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Metabolic Safety of Growth Hormone in Type 1 Diabetes and Idiopathic Growth Hormone Deficiency
Metabolic Safety of Growth Hormone in Type 1 Diabetes and Idiopathic Growth Hormone Deficiency Walter Bonfig, MD1, Katharina Molz, MD2, Joachim Woelfle, MD, PhD3, Sabine E. Hofer, MD4, Berthold P. Hauffa, MD, PhD5, Eckhard Schoenau, MD, PhD6, Sven Golembowski, MD7, Stefan A. Wudy, MD, PhD8, and Reinhard W. Holl, MD, PhD2, on behalf of the Diabetes Patienten Verlaufsdocumentationsystem Initiative of the German Working Group for Pediatric Diabetology and the German Bundesministerium fu¨r Bildung und Forschung Competence Net for Diabetes Mellitus* Objective To evaluate metabolic consequences of growth hormone (GH) treatment in children with type 1 diabetes.
Study design This study is an analysis of metabolic changes in 37 patients with childhood-onset GH deficiency and type 1 diabetes, documented in the Diabetes Patienten Verlaufsdocumentationsystem database. Main outcome measures were changes in hemoglobin A1c and daily insulin requirements during GH therapy in children with GH deficiency and type 1 diabetes compared with a large cohort of adolescents with type 1 diabetes. Results Thirty-seven patients with type 1 diabetes and a diagnosis of idiopathic GH deficiency after onset of diabetes were compared with 48 856 patients with type 1 diabetes. After adjustment for age, sex, duration of diabetes, and migration background, a significant difference in mean daily insulin requirement was seen between the 2 groups (1.0 IU/kg/day in subjects with GH deficiency and type 1 diabetes vs 0.85 IU/kg/day in controls; P < .01) and height-SDS ( 2.0 in subjects with GH deficiency and diabetes vs +0.03 in controls; P < .0001). There was no significant between-group difference in hemoglobin A1 concentration, however (8.1% 1.4% in patients with GH deficiency and type 1 diabetes vs 8.2% 1.7% in those with type 1 diabetes only; P > .05). Conclusion An increased daily insulin requirement should be considered in patients with type 1 diabetes treated with GH. With adequate adaptation of insulin dosage, metabolic control is not impaired during GH treatment. (J Pediatr 2013;163:1095-98).
W
ith the use of actual diagnostic criteria, the prevalence of growth hormone (GH) deficiency is estimated to be between 1:3500 and 1:8700. GH deficiency may present in the neonatal period if caused by genetic disorders, but the average age at diagnosis is 6-8 years.1 In most cases, GH deficiency represents a relative lack of GH secretion, leading to decreased growth velocity, retardation of bone maturation, and short stature (“idiopathic” GH deficiency). GH also plays an important role in glucose, lipid, and protein metabolism.2 Both GH deficiency and GH excess are associated with disturbances of carbohydrate metabolism. GH decreases glucose oxidation and glucose uptake by muscle and increases gluconeogenesis, resulting in “insulin antagonist” effects. The incidence of type 1 diabetes is increasing, especially in the younger age groups (age <5 years).3 Early diabetes onset and a mean hemoglobin A1c (HbA1c) value >7.0% (>53 mmol/mol) are negatively correlated with adult height.4 Thus, evaluation for short stature and diagnosis of GH deficiency in children with diabetes might become more frequent in the future. To date, there are no published data regarding the metabolic safety of GH treatment in children with GH deficiency and type 1 diabetes.
Methods The Diabetes Patienten Verlaufsdocumentationsystem (DPV) Initiative comprises the DPV software for prospective diabetes documentation, a benchmarking and quality control procedure, and a cumulative diabetes research database. More than 300 pediatric diabetes centers in Germany and Austria participate in the DPV. Anonymized data are transferred biannually. The data are verified, corrected at the originating center if necessary, and then entered into the dataDPV GH HbA1c H-SDS IGF
Diabetes Patienten Verlaufsdocumentationsystem Growth hormone Hemoglobin A1c Height-SDS Insulin-like growth factor
From the 1Division of Pediatric Endocrinology, Department of Pediatrics, Technical University Mu¨nchen, Munich, Germany; 2Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany; 3 Division of Pediatric Endocrinology, University of Bonn, Bonn, Germany; 4Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria; 5Department of Pediatrics, University of Essen, Essen, Germany; 6 € ln, Cologne, Department of Pediatrics, University of Ko Germany; 7Department of Pediatrics, Sana Klinikum 8 Berlin Lichtenberg, Berlin, Germany; and Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany *A list of centers that participated in the DPV Initiative of the German Working Group for Pediatric Diabetology and the German Bundesministerium fu¨r Bildung und Forschung Competence Net for Diabetes Mellitus is available at www.jpeds.com (Appendix). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.04.045
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base using the DPV software for standardized prospective longitudinal documentation of diabetes in children. Each center complies with local ethical and data management guidelines. All data for this study were collected during routine care procedures. Our study cohort comprised 50 children with type 1 diabetes and isolated idiopathic GH deficiency. In 13 children, the diagnosis of GH deficiency was established before the onset of type 1 diabetes, and these children were excluded from our analysis. In the other in 37 children, GH deficiency was diagnosed during follow-up of type 1 diabetes. In 21 children, complete longitudinal data on height-SDS (H-SDS), HbA1c, daily insulin requirement, mode of insulin therapy (ie, multiple daily injections or continuous subcutaneous insulin infusion), and body mass index SDS were available. The diagnosis of GH deficiency was based on clinical findings (including below-average growth velocity, retarded bone age, and low insulin-like growth factor [IGF]-1 and IGFbinding protein 3 levels) and confirmed by 2 different GH provocative tests (clonidine, arginine, or insulin tolerance test) or by measurement of overnight spontaneous GH secretion in all patients. GH deficiency was marked by fewer than 2 GH peaks and a mean GH concentration <3.2 ng/mL [0.149 nmol/L]. GH testing was performed in accordance with national guidelines for diagnosis of GH deficiency.5 The GH cutoff level for provocative testing was 8 ng/mL (0.372 nmol/L). Tests were performed after a 10-hour fasting phase. Sex steroid priming was provided with 0.12 mg of ethinyl estradiol in prepubertal girls aged >10 years and with 100 mg of testosterone in prepubertal boys aged >11 years. After diagnosis of GH deficiency, cerebral magnetic resonance imaging was performed to rule out hypothalamic or hypophyseal masses. Patients received a GH dose of 25-35 mg/kg body weight/day. Height was measured at the diabetes centers with the patients standing, using a wall-mounted stadiometer. H-SDS was calculated using contemporary national reference data from Kromeyer-Hauschild et al6 and Zellner et al.7 Glycemic control was assessed based on HbA1c level, measured using the methodology established at each individual center. To adjust for differences among participating laboratories, the HbA1c data were mathematically standardized according to the values from the Diabetes Control and Complications Trial,8 with a reference range of 4.05%-6.05% corresponding to 20.77-42.62 mmol/mol.
Vol. 163, No. 4 Daily insulin requirements were calculated as units per kg body weight per day (IU/kg/day) before GH treatment and at the time of evaluation at age <16 years. Only patients of chronological age <16 years were included in the analysis, given our focus on evaluating the metabolic effect of ongoing GH therapy. Statistical analyses (ie, descriptive data analysis, calculation of SDS, and regression analysis as a hierarchic linear regression model) were carried out using SAS version 9.2 (SAS Institute, Cary, North Carolina). A P value <.05 was considered to indicate statistical significance.
Results GH deficiency was diagnosed during follow-up of type 1 diabetes at a median age of 13.3 years (range, 11.7-14.4 years). The median patient age was 5.5 years at diabetes onset and 15.1 years at evaluation. The mean daily insulin dose was significantly higher in the patients with GH deficiency and type 1 diabetes compared with the 48 856 controls with type 1 diabetes alone (1.0 0.4 IU/kg/day vs 0.85 0.3 IU/kg/day; P < .05) (Table I). This difference persisted when the daily insulin dose was adjusted for age, sex, duration of diabetes, migration background, and mode of insulin therapy (ie, multiple daily injections or continuous subcutaneous insulin infusion). Mean and median HbA1c values did not differ significantly between the 2 groups (Table I). There was still no significant between-group difference after adjustment of HbA1c for age, sex, duration of diabetes, and migration background. Lipid profiles differed significantly in the 2 groups, with higher mean total cholesterol and low-density lipoprotein cholesterol levels in the patients with GH deficiency and type 1 diabetes (total cholesterol, 189.1 33.9 mg/dL vs 177.6 39.9 mg/dL; low-density lipoprotein cholesterol, 102.8 30.3 mg/dL vs 93.5 33.6 mg/dL; P < .05). The mean high-density lipoprotein cholesterol level was comparable in the 2 groups (65.2 mg/dL in the patients with GH deficiency and type 1 diabetes vs 60.9 mg/dL in those with type 1 diabetes only). Longitudinal data on H-SDS, daily insulin requirement, and HbA1c were available in a subset of 21 patients with GH deficiency and type 1 diabetes. In this subset, the median age was 5.2 years at the onset of diabetes and 12.4 years at the diagnosis of GH deficiency. Before the initiation of GH treatment, the median H-SDS was 2.3. The median daily insulin dosage
Table I. Auxologic and metabolic data at evaluation in patients with GH deficiency and type 1 diabetes compared with a large control group
Age at diagnosis of type 1 diabetes, years,mean SD Age at evaluation, years, mean SD HbA1c, %, mean SD H-SDS, mean SD Body mass index SDS, mean SD Daily insulin dose, IU/kg/day, mean SD
GH deficiency and type 1 diabetes (n = 37)
GH deficiency and type 1 diabetes with longitudinal data (n = 21)
Controls (n = 48 856)
6.2 3.6 13.2 3.1 8.1 1.4 2.0 1 0.2 1 1.0 0.4
6.3 4.0 13.3 2.9 8.2 1.4 2.0 0.9 0.1 1.0 1.1 0.4
8.1 4* 12.8 3.4 8.2 1.7 0.03 1.1* 0.5 0.9* 0.85 0.3*
*P < .05.
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October 2013 was 0.69 IU/kg/day, not statistically significantly different from that in the 48 856 controls without GH deficiency (Table II). After adjustment for age, sex, duration of diabetes, migration background, and mode of insulin therapy, there still were no significant between-group differences. There also was no significant difference in mean HbA1c before the initiation of GH treatment (7.6% 1.4% in patients with GH deficiency vs 8.0% 1.5% in controls; P > .05). The patients with GH deficiency and type 1 diabetes had a median age of 15.1 years at the time of reevaluation during GH therapy. Unexpectedly, H-SDS had increased only to 2.0 0.9 after 2 years of GH treatment, indicating reduced efficacy of GH therapy in the patients with diabetes (Table II). In a regression model, catch-up growth (ie, gain in H-SDS) was significantly influenced by HbA1c concentration (estimate, 0.22 0.08: P < .05), indicating that worse metabolic control inhibits catch-up growth in patients with GH deficiency and type 1 diabetes. During GH treatment, daily insulin requirement rose significantly, to 1.1 0.4 IU/kg/day (P < .0001). With this increased daily insulin dose, the patients with GH deficiency and type 1 diabetes were able to achieve similar metabolic control as those without GH deficiency (HbA1c, 8.2% 1.4% vs 8.2% 1.7%; P > .05). Moreover, the frequency of hypoglycemia did not differ between the 2 groups (P > .05).
Discussion We have shown that although GH treatment leads to a significantly higher insulin demand, with adequate adjustment of insulin doses, metabolic control does not worsen during GH treatment in patients with type 1 diabetes. Thus, once GH deficiency is diagnosed in a child with diabetes, the impact of GH treatment on metabolic changes must be considered. Existing type 1 diabetes is not a contraindication for GH treatment in children with GH deficiency. Moreover, onset of type 1 diabetes is not a reason to discontinue GH treatment in a child with GH deficiency.7 Of note, our patients with type 1 diabetes were older at the time of diagnosis of GH deficiency compared with the average age of diagnosis of GH deficiency in children without diabetes. Potentially, physicians are more hesitant to perform GH stimulation testing
in short children with type 1 diabetes, attributing their poor growth to poor diabetes control. As a result, optimal metabolic control is generally attempted in children with diabetes with growth failure without testing for other etiologies. Unexpectedly, we found reduced efficacy of GH treatment in children with GH deficiency and type 1 diabetes, with a median height gain of only 0.3 SDS over a 2-year course of treatment. Possible explanations for this finding might be the late diagnosis and start of GH treatment, inadequate GH dosage out of concern for metabolic side effects, or hepatic GH resistance in patients with diabetes.9-11 Unfortunately, GH doses are not documented for all patients in the DPV database, and thus these data were not available for analysis. It might be interesting to study the efficacy of GH treatment in patients with type 1 diabetes by analyzing data from the established GH observational studies, which focus more on GH dosage and IGF-1 concentrations. A significant influence of metabolic diabetes control (based on HbA1c value) on catch-up growth could be demonstrated in a regression model using our data. To date, only isolated patients with type 1 diabetes and treatment of GH deficiency have been reported in the literature. In a case report, Quintos et al12 described a boy with autoimmune polyglandular syndrome type 3 (type 1 diabetes and autoimmune thyroiditis) and GH deficiency diagnosed at age 8.5 years. The boy was treated with GH until he reached nearadult height, which was close to his midparental target height. This case report indicated that GH treatment can be effective in single patients with type 1 diabetes, but provided no data on the metabolic changes related to GH treatment in this patient. In a second case report, Pun and Chandurkar13 described a girl with autoimmune polyglandular syndrome type 1 with juvenile idiopathic arthritis, hypoparathyroidism, type 1 diabetes, Addison’s disease, chronic mucocutaneous candidiasis, GH deficiency, ovarian failure, alopecia, and pernicious anemia. This patient was treated with GH, but treatment was not initiated until a chronological age of 16 years (bone age, 8 years). GH treatment was not very effective in this patient, possibly related to the late start of treatment and particularly to the cooccurrence of ovarian failure and Addison disease, diagnosed at age 15 and 12 years, respectively. In contrast to the foregoing case reports, 2 large studies reported an increased incidence of type 2 diabetes in children
Table II. Longitudinal data after 2 years in 21 patients with GH deficiency and type 1 diabetes during GH treatment
H-SDS, median H-SDS, mean SD Body mass index SDS, median Body mass index SDS, mean SD HbA1c, %, median HbA1c, %, mean SD Daily insulin dose, IU/kg/day, median Daily insulin dose, IU/kg/day, mean SD
GH deficiency and type 1 diabetes with longitudinal data (n = 21) before initiation of GH treatment 2.3 2.1 0.8 0.3 0.1 1.1 7.3 7.6 1.4 0.69 0.74 0.3
DPV controls (n = 48 856)
GH deficiency and type 1 diabetes with longitudinal data (n = 21) at reevaluation during GH treatment
DPV controls (n = 48 856)
0.05 0.05 1.1* 0.4 0.4 0.9* 7.7 8.0 1.5* 0.78 0.8 0.3
2 2.0 0.9 0.1 0.1 1.0 8.1 8.2 1.4 1.05 1.1 0.4
0.04 0.03 1.1* 0.5 0.5 0.9* 7.9 8.2 1.7 0.83 0.85 0.3*
*P < .05.
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and adolescents with type 2 diabetes and also in adults treated with GH.14,15 Child et al15 compared the incidence of type 1 and type 2 diabetes in patients aged <20 years in the Genetics and Neuroendocrinology of Short Stature International Study observational research program with the US SEARCH for Diabetes in Youth study and found an increased incidence was found for type 2 diabetes, but not for type 1 diabetes, in children treated with GH. Based on these findings, monitoring of glucose metabolism is recommended during GH treatment, especially in patients with preexisting risk factors, such as obesity. Cutfield et al16 reported that GH treatment did not affect the incidence of type 1 diabetes in any age group studied. An increased daily insulin requirement must be considered in patients with type 1 diabetes receiving GH treatment. With adequate adaptation of insulin dosage, metabolic control does not worsen during GH treatment; thus, GH treatment in children with type 1 diabetes is feasible. The question of reduced efficacy of GH treatment in children with type 1 diabetes should be investigated prospectively in clinical studies and analyzed in established GH company observational databases. n Submitted for publication Jan 8, 2013; last revision received Mar 11, 2013; accepted Apr 23, 2013. Reprint requests: Dr med Walter Bonfig, Division of Pediatric Endocrinology, €t Mu¨nchen, Ko € lner Platz 1, Department of Pediatrics, Technische Universita 80804 Mu¨nchen, Germany. E-mail: [email protected]
References 1. Ranke M, Reiter EO, Price DA. Idiopathic growth hormone deficiency in KIGS: selected aspects. In: Ranke M, Price DA, Reiter EO, eds. Growth hormone therapy in pediatrics: 20 years of KIGS. Basel, Switzerland: Karger; 2007. p. 116-35. 2. Moller N, Jorgensen JO. Effects of growth hormone on glucose, lipid and protein metabolism in human subjects. Endocr Rev 2009;30:152-77. 3. Ehehalt S, Dietz K, Willasch AM, Neu A , DIARY-Group Baden-Wuerttemberg. Prediction model for the incidence and prevalence of type 1 diabetes in childhood and adolescence: evidence for a cohort-dependent increase within the next two decades in Germany. Pediatr Diabetes 2007;12:15-20.
