Phenylketonuria (PKU) is a genetic metabolic disorder caused by deficient conversion of phenylalanine (Phe) to tyrosine by the enzyme Phe hydroxylase (PAH), resulting in high blood levels of Phe. Milder forms of hyperphenylalaninemia (HPA) can be caused by PAH deficiency with residual enzyme activity. Atypical PKU is rare and arises from a lack of the enzymatic cofactor tetrahydrobiopterin or other rare conditions, such as PCBD1 mutations. High concentrations of Phe are particularly associated with severe neurological complications (1,2). Due to the need for a protein-restricted diet, with a reduction in Phe intake and substitution of other amino acids, an association between PKU and obesity has been discussed (3). Furthermore, recessive mutations in PCBD1 can cause diabetes, and this mutation has also been identified in individuals with HPA or PKU (2).

Therefore, this study aimed to investigate the presence of HPA or PKU among individuals with diabetes and, second, to analyze the potential influence on diabetes treatment, glucose control, and other metabolic characteristics.

Cross-sectional data from the Diabetes Patient Follow-up (DPV) registry were analyzed (https://buster.zibmt.uni-ulm.de/projekte/DPV/). According to the ICD-10 codes and specific free-text strings recorded in the registry, we defined the following groups: classic PKU, HPA, atypical PKU, and HPA not further classified. Analysis of anonymized routine data within the DPV initiative has been approved by the Ethics Committee of the University of Ulm, Ulm, Germany (no. 314/21).

Up to June 2024, 170,827 people with diabetes of any type, born after 1970 and living in Germany, were documented in the DPV registry. Thirty-four individuals were coded with any type of HPA: 12 with classic PKU, 18 with HPA, 2 with atypical PKU, and 2 not further classified. Of these 34 individuals, 29 were coded with type 1 diabetes, 2 with type 2 diabetes, 2 with gestational diabetes, and 1 with specific types of diabetes due to other causes. Because of the small number of individuals with type 2 diabetes or other types of diabetes and concomitant HPA or PKU, we included only patients with type 1 diabetes (n = 114,117) in further analysis. The observed frequency of HPA overall (1:3,935; absolute n = 29) and PKU in particular (1:9,510; absolute n = 12) among individuals with type 1 diabetes are comparable with the previously estimated prevalence of HPA (1:5,189) and PKU (1:10,041) in Germany (both P > 0.05). A propensity score–matched cohort (nearest-neighbors matching, 2:1 ratio) with 58 individuals with type 1 diabetes without HPA or PKU was built to compare clinical characteristics. Daily insulin dose, BMI standard deviation score, and HbA1c were comparable. Furthermore, no differences were found in lipid profiles, blood pressure, onset of puberty, microalbuminuria, diabetic ketoacidosis, and severe hypoglycemia (Table 1), and this was true for comparisons of individuals with PKU in particular (n = 12) and all individuals with any type of HPA (n = 14) (data not shown).

Table 1

Comparison of characteristics of individuals with type 1 diabetes with and without HPA

