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

Kód výsledku v 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>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30202 - Endocrinology and metabolism (including diabetes, hormones)

Projekt

<a href="/cs/project/LX22NPO5104" target="_blank" >LX22NPO5104: Národní institut pro výzkum metabolických a kardiovaskulárních onemocnění</a><br>

Návaznosti

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

Rok uplatnění

2023

Kód důvěrnosti údajů

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