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Vol. 163, No. 4 4. Bonfig W, Kapellen T, Dost A, Fritsch M, Rohrer T, Wolf J, et al. Growth in children with type 1 diabetes. J Pediatr 2012;160:900-3. 5. Binder G. Recommendations for actions according to the guideline growth hormone deficiency in children and adolescents. Monatsschr Kinderheilkd 2012;160:589-90 (in German). 6. Kromeyer-Hauschild K, Wabitsch M, Kunze D, Geller F, Geiß HC, Hesse V, et al. Percentiles for body-mass-index for children and adolescents using multiple German cohorts. Monatsschr Kinderheilk 2001;149: 807-18 (in German). 7. Zellner K, Jaeger U, Kromeyer-Hauschild K. Height, weight, and BMI of schoolchildren in Jena, Germany: are the secular changes leveling off? Econ Hum Biol 2004;2:281-94. 8. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86. 9. Chiarelli F, Giannini C, Mohn A. Growth, growth factors and diabetes. Eur J Endocrinol 2004;151:109-17. 10. Mercado M, Baumann G. Characteristics of the somatotropic axis in insulin-dependent diabetes mellitus. Arch Med Res 1995;26:101-9. 11. Holl RW, Siegler B, Scherbaum WA, Heinze E. The serum growth hormone-binding protein is reduced in young patients with insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1993; 76:165-7. 12. Quintos JB, Grover M, Boney CM, Salas M. Autoimmune polyglandular syndrome type 3 and growth hormone deficiency. Pediatr Diabetes 2010; 11:438-42. 13. Pun T, Chandurkar V. Growth hormone deficiency, short stature, and juvenile rheumatoid arthritis in a patient with autoimmune polyglandular syndrome type 1: case report and brief review of the literature. ISRN Endocrinol 2011;2011:462759. 14. Luger A, Mattsson AF, Koitowska-Hagstrom M, Thunander M, Goth M, Verhelst J, et al. Incidence of diabetes mellitus and evolution of glucose parameters in growth hormone–deficient subjects during growth hormone replacement therapy: a long-term observational study. Diabetes Care 2012;35:57-62. 15. Child CJ, Zimmermann AG, Scott RS, Cutler GB, Battelino T, Blum WF. GeNeSIS International Advisory Board. Prevalence and incidence of diabetes mellitus in GH-treated children and adolescents: analysis from the GeNeSIS observational research program. J Clin Endocrinol Metab 2011; 96:1025-34. 16. Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB, et al. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth hormone treatment. Lancet 2000;355:610-3.
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Appendix We thank the following centers for contributing their data to this study and participating in the DPV Initiative of the German Working Group for Pediatric Diabetology and the German BMBP Competence Net for Diabetes Mellitus: Aachen-Innere RWTH Aachen-Uni-Kinderklinik RWTH Aalen Kinderklinik Ahlen St Franziskus Kinderklinik Alt€ otting Zentrum Inn-Salzach Alt€ otting-Burghausen Innere Medizin Amstetten Klinikum Mostviertel Kinderklinik Arnsberg-Hu¨sten Karolinenhosp. Kinderabteilung Asbach Kamillus-Klinik Innere Aue Helios Kinderklink Augsburg Innere Augsburg Kinderklinik Zentralklinikum Aurich Kinderklinik Bad Aibling Internist Praxis Bad Driburg/Bad Hermannsborn Innere Bad Hersfeld Innere Bad Hersfeld Kinderklinik Bad Kreuznach–St Marienw€ orth-Innere Bad Krozingen Klinik Lazariterhof Park-Klinikum Bad K€ osen Kinder-Rehaklinik Bad Lauterberg Diabeteszentrum Innere Bad Mergentheim-Diabetesfachklinik Bad Mergentheim-Gemeinschaftspraxis DM-dorf Alth Bad Oeynhausen Herz und Diabeteszentrum NRW Bad Orb Spessart Klinik Bad Reichenhall Kreisklinik Innere Med Bad Salzungen Kinderklinik Bad S€ackingen Hochrheinklinik Innere Bad Waldsee Kinderarztpraxis Bautzen Oberlausitz KK Bayreuth Innere Medizin Berchtesgaden CJD Berchtesgaden MVZ Innere Med Berlin DRK-Kliniken Berlin Endokrinologikum Berlin Evang Krankenhaus K€ onigin Elisabeth Berlin Kinderklinik Lindenhof, Sana Klinikum Licht Berlin Klinik St Hedwig Innere Berlin Oskar Zieten Krankenhaus Innere Berlin Schlosspark-Klinik Innere Berlin St Josephskrankenhaus Innere Berlin Virchow-Kinderklinik Berlin Vivantes Hellersdorf Innere Bielefeld Kinderklinik Gilead Bocholt Kinderklinik Bochum Universit€atskinderklinik St Josef Bonn Uni-Kinderklinik Bottrop Kinderklinik Bottrop Knappschaftskrankenhaus Innere Braunschweig Kinderarztpraxis
Bremen-Kinderklinik Nord Bremen-Mitte Innere Bremen Kinderklinik St Ju¨rgenstrasse Bremen-Epidemiologieprojekt Bremerhaven Kinderklinik B€ oblingen Kinderklinik Celle Kinderklinik Chemnitz Kinderklinik Chemnitz-Hartmannsdorf Innere Medizin-DIAKOMED-1 Coesfeld Kinderklinik Coesfeld/Du¨lmen Innere Med Darmstadt Innere Medizin Darmstadt Kinderklinik Prinz Margaret Datteln Vestische Kinderklinik Deggendorf Kinderarztpraxis Deggendorf Kinderklinik Deggendorf Medizinische Klinik II Delmenhorst Kinderklinik Dessau Kinderklinik Detmold Kinderklinik Dornbirn Kinderklinik Dortmund Kinderklinik Dortmund Knappschaftskrankenhaus Innere Dortmund Medizinische Kliniken Nord Dortmund-Hombruch, Marienhospital Dortmund-St Josefshospital Innere Dresden Neustadt Kinderklinik Dresden Uni-Kinderklinik Duisburg Evang und Johanniter Krhs, Innere Duisburg Kinderklinik Duisburg Malteser St Anna Innere Duisburg Malteser St Johannes Duisburg-Huckingen Du¨ren-Birkesdorf Kinderklinik Du¨sseldorf Uni-Kinderklinik Eberswalde Klinikum Barnim Werner Forßmann - Inner Erfurt Kinderklinik Erlangen Uni Innere Medizin Erlangen Uni-Kinderklinik Essen Diabetes-Schwerpunktpraxis Dr Best Essen Elisabeth Kinderklinik Essen Uni-Kinderklinik Esslingen Klinik fu¨r Kinder und Jugendliche Eutin Kinderklinik Eutin St-Elisabeth Innere Feldkirch Kinderklinik Forchheim Diabeteszentrum SPP Frankenthal Kinderarztpraxis Frankfurt Diabeteszentrum Rhein-Main-Erwachsenendi Frankfurt Uni-Kinderklinik Frankfurt Uni-Klinik Innere Freiburg St Josef Kinderklinik Freiburg Uni Innere Freiburg Uni-Kinderklinik Friedberg Innere Klinik Friedrichshafen Kinderklinik Fulda Innere Medizin
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Fulda Kinderklinik Fu¨rth Kinderklinik Gaissach Fachklinik der Deutschen Rentenversicheru Garmisch-Partenkirchen Kinderklinik Geislingen Klinik Helfenstein Innere Gelnhausen Innere Gelnhausen Kinderklinik Gelsenkirchen Kinderklinik Marienhospital Gera Kinderklinik Gießen Ev Krankenhaus Mittelhessen Gießen Uni-Kinderklinik Graz Universit€ats-Kinderklinik G€ oppingen Innere Medizin G€ oppingen Kinderklinik am Eichert G€ orlitz St€adtische Kinderklinik G€ ottingen Uni-Kinderklinik Gu¨strow Innere Hachenburg Kinderpraxis Hagen Kinderklinik Halle Uni-Kinderklinik Halle-D€ olau St€adtische Kinderklinik Hamburg Altonaer Kinderklinik Hamburg Endokrinologikum Hamburg Kinderklinik Wilhelmstift Hamburg-Nord Kinder-MVZ Hameln Kinderklinik Hamm Kinderklinik Hanau Kinderklinik Hanau St Vincenz - Innere Hannover Henriettenstift - Innere Hannover Kinderklinik MHH Hannover Kinderklinik auf der Bult Haren Kinderarztpraxis Heide Kinderklinik Heidelberg Uni-Kinderklinik Heidelberg Uniklinik Innere Heidenheim Arztpraxis Allgemeinmed Heidenheim Kinderklinik Heilbronn Innere Klinik Heilbronn Kinderklinik Herdecke Kinderklinik Herford Innere Med I Herford Kinderarztpraxis Herford Klinikum Kinder & Jugendliche Heringsdorf Inselklinik Hermeskeil Kinderpraxis Herne Evan Krankenhaus Innere Herten St Elisabeth Innere Medizin Herzberg Kreiskrankenhaus Innere Hildesheim Innere Hildesheim Kinderarztpraxis Hildesheim Klinikum Kinderklinik Hinrichsegen-Bruckmu¨hl Diabetikerjugendhaus Hof Kinderklinik Homburg Uni-Kinderklinik Saarland Idar Oberstein Innere Ingolstadt Klinikum Innere 1098.e2
Vol. 163, No. 4 Innsbruck Universit€atskinderklinik Iserlohn Innere Medizin Itzehoe Kinderklinik Jena Uni-Kinderklinik Kaiserslautern Kinderarztpraxis Dr Geist Kaiserslautern-Westpfalzklinikum Kinderklinik Kamen Hellmig-Krankenhaus Karlsburg Klinik fu¨r Diabetes & Stoffwechsel Karlsruhe St€adtische Kinderklinik Kassel Klinikum Kinder- und Jugendmedizin Kassel Rot-Kreuz-Krankenhaus Innere Kassel St€adtische Kinderklinik Kaufbeuren Innere Medizin Kempen Heilig Geist - Innere Kiel St€adtische Kinderklinik Kiel Universit€ats-Kinderklinik Kirchen DRK Klinikum Westerwald, Kinderklinik Kirchheim-Nu¨rtingen Innere Kleve Innere Medizin Koblenz Kemperhof 1 Med Klinik Koblenz Kinderklinik Kemperhof Konstanz Innere Klinik Konstanz Kinderklinik Krefeld Innere Klinik Krefeld Kinderklinik Krefeld-Uerdingen St Josef Innere Kreischa-Zscheckwitz, Klinik Bavaria K€ oln Kinderklinik Amsterdamerstrasse K€ oln Uni-Kinderklinik Landau/Annweiler Innere Landshut Kinderklink Lappersdorf Kinderarztpraxis Leipzig Uni-Kinderklinik Leoben LKH Kinderklinik Leverkusen Kinderklinik Lienz BKH Kinderklinik Limburg Innere Medizin Lindenfels Luisenkrankenhaus Innere Lingen Kinderklinik St Bonifatius Linz Krankenhaus Barmherzige Schwestern Kardiologi Linz Krankenhaus der Barmherzigen Schwestern Inter Linz Landes-Kinderklinik Lippstadt Evangelische Kinderklinik Ludwigsburg Innere Medizin Ludwigsburg Kinderklinik Ludwigshafen Kinderklinik St Anna-Stift Ludwigshafen diabetol SPP Lu¨beck Uni-Kinderklinik Lu¨beck Uni-Klinik Innere Medizin Lu¨denscheid M€arkische Kliniken - Kinder & Jugendme Lu¨nen Klinik am Park Magdeburg St€adtisches Klinikum Innere Magdeburg Uni-Kinderklinik Mainz Uni-Kinderklinik Mannheim Uni-Kinderklinik Mannheim Uniklinik Innere Medizin Marburg - UKGM Endokrinologie & Diabetes Bonfig et al
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October 2013 Marburg Uni-Kinderklinik Marienhaus Klinikum St Elisabeth Marktredwitz Innere Medizin Marpingen-SPP Mechernich Kinderklinik Memmingen Kinderklinik Merzig Kinderklinik Minden Kinderklinik Moers - St Josefskrankenhaus Innere Moers Kinderklinik Murnau am Staffelsee - SPP Groß Mutterstadt Kinderarztpraxis M€ odling Kinderklinik M€ olln Reha-Klinik Hellbachtal M€ onchengladbach Kinderklinik Rheydt Elisabethkrank Mu¨hlacker Enzkreiskliniken Innere Mu¨hldorf Gemeinschaftspraxis Mu¨nchen 3 Orden Kinderklinik Mu¨nchen Diabetes-Zentrum Su¨d Mu¨nchen Kinderarztpraxis diabet SPP Mu¨nchen Schwerpunktpraxis Evers Mu¨nchen von Haunersche Kinderklinik Mu¨nchen-Gauting Kinderarztzentrum Mu¨nchen-Harlaching Kinderklinik Mu¨nchen-Schwabing Kinderklinik Mu¨nster Herz Jesu Innere Mu¨nster St Franziskus Kinderklinik Mu¨nster Uni-Kinderklinik Mu¨nster p€adiat Schwerpunktpraxis Ziegler Nagold Kreiskrankenhaus Innere Nauen Havellandklinik Neuburg Kinderklinik Neunkirchen Innere Medizin Neunkirchen Marienhausklinik Kohlhof Kinderklinik Neuss Lukaskrankenhaus Kinderklinik Neuwied Kinderklinik Elisabeth Nidda Bad Salzhausen Klinik Rabenstein/Innere-1 Re Nidda Bad Salzhausen Klinik Rabenstein/Innere-2 Re Nu¨rnberg Cnopfsche Kinderklinik Nu¨rnberg Zentrum f Neugeb, Kinder & Jugendl Oberhausen Innere Oberhausen Kinderklinik Oberhausen Kinderpraxis Oberhausen StClemens Hospitale Sterkrade Offenbach/Main Innere Medizin Offenbach/Main Kinderklinik Offenburg Kinderklinik Oldenburg Kinderklinik Oldenburg Schwerpunktpraxis Oschersleben MEDIGREIF B€ ordekrankenhaus Osnabru¨ck Christliches Kinderhospital Osterkappeln Innere Ottobeuren Kreiskrankenhaus Oy-Mittelberg Hochgebirgsklinik Kinder-Reha Paderborn St Vincenz Kinderklinik Papenburg Marienkrankenhaus Kinderklinik Passau Kinderarztpraxis
Passau Kinderklinik Pforzheim Kinderklinik Pfullendorf Innere Medizin Pirmasens St€adtisches Krankenhaus Innere Plauen Vogtlandklinikum Prenzlau Krankenhaus Innere Rastatt Gemeinschaftspraxis Rastatt Kreiskrankenhaus Innere Ravensburg Kinderklink St Nikolaus Recklinghausen Dialysezentrum Innere Regensburg Kinderklinik St Hedwig Remscheid Kinderklinik Rendsburg Kinderklinik Reutlingen Kinderarztpraxis Reutlingen Kinderklinik Reutlingen Klinikum Steinenberg Innere Rheine Mathiasspital Kinderklinik Rosenheim Innere Medizin Rosenheim Kinderklinik Rosenheim Schwerpunktpraxis Rostock Uni-Kinderklinik Rostock Universit€at Innere Medizin Rotenburg/Wu¨mme Kinderklinik Ru¨sselsheim Kinderklinik Saaldorf-Surheim Diabetespraxis Saalfeld Thu¨ringenklinik Kinderklinik Saarbru¨cken Kinderklinik Winterberg Saarbru¨cken Kinderklinik Winterberg 2 Saarlouis Kinderklinik Salzburg Kinderklinik Scheidegg Prinzregent Luitpold Scheidegg Reha-Kinderklinik Maximilian Schw Gmu¨nd Stauferklinik Kinderklinik Schweinfurt Kinderklinik Schwerin Innere Medizin Schwerin Kinderklinik Schw€abisch Hall Diakonie Innere Medizin Schw€abisch Hall Diakonie Kinderklinik Siegen Kinderklinik Singen - Hegauklinik Kinderklinik Sinsheim Innere Spaichingen Innere St Augustin Kinderklinik St P€ olten Kinderklinik Stade Kinderklinik Stolberg Kinderklinik Stuttgart Bethesda Agaplesion Stuttgart Olgahospital Kinderklinik Suhl Kinderklinik Sylt Rehaklinik Tettnang Innere Medizin Timmendorfer Strand Traunstein Praxis Drs Voll & Belleville Trier Kinderklinik der Borrom€aerinnen Trostberg Innere Tu¨bingen Uni-Kinderklinik Ulm Endokrinologikum
Metabolic Safety of Growth Hormone in Type 1 Diabetes and Idiopathic Growth Hormone Deficiency
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Ulm Schwerpunktpraxis Bahnhofsplatz Ulm Uni Innere Medizin Ulm Uni-Kinderklinik Vechta Kinderklinik Viersen Kinderkrankenhaus St Nikolaus Villach Kinderklinik Villingen-Schwenningen SPP Villingen-Schwenningen SPP Degenhardt Villingen-Schwenningen Schwarzwald-Baar-Klinikum I Waiblingen Kinderklinik Waldshut Kinderpraxis Waldshut-Tiengen Kinderpraxis Biberbau Weiden Kinderklinik Weingarten Kinderarztpraxis Weisswasser Kreiskrankenhaus Wels Klinikum Wernberg-K€ oblitz SPP Wetzlar Schwerpunkt-Praxis Wetzlar/Braunfels Innere
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Vol. 163, No. 4 Wien 3 Med Hietzing Innere Wien Preyersches Kinderspital Wien Rudolfstiftung Wien SMZ Ost Donauspital Wien Uni Innere Med III Wien Uni-Kinderklinik Wien Wilhelminenspital 5 Med Abteilung Wiesbaden Horst-Schmidt-Kinderkliniken Wiesbaden Kinderklinik DKD Wilhelmshaven Reinhard-Nieter-Kinderklinik Wilhelmshaven St Willehad Innere Wittenberg Innere Medizin Wittenberg Kinderklinik Wolgast Innere Medizin Worms - Weierhof Worms Kinderklinik Wuppertal Kinderklinik
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Study design This study is an analysis of metabolic changes in 37 patients with childhood-onset GH deficiency and type 1 diabetes, documented in the Diabetes Patienten Verlaufsdocumentationsystem database. Main outcome measures were changes in hemoglobin A1c and daily insulin requirements during GH therapy in children with GH deficiency and type 1 diabetes compared with a large cohort of adolescents with type 1 diabetes. Results Thirty-seven patients with type 1 diabetes and a diagnosis of idiopathic GH deficiency after onset of diabetes were compared with 48 856 patients with type 1 diabetes. After adjustment for age, sex, duration of diabetes, and migration background, a significant difference in mean daily insulin requirement was seen between the 2 groups (1.0 IU/kg/day in subjects with GH deficiency and type 1 diabetes vs 0.85 IU/kg/day in controls; P < .01) and height-SDS ( 2.0 in subjects with GH deficiency and diabetes vs +0.03 in controls; P < .0001). There was no significant between-group difference in hemoglobin A1 concentration, however (8.1% 1.4% in patients with GH deficiency and type 1 diabetes vs 8.2% 1.7% in those with type 1 diabetes only; P > .05). Conclusion An increased daily insulin requirement should be considered in patients with type 1 diabetes treated with GH. With adequate adaptation of insulin dosage, metabolic control is not impaired during GH treatment. (J Pediatr 2013;163:1095-98).
