Targeting senescence as a promising approach to treatment of type 2 diabetes mellitus and its comorbidities

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023001%3A_____%2F23%3A00084323" target="_blank" >RIV/00023001:_____/23:00084323 - isvavai.cz</a>

Result on the web

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DOI - Digital Object Identifier

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Result language

angličtina

Original language name

Targeting senescence as a promising approach to treatment of type 2 diabetes mellitus and its comorbidities

Original language description

Introduction: Despite extensive research, limited efficacy of current therapies used for patients with obesity and type 2 diabetes mellitus (T2DM) have prompted a search for novel therapeutic options, such as targeting cellular senescence. Our goal was testing the MitoTam, a potential anti-cancer agent with senolytic activity, on pathologies related to T2DM.Methods: C57BL/6 mice fed with standard or high fat diet for 8 month were treated with MitoTam (2 mg/kg body weight) given i.p. twice per week/4 weeks.Results: Compared to non-treated mice MitoTam improved glucose parameters (fasting glucose 6.2 ± 1.1 mmoL/L vs. 9.8 ± 1.2 mmoL/L) and reduced body weight (35.6 ± 3.2 g vs. 45.2 ± 4.1 g), with most pronounced reduction of visceral adipose tissue (2.1 ± 0.4 g vs. 3.4 ± 0.3 g). Glucose-lowering effect of MitoTam was linked to improvement of T2DM-related hormones profile (insulin 0.4 ± 0.2 ng/mL vs. 2.3 ± 1.8 ng/mL; leptin 4.8 ± 1.9 ng/mL vs. 9.7 ± 1.1 ng/mL; GIP 0.7 ± 0.2 ng/mL vs. 1.2 ± 0.6 ng/mL) and was accompanied by reduced lipid accumulation in liver. Lower senescent cell burden in various tissues also resulted in lower level of circulating inflammatory mediators that enhance metabolic dysfunction. Moreover, decreased presence of senescent cells reduced kidney fibrosis, a frequently occurring complication of T2DM that worsen its progression. Mice treated with MitoTam showed lower accumulation of fibrotic cells and microenvironment in kidney followed by decreased kidney injury and secretion of injury molecules (KIM-1 98.8 ± 6.8 ng/mL vs. 82.1 ± 8.9 ng/mL; Cystatin C 1.71 ± 0.17 μg/mL vs. 1.54 ± 0.13 μg/mL) playing negative role in development of cardiovascular diseases in patients with T2DM.Conclusion: Targeting senescence with MitoTam represents a novel approach to the treatment of T2DM and its related comorbidities. Since MitoTam has recently successfully carried out Phase 1/1b clinical trial for metastatic solid tumour patients with excellent safety profile, this compound has a potential to be translated into the clinic also for T2DM.

Czech name

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Czech description

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Type

O - Miscellaneous

CEP classification

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OECD FORD branch

30202 - Endocrinology and metabolism (including diabetes, hormones)

Project

<a href="/en/project/LX22NPO5104" target="_blank" >LX22NPO5104: National Institute for Research of Metabolic and Cardiovascular Diseases</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů