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Nieuwe inzichten in therapeutische mogelijkheden bij diabetes mellitus type 1

Van symptoombestrijding naar personalized medicine

  • Published:
Tijdschrift voor Kindergeneeskunde

Samenvatting

Diabetes mellitus type 1 (T1D) ontstaat ten gevolge van een auto-immuungemedieerde progressieve destructie van insuline-producerende β-cellen. Hoewel de insulinetherapie in de loop der jaren sterk verbeterd is, beperkt deze zich tot symptoombestrijding. Hierbij wordt het doel van glykemische controle meestal niet gehaald.

Het afgelopen decennium zijn vele nieuwe inzichten in de pathogenese van type 1-diabetes ontstaan. Dankzij studies in de pancreatische laesie van T1D-patiënten werd eenduidig bewijs voor een lokale auto-immuunreactie geleverd. Hierbij werd zowel het doelwit als de agressor geïdentificeerd. Bovendien bleken meer β-cellen behouden te zijn dan op basis van β-celfunctie werd verwacht. Dit onderstreept het nut van interventietherapie ten behoeve van β-celpreservatie, ook lang na diagnose. Het meest verrassend bleek de variatie in ontstekingsreacties binnen één pancreas en tussen patiënten.

De ontrafeling van het ziektemechanisme biedt de gelegenheid om interventies te ontwikkelen en te toetsen. Gezien de prevalentie en de lange ziekteduur bestaat nu juist bij kinderen de grootste behoefte om de interventie te toetsen. De regelgeving in Nederland staat dit echter voor deze patiëntengroep niet toe. In het verleden zijn kortetermijnsuccessen geboekt met immunosuppressiva, maar bijwerkingen van een lange afweeronderdrukking lijken onaanvaardbaar. Moderne interventies richten zich dan ook op subtielere immuunmodulatie. De klinische resultaten leken aanvankelijk beperkt. Het trialontwerp hield echter geen rekening met patiënt-en ziekteheterogeniteit, waardoor de effectiviteit van deze therapieën mogelijk wordt onderschat. Met deze nieuwe inzichten van heterogeniteit in patiënt, pathogenese en therapie-uitkomsten zullen aankomende trials zich moeten gaan richten op therapie op maat: personalized medicine, waarbij specifieke aandacht voor interventie bij kinderen wenselijk is.

Summary

Diabetes mellitus type 1 (T1D) is the consequence of immunemediated destruction of the insulin producing β-cells. Despite substantially improved metabolic control with insulin pumps and continuous glucose monitors, the auto-immune destruction of β-cells is not stopped and in most patients optimal glycemic control cannot be achieved.

The last decade has shown significantly increased knowledge of the immunopathology. Histopathologic studies of pancreata of T1D donors revealed infiltrating leukocytes as the likely aggressors. Furthermore at time of diagnosis patients have more β-cells as initially estimated, while β-cell function does not equal β-cell mass. The most surprising finding was the heterogeneous immunopathology within one pancreas and between patients. These new and altered insights in the disease mechanism allow translation into new immunotherapeutic intervention strategies to halt the auto-immune process. As especially children have unmet medical needs and may benefit from immunotherapy it is essential to investigate new interventions in young patients.

Unfortunately Dutch legislation will not allow medical intervention studies in children, safety permitting, even if efficacy in adults cannot be demonstrated.

Since the 1980’s it is known that non-specific immune suppression can temporarily preserve β-cell function in T1D, but at cost of unacceptable risks. In the last decade more elegant immune interventions were designed avoiding the complications of severe immune suppression. Even though intervention trials showed no overall protective effect at first face, efficacy was seen in patient subgroups. It is conceivable that patient and disease heterogeneity influences the efficacy of immunotherapies, reducing the chance of one magic bullet as intervention for the T1D population at large. Therefore, future trials need to identity the most appropriate target population with special attention to children to implement personalized medicine in future T1D care.

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Authors and Affiliations

  1. afdeling Immunohematologie en Bloedtransfusie, Leids Universitair Medisch Centrum, Leiden, The Netherlands

    J. van Heiningen, F.M. Keij &  B.O. Roep

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  1. J. van Heiningen
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  2. F.M. Keij
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  3. B.O. Roep
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Correspondence to J. van Heiningen.

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Drs. Jacqueline van Heiningen, Fleur M. Keij en prof.dr. Bart O. Roep, afdeling Immunohematologie en Bloedtransfusie, Leids Universitair Medisch Centrum, Leiden.

Correspondentieadres: J. van Heiningen, afdeling Immunohematologie en Bloedtransfusie, LUMC, Leiden,j.van_heiningen@lumc.nl. Belangenconflict: geen gemeld.

Financiële ondersteuning: Diabetes Fonds Nederland, Stichting diabetesonderzoek in Nederland (DON) en Juvenile Diabetes Research Foundation(JDRF).

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van Heiningen, J., Keij, F. & Roep, B. Nieuwe inzichten in therapeutische mogelijkheden bij diabetes mellitus type 1. Tijdschr Kindergeneeskd 83, 9–17 (2015). https://doi.org/10.1007/s12456-015-0004-6

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