ParameterIndividuals with type 1 diabetesP value
With any type of HPAnWithout HPAn
Age at diabetes diagnosis (years) 9.45 (4.65; 12.09) 29 9.48 (4.79; 12.22) 58 0.97 
BMI-SDS (AGA) 0.60 (−0.20; 1.43) 28 0.55 (−0.08; 1.26) 57 0.54 
HbA1c (MOM-DCCT) (%) 7.47 (6.73; 9.26) 28 7.39 (6.55; 8.28) 57 0.57 
Daily insulin dose (IU/kg/day) 0.80 (0.58; 1.18) 28 0.73 (0.58; 0.90) 57 0.19 
Cholesterol (mg/dL)      
 Total 162.00 (137.00; 193.00) 25 174.00 (145.47; 198.00) 44 0.26 
 HDL 53.90 (48.20; 64.55) 20 57.00 (45.51; 63.45) 40 0.86 
 LDL 85.50 (68.30; 107.50) 20 103.00 (78.00; 126.00) 39 0.16 
Triglyceride (mg/dL) 102.00 (86.00; 134.00) 21 83.50 (60.00; 131.00) 43 0.10 
Blood pressure (mmHg)      
 Systolic 119.50 (110.75; 128.00) 28 120.00 (113.00; 131.00) 57 0.56 
 Diastolic 68.50 (64.75; 75.00) 28 72.00 (67.00; 77.00) 57 0.07 
Insulin pump (%) 51.72 29 46.55 58 0.65 
Hypertension (%) 13.79 29 18.97 58 0.55 
Dyslipidemia (%) 24.14 29 24.14 58 1.00 
Diabetic ketoacidosis (%) 3.45 29 0.00 58 0.15 
Severe hypoglycemia (%) 3.45 29 12.07 58 0.19 
Microalbuminuria (%) 5.88 17 5.56 36 0.96 
Prepuberty (%) 24.14 29 17.24 58 0.44 
Puberty (%) 20.69 29 25.86 58 0.60 
Postpuberty (%) 44.83 29 51.72 58 0.54 
GISD (%)      
 20% least deprived 31.03 29 5.17 58 <0.01 
 21–40% 20.69 29 20.69 58 1.00 
 41–60% 10.34 29 31.03 58 0.03 
 61–80% 17.24 29 13.79 58 0.67 
 20% most deprived 20.69 29 22.41 58 0.85 
ParameterIndividuals with type 1 diabetesP value
With any type of HPAnWithout HPAn
Age at diabetes diagnosis (years) 9.45 (4.65; 12.09) 29 9.48 (4.79; 12.22) 58 0.97 
BMI-SDS (AGA) 0.60 (−0.20; 1.43) 28 0.55 (−0.08; 1.26) 57 0.54 
HbA1c (MOM-DCCT) (%) 7.47 (6.73; 9.26) 28 7.39 (6.55; 8.28) 57 0.57 
Daily insulin dose (IU/kg/day) 0.80 (0.58; 1.18) 28 0.73 (0.58; 0.90) 57 0.19 
Cholesterol (mg/dL)      
 Total 162.00 (137.00; 193.00) 25 174.00 (145.47; 198.00) 44 0.26 
 HDL 53.90 (48.20; 64.55) 20 57.00 (45.51; 63.45) 40 0.86 
 LDL 85.50 (68.30; 107.50) 20 103.00 (78.00; 126.00) 39 0.16 
Triglyceride (mg/dL) 102.00 (86.00; 134.00) 21 83.50 (60.00; 131.00) 43 0.10 
Blood pressure (mmHg)      
 Systolic 119.50 (110.75; 128.00) 28 120.00 (113.00; 131.00) 57 0.56 
 Diastolic 68.50 (64.75; 75.00) 28 72.00 (67.00; 77.00) 57 0.07 
Insulin pump (%) 51.72 29 46.55 58 0.65 
Hypertension (%) 13.79 29 18.97 58 0.55 
Dyslipidemia (%) 24.14 29 24.14 58 1.00 
Diabetic ketoacidosis (%) 3.45 29 0.00 58 0.15 
Severe hypoglycemia (%) 3.45 29 12.07 58 0.19 
Microalbuminuria (%) 5.88 17 5.56 36 0.96 
Prepuberty (%) 24.14 29 17.24 58 0.44 
Puberty (%) 20.69 29 25.86 58 0.60 
Postpuberty (%) 44.83 29 51.72 58 0.54 
GISD (%)      
 20% least deprived 31.03 29 5.17 58 <0.01 
 21–40% 20.69 29 20.69 58 1.00 
 41–60% 10.34 29 31.03 58 0.03 
 61–80% 17.24 29 13.79 58 0.67 
 20% most deprived 20.69 29 22.41 58 0.85 

Characteristics of study cohort after matching are shown. Matching was performed for age, sex, migration background, diabetes duration, and current year of treatment (propensity score method: greedy-matching algorithm). The limit of significance of two-sided tests was set at P < 0.05. Values are presented as median with lower (Q1) and upper (Q3) quartiles or as proportions. BMI-SDS, BMI SD score; AGA, German Working Group on Obesity in Children and Adolescents; GISD, German Index of Socioeconomic Deprivation. MOM-DCCT, multiple of the mean transformation method–Diabetes Control and Complications Trial.

This is the first study to evaluate the presence of HPA or PKU in a cohort of 170,827 individuals with diabetes and to examine a possible influence of HPA on glycemic control and metabolic characteristics. The frequencies of HPA overall and classic PKU among individuals with type 1 diabetes are comparable with the previously estimated prevalences of HPA and PKU for Germany.

However, based on genetic factors (1,2), gut microbiome (4,5), and dietary changes (3), a possible association between PKU and diabetes in general used to be assumed. Some hypotheses state that maturation of the gut microbiome plays an important role in the development of the immune system. Interestingly, the microbiome of individuals with PKU showed lower levels of Faecalibacterium that produce short-chain fatty acids, like in type 1 diabetes, leading to reduced production of short-chain fatty acids overall. These bacteria possess anti-inflammatory properties, and their reduction could promote the occurrence of autoimmune diseases such as type 1 diabetes (5). Furthermore, it has been shown that recessive mutations in PCBD1 can cause an early-onset monogenic diabetes. In individuals with HPA or PKU, mutations with PCBD1 have also been identified. PCBD1 also seems to enhance HNF1A activity and could influence the pancreatic progenitor pool during embryogenesis, leading to reduced pancreatic β-cell mass (2). In addition, dietary modifications such as reduced protein intake and different amino acid profiles could not only influence the risk of islet autoimmunity but also represent a higher risk for overweight and type 2 diabetes (3).

