Ketogenic diets and β-hydroxybutyrate in the prevention and treatment of diabetic kidney disease: current progress and future perspectives

Abstract

Diabetic kidney disease (DKD) is the main cause of end-stage renal disease. Ketogenic diets (KD) is a high-fat, low-carbohydrate diet. KD produces ketone bodies to supplement energy in the case of insufficient glucose in the body. β-Hydroxybutyrate (BHB) is the main component of ketone bodies. BHB serves as "ancillary fuel" substituting (but also inducing) anti-oxidative, anti-inflammatory, and cardio-protective features by binding to several target proteins, including histone acylation modification, or G protein-coupled receptors (GPCRs). KD have been used to treat epilepsy, obesity, type-2 diabetes mellitus, polycystic ovary syndrome, cancers, and other diseases. According to recent research, KD and the induced BHB delay DKD progression by improving the metabolism of glucose and lipids, regulating autophagy, as well as alleviating inflammation, oxidative stress and fibrosis. However, due to some side-effects, the role and mechanism of action of KD and BHB in the prevention and treatment of DKD are controversial. This review focuses on recent progress in the research of KD and BHB in clinical and preclinical studies of DKD, and provides new perspectives for DKD treatment.

Keywords: Diabetic kidney disease (DKD); Ketogenic diets (KD); β-hydroxybutyrate (BHB).

Fig. 1

Ketogenic diets (KD) in the treatment of diabetic kidney disease (DKD): a double-edged sword. KD improve glycolipid metabolism, bodyweight loss, and alleviate insulin resistance. However, they may lead to side-effects such as hyperlipidemia, gastrointestinal discomfort, osteoporosis, or kidney stones. Dotted lines mean that the process needs to be verified. Solid lines denote that the process has been proven

Fig. 2

Overview of the potential mechanism of ketogenic diets or BHB in protecting the kidneys and alleviating DKD. Ketogenic diets induce the synthesis of ketone bodies (mainly BHB) as an alternative energy source in the liver. BHB activates AMPK and inhibits mTORC1, which promotes autophagy and lipolysis, and alleviates ROS and fibrosis in DKD. BHB also enhances BDH1 expression in mitochondria, or inhibits GSK3β in the cytoplasm, which promotes nuclear translocation of Nrf2 and transcription/activation of antioxidant genes such as HO-1 and NQO-1. BHB enters cells through MCT1 and MCT2, and then inhibits HDAC directly. It increases expression of H3K9ac and the transcription of FOXO3a and Mt2, and antioxidant-stress enzymes such as MnSOD and catalase. BHB can be catalyzed to produce the BHB coenzyme A (BHB-CoA) by acyl-CoA synthetase 2 (ACSS2), which promotes H3K9bhb and transcriptional activation of MMP-2, and reduces the expression of COL IV. BHB may bind to the TGF-β receptor, promoting the phosphorylation of Smad2 and Smad3, which enhance the expression of p21 and p27. However, BHB may also promote the generation of collagen fibers and TGF-β1 through the same pathway.BHB enhances the production of NAD⁺ in mitochondria, activates SIRT1, which may lead to increased H3K9ac, thereby promoting the transcription of FOXO1 and PGC-1α. It also decreases the expression of TNF-α and IL-6, while increasing the levels of antioxidant enzymes such as MnSOD and catalase