Definition, Classification, Diagnosis and Differential Diagnosis of Diabetes Mellitus: Update 2023

Notice Of Update

The DDG clinical practice guidelines are updated regularly during the second half of the calendar year. Please ensure that you read and cite the respective current version.

Updates To Content Compared To The Previous Year’s Version

Change 1: Various changes in the section “Diagnostic approach for diagnosing diabetes” and “Pre-analytics of glucose measurement”. The new requirements for pre-analysis and analysis of glucose determination in accordance with the revised guideline of the German Medical Association for quality assurance of laboratory medical examinations (Rili-BAEK) are listed.

Reason: In May 2023, an updated version of the Rili-BAEK was published.

If applicable, supporting references: [13]

Change 2: The formulation on the reliability of HbA_1c in renal insufficiency has been adjusted.

Reason: Alignment with the clinical practice guideline “Nephropathy and Diabetes”.

If applicable, supporting references: [23]

Change 3: New section “Determination of ketone bodies”.

Reason: Measurement of ketone bodies is required in some clinical situations to determine the need for insulin therapy. Urine diagnostics, in which acetoacetate is measured, are delayed, and urine samples cannot be obtained easily at any time. On the other hand, measuring β-hydroxybutyrate in plasma or blood makes it possible to assess the risk of ketoacidosis more quickly.

If applicable, supporting references: [36] [37]

Change 4: Addition of the section “Differential diagnosis” to include a summarised description of the course of the development of type 1 or type 2 diabetes.

Reason: The differential diagnosis of type 1 and type 2 diabetes is summarised and thus easier for readers to understand.

Change 5: Removal of flow chart for differential diagnosis of type 1, type 2 diabetes and MODY

Reason: Due to the sometimes considerable fluctuations that can occur in the determination of C-peptide or autoantibodies depending on the laboratory and method, and due to the lack of standardisation in this context, the flow diagram has been removed. The diagnostic algorithm shown in this figure is still cited in the text, but it also points out the variability in the determination of C-peptide and autoantibodies.

Change 6: The “Outlook” section addresses the subtyping of type 1 and type 2 diabetes.

Reason: Subtyping is increasingly being discussed and is already being used in type 2 diabetes. A detailed analysis of the subtyping is still missing, so that no conclusive assessment is possible yet.

If applicable, supporting references: [64] [65]

Change 7: Brief discussion of diabetes diagnosis in clinics in the “Outlook” section.

Reason: There is a lack of systematic diabetes screening in clinics. The diagnostic algorithm is also not easily applicable. However, there is no national or international consensus on the glucose threshold above which a diabetes diagnosis is likely in inpatients. The additional measurement of HbA_1c may be useful in reducing the proportion of patients with undiagnosed diabetes.