W
ith the use of actual diagnostic criteria, the prevalence of growth hormone (GH) deficiency is estimated to be between 1:3500 and 1:8700. GH deficiency may present in the neonatal period if caused by genetic disorders, but the average age at diagnosis is 6-8 years.1 In most cases, GH deficiency represents a relative lack of GH secretion, leading to decreased growth velocity, retardation of bone maturation, and short stature (“idiopathic” GH deficiency). GH also plays an important role in glucose, lipid, and protein metabolism.2 Both GH deficiency and GH excess are associated with disturbances of carbohydrate metabolism. GH decreases glucose oxidation and glucose uptake by muscle and increases gluconeogenesis, resulting in “insulin antagonist” effects. The incidence of type 1 diabetes is increasing, especially in the younger age groups (age <5 years).3 Early diabetes onset and a mean hemoglobin A1c (HbA1c) value >7.0% (>53 mmol/mol) are negatively correlated with adult height.4 Thus, evaluation for short stature and diagnosis of GH deficiency in children with diabetes might become more frequent in the future. To date, there are no published data regarding the metabolic safety of GH treatment in children with GH deficiency and type 1 diabetes.
Methods The Diabetes Patienten Verlaufsdocumentationsystem (DPV) Initiative comprises the DPV software for prospective diabetes documentation, a benchmarking and quality control procedure, and a cumulative diabetes research database. More than 300 pediatric diabetes centers in Germany and Austria participate in the DPV. Anonymized data are transferred biannually. The data are verified, corrected at the originating center if necessary, and then entered into the dataDPV GH HbA1c H-SDS IGF
Diabetes Patienten Verlaufsdocumentationsystem Growth hormone Hemoglobin A1c Height-SDS Insulin-like growth factor
From the 1Division of Pediatric Endocrinology, Department of Pediatrics, Technical University Mu¨nchen, Munich, Germany; 2Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany; 3 Division of Pediatric Endocrinology, University of Bonn, Bonn, Germany; 4Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria; 5Department of Pediatrics, University of Essen, Essen, Germany; 6 € ln, Cologne, Department of Pediatrics, University of Ko Germany; 7Department of Pediatrics, Sana Klinikum 8 Berlin Lichtenberg, Berlin, Germany; and Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany *A list of centers that participated in the DPV Initiative of the German Working Group for Pediatric Diabetology and the German Bundesministerium fu¨r Bildung und Forschung Competence Net for Diabetes Mellitus is available at www.jpeds.com (Appendix). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.04.045
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base using the DPV software for standardized prospective longitudinal documentation of diabetes in children. Each center complies with local ethical and data management guidelines. All data for this study were collected during routine care procedures. Our study cohort comprised 50 children with type 1 diabetes and isolated idiopathic GH deficiency. In 13 children, the diagnosis of GH deficiency was established before the onset of type 1 diabetes, and these children were excluded from our analysis. In the other in 37 children, GH deficiency was diagnosed during follow-up of type 1 diabetes. In 21 children, complete longitudinal data on height-SDS (H-SDS), HbA1c, daily insulin requirement, mode of insulin therapy (ie, multiple daily injections or continuous subcutaneous insulin infusion), and body mass index SDS were available. The diagnosis of GH deficiency was based on clinical findings (including below-average growth velocity, retarded bone age, and low insulin-like growth factor [IGF]-1 and IGFbinding protein 3 levels) and confirmed by 2 different GH provocative tests (clonidine, arginine, or insulin tolerance test) or by measurement of overnight spontaneous GH secretion in all patients. GH deficiency was marked by fewer than 2 GH peaks and a mean GH concentration <3.2 ng/mL [0.149 nmol/L]. GH testing was performed in accordance with national guidelines for diagnosis of GH deficiency.5 The GH cutoff level for provocative testing was 8 ng/mL (0.372 nmol/L). Tests were performed after a 10-hour fasting phase. Sex steroid priming was provided with 0.12 mg of ethinyl estradiol in prepubertal girls aged >10 years and with 100 mg of testosterone in prepubertal boys aged >11 years. After diagnosis of GH deficiency, cerebral magnetic resonance imaging was performed to rule out hypothalamic or hypophyseal masses. Patients received a GH dose of 25-35 mg/kg body weight/day. Height was measured at the diabetes centers with the patients standing, using a wall-mounted stadiometer. H-SDS was calculated using contemporary national reference data from Kromeyer-Hauschild et al6 and Zellner et al.7 Glycemic control was assessed based on HbA1c level, measured using the methodology established at each individual center. To adjust for differences among participating laboratories, the HbA1c data were mathematically standardized according to the values from the Diabetes Control and Complications Trial,8 with a reference range of 4.05%-6.05% corresponding to 20.77-42.62 mmol/mol.
Vol. 163, No. 4 Daily insulin requirements were calculated as units per kg body weight per day (IU/kg/day) before GH treatment and at the time of evaluation at age <16 years. Only patients of chronological age <16 years were included in the analysis, given our focus on evaluating the metabolic effect of ongoing GH therapy. Statistical analyses (ie, descriptive data analysis, calculation of SDS, and regression analysis as a hierarchic linear regression model) were carried out using SAS version 9.2 (SAS Institute, Cary, North Carolina). A P value <.05 was considered to indicate statistical significance.
Results GH deficiency was diagnosed during follow-up of type 1 diabetes at a median age of 13.3 years (range, 11.7-14.4 years). The median patient age was 5.5 years at diabetes onset and 15.1 years at evaluation. The mean daily insulin dose was significantly higher in the patients with GH deficiency and type 1 diabetes compared with the 48 856 controls with type 1 diabetes alone (1.0 0.4 IU/kg/day vs 0.85 0.3 IU/kg/day; P < .05) (Table I). This difference persisted when the daily insulin dose was adjusted for age, sex, duration of diabetes, migration background, and mode of insulin therapy (ie, multiple daily injections or continuous subcutaneous insulin infusion). Mean and median HbA1c values did not differ significantly between the 2 groups (Table I). There was still no significant between-group difference after adjustment of HbA1c for age, sex, duration of diabetes, and migration background. Lipid profiles differed significantly in the 2 groups, with higher mean total cholesterol and low-density lipoprotein cholesterol levels in the patients with GH deficiency and type 1 diabetes (total cholesterol, 189.1 33.9 mg/dL vs 177.6 39.9 mg/dL; low-density lipoprotein cholesterol, 102.8 30.3 mg/dL vs 93.5 33.6 mg/dL; P < .05). The mean high-density lipoprotein cholesterol level was comparable in the 2 groups (65.2 mg/dL in the patients with GH deficiency and type 1 diabetes vs 60.9 mg/dL in those with type 1 diabetes only). Longitudinal data on H-SDS, daily insulin requirement, and HbA1c were available in a subset of 21 patients with GH deficiency and type 1 diabetes. In this subset, the median age was 5.2 years at the onset of diabetes and 12.4 years at the diagnosis of GH deficiency. Before the initiation of GH treatment, the median H-SDS was 2.3. The median daily insulin dosage
Table I. Auxologic and metabolic data at evaluation in patients with GH deficiency and type 1 diabetes compared with a large control group
Age at diagnosis of type 1 diabetes, years,mean SD Age at evaluation, years, mean SD HbA1c, %, mean SD H-SDS, mean SD Body mass index SDS, mean SD Daily insulin dose, IU/kg/day, mean SD
GH deficiency and type 1 diabetes (n = 37)
GH deficiency and type 1 diabetes with longitudinal data (n = 21)
Controls (n = 48 856)
6.2 3.6 13.2 3.1 8.1 1.4 2.0 1 0.2 1 1.0 0.4
6.3 4.0 13.3 2.9 8.2 1.4 2.0 0.9 0.1 1.0 1.1 0.4
8.1 4* 12.8 3.4 8.2 1.7 0.03 1.1* 0.5 0.9* 0.85 0.3*
*P < .05.
