Abstract
In the present study, we aimed to evaluate the effect of Sirt1, Sirt3 and combined activation in high fructose diet-induced insulin resistance rat heart and assessed the cardiac function focusing on mitochondrial health and function. We administered the Sirt1 activator; SRT1720 (5 mg/kg, i.p.), Sirt3 activator; Oroxylin-A (10 mg/kg i.p.) and the combination; SRT1720 + Oroxylin-A (5 mg/kg and 10 mg/kg i.p.) daily from 12th week to 20th weeks of study. We observed significant perturbations of most of the cardiac structural and functional parameters in high fructose diet-fed animals. Administration of SRT1720 and Oroxylin-A improved perturbed cardiac structural and functional parameters by decreasing insulin resistance, oxidative stress, and improving mitochondrial function by enhancing mitochondrial biogenesis, OXPHOS expression and activity in high fructose diet-induced insulin-resistant rats. However, we could not observe the synergistic effect of SRT1720 and Oroxylin-A combination. Similar to in-vivo study, perturbed mitochondrial function and oxidative stress observed in insulin-resistant H9c2 cells were improved after activation of Sirt1 and Sirt3. We observed that Sirt1 activation enhances Sirt3 expression and mitochondrial biogenesis, and the opposite effects were observed after Sirt1 inhibition in cardiomyoblast cells. Taken together our results conclude that activation of Sirt1 alone could be a potential therapeutic target for diabetes-associated cardiovascular complications.
Highlights
Diabetes mellitus is a group of metabolic disorder characterized by hyperglycemia, caused by defects in insulin secretion, action, or both [1]
High fructose diet (HFD) significantly (p < 0.05) increased fasting blood glucose, insulin-resistance, serum insulin levels, and HOMA-IR in high fructose diet-fed (HFD) rats when compared with control diet-fed rats
The effect of sirtuin activation on insulin resistance was further validated by performing an in-vitro 2-NBDG uptake assay on palmitate-induced insulin-resistant cardiomyoblast (H9c2) cells
Summary
Diabetes mellitus is a group of metabolic disorder characterized by hyperglycemia, caused by defects in insulin secretion, action, or both [1]. Worldwide the prevalence of diabetes is estimated to increase from 8.8% in 2017 to 9.9% by the year 2045 [2]. People suffering from diabetes mellitus are at increased risk for cardiovascular disease. 70% of the mortality is due to diabetes-associated cardiac complications. As the heart is a continuous functioning organ, it needs a high amount of energy in the form of molecular ATP from mitochondria. The health of cardiac mitochondria plays an important role in the proper functioning of the heart. None of the current anti-diabetic drugs and adjuvant therapy such as ACE Inhibitors, SGLT2 inhibitors, DPP-IV inhibitors, and angiotensin receptor blockers
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