adjusted to correspond to a fixed level of HbA1c of 8%. At onset age 4, the probability for any retinopathy increases gradually during the next 8 years followed by a more steep increase in
Fig. 1. Model, based on multiple regression analysis, of the calculated probability of any retinopathy in 1995 as a function of onset age, age, and HbA1c. The HbA1c level is arbitrary set at 8% corresponding to the results of the intensively treated adolescents of the DCCT study.
risk after the initiation of puberty. Thereafter, the pubertal component markedly influences the development of microvascular injury. The figure shows that after 11.7 years with diabetes, 50% of that patients with onset age of 12 or 16 years have developed retinopathy, while it takes 14.7 years for patients with onset age of 4 years. Mean postpubertal diabetes duration to any retinopathy was significantly shorter (9.4 years) in patients with prepubertal onset of the disease compared to patients with postpubertal onset (11.8 years) ( P = .0004). In the cohort, the frequency of elevated AER increased from 4% in 1989 to 12.7% in 1995. None of the patients in the age group 12– 15 years had microalbuminuria, while the frequency increased to 14% in patients more than 15 years of age. By multiple logistic regression analysis, elevated AER was significantly related to poor long-term metabolic control (HbA1c) ( P < .001) and high AER 6 years previously ( P < .001), but we could not demonstrate any relationship between elevated AER (>20 Ag/min) in 1995 and diabetes duration irrespective of onset age.
4. Discussion Microvascular complications in kidneys, eyes, and nerves are usually diagnosed after puberty and relate to the quality of blood glucose control in the preceding years (Caprio & Tamborlane, 1994; DCCT Research Group, 1993a, 1993b; Mathiesen, Rønn, Storm, Foght, & Deckert, 1994; Olsen et al., 2000; Williamson et al., 1986). Recent data show that the prepubertal diabetes duration also contributes to the development of microvascular complications (Bonney et al., 1995; Coonrod, Lloyd, & Ellis, 1993; Donahugue et al., 2000; Donahugue et al., 1997; McNally, Raymond, Swift, & Burden, 1993). As in the present investigation, data from two recent German
B.S. Olsen et al. / Journal of Diabetes and Its Complications 18 (2004) 160–164
studies (Danne et al., 1994; Holl, Grabert, Thon, & Heinze, 1998) demonstrated that in young patients with retinopathy and prepubertal onset of disease, the diabetes duration after puberty is significantly shorter compared to patients with a pubertal onset of disease. It is thus obvious that the prepubertal diabetes duration contributes to the development of retinopathy but to a lesser degree than the period after initiation of puberty. In Denmark, the mean age for entering Tanner Stage 2 is 11.7 years for girls and 12.7 for boys (Juul et al., 1994), and therefore diabetes onset before this age was considered prepubertal while diabetes onset after was considered pubertal. Individual Tanner staging would have been a more precise measurement of puberty but was not available in the present study. However, delayed puberty is not prevalent in diabetic children, and previous studies have shown that age is a suitable predictor of puberty (Kostraba et al., 1989). When examining the development of retinopathy, diabetes duration after initiation of puberty contributed two times more than the diabetes duration before puberty. This is significantly more than shown in the Wisconsin Epidemiological Study, where diabetes duration after menarche contributed 1.3 times more than the premenarcheal duration (Klein, Moss, & Klein). In contrast to the present study, the Wisconsin Epidemiological Study defined puberty as a menarcheal age, which is roughly 13 years of age in the Western world (Cole, 2000; Helm, Mu¨nster, and Schmidt, 1998). Thus, these patients had a longer prepubertal diabetes duration compared to our patients, which may explain the difference in contribution of the pre- and postpubertal diabetes duration. Donahugue defined puberty by gonadarche occurring at 11.4 years in girls and 12.6 years in boys. Odds ratios for the prepubertal significance for retinopathy were 1.22 and 1.32 for postpubertal duration (Donaghue et al., 1997), which were in agreement with our findings. Persistent microalbuminuria (AER >20 Ag/min) is a strong predictor for overt diabetic nephropathy and is diagnosed in 30– 40% of adults and 20– 25% of adolescents with type 1 diabetes (Holl et al., 1999; Janner, Knill, Dien, Zuppinger, & Mullis, 1994; Microalbuminuria Collaborative Study Group, 1992; Olsen et al., 1999; Shield, 1994; Williamson et al., 1986). The prevalence of elevated AER increases after 10 –15 years of diabetes duration and then levels off or declines (Holl et al., 1999; Janner et al., 1994; Olsen et al., 1999; Shield, 1994). Particularly, studies in adults have shown that long diabetes duration is associated with raised urinary albumin (Microalbuminuria Collaborative Study Group, 1992). In children and adolescents, the role of diabetes duration is, however, more controversial. Some pediatric and adolescent studies have shown a possible association (Holl et al., 1999) while others dispute this (Coonrod et al., 1993; Janner et al., 1994; Mortensen et al., 1994; Rudberg, Ullmann, & Dahlquist, 1993). By multiple regression analysis, no correlation between diabetes duration and elevated AER was found in the present study.
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Diabetic retinopathy and nephropathy are often found simultaneously; however, the pathogenesis of the two complications may be different. After 20 years with diabetes, most patients have retinopathy whereas less than 50% have nephropathy (Olsen et al., 1999). Poor long-term metabolic control and long diabetes duration are obviously not sufficient to cause diabetic nephropathy. Other factors such as genetic predisposition, hemodynamic changes in the kidneys, and smoking may be equal important contributors, diluting the significance of diabetes duration (Rudberg et al., 1993). The DCCT study (DCCT Research Group, 1993a, 1993b) verified a close relationship between good metabolic control and fewer microvascular complications in kidneys, eyes, and nerves in adults (DCCT Research Group, 1993a) and adolescents (DCCT Research Group, 1993b). Newer studies have shown the same correlation in even younger patients as well (Olsen et al., 2000). The present study confirmed that the years before puberty contribute to the overall risk of developing microvascular injury but modest compared to the postpubertal duration of diabetes. Persistent poor blood glucose control in childhood is related is to the development of microvascular complications. This emphasises the need for optimising blood glucose control in all children irrespective of age.
References Bonney, M., Hing, S. J., Fung, A. T. W., Stephens, J. M., Fairchild, J. M., Donahugue, K. C., Howard, N. J., & Silink, M. (1995). Development and progression of diabetic retinopathy: Adolescents at risk. Diabetic Medicine, 12, 967 – 973. Caprio, S., & Tamborlane, W. V. (1994). The effect of puberty on insulin action and secretion. Seminars in Reproductive Endocrinology, 12, 90 – 96. Cole, T. J. (2000). Secular trends in growth. Proceedings of the Nutrition Society, 59, 317 – 324. Coonrod, B. A., Lloyd, C. E., & Ellis, D. (1993). Predictors of microalbuminuria in individuals with IDDM. Pittsburgh epidemiology of diabetes complications study. Diabetes Care, 16, 1376 – 1383. Dahlquist, G., & Rudberg, S. (1987). The prevalence of microalbuminuria in diabetic children and adolescents and its relation to puberty. Acta Paediatrica Scandinavica, 76, 795 – 800. Danne, T., Kordonouri, O., Ho¨vener, G., & Weber, B. (1997). Diabetic angiopathy in children. Diabetic Medicine, 14, 1012 – 1025. Danne, Th., Weber, B., Hartmann, R., Enders, I., Burger, W., & Ho¨vener, G. (1994). Long-term glycaemic control has a non-linear association with the frequency of background retinopathy in adolescents with type 1 diabetes. Follow-up of the Berlin Retinopathy Study. Diabetes Care, 17, 1390 – 1396. Diabetes Control and Complications Trial Research Group. (1993a). Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes control and complications trial. Jornal de Pediatria, 125, 177 – 188. Diabetes Control and Complications Trial Research Group. (1993b). The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine, 329, 977 – 986. Donahugue, K. C., Fairchild, J. M., Chan, A., Hing, S., Cutler, L. R.,