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October 2013 was 0.69 IU/kg/day, not statistically significantly different from that in the 48 856 controls without GH deficiency (Table II). After adjustment for age, sex, duration of diabetes, migration background, and mode of insulin therapy, there still were no significant between-group differences. There also was no significant difference in mean HbA1c before the initiation of GH treatment (7.6% 1.4% in patients with GH deficiency vs 8.0% 1.5% in controls; P > .05). The patients with GH deficiency and type 1 diabetes had a median age of 15.1 years at the time of reevaluation during GH therapy. Unexpectedly, H-SDS had increased only to 2.0 0.9 after 2 years of GH treatment, indicating reduced efficacy of GH therapy in the patients with diabetes (Table II). In a regression model, catch-up growth (ie, gain in H-SDS) was significantly influenced by HbA1c concentration (estimate, 0.22 0.08: P < .05), indicating that worse metabolic control inhibits catch-up growth in patients with GH deficiency and type 1 diabetes. During GH treatment, daily insulin requirement rose significantly, to 1.1 0.4 IU/kg/day (P < .0001). With this increased daily insulin dose, the patients with GH deficiency and type 1 diabetes were able to achieve similar metabolic control as those without GH deficiency (HbA1c, 8.2% 1.4% vs 8.2% 1.7%; P > .05). Moreover, the frequency of hypoglycemia did not differ between the 2 groups (P > .05).
Discussion We have shown that although GH treatment leads to a significantly higher insulin demand, with adequate adjustment of insulin doses, metabolic control does not worsen during GH treatment in patients with type 1 diabetes. Thus, once GH deficiency is diagnosed in a child with diabetes, the impact of GH treatment on metabolic changes must be considered. Existing type 1 diabetes is not a contraindication for GH treatment in children with GH deficiency. Moreover, onset of type 1 diabetes is not a reason to discontinue GH treatment in a child with GH deficiency.7 Of note, our patients with type 1 diabetes were older at the time of diagnosis of GH deficiency compared with the average age of diagnosis of GH deficiency in children without diabetes. Potentially, physicians are more hesitant to perform GH stimulation testing
in short children with type 1 diabetes, attributing their poor growth to poor diabetes control. As a result, optimal metabolic control is generally attempted in children with diabetes with growth failure without testing for other etiologies. Unexpectedly, we found reduced efficacy of GH treatment in children with GH deficiency and type 1 diabetes, with a median height gain of only 0.3 SDS over a 2-year course of treatment. Possible explanations for this finding might be the late diagnosis and start of GH treatment, inadequate GH dosage out of concern for metabolic side effects, or hepatic GH resistance in patients with diabetes.9-11 Unfortunately, GH doses are not documented for all patients in the DPV database, and thus these data were not available for analysis. It might be interesting to study the efficacy of GH treatment in patients with type 1 diabetes by analyzing data from the established GH observational studies, which focus more on GH dosage and IGF-1 concentrations. A significant influence of metabolic diabetes control (based on HbA1c value) on catch-up growth could be demonstrated in a regression model using our data. To date, only isolated patients with type 1 diabetes and treatment of GH deficiency have been reported in the literature. In a case report, Quintos et al12 described a boy with autoimmune polyglandular syndrome type 3 (type 1 diabetes and autoimmune thyroiditis) and GH deficiency diagnosed at age 8.5 years. The boy was treated with GH until he reached nearadult height, which was close to his midparental target height. This case report indicated that GH treatment can be effective in single patients with type 1 diabetes, but provided no data on the metabolic changes related to GH treatment in this patient. In a second case report, Pun and Chandurkar13 described a girl with autoimmune polyglandular syndrome type 1 with juvenile idiopathic arthritis, hypoparathyroidism, type 1 diabetes, Addison’s disease, chronic mucocutaneous candidiasis, GH deficiency, ovarian failure, alopecia, and pernicious anemia. This patient was treated with GH, but treatment was not initiated until a chronological age of 16 years (bone age, 8 years). GH treatment was not very effective in this patient, possibly related to the late start of treatment and particularly to the cooccurrence of ovarian failure and Addison disease, diagnosed at age 15 and 12 years, respectively. In contrast to the foregoing case reports, 2 large studies reported an increased incidence of type 2 diabetes in children
Table II. Longitudinal data after 2 years in 21 patients with GH deficiency and type 1 diabetes during GH treatment
H-SDS, median H-SDS, mean SD Body mass index SDS, median Body mass index SDS, mean SD HbA1c, %, median HbA1c, %, mean SD Daily insulin dose, IU/kg/day, median Daily insulin dose, IU/kg/day, mean SD
GH deficiency and type 1 diabetes with longitudinal data (n = 21) before initiation of GH treatment 2.3 2.1 0.8 0.3 0.1 1.1 7.3 7.6 1.4 0.69 0.74 0.3
DPV controls (n = 48 856)
GH deficiency and type 1 diabetes with longitudinal data (n = 21) at reevaluation during GH treatment
DPV controls (n = 48 856)
0.05 0.05 1.1* 0.4 0.4 0.9* 7.7 8.0 1.5* 0.78 0.8 0.3
2 2.0 0.9 0.1 0.1 1.0 8.1 8.2 1.4 1.05 1.1 0.4
0.04 0.03 1.1* 0.5 0.5 0.9* 7.9 8.2 1.7 0.83 0.85 0.3*
*P < .05.
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and adolescents with type 2 diabetes and also in adults treated with GH.14,15 Child et al15 compared the incidence of type 1 and type 2 diabetes in patients aged <20 years in the Genetics and Neuroendocrinology of Short Stature International Study observational research program with the US SEARCH for Diabetes in Youth study and found an increased incidence was found for type 2 diabetes, but not for type 1 diabetes, in children treated with GH. Based on these findings, monitoring of glucose metabolism is recommended during GH treatment, especially in patients with preexisting risk factors, such as obesity. Cutfield et al16 reported that GH treatment did not affect the incidence of type 1 diabetes in any age group studied. An increased daily insulin requirement must be considered in patients with type 1 diabetes receiving GH treatment. With adequate adaptation of insulin dosage, metabolic control does not worsen during GH treatment; thus, GH treatment in children with type 1 diabetes is feasible. The question of reduced efficacy of GH treatment in children with type 1 diabetes should be investigated prospectively in clinical studies and analyzed in established GH company observational databases. n Submitted for publication Jan 8, 2013; last revision received Mar 11, 2013; accepted Apr 23, 2013. Reprint requests: Dr med Walter Bonfig, Division of Pediatric Endocrinology, €t Mu¨nchen, Ko € lner Platz 1, Department of Pediatrics, Technische Universita 80804 Mu¨nchen, Germany. E-mail: [email protected]
References 1. Ranke M, Reiter EO, Price DA. Idiopathic growth hormone deficiency in KIGS: selected aspects. In: Ranke M, Price DA, Reiter EO, eds. Growth hormone therapy in pediatrics: 20 years of KIGS. Basel, Switzerland: Karger; 2007. p. 116-35. 2. Moller N, Jorgensen JO. Effects of growth hormone on glucose, lipid and protein metabolism in human subjects. Endocr Rev 2009;30:152-77. 3. Ehehalt S, Dietz K, Willasch AM, Neu A , DIARY-Group Baden-Wuerttemberg. Prediction model for the incidence and prevalence of type 1 diabetes in childhood and adolescence: evidence for a cohort-dependent increase within the next two decades in Germany. Pediatr Diabetes 2007;12:15-20.
