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Evaluation of linagliptin and insulin combined therapy on unfolded protein response in type 1 diabetic mouse heart
Züleyha Doğanyiğit1, Aslı Okan1, Serpil Taheri2
1Faculty of Medicine, Department of Histology and Embryology, Yozgat Bozok University, Yozgat, Turkey.
Abstract:
The aim of this study is to reveal the effects of the use of linagliptin, a DPP-4 inhibitor due to its beneficial cardiovascular effects, on endoplasmic reticulum stress (ERS) signaling, which is involved in the pathogenesis of cardiovascular complications related to type 1 diabetes. BALB/c female mice (n = 72) were divided into six groups: control, diabetes+insulin, diabetes+linagliptin, diabetes+linagliptin+insulin, diabetes+TUDCA, and diabetes+TUDCA+insulin. Immunohistochemistry and western blot method, qRT-PCR, ELISA method, and malondialdehyde (MDA) measurements were performed. Linagliptin administered to the type 1 diabetic mouse heart significantly reduced the expression levels of the total and cleaved forms of ATF6, ATF4, and p-JNK, caspase 3. Immunohistochemical and western blot analyses revealed that cleaved caspase 3 protein expression was significantly increased in the diabetes+insulin group compared to the other groups. According to ELISA findings, TUDCA was more effective in reducing NOX 1 and MDA levels than linagliptin. While linagliptin decreased the Chop mRNA level, no change was observed in the Grp78 mRNA level. Our findings showed that there was not much difference between the administration of linagliptin alone or in combination with insulin. Our study reveals that linagliptin is an effective therapeutic agent on ERS and apoptotic UPR in type 1 diabetic hearts.
Insights
Linagliptin, a DPP-4 inhibitor, effectively reduces endoplasmic reticulum stress (ERS) and apoptosis in type 1 diabetic mouse hearts. This suggests linagliptin is a promising therapeutic for diabetic cardiovascular complications.
Area of Science:
- Cardiovascular Research
- Diabetology
- Molecular Biology
Background:
- Type 1 diabetes (T1D) is associated with cardiovascular complications.
- Endoplasmic reticulum stress (ERS) and apoptosis play roles in T1D cardiovascular pathogenesis.
- DPP-4 inhibitors, like linagliptin, show potential cardiovascular benefits.
Purpose of the Study:
- To investigate the effects of linagliptin on ERS signaling in the context of T1D.
- To evaluate linagliptin's impact on apoptotic pathways in T1D hearts.
Main Methods:
- BALB/c female mice were used, divided into six experimental groups.
- Techniques included immunohistochemistry, Western blot, qRT-PCR, ELISA, and malondialdehyde (MDA) measurements.
- Key markers of ERS and apoptosis were assessed.
Main Results:
- Linagliptin significantly reduced ATF6, ATF4, p-JNK, and caspase 3 expression in T1D mouse hearts.
- Cleaved caspase 3 was elevated in the diabetes+insulin group compared to others.
- Tauroursodeoxycholic acid (TUDCA) showed greater efficacy than linagliptin in reducing NOX 1 and MDA levels.
Conclusions:
- Linagliptin demonstrates therapeutic efficacy against ERS and apoptotic unfolded protein response (UPR) in T1D hearts.
- Linagliptin's effectiveness was comparable whether administered alone or with insulin.
- These findings highlight linagliptin as a potential treatment for cardiovascular issues in T1D.