However, despite these previously reported possible associations between HPA and PKU and different types of diabetes, this analysis of a diabetes registry with a nationwide coverage of >90% of pediatric individuals with diabetes has shown that HPA and PKU is not more common in individuals with type 1 diabetes than in the general population. Moreover, HPA and PKU seem to have no influence on diabetes management and other metabolic parameters.

Acknowledgments. We thank all participating centers of the DPV (all centers are listed in the Appendix below). Special thanks goes to A. Hungele and R. Ranz for support and the development of the DPV documentation software.

Funding. This study was supported by the German Federal Ministry for Education and Research within the German Center for Diabetes Research (DZD) (82DZD14A02). Further financial support was received from the German Robert Koch Institute (RKI) and the German Diabetes Association (DDG). Sponsors were not involved in data acquisition or analysis.

Duality of Interest. S.M. states that she has received travel expense support and honoraria for speaking and consulting activities from Biomarin, Lilly Germany, Novo Nordisk, and Sanofi. S.M.S. is an employee of Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. S.M., R.W.H., and N.P. designed the analysis. S.M., J.H., S.K., R.S.D., K.O.-S., M.P., S.B.-D.P., and S.M.S. collected the data. S.S. performed the statistical analyses. S.M., S.S., R.W.H., S.M.S., and N.P. interpreted data. S.M. researched literature and wrote the manuscript. J.H., S.S., S.K., R.S.D., K.O.-S., M.P., S.B.-D.P., N.P., R.W.H., S.M.S., and S.M. reviewed the manuscript. N.P. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Handling Editors. The journal editors responsible for overseeing the review of the manuscript were John B. Buse and Adrian Vella.

APPENDIX All participating DPV centers are Aachen Uni-Kinderklinik RWTH, Augsburg Uni-Kinderklinik, Bad Hersfeld Kinderklinik, Bad Oeynhausen Herz-und Diabeteszentrum NRW, Berlin DRK-Kliniken Pädiatrie, Bochum Universitätskinderklinik St. Josef, Bonn Uni-Kinderklinik, Bottrop Kinderklinik, Chemnitz Kinderklinik, Coburg Kinderklinik, Coesfeld Kinderklinik, Dresden Uni-Kinderklinik, Duisburg Evang. und Johanniter Krks Innere, Düsseldorf Uni-Kinderklinik, Erlangen Uni-Kinderklinik, Essen Kinderarztpraxis, Frankfurt-Sachsenhausen Innere, Fürth Kinderklinik, Geislingen Klinik Helfenstein Innere, Gelsenkirchen Kinderklinik Marienhospital, Gießen Uni-Kinderklinik, Göppingen Kinderklinik am Eichert, Hamburg Kinderklinik Wilhelmstift, Hameln Kinderklinik, Hanau Kinderklinik, Hanau diabetol. Schwerpunktpraxis, Hannover Kinderklinik MHH, Heide Kinderklinik, Heidelberg Uni-Kinderklinik, Heidenheim Kinderklinik, Heringsdorf Inselklinik, Hildesheim Bernward Krks Kinderheilkunde, Itzehoe Kinderklinik, Karlsburg Klinik für Diabetes & Stoffwechsel, Karlsruhe Städtische Kinderklinik, Kassel Städtische Kinderklinik, Konstanz Kinderklinik, Köln Kinderklinik Amsterdamerstrasse, Köln Uni-Kinderklinik, Landshut Kinderklink, Leipzig Uni-Kinderklinik, Lübeck Uni-Kinderklinik, Lüdenscheid Märkische Kliniken - Kinder & Jugendmedizin, Magdeburg Uni-Kinderklinik, Minden Kinderklinik, Moers Kinderklinik, Mutterstadt Kinderarztpraxis, Mönchengladbach Kinderklinik Rheydt Elisabethkrankenhaus, München von Haunersche Kinderklinik, Neuburg Kinderklinik, Nürnberg Cnopfsche Kinderklinik, Offenburg Kinderklinik, Oldenburg Schwerpunktpraxis Pädiatrie, Paderborn St. Vincenz Kinderklinik, Pforzheim Kinderklinik, Reutlingen Klinikum Steinenberg Innere, Rostock Uni-Kinderklinik, Rotenburg/Wümme Agaplesion Diakonieklinikum Kinderabteilung, Schweinfurt Kinderklinik, Siegen Kinderklinik, Traunstein Kinderklinik, Trier Kinderklinik der Borromäerinnen, Waldshut Kinderpraxis, Waldshut-Tiengen Kinderpraxis Biberbau, andWinnenden Rems-Murr Kinderklinik.

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