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Kilo, C., & Silink, M. (2000). Do all prepubertal years of diabetes duration contribute to diabetes complications in early adulthood. Journal of Pediatric Endocrinology & Metabolism, 13 (Suppl. 4) ( p. 1227) (Abstract No. 72). Donahugue, K. C., Fung, A. T. W., Hing, S., Fairchild, J., King, J., Chan, A., Howard, N. J., & Silink, M. (1997). The effect of prepubertal diabetes duration on diabetes. Diabetes Care, 20, 77 – 80. Helm, P., Mu¨nster, K. R., & Schmidt, L. (1998). Determination of menarche and primary amenorrhea. Ugeskrift for Læger, 160, 7430 – 7433. Hoey, H., Aanstoot, H.-J., Chiarelli, F., Daneman, D., Danne, T., Dorchy H., Fittzgerald, M., Garandeau, P., Greene, S., Holl, R., Hougaard, P., Kaprio, S., Kocova, M., Lynggaard, H., Martul, P., Matsuura, N., McGee, H. M., Mortensen, H. B., Robertson, K., Schoenle, E., Sovik, ˚ man, J., for the Hvidøre Study O., Swift, P., Tsou, R. M., Vanelli, M., A Group on Childhood Diabetes (2001). Persistent differences among centers over 3 years in glycaemic control and hypoglycemia in a study of 3805 children and adolescents with type 1 diabetes from the Hvidøre Study Group. Diabetes Care, 24, 1342 – 1347. Holl, R. W., Grabert, M., Thon, A., & Heinze, E. (1999). Urinary excretion of albumin in adolescents with type 1 diabetes. Persistent versus intermittent microalbuminuria and relationship to duration of diabetes, sex and metabolic control. Diabetes Care, 22, 1555 – 1560. Holl, R. W., Lang, G. E., Grabert, M., Heinze, E., Lang, G. K., & Debatin, K. M. (1998). Diabetic retinopathy in pediatric patients with type 1 diabetes: Effect of diabetes duration, prepubertal and pubertal onset of diabetes and metabolic control. Jornal de Pediatria, 132, 790 – 794. Janner, M., Knill, S. E., Diem, P., Zuppinger, K. A., & Mullis, P. E. (1994). Persistent microalbuminuria in adolescents with type 1 (insulin dependent) diabetes mellitus is associated to early rather than late puberty. Results of a prospective longitudinal study. European Journal of Pediatrics, 153, 403 – 408. Juul, A., Bang, P., Hertel, N. T., Main, K., Dalgaard, P., Jørgensen, K, Mu¨ller, J, Hall, K, Skakkebaek, N. E. (1994). Serum insulin-like growth factor-1 in 1030 healthy children adolescents, and adults: Relation to age, sex, stage of puberty, testicular size, and body mass index. Journal of Clinical Endocrinology and Metabolism, 78, 744 – 752. Klein, B. E. K., Moss, S. E., & Klein, R. (1990). Is menarche associated with retinopathy? Diabetes Care, 13, 1034 – 1038. Kostraba, J. M., Dorman, J. S., Orchaard, T. J., Becker, D. J., Ohki, Y., Ellis, D., Doft, B. H., Lobes, L. A., LaPorte, R. E., & Drask, A. (1989). Contribution of diabetes duration before puberty to development of microvascular complications in IDDM subjects. Diabetes Care, 12, 686 – 693. Mathiesen, E. R., Rønn, B., Storm, B., Foght, H., & Deckert, T. (1994).