^† First Authors: Stefan Pleus, Andrea Tytko

Publication History

Article published online:
20 February 2024

• References

• 1 Akturk HK, Kahramangil D, Sarwal A. et al. Immune checkpoint inhibitorinduced Type 1 diabetes: a systematic review and meta-analysis. Diabet Med 2019; 36: 1075-1081
• 2 Chen X, Affinati AH, Lee Y. et al. Immune Checkpoint Inhibitors and Risk of Type 1 Diabetes. Diabetes Care 2022; 45: 1170-1176
• 3 The HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008; 358: 1991-2002
• 4 Gemeinsamer Bundesausschuss (G-BA). Im Internet: https://www.g-ba.de/themen/methodenbewertung/ambulant/frueherkennung-krankheiten/erwachsene/schwangerschaft-mutterschaft/
• 5 Deutsche Diabetes Gesellschaft und Deutsche Gesellschaft für Gynäkologie und Geburtshilfe. Hrsg. S3-Leitlinie Gestationsdiabetes mellitus (GDM), Diagnostik, Therapie und Nachsorge. AWMF-Registernummer: 057-008. 2018. Im Internet (Stand: 14.08.2019): 2. Auflage: https://www.awmf.org/uploads/tx_szleitlinien/057-008l_S3_Gestationsdiabetes-mellitus-GDM-Diagnostik-Therapie-Nachsorge_2019-06.pdf
• 6 Kleinwechter H. Gestational diabetes mellitus. update 2022. MMW Fortschr Med 2022; 164: 29-34
• 7 ElSayed NA, Aleppo G, Aroda VR. et al. 2. Classification and Diagnosis of Diabetes: Standards of Care in Diabetes-2023. Diabetes Care 2023; 46: S19-S40
• 8 World Health Organization. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia. 2006
• 9 International Diabetes Federation. IDF Diabetes Atlas 10th Edition. Im Internet: https://diabetesatlas.org/data/en/
• 10 Crowther CC, Samuel D, McCowan LME. et al. Lower versus Higher Glycemic Criteria for Diagnosis of Gestational Diabetes. N Engl J Med 2022; 387: 587-598
• 11 Pleus S, Heinemann L, Freckmann G. et al. Glukosemessung in der Diabetesdiagnostik und -therapie: Laboratoriumsmedizinische Untersuchung inkl. Patientennaher Sofortdiagnostik, Blutglukoseselbstmesung und kontinuierliches Glukosemonitoring. Diabetol Stoffwechs 2022; 17: 52-60
• 12 Freckmann G, Heinemann L, Pleus S. et al. Messqualität bei der Glukosemessung im Rahmen der Diabetesdiagnose und -therapie in Deutschland. Dtsch Med Wochenschr 2022; 147: 413-417
• 13 Richtlinie der Bundesärztekammer zur Qualitätssicherung laboratoriumsmedizinischer Untersuchungen. Deutsches Ärzteblatt 2023; DOI: 10.3238/arztebl.2023.rili_baek_QS_Labor.
• 14 Fischer MM, Hannemann A, Winter T. et al. Relative Efficacy of Different Strategies for Inhibition of in Vitro Glycolysis. Clin Chem 2021; 67: 1032-1034
• 15 Heinemann L, Adamczewski H. Neumann Ch et al. Gemeinsames Positionspapier der Kommission Labordiagnostik in der Diabetologie der DDG und DGKL und der Kommission Apotheker in der Diabetologie BAK/DDG zur Herstellung einer oGTT-Lösung für die Diagnose eines Diabetes einschließlich eines Gestationsdiabetes. Diabetol Stoffwechs 2020; 15: 470-471
• 16 Krüger M, Heinemann L. Verfügbarkeit von Fertiglösungen für den oGTT: ein Update. Diabetes Stoffw. Herz 2023; 23: 90-91
• 17 Heil W, Jachtmann A, Rick W. Zur Reproduzierbarkeit der Ergebnisse des oralen Glucose-Toleranz-Tests. Lab Med 1990; 14: 440-444
• 18 Landgraf R. HbA1c in der Diabetes-Diagnostik. Der Goldstandard? Diabetes aktuell 2021; 19: 22-29
• 19 Heinemann L, Freckmann G. Quality of HbA1c Measurement in the Practice: The German Perspective. J Diabetes Sci Technol 2015; 9: 687-695
• 20 Heinemann L, Kaiser P, Freckmann G. et al. Higher HbA1c Measurement Quality Standards are Needed for Follow-Up and Diagnosis: Experience and Analyses from Germany. Horm Metab Res 2018; 50: 728-734
• 21 Richtlinie der Bundesärztekammer zur Qualitätssicherung laboratoriumsmedizinischer Untersuchungen. Deutsches Ärzteblatt 2019; DOI: 10.3238/arztebl.2019.rili_baek_QS_Labor20192312.
