Ketogenic Diet Ameliorates Cardiac Dysfunction via Balancing Mitochondrial Dynamics and Inhibiting Apoptosis in Type 2 Diabetic Mice

Abstract

The ketogenic diet (KD) has been widely used in clinical studies and shown to hace an anti-diabetic effect, but the underlying mechanisms have not been fully elaborated. Our aim was to investigate the effects and the underling mechanisms of the KD on cardiac function in db/db mice. In the present study, db/db mice were subjected to a normal diet (ND) or KD. Fasting blood glucose, cardiac function and morphology, mitochondrial dynamics, oxidative stress, and apoptosis were measured 8 weeks post KD treatment. Compared with the ND, the KD improved glycemic control and protected against diabetic cardiomyopathy in db/db mice, and improved mitochondrial function, as well as reduced oxidative stress were observed in hearts. In addition, KD treatment exerted an anti-apoptotic effect in the heart of db/db mice. Further data showed that the PI3K/Akt pathway was involved in this protective effect. Our data demonstrated that KD treatment ameliorates cardiac dysfunction by inhibiting apoptosis via activating the PI3K-Akt pathway in type 2 diabetic mice, suggesting that the KD is a promising lifestyle intervention to protect against diabetic cardiomyopathy.

Ketogenic Diet Suppressed T‐Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria‐Associated Membranes and Inhibiting Mitochondrial Function

“…Our results were supported by a recent population-based study, which concluded a deleterious result on the coronary artery conferred by low-carbohydrate diet that is similar to KD [3]. However, the findings of the current study supporting the unflavored role of KD in diabetes is sharply in contrast to the previous study, showing beneficial effects of KD in cardiomyocyte survival and interstitial fibrosis [4]. The differences of animal characteristics could be the most plausible explanation of this discrepancy.…”

“…The serum insulin levels also supported the distinct characteristics of the animal used in our and the previous study. Levels of serum insulin were dramatically decreased in db/db mice in the study by Guo et al [4], while it is well acknowledged that hyperinsulin is one of the basic characteristics of db/db mice as found in the current and many other studies [19,29,30], which is the basic pathophysiological alterations of T2DM. Therefore, the animal used in the current study, which reflects the canonical T2DM leading to cardiac remodeling, is distinct from the previous one and this could cause different responses to KD treatment.…”

“…9 Oxidative Medicine and Cellular Longevity without concurrent systolic defects [19]. However, the abovementioned study showed a significant reduction of LVEF in db/db mice [4], which implied a late stage of DCM or other coexistent causes of cardiac insults. The serum insulin levels also supported the distinct characteristics of the animal used in our and the previous study.…”

“…However, on the other hand, it has been linked to vascular insult recently [3]. In the field of cardiac remodeling, KD is reported to be associated with improved cardiac function, cardiomyocyte survival, and attenuated cardiac fibrosis in both T2DM and aging mice [4,5]. In contrast, ketogenic diet was shown to be associated with cardiac remodeling in hypertensive rats [6].…”

Ketogenic Diet Prevents Heart Failure from Defective Mitochondrial Pyruvate Metabolism

“…Additionally, there is substantial literature describing improvement in rodent cardiomyopathy models using "non-ketogenic" high fat or PUFA-enriched diets in the absence of obesity 58 . Interestingly, ketogenic diet was recently shown to improve cardiac remodeling in the obese db/db mouse model 59 , potentially due to the improved insulin sensitivity with significant carbohydrate restriction. However, in the setting of obesity and insulin resistance, increased dietary fat may add to cardiac lipid accumulation or "lipotoxicity" 60 .…”