The natural course of microalbuminuria in insulin-dependent diabetes: A 10-year prospective study. Diabetic Medicine, 12, 482 – 487. McNally, P. G., Raymond, N. T., Swift, P. G. F., & Burden, A. C. (1993). Does the prepubertal duration of diabetes influence the onset of microvascular complications? Diabetic Medicine, 10, 906 – 908. Microalbuminuria collaborative study group. (1992). Microalbuminuria in type 1 diabetic patients. Prevalence and clinical characteristics. Diabetes Care, 15, 495 – 501. Mortensen, H. B., Hartling, S. G., Petersen, K. E., and the Danish Study Group Diabetes in Childhood (1998). A nation-wide cross-sectional study of glycosylated haemoglobin in Danish children with type 1 diabetes. Diabetic Medicine, 5, 871 – 876. Mortensen, H. B., Hougaard, P., Ibsen, K. K., Parving, H.-H., and the Danish Study Group of Diabetes in Childhood. (1994). Relationship between blood pressure and urinary albumin excretion rate in young Danish type 1 diabetic patients: Comparison to non-diabetic children. Diabetic Medicine, 11, 155 – 161. Olsen, B. S., Johannesen, J., Sjølie, A. K., Borch-Johnsen, K., Hougaard P., Thorsteinsson, B., Pramming, S., Marinelli, K., Mortensen, H. B., and the Danish Study Group of Diabetes in Childhood. (1999). Metabolic control and prevalence of microvascular complications in young Danish patients with type 1 diabetes. Diabetic Medicine, 16, 79 – 85. Olsen, B. S., Sjølie, A. K., Hougaard, P., Johannesen, J., Borch-Johnsen, K., Marinelli, K., Thorsteinsson, B., Pramming, S., Mortensen, H. B., & the Danish Study Group of Diabetes in Childhood. (2000). A 6-year nation-wide cohort study of glycaemic control in young people with type 1 diabetes. Risk markers for the development of retinopathy, nephropathy and neuropathy. J Diabetes Complications 14, 295 – 300. Rogers, G. R., White, N. H., Shalwitz, R. A., Palmberg, P., Smith, M. E., & Santiago, J. V. (1987). The effect of puberty on the development of early diabetic microvascular disease in insulin-dependent diabetes. Diabetes Research and Clinical Practice, 3, 39 – 44. Rudberg, S., Ullmann, E., & Dahlquist, G. (1993). Relationship between early metabolic control and the development of microalbuminuria — A longitudinal study in children with type 1 (insulin-dependent) diabetes mellitus. Diabetologia, 36, 1309 – 1314. Shield, J. P. H. (1994). Microalbuminuria and nephropathy in childhood diabetes. Practical Diabetes, 11, 146 – 149. Williamson, J. R., Rowold, E., Chang, K., Marvel, J., Tomlinson, M., Sherman, W. R., Ackerman, K. E., Berger, R. A., & Kilo, C. (1986). Sex-steroid dependency of diabetes-induced changes in polyol metabolism, vascular permeability and collagen cross-linking. Diabetes, 35, 20 – 27.
The significance of the prepubertal diabetes duration for the development of retinopathy and nephropathy in patients with type 1 diabetes Birthe S. Olsen a,*, Anne Katrin Sjølie b, Philip Hougaard c, Jesper Johannesen d, Karin Marinelli a, Bent Brock Jacobsen e, Henrik B. Mortensen a and the Danish Study Group of Diabetes in Childhood1 a
Department of Paediatrics, Glostrup University Hospital, DK-2600 Glostrup, Denmark b Department of Ophthalmology, A˚rhus University Hospital, Denmark c Novo Research Institute, Bagsvaerd, Denmark d Steno Diabetes Center, Gentofte, Denmark e Department of Paediatrics, Odense University Hospital, DK-2600 Glostrup, Denmark Received 24 September 2002; accepted 9 June 2003
Abstract Objective: A Danish nationwide prospective cohort of children and adolescents with type 1 diabetes was followed for 8 years to study the effect of the prepubertal duration of diabetes on early retinopathy and elevated albumin excretion rate (AER) ( > 20 Ag/min). Research Design and Methods: In 1989, blood glucose control (HbA1c) and AER was investigated in approximately 80% of all Danish children and adolescents with type 1 diabetes. A cohort of 339 young patients were restudied in 1995 including physical examination, demographic data, HbA1c, AER, and fundus photography with central reading. Among the patients, a number of 304 had a prepubertal onset of diabetes defined as an onset age less than 11.7 years in girls and 12.9 years in boys. Microalbuminuria was defined as an AER of 20 – 150 Ag min 1 and macroalbuminuria as AER >150 Ag min 1 in two out of three timed overnight urine samples. Results: At the follow-up in 1995 – 1996, no patients were younger than 12 years of age. The prevalence of any level of retinopathy was 17.7% in the age group 12 – 15 years, 