• 22 Pani LN, Korenda L, Meigs JB. et al. Effect of aging on A1C levels in individuals without diabetes: evidence from the Framingham Offspring Study and the National Health and Nutrition Examination Survey 2001-2004. Diabetes Care. 2008 31. 1991-1996
• 23 Merker L, Ebert T, Guthoff M. et al. Nephropathie bei Diabetes. Diabetol Stoffwechs 2022; 17: S327-S331
• 24 Baker L, Maley JH, Arévalo A. et al. Real-world characterization of blood glucose control and insulin use in the intensive care unit. Sci Rep 2020; 10: 10718
• 25 Pieri M, Paleari R, Dalfrá MG. et al. Reference intervals for HbA1c partitioned for gender and age: a multicenter study. Acta Diabetol 2016; 53: 1053-1056
• 26 Roth J, Müller N, Lehmann T. et al. HbA1c and Age in Non-Diabetic Subjects: An Ignored Association?. Exp Clin Endocrinol Diabetes 2016; 124: 637-642
• 27 Masuch A, Friedrich N, Roth J. et al. Preventing misdiagnosis of diabetes in the elderly: age-dependent HbA1c reference intervals derived from two population-based study cohorts. BMC Endocr Disord 2019; 19: 20
• 28 Ma Q, Liu H, Xiang G. et al. Association between glycated hemoglobin A1c levels with age and gender in Chinese adults with no prior diagnosis of diabetes mellitus. Biomed Rep 2016; 4: 737-740
• 29 Wu L, Lin H, Gao J. et al. Effect of age on the diagnostic efficiency of HbA1c for diabetes in a Chinese middle-aged and elderly population: The Shanghai Changfeng Study. PLoS One 2017; 12: e0184607
• 30 Qi J, Su Y, Song Q. et al. Reconsidering the HbA1c Cutoff for Diabetes Diagnosis Based on a Large Chinese Cohort. Exp Clin Endocrinol Diabetes 2021; 129: 86-92
• 31 Ozarda Y, Sikaris K, Streichert T. et al. Distinguishing reference intervals and clinical decision limits – A review by the IFCC Committee on Reference Intervals and Decision Limits. Crit Rev Clin Lab Sci 2018; 55: 420-431
• 32 The DECODE-study group on behalf of the European Diabetes Epidemiology Group. Is fasting glucose sufficient to define diabetes? Epidemiological data from 20 European studies. Diabetologia 1999; 42: 647-654
• 33 vanʼt Riet E, Alssema M, Rijkelijkhuizen JM. et al. Relationship between A1C and glucose levels in the general Dutch population: the new Hoorn study. Diabetes Care 2010; 33: 61-66
• 34 Peter A, Fritsche A, Stefan N. et al. Diagnostic value of hemoglobin A1c for type 2 diabetes mellitus in a population at risk. Exp Clin Endocrinol Diabetes 2011; 119: 234-237
• 35 Keutmann S, Zylla S, Dahl M. et al. Measurement Uncertainty Impacts Diagnosis of Diabetes Mellitus: Reliable Minimal Difference of Plasma Glucose Results. Diabetes Ther 2020; 11: 293-303
• 36 Taboulet P, Deconinck N, Thurel A. et al. Correlation between urine ketones (acetoacetate) and capillary blood ketones (3-beta-hydroxybutyrate) in hyperglycaemic patients. Diabetes Metab 2007; 33: 135-139
• 37 Glaser N, Fritsch M, Priyambada L. et al. ISPAD clinical practice consensus guidelines 2022: Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes 2022; 23: 835-856
• 38 Thaler M, Roos M, Petersmann A. et al. Auto-Antikörper-Diagnostik in der Diabetologie – Aktueller Stand der Analytik und klinische Anwendung in Deutschland. Diabetol Stoffwechs 2022; 17: 382-388
• 39 Ahlqvist E, Storm P, Käräjämäki A. et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol 2018; 6: 361-369
• 40 Wagner R, Heni M, Tabák AG. et al. Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes. Nat Med 2021; 27: 49-57
• 41 Herder C, Roden M. A novel diabetes typology: towards precision diabetology from pathogenesis to treatment. Diabetologia 2022; 65: 1770-1781
• 42 Hörber S, Achenbach P, Schleicher E. et al. Harmonization of immunoassays for biomarkers in diabetes mellitus. Biotechnol Adv 2020; 39: 107359