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Vol. 163, No. 4 4. Bonfig W, Kapellen T, Dost A, Fritsch M, Rohrer T, Wolf J, et al. Growth in children with type 1 diabetes. J Pediatr 2012;160:900-3. 5. Binder G. Recommendations for actions according to the guideline growth hormone deficiency in children and adolescents. Monatsschr Kinderheilkd 2012;160:589-90 (in German). 6. Kromeyer-Hauschild K, Wabitsch M, Kunze D, Geller F, Geiß HC, Hesse V, et al. Percentiles for body-mass-index for children and adolescents using multiple German cohorts. Monatsschr Kinderheilk 2001;149: 807-18 (in German). 7. Zellner K, Jaeger U, Kromeyer-Hauschild K. Height, weight, and BMI of schoolchildren in Jena, Germany: are the secular changes leveling off? Econ Hum Biol 2004;2:281-94. 8. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86. 9. Chiarelli F, Giannini C, Mohn A. Growth, growth factors and diabetes. Eur J Endocrinol 2004;151:109-17. 10. Mercado M, Baumann G. Characteristics of the somatotropic axis in insulin-dependent diabetes mellitus. Arch Med Res 1995;26:101-9. 11. Holl RW, Siegler B, Scherbaum WA, Heinze E. The serum growth hormone-binding protein is reduced in young patients with insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1993; 76:165-7. 12. Quintos JB, Grover M, Boney CM, Salas M. Autoimmune polyglandular syndrome type 3 and growth hormone deficiency. Pediatr Diabetes 2010; 11:438-42. 13. Pun T, Chandurkar V. Growth hormone deficiency, short stature, and juvenile rheumatoid arthritis in a patient with autoimmune polyglandular syndrome type 1: case report and brief review of the literature. ISRN Endocrinol 2011;2011:462759. 14. Luger A, Mattsson AF, Koitowska-Hagstrom M, Thunander M, Goth M, Verhelst J, et al. Incidence of diabetes mellitus and evolution of glucose parameters in growth hormone–deficient subjects during growth hormone replacement therapy: a long-term observational study. Diabetes Care 2012;35:57-62. 15. Child CJ, Zimmermann AG, Scott RS, Cutler GB, Battelino T, Blum WF. GeNeSIS International Advisory Board. Prevalence and incidence of diabetes mellitus in GH-treated children and adolescents: analysis from the GeNeSIS observational research program. J Clin Endocrinol Metab 2011; 96:1025-34. 16. Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB, et al. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth hormone treatment. Lancet 2000;355:610-3.
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Appendix We thank the following centers for contributing their data to this study and participating in the DPV Initiative of the German Working Group for Pediatric Diabetology and the German BMBP Competence Net for Diabetes Mellitus: Aachen-Innere RWTH Aachen-Uni-Kinderklinik RWTH Aalen Kinderklinik Ahlen St Franziskus Kinderklinik Alt€ otting Zentrum Inn-Salzach Alt€ otting-Burghausen Innere Medizin Amstetten Klinikum Mostviertel Kinderklinik Arnsberg-Hu¨sten Karolinenhosp. Kinderabteilung Asbach Kamillus-Klinik Innere Aue Helios Kinderklink Augsburg Innere Augsburg Kinderklinik Zentralklinikum Aurich Kinderklinik Bad Aibling Internist Praxis Bad Driburg/Bad Hermannsborn Innere Bad Hersfeld Innere Bad Hersfeld Kinderklinik Bad Kreuznach–St Marienw€ orth-Innere Bad Krozingen Klinik Lazariterhof Park-Klinikum Bad K€ osen Kinder-Rehaklinik Bad Lauterberg Diabeteszentrum Innere Bad Mergentheim-Diabetesfachklinik Bad Mergentheim-Gemeinschaftspraxis DM-dorf Alth Bad Oeynhausen Herz und Diabeteszentrum NRW Bad Orb Spessart Klinik Bad Reichenhall Kreisklinik Innere Med Bad Salzungen Kinderklinik Bad S€ackingen Hochrheinklinik Innere Bad Waldsee Kinderarztpraxis Bautzen Oberlausitz KK Bayreuth Innere Medizin Berchtesgaden CJD Berchtesgaden MVZ Innere Med Berlin DRK-Kliniken Berlin Endokrinologikum Berlin Evang Krankenhaus K€ onigin Elisabeth Berlin Kinderklinik Lindenhof, Sana Klinikum Licht Berlin Klinik St Hedwig Innere Berlin Oskar Zieten Krankenhaus Innere Berlin Schlosspark-Klinik Innere Berlin St Josephskrankenhaus Innere Berlin Virchow-Kinderklinik Berlin Vivantes Hellersdorf Innere Bielefeld Kinderklinik Gilead Bocholt Kinderklinik Bochum Universit€atskinderklinik St Josef Bonn Uni-Kinderklinik Bottrop Kinderklinik Bottrop Knappschaftskrankenhaus Innere Braunschweig Kinderarztpraxis
Bremen-Kinderklinik Nord Bremen-Mitte Innere Bremen Kinderklinik St Ju¨rgenstrasse Bremen-Epidemiologieprojekt Bremerhaven Kinderklinik B€ oblingen Kinderklinik Celle Kinderklinik Chemnitz Kinderklinik Chemnitz-Hartmannsdorf Innere Medizin-DIAKOMED-1 Coesfeld Kinderklinik Coesfeld/Du¨lmen Innere Med Darmstadt Innere Medizin Darmstadt Kinderklinik Prinz Margaret Datteln Vestische Kinderklinik Deggendorf Kinderarztpraxis Deggendorf Kinderklinik Deggendorf Medizinische Klinik II Delmenhorst Kinderklinik Dessau Kinderklinik Detmold Kinderklinik Dornbirn Kinderklinik Dortmund Kinderklinik Dortmund Knappschaftskrankenhaus Innere Dortmund Medizinische Kliniken Nord Dortmund-Hombruch, Marienhospital Dortmund-St Josefshospital Innere Dresden Neustadt Kinderklinik Dresden Uni-Kinderklinik Duisburg Evang und Johanniter Krhs, Innere Duisburg Kinderklinik Duisburg Malteser St Anna Innere Duisburg Malteser St Johannes Duisburg-Huckingen Du¨ren-Birkesdorf Kinderklinik Du¨sseldorf Uni-Kinderklinik Eberswalde Klinikum Barnim Werner Forßmann - Inner Erfurt Kinderklinik Erlangen Uni Innere Medizin Erlangen Uni-Kinderklinik Essen Diabetes-Schwerpunktpraxis Dr Best Essen Elisabeth Kinderklinik Essen Uni-Kinderklinik Esslingen Klinik fu¨r Kinder und Jugendliche Eutin Kinderklinik Eutin St-Elisabeth Innere Feldkirch Kinderklinik Forchheim Diabeteszentrum SPP Frankenthal Kinderarztpraxis Frankfurt Diabeteszentrum Rhein-Main-Erwachsenendi Frankfurt Uni-Kinderklinik Frankfurt Uni-Klinik Innere Freiburg St Josef Kinderklinik Freiburg Uni Innere Freiburg Uni-Kinderklinik Friedberg Innere Klinik Friedrichshafen Kinderklinik Fulda Innere Medizin
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Fulda Kinderklinik Fu¨rth Kinderklinik Gaissach Fachklinik der Deutschen Rentenversicheru Garmisch-Partenkirchen Kinderklinik Geislingen Klinik Helfenstein Innere Gelnhausen Innere Gelnhausen Kinderklinik Gelsenkirchen Kinderklinik Marienhospital Gera Kinderklinik Gießen Ev Krankenhaus Mittelhessen Gießen Uni-Kinderklinik Graz Universit€ats-Kinderklinik G€ oppingen Innere Medizin G€ oppingen Kinderklinik am Eichert G€ orlitz St€adtische Kinderklinik G€ ottingen Uni-Kinderklinik Gu¨strow Innere Hachenburg Kinderpraxis Hagen Kinderklinik Halle Uni-Kinderklinik Halle-D€ olau St€adtische Kinderklinik Hamburg Altonaer Kinderklinik Hamburg Endokrinologikum Hamburg Kinderklinik Wilhelmstift Hamburg-Nord Kinder-MVZ Hameln Kinderklinik Hamm Kinderklinik Hanau Kinderklinik Hanau St Vincenz - Innere Hannover Henriettenstift - Innere Hannover Kinderklinik MHH Hannover Kinderklinik auf der Bult Haren Kinderarztpraxis Heide Kinderklinik Heidelberg Uni-Kinderklinik Heidelberg Uniklinik Innere Heidenheim Arztpraxis Allgemeinmed Heidenheim Kinderklinik Heilbronn Innere Klinik Heilbronn Kinderklinik Herdecke Kinderklinik Herford Innere Med I Herford Kinderarztpraxis Herford Klinikum Kinder & Jugendliche Heringsdorf Inselklinik Hermeskeil Kinderpraxis Herne Evan Krankenhaus Innere Herten St Elisabeth Innere Medizin Herzberg Kreiskrankenhaus Innere Hildesheim Innere Hildesheim Kinderarztpraxis Hildesheim Klinikum Kinderklinik Hinrichsegen-Bruckmu¨hl Diabetikerjugendhaus Hof Kinderklinik Homburg Uni-Kinderklinik Saarland Idar Oberstein Innere Ingolstadt Klinikum Innere 1098.e2
Vol. 163, No. 4 Innsbruck Universit€atskinderklinik Iserlohn Innere Medizin Itzehoe Kinderklinik Jena Uni-Kinderklinik Kaiserslautern Kinderarztpraxis Dr Geist Kaiserslautern-Westpfalzklinikum Kinderklinik Kamen Hellmig-Krankenhaus Karlsburg Klinik fu¨r Diabetes & Stoffwechsel Karlsruhe St€adtische Kinderklinik Kassel Klinikum Kinder- und Jugendmedizin Kassel Rot-Kreuz-Krankenhaus Innere Kassel St€adtische Kinderklinik Kaufbeuren Innere Medizin Kempen Heilig Geist - Innere Kiel St€adtische Kinderklinik Kiel Universit€ats-Kinderklinik Kirchen DRK Klinikum Westerwald, Kinderklinik Kirchheim-Nu¨rtingen Innere Kleve Innere Medizin Koblenz Kemperhof 1 Med Klinik Koblenz Kinderklinik Kemperhof Konstanz Innere Klinik Konstanz Kinderklinik Krefeld Innere Klinik Krefeld Kinderklinik Krefeld-Uerdingen St Josef Innere Kreischa-Zscheckwitz, Klinik Bavaria K€ oln Kinderklinik Amsterdamerstrasse K€ oln Uni-Kinderklinik Landau/Annweiler Innere Landshut Kinderklink Lappersdorf Kinderarztpraxis Leipzig Uni-Kinderklinik Leoben LKH Kinderklinik Leverkusen Kinderklinik Lienz BKH Kinderklinik Limburg Innere Medizin Lindenfels Luisenkrankenhaus Innere Lingen Kinderklinik St Bonifatius Linz Krankenhaus Barmherzige Schwestern Kardiologi Linz Krankenhaus der Barmherzigen Schwestern Inter Linz Landes-Kinderklinik Lippstadt Evangelische Kinderklinik Ludwigsburg Innere Medizin Ludwigsburg Kinderklinik Ludwigshafen Kinderklinik St Anna-Stift Ludwigshafen diabetol SPP Lu¨beck Uni-Kinderklinik Lu¨beck Uni-Klinik Innere Medizin Lu¨denscheid M€arkische Kliniken - Kinder & Jugendme Lu¨nen Klinik am Park Magdeburg St€adtisches Klinikum Innere Magdeburg Uni-Kinderklinik Mainz Uni-Kinderklinik Mannheim Uni-Kinderklinik Mannheim Uniklinik Innere Medizin Marburg - UKGM Endokrinologie & Diabetes Bonfig et al
ORIGINAL ARTICLES
October 2013 Marburg Uni-Kinderklinik Marienhaus Klinikum St Elisabeth Marktredwitz Innere Medizin Marpingen-SPP Mechernich Kinderklinik Memmingen Kinderklinik Merzig Kinderklinik Minden Kinderklinik Moers - St Josefskrankenhaus Innere Moers Kinderklinik Murnau am Staffelsee - SPP Groß Mutterstadt Kinderarztpraxis M€ odling Kinderklinik M€ olln Reha-Klinik Hellbachtal M€ onchengladbach Kinderklinik Rheydt Elisabethkrank Mu¨hlacker Enzkreiskliniken Innere Mu¨hldorf Gemeinschaftspraxis Mu¨nchen 3 Orden Kinderklinik Mu¨nchen Diabetes-Zentrum Su¨d Mu¨nchen Kinderarztpraxis diabet SPP Mu¨nchen Schwerpunktpraxis Evers Mu¨nchen von Haunersche Kinderklinik Mu¨nchen-Gauting Kinderarztzentrum Mu¨nchen-Harlaching Kinderklinik Mu¨nchen-Schwabing Kinderklinik Mu¨nster Herz Jesu Innere Mu¨nster St Franziskus Kinderklinik Mu¨nster Uni-Kinderklinik Mu¨nster p€adiat Schwerpunktpraxis Ziegler Nagold Kreiskrankenhaus Innere Nauen Havellandklinik Neuburg Kinderklinik Neunkirchen Innere Medizin Neunkirchen Marienhausklinik Kohlhof Kinderklinik Neuss Lukaskrankenhaus Kinderklinik Neuwied Kinderklinik Elisabeth Nidda Bad Salzhausen Klinik Rabenstein/Innere-1 Re Nidda Bad Salzhausen Klinik Rabenstein/Innere-2 Re Nu¨rnberg Cnopfsche Kinderklinik Nu¨rnberg Zentrum f Neugeb, Kinder & Jugendl Oberhausen Innere Oberhausen Kinderklinik Oberhausen Kinderpraxis Oberhausen StClemens Hospitale Sterkrade Offenbach/Main Innere Medizin Offenbach/Main Kinderklinik Offenburg Kinderklinik Oldenburg Kinderklinik Oldenburg Schwerpunktpraxis Oschersleben MEDIGREIF B€ ordekrankenhaus Osnabru¨ck Christliches Kinderhospital Osterkappeln Innere Ottobeuren Kreiskrankenhaus Oy-Mittelberg Hochgebirgsklinik Kinder-Reha Paderborn St Vincenz Kinderklinik Papenburg Marienkrankenhaus Kinderklinik Passau Kinderarztpraxis
Passau Kinderklinik Pforzheim Kinderklinik Pfullendorf Innere Medizin Pirmasens St€adtisches Krankenhaus Innere Plauen Vogtlandklinikum Prenzlau Krankenhaus Innere Rastatt Gemeinschaftspraxis Rastatt Kreiskrankenhaus Innere Ravensburg Kinderklink St Nikolaus Recklinghausen Dialysezentrum Innere Regensburg Kinderklinik St Hedwig Remscheid Kinderklinik Rendsburg Kinderklinik Reutlingen Kinderarztpraxis Reutlingen Kinderklinik Reutlingen Klinikum Steinenberg Innere Rheine Mathiasspital Kinderklinik Rosenheim Innere Medizin Rosenheim Kinderklinik Rosenheim Schwerpunktpraxis Rostock Uni-Kinderklinik Rostock Universit€at Innere Medizin Rotenburg/Wu¨mme Kinderklinik Ru¨sselsheim Kinderklinik Saaldorf-Surheim Diabetespraxis Saalfeld Thu¨ringenklinik Kinderklinik Saarbru¨cken Kinderklinik Winterberg Saarbru¨cken Kinderklinik Winterberg 2 Saarlouis Kinderklinik Salzburg Kinderklinik Scheidegg Prinzregent Luitpold Scheidegg Reha-Kinderklinik Maximilian Schw Gmu¨nd Stauferklinik Kinderklinik Schweinfurt Kinderklinik Schwerin Innere Medizin Schwerin Kinderklinik Schw€abisch Hall Diakonie Innere Medizin Schw€abisch Hall Diakonie Kinderklinik Siegen Kinderklinik Singen - Hegauklinik Kinderklinik Sinsheim Innere Spaichingen Innere St Augustin Kinderklinik St P€ olten Kinderklinik Stade Kinderklinik Stolberg Kinderklinik Stuttgart Bethesda Agaplesion Stuttgart Olgahospital Kinderklinik Suhl Kinderklinik Sylt Rehaklinik Tettnang Innere Medizin Timmendorfer Strand Traunstein Praxis Drs Voll & Belleville Trier Kinderklinik der Borrom€aerinnen Trostberg Innere Tu¨bingen Uni-Kinderklinik Ulm Endokrinologikum
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Ulm Schwerpunktpraxis Bahnhofsplatz Ulm Uni Innere Medizin Ulm Uni-Kinderklinik Vechta Kinderklinik Viersen Kinderkrankenhaus St Nikolaus Villach Kinderklinik Villingen-Schwenningen SPP Villingen-Schwenningen SPP Degenhardt Villingen-Schwenningen Schwarzwald-Baar-Klinikum I Waiblingen Kinderklinik Waldshut Kinderpraxis Waldshut-Tiengen Kinderpraxis Biberbau Weiden Kinderklinik Weingarten Kinderarztpraxis Weisswasser Kreiskrankenhaus Wels Klinikum Wernberg-K€ oblitz SPP Wetzlar Schwerpunkt-Praxis Wetzlar/Braunfels Innere
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Vol. 163, No. 4 Wien 3 Med Hietzing Innere Wien Preyersches Kinderspital Wien Rudolfstiftung Wien SMZ Ost Donauspital Wien Uni Innere Med III Wien Uni-Kinderklinik Wien Wilhelminenspital 5 Med Abteilung Wiesbaden Horst-Schmidt-Kinderkliniken Wiesbaden Kinderklinik DKD Wilhelmshaven Reinhard-Nieter-Kinderklinik Wilhelmshaven St Willehad Innere Wittenberg Innere Medizin Wittenberg Kinderklinik Wolgast Innere Medizin Worms - Weierhof Worms Kinderklinik Wuppertal Kinderklinik
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