Effect of Metformin on T2D-Induced MAM Ca2+ Uncoupling and Contractile Dysfunction in an Early Mouse Model of Diabetic HFpEF

Abstract

Diabetic cardiomyopathy (DCM) is a leading complication in type 2 diabetes patients. Recently, we have shown that the reticulum-mitochondria Ca2+ uncoupling is an early and reversible trigger of the cardiac dysfunction in a diet-induced mouse model of DCM. Metformin is a first-line antidiabetic drug with recognized cardioprotective effect in myocardial infarction. Whether metformin could prevent the progression of DCM remains not well understood. We therefore investigated the effect of a chronic 6-week metformin treatment on the reticulum-mitochondria Ca2+ coupling and the cardiac function in our high-fat high-sucrose diet (HFHSD) mouse model of DCM. Although metformin rescued the glycemic regulation in the HFHSD mice, it did not preserve the reticulum-mitochondria Ca2+ coupling either structurally or functionally. Metformin also did not prevent the progression towards cardiac dysfunction, i.e., cardiac hypertrophy and strain dysfunction. In summary, despite its cardioprotective role, metformin is not sufficient to delay the progression to early DCM.

Mitochondria-associated endoplasmic reticulum membrane (MAM): a dark horse for diabetic cardiomyopathy treatment

“…Therefore, metformin might be a promising drug for the treatment of DCM via MAM. Maya et al showed that metformin improved blood glucose levels and insulin sensitivity in HFHSD mice; however, it could not prevent the alteration of MAM Ca 2+ coupling in cardiomyocytes and ameliorate the progression of DCM [ 124 ]. These findings further underscore the critical role of MAM Ca 2+ coupling as a potential therapeutic target for DCM and highlight the essential drug specificity of targeting MAM.…”

Broadening horizons: the contribution of mitochondria-associated endoplasmic reticulum membrane (MAM) dysfunction in diabetic kidney disease

“…However, targeting MAM-related proteins does not necessarily alter the MAM itself. For example, a study by Maya et al showed that although metformin treatment improves blood glucose levels and insulin sensitivity to some extent in diabetic mice, it does not prevent the changes in MAM Ca 2+ coupling in cardiac muscle cells and the resulting heart dysfunction induced by T2D 157 . On the other hand, Wei et al found that activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) by capsaicin alleviated mitochondrial dysfunction caused by high glucose in podocytes and was accompanied by a reduction in MAM formation and decreased Ca 2+ transport from the ER to mitochondria 158 .…”

Ginsenoside Rg1 improved diabetes through regulating the intestinal microbiota in high‐fat diet and streptozotocin‐induced type 2 diabetes rats

“…The correlation between oxidative stress, inflammatory response, and the gut microbiota supported the utilization of ginsenoside Rg1 as a potential treatment for T2D. Metformin was used as a positive control drug, which was the first line of treatment for patients with T2D (Dia et al, 2022).…”