45.4% from 16 to 20 years, and increased to 67.6% in patients more than 20 years of age. Diabetic retinopathy was significantly associated to poor longterm metabolic control (HbA1c) ( P < .0001) and to diabetes duration both in patients with a prepubertal onset of disease as well as patients with a pubertal ( P < .001) onset of disease. However, the pubertal diabetes duration contributed two times more than the prepubertal diabetes duration. Mean postpubertal diabetes duration to any retinopathy was significantly shorter (9.4 years) in patients with prepubertal onset of the disease compared to patients with postpubertal onset (11.8 years) ( P = .0004). In total, the prevalence of elevated AER (>20 Ag/min) increased from 4% in 1989 to 13% in 1995. None of the patients younger than 15 years of age had elevated AER, while the prevalence of elevated AER was about 14% from 15 years of age and onwards. Elevated AER in 1995 was significantly related to long-term metabolic control ( P < .001) and elevated AER in the preceding years ( P < .001) but was not correlated to diabetes duration neither before nor after the age of 12 years. Conclusion: The prepubertal diabetes duration is significantly associated with the development of diabetic retinopathy. The period, however, contributes less compared to the years after puberty. In concert with other studies, we found no association between raised AER and diabetes duration. This may be explained by the fact that other factors are more significant and dilute the significance of diabetes duration. Nonetheless, it seems prudent to optimise blood glucose control irrespective of age. D 2004 Elsevier Inc. All rights reserved. Keywords: Type 1 diabetes; Pre-pubertal diabetes duration; Glycosylated haemoglobin; Diabetic retinopathy; Diabetic nephropathy; Adolescents
* Corresponding author. Tel.: +45-43233020; fax: +45-43233964. E-mail address: [email protected] (B.S. Olsen). 1 Members of the Danish Study group of Diabetes in Childhood: Managing Committee: HB Mortensen, S. Krabbe, B. Brock Jacobsen, T. Mandrup. ˚ rhus), J. Haar (Viborg), L.P. Hansen (Sønderborg), K. Henriksen (Nykøbing Falster), Participating Departments: O. Andersen (Hillerød), N. Birkebæk (A B. Brock Jacobsen (Odense), T. Klinge (Holbæk), S. Krabbe (Næstved), J. Kreutzfeldt (Kolding), H.T. Lund (Randers), J. Løchte (Bornholm), B. Marner (Sundby), H.B. Mortensen (Glostrup), M. Muff (Hjørring), I. Leer Pedersen (Herning), Jørn Nerup (Steno Diabetes Center), I.M. Nielsen (Hvidovre), ˚ lborg), H. Sardemann (Roskilde). C. Pedersen (Esbjerg), M. Rix (A 1056-8727/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/S1056-8727(03)00073-4
B.S. Olsen et al. / Journal of Diabetes and Its Complications 18 (2004) 160–164
1. Introduction Unsatisfactory blood glucose control is a common finding in young patients with type 1 diabetes. Noncompliance, psychological problems, and decreased insulin sensitivity contribute to poor control and may lead to impaired quality of life and the development of microvascular complications in kidneys and eyes (Dahlquist & Rudberg, 1987; Diabetes Control and Complications Trial (DCCT) Research Group, 1993a, 1993b; Hoey et al., for the Hvidøre Study Group on Childhood Diabetes, 2001; Mortensen, Hartling, Petersen, & Danish Study Group Diabetes in Childhood, 1998; Mortensen, Houggard, Ibsen, Parving, & the Danish Study Group of Diabetes in Childhood, 1994; Olsen et al., 1999; Olsen et al., 2000; Rogers et al., 1987). The fact that early microvascular complications rarely are present before puberty (Danne, Kordonouri, Ho¨vener, & Weber, 1997; Mortensen et al., 1998) led to the hypothesis that the prepubertal period had minor impact on the development of complications. Recent papers, however, have established that even young patients with diabetes are vulnerable to microvascular complications of diabetes (Dahlquist & Rudberg, 1987; DCCT Research Group, 1993b; Olsen et al., 1999; Olsen et al., 2000). A Danish nationwide cohort of children and adolescents with type 1 diabetes was followed for 8 years with assessment of metabolic control and development of microvascular complications (Olsen et al., 1999; Olsen et al., in press). Approximately 60% of the young patients developed abnormalities in the eyes and 15% elevated albumin excretion rate (AER). Here we report on the significance of the preand postpubertal diabetes duration in relation to the development of retinopathy and increased AER in this cohort of children and adolescents.
