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Projekt Druckansicht

Harnblasenhypertrophie bei experimentellem Diabetes mellitus

Antragstellerinnen / Antragsteller Dr. Jennifer Kirwan; Professor Dr. Martin C. Michel
Fachliche Zuordnung Pharmakologie
Förderung Förderung von 2019 bis 2023
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 427465081
 
Erstellungsjahr 2024

Zusammenfassung der Projektergebnisse

Our project focused on diabetes-associated enlargement of the urinary bladder, underlying mechanisms and associated functional alterations. Special focus was applied to type 2 diabetes (T2DM), treatments for T2DM, studies in female animals, and metabolomic alterations. We were able to generate data from 22 different studies comprising 11 different rodent models of type 1 diabetes (T1DM) and T2DM. We consider it an exceptional achievement that 19 of those studies were based on surplus tissue from experiments performed for other purposes, thereby implementing the 3R principles. We found bladder enlargement to be present in all models of T1DM and in many but not all of T2DM. However, presence or degree of bladder enlargement was only poorly related to disease severity as assessed by blood glucose levels. Two dedicated studies in female rats and six mouse studies using both sexes found that sex differences existed in some models but were absent in others. Treatment studies with six medications representing five drug classes showed that effects on bladder enlargement (the primary endpoint of the overall project) correlated only moderately with those on glucose levels. Various mechanistic studies and marker measurements did not support previously reported pathophysiological hypotheses, most importantly clearly rejected the diuretic polyuria hypothesis. The perhaps most exciting findings from our project come from analyses of the metabolome of bladder muscle was compared to heart and skeletal muscle. Large scale changes across the metabolome were seen between healthy and diabetic bladders. Approximately 9% of metabolites were changed in the treated versus diabetic group in the type 1 model of diabetes. Most of the metabolites involved had known structural functions and included ceramides and sphingomyelins. Pathway mapping suggest a limited number of key metabolites that influence this process and may reflect possible treatment targets in the future. Of note, the changes in ceramide and sphingomyelin metabolites were the strongest differentiating factor between the bladder and other types of muscle. Additional follow up studies showed sphingosine kinase-1- phosphate-receptor type 2 is the major receptor responsible for mediating bladder contractions. An extension of the original project allowed the analysis of a large clinical trial of 5775 men which determined that diabetes as a co-variate only explained a small extent of the nocturia seen in benign prostatic hyperplasia. Following completion of the budget-neutral extension of our project, we are happy to summarize our results and achievements. Our project had 5 specific aims: 1. Explore urinary bladder enlargement across a larger variety of diabetes models, particularly of type 2 diabetes and in females. 2. Test the ability of treatments other than insulin to prevent and/or reverse diabetesassociated bladder enlargement. 3. Characterize changes in smooth muscle reactivity in rat models of both sexes and including treatment with oral antidiabetic and antihypertrophic drugs. 4. Explore changes in metabolome in type 1 and type 2 diabetes models, including both sexes and treatment with oral antidiabetic and antihypertrophic drugs. 5. Explore organismic, tissue, molecular and cellular mechanisms underlying bladder hypertrophy and fibrosis.

Projektbezogene Publikationen (Auswahl)

 
 

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