• 43 Lampasona V, Pittman DL, William AJ. et al. Islet Autoantibody Standardization Program 2018 Workshop: Interlaboratory Comparison of Glutamic Acid Decarboxylase Autoantibody Assay Performance. Clin Chem 2019; 65: 1141-1152
• 44 Jones AG, Hattersley AT. The clinical utility of C-peptide measurement in the care of patients with diabetes. Diabet Med 2013; 30: 803-817
• 45 Fritsche A, Heni M, Peter A. et al. Considering Insulin Secretory Capacity as Measured by a Fasting C-Peptide/Glucose Ratio in Selecting Glucose-Lowering Medications. Exp Clin Endocrinol Diabetes 2022; 130: 200-204
• 46 Matthews DR, Hosker JP, Rudenski AS. et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
• 47 Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care 2004; 27: 1487-1495
• 48 Zavaroni I, Deferrari G, Lugari R. et al. Renal metabolism of C-peptide in man. J Clin Endocrinol Metab 1987; 65: 494-498
• 49 Bonser AM, Garcia-Webb P. C-peptide measurement: methods and clinical utility. Crit Rev Clin Lab Sci 1984; 19: 297-352
• 50 DʼElia JA, Mulla CH, Liu J. et al. Variations in glucose/C-peptide ratio in patients with type 2 diabetes associated with renal function. Diabetes Res Clin Pract 2019; 150: 1-7
• 51 Nationale Versorgungsleitlinie Typ-2-Diabetes. Teilpublikation der Langfassung Version 1. 2021. AWMF Register Nr. nvl-001. Im Internet: www.leitlinien.de/themen/diabetes
• 52 Holt RIG, DeVries JH, Hess-Fischl A. et al. The Management of Type 1 Diabetes in Adults. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2021; 44: 2589-2625
• 53 Besser REJ, Bell KJ, Couper JJ. et al. ISPAD clinical practice consensus guidelines 2022: Stages of type 1 diabetes in children and adolescents https://www.ispad.org/resource/resmgr/consensus_guidelines_2018_/guidelines2022/ch._2_pediatric_diabetes_-_2.pdf
• 54 Rewers M, Ludvigsson J. Environmental risk factors for type 1 diabetes. Lancet 2016; 387: 2340-2348
• 55 Ziegler AG, Rewers M, Simell O. et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 2013; 309: 2473-2479
• 56 Sims EK, Besser REJ, Dayan C. et al. Screening for Type 1 Diabetes in the General Population: A Status Report and Perspective. Diabetes 2022; 71: 610-623
• 57 Buzzetti R, Zampetti S, Maddaloni E. Adult-onset autoimmune diabetes: current knowledge and implications for management. Nat Rev Endocrinol 2017; 13: 674-686
• 58 Leslie RD, Evans-Molina C, Freund-Brown J. et al. Adult-Onset Type 1 Diabetes: Current Understanding and Challenges. Diabetes Care 2021; 44: 2449-2456
• 59 Harding JL, Wander PL, Zhang X. et al. The Incidence of Adult-Onset Type 1 Diabetes: A Systematic Review From 32 Countries and Regions. Diabetes Care 2022; 45: 994-1006
• 60 Badenhoop K. MODY und andere monogenetische Diabetesformen. Diabetologe 2017; 13: 453-463
• 61 Bojunga J, Schlereth F. Type 3c diabetes mellitus-prevalence, diagnosis, special aspects of treatment. Diabetologe 2018; 14: 269-277
• 62 Kufeldt J, Kovarova M, Adolph M. et al. Prevalence and Distribution of Diabetes Mellitus in a Maximum Care Hospital: Urgent Need for HbA1c-Screening. Exp Clin Endocrinol Diabetes 2018; 126: 123-129
• 63 Ahuja V, Aronen P, Pramodkumar TA. et al. Accuracy of 1-hour plasma glucose during the oral glucose tolerance test in diagnosis of type 2 diabetes in adumts: A meta-analsis. Diabetes Care 2021; 44: 1062-1069
• 64 Zaharia OP, Strassburger K, Strom A. et al. Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study. Lancet Diabetes Endocrinol 2019; 7: 684-694
• 65 Achenbach P, Hippich M, Zapardiel-Gonzalo J. et al. A classification and regression tree analysis identifies subgroups of childhood type 1 diabetes. EBioMedicine 2022; 82: 104118
• 66 Broome DT, Pantalone KM, Kashyap SR. et al. Approach to the Patient with MODY-Monogenic Diabetes. J Clin Endocrinol Metab 2021; 106: 237-250