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childhood and adolescence was chosen as 11.7 years in girls and 12.9 years in boys corresponding to the mean age for Tanner Stage 2 in Danish girls and boys (Juul et al., 1994). Using this classification, 304 had a prepubertal onset of diabetes. For further demographic data, see Table 1. Clinical information and HbA1c, analysed centrally at Glostrup, were registered in all patients in 1987, 1989, and 1995. Likewise timed, overnight AER was centrally determined in 1989 and 1995, while fundus photography was assessed by the same ophthalmologist in 1995. During the observation period 1989 – 1995, the method for HbA1c determination changed from an isoelectric focusing method (Ampholine PAG plate, cat. no. 1804-131; LKB-Products, Bromma Sweden), normal range 4.0 –6.5 (mean 5.3%), to a high pressure liquid chromatographic method Hi-Auto A1c (Type 8121, Kyoto Daiichi Kagaku, Kyoto, Japan), normal range 4.3 – 5.8 (mean 5.3%). The adjusted reference interval for HbA1c determined by calibration of Hi-Auto A1c(x) to isoelectric focusing values ( y) was 4.5 – 5.7, mean 5.1% (mean F 2 S.D.), calculated from the regression equation y = 0.877x + 1.47, obtained by comparison of the two assays. The relationship of HbA1c analysed at our department and in the American DCCT was established by direct sample exchange. For the Glostrup centre, the mean HbA1c was 7.70 (S.E. = 0.28) and for the DCCT reference laboratory 7.52 (S.E = 0.29). The average difference was 0.18% (S.E. = 0.03), implying that the Glostrup centre gave a higher value (95% confidence interval for the difference: 0.12 – 0.24%). The albumin concentration in two out of three consecutive overnight timed urine samples were analysed by an immunoturbidimetric method with an interassay CV of 7% and a detection limit of 1 mg 1. Microalbuminuria was defined as an AER of 20 –150 Ag min 1 and macroalbuminuria as AER >150 Ag min 1 in two out of three overnight urine samples. Systolic and diastolic blood
2. Patients and methods This prospective nationwide multicenter 8-year cohort study involved 19 pediatric departments and six departments of internal medicine. Blood and urine samples were collected from 339 patients (47% of the inception cohort) on three occasions, in 1987, 89, and 95. The original cohort from 1987 to 1989 has previously been described in detail; however, in brief, 720 young patients participated in the surveys of 1987 and 1989. In 1989, this accounted for approximately 60% of all young patients with diabetes in Denmark. All 720 patients were invited to participate in the follow-up study in 1995. Of these patients, 108 declined to participate, 152 did not respond, 11 had emigrated, 2 were not traceable, 2 were dead, and 106 had accepted to participate but failed to show up. Multiple regression analysis showed that those who did not participate in 1995 were significantly older and had significantly poorer metabolic control in 1989 compared to the participating patients (Olsen et al., 1999). In the present study, distinction between
Table 1 Demographic characteristics of diabetic subjects at the follow-up in 1995 – 1996 by pubertal status at onset of disease Onset of diabetes before Onset of the age of diabetes z12 years 12 (prepubertal) (pubertal/postpubertal) P Number of patients Sex (m/f ) Mean age (years) (mean F S.D.). Mean age at diabetes onset (years) (mean F S.D.). Mean diabetes duration (years) (mean F S.D.). Mean diabetes duration after puberty (z12 years of age) (years) (mean F S.D.).
304 156/148 20.4 (F3.2)
49 32/17 24.2 (F1.3)
< .0001
13.6 (F1.0)
< .0001
13.8 (F3.2)
10.7 (F1.3)
< .0001
8.4 (F3.2)
11.4 (F1.6)
< .0001
6.6 (F3.05)
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pressure were recorded locally under standardised conditions (Mortensen et al., 1994) for all patients with a semiautomatic apparatus (Digital blood pressure meter UA-751, Takeda Medical, Tokyo, Japan). Colour retinal photographs were taken using a 40j to 60j retinal camera and included two fields of each eye, macular – temporal field, and disc/nasal field, recording a retinal view of f80j horizontally by 45j vertically. Assessment of diabetic retinopathy was carried out centrally by a trained reader using the ‘‘EURODIAB-Hammersmith grading system’’ (Olsen et al., 1999). Retinopathy was classified into five levels: 0 = none, 1 = minimal, 2 = moderate, 3 = severe nonproliferative retinopathy, and 4 = proliferative retinopathy. For most evaluations, Levels 1 –4 were combined into ‘‘any retinopathy.’’ 2.1. Statistical analysis Summary statistics are given as mean F S.D. Comparison between groups was performed with unpaired t test and chi-square test. The prevalence of diabetic complications in kidneys and eyes was evaluated by a backward stepwise multiple logistic regression analysis where the dependent responses were AER z 20 Ag/min and any retinopathy (both 1995). Variables included in the model were sex, age, diabetes duration before and after the chronological age of 11.7 years in females and 12.9 years in males, HbA1c, insulin dose, log AER, BMI, systolic, and diastolic blood pressure. P values < .05 were considered significant. Only the final model is reported.
3. Results In 1995, diabetic retinopathy (all levels) was present in 57.6% of the patients. The prevalence of retinopathy increased with age from 17.7% in the age group 12 –15 years to 67.6% in patients more than 20 years of age. By multiple regression analysis, long-term metabolic control ( P < .0001) and diabetes duration before puberty (11.7 years for girls and 12.9 years for boys) ( P < .05), as well as diabetes duration after the onset of puberty ( P < .001), were significantly associated to the development of diabetic retinopathy. The regression coefficient for prepubertal and pubertal diabetes duration was 0.156 (S.E = 0.048) and 0.311 (S.E = 0.054) per year, respectively. This corresponds to odds ratios of 1.17 (1.06 –1.28) and 1.37 (1.23 – 1.52) per year and a two times greater contribution of the postpubertal diabetes duration. The significance of the pre- and postpubertal diabetes duration for the development of diabetic retinopathy according to the regression model is shown in Fig. 1. The logit transformed curve illustrates four different onset ages, 4, 8, 12, and 16 years and are adjusted to correspond to a fixed level of HbA1c of 8%. At onset age 4, the probability for any retinopathy increases gradually during the next 8 years followed by a more steep increase in
Fig. 1. Model, based on multiple regression analysis, of the calculated probability of any retinopathy in 1995 as a function of onset age, age, and HbA1c. The HbA1c level is arbitrary set at 8% corresponding to the results of the intensively treated adolescents of the DCCT study.
risk after the initiation of puberty. Thereafter, the pubertal component markedly influences the development of microvascular injury. The figure shows that after 11.7 years with diabetes, 50% of that patients with onset age of 12 or 16 years have developed retinopathy, while it takes 14.7 years for patients with onset age of 4 years. Mean postpubertal diabetes duration to any retinopathy was significantly shorter (9.4 years) in patients with prepubertal onset of the disease compared to patients with postpubertal onset (11.8 years) ( P = .0004). In the cohort, the frequency of elevated AER increased from 4% in 1989 to 12.7% in 1995. None of the patients in the age group 12– 15 years had microalbuminuria, while the frequency increased to 14% in patients more than 15 years of age. By multiple logistic regression analysis, elevated AER was significantly related to poor long-term metabolic control (HbA1c) ( P < .001) and high AER 6 years previously ( P < .001), but we could not demonstrate any relationship between elevated AER (>20 Ag/min) in 1995 and diabetes duration irrespective of onset age.
4. Discussion Microvascular complications in kidneys, eyes, and nerves are usually diagnosed after puberty and relate to the quality of blood glucose control in the preceding years (Caprio & Tamborlane, 1994; DCCT Research Group, 1993a, 1993b; Mathiesen, Rønn, Storm, Foght, & Deckert, 1994; Olsen et al., 2000; Williamson et al., 1986). Recent data show that the prepubertal diabetes duration also contributes to the development of microvascular complications (Bonney et al., 1995; Coonrod, Lloyd, & Ellis, 1993; Donahugue et al., 2000; Donahugue et al., 1997; McNally, Raymond, Swift, & Burden, 1993). As in the present investigation, data from two recent German
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studies (Danne et al., 1994; Holl, Grabert, Thon, & Heinze, 1998) demonstrated that in young patients with retinopathy and prepubertal onset of disease, the diabetes duration after puberty is significantly shorter compared to patients with a pubertal onset of disease. It is thus obvious that the prepubertal diabetes duration contributes to the development of retinopathy but to a lesser degree than the period after initiation of puberty. In Denmark, the mean age for entering Tanner Stage 2 is 11.7 years for girls and 12.7 for boys (Juul et al., 1994), and therefore diabetes onset before this age was considered prepubertal while diabetes onset after was considered pubertal. Individual Tanner staging would have been a more precise measurement of puberty but was not available in the present study. However, delayed puberty is not prevalent in diabetic children, and previous studies have shown that age is a suitable predictor of puberty (Kostraba et al., 1989). When examining the development of retinopathy, diabetes duration after initiation of puberty contributed two times more than the diabetes duration before puberty. This is significantly more than shown in the Wisconsin Epidemiological Study, where diabetes duration after menarche contributed 1.3 times more than the premenarcheal duration (Klein, Moss, & Klein). In contrast to the present study, the Wisconsin Epidemiological Study defined puberty as a menarcheal age, which is roughly 13 years of age in the Western world (Cole, 2000; Helm, Mu¨nster, and Schmidt, 1998). Thus, these patients had a longer prepubertal diabetes duration compared to our patients, which may explain the difference in contribution of the pre- and postpubertal diabetes duration. Donahugue defined puberty by gonadarche occurring at 11.4 years in girls and 12.6 years in boys. Odds ratios for the prepubertal significance for retinopathy were 1.22 and 1.32 for postpubertal duration (Donaghue et al., 1997), which were in agreement with our findings. Persistent microalbuminuria (AER >20 Ag/min) is a strong predictor for overt diabetic nephropathy and is diagnosed in 30– 40% of adults and 20– 25% of adolescents with type 1 diabetes (Holl et al., 1999; Janner, Knill, Dien, Zuppinger, & Mullis, 1994; Microalbuminuria Collaborative Study Group, 1992; Olsen et al., 1999; Shield, 1994; Williamson et al., 1986). The prevalence of elevated AER increases after 10 –15 years of diabetes duration and then levels off or declines (Holl et al., 1999; Janner et al., 1994; Olsen et al., 1999; Shield, 1994). Particularly, studies in adults have shown that long diabetes duration is associated with raised urinary albumin (Microalbuminuria Collaborative Study Group, 1992). In children and adolescents, the role of diabetes duration is, however, more controversial. Some pediatric and adolescent studies have shown a possible association (Holl et al., 1999) while others dispute this (Coonrod et al., 1993; Janner et al., 1994; Mortensen et al., 1994; Rudberg, Ullmann, & Dahlquist, 1993). By multiple regression analysis, no correlation between diabetes duration and elevated AER was found in the present study.
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Diabetic retinopathy and nephropathy are often found simultaneously; however, the pathogenesis of the two complications may be different. After 20 years with diabetes, most patients have retinopathy whereas less than 50% have nephropathy (Olsen et al., 1999). Poor long-term metabolic control and long diabetes duration are obviously not sufficient to cause diabetic nephropathy. Other factors such as genetic predisposition, hemodynamic changes in the kidneys, and smoking may be equal important contributors, diluting the significance of diabetes duration (Rudberg et al., 1993). The DCCT study (DCCT Research Group, 1993a, 1993b) verified a close relationship between good metabolic control and fewer microvascular complications in kidneys, eyes, and nerves in adults (DCCT Research Group, 1993a) and adolescents (DCCT Research Group, 1993b). Newer studies have shown the same correlation in even younger patients as well (Olsen et al., 2000). The present study confirmed that the years before puberty contribute to the overall risk of developing microvascular injury but modest compared to the postpubertal duration of diabetes. Persistent poor blood glucose control in childhood is related is to the development of microvascular complications. This emphasises the need for optimising blood glucose control in all children irrespective of age.
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