Table 2 Main improvements and underlying mechanisms of the KD exerts on the diseases below

Gannon et al.⁹³; Nuttall et al.⁹⁴; Dashti et al.⁹⁵; Hussain et al.⁹⁶

Reduction of blood glucose

Glucose transporter type 4 and O-GlcNAc-modified proteins may be involved

Reduction of hemoglobin A1c

Reduction of blood insulin level

Improved insulin resistance

Westerterp-Plantenga et al.¹¹⁹; Veldhorst et al.¹²⁰; Sumithran et al.¹²¹; Johnstone et al.¹²²; Laeger et al.¹²³

Increased satiety

Increased concentrations of “satiety” regulating hormones and direct suppression of appetite by ketone bodies

Yang et al.¹²⁴

Reduction in lipogenesis

Improved insulin resistance

Ma et al.¹²⁵

Increased lipolysis

Increased expression of lipolytic enzymes

Tagliabue et al.¹²⁶; Paoli et al.¹²⁷

Higher metabolic efficiency in consuming fats

Reduction in the resting respiratory quotient

Fine & Feinman¹²⁸; Feinman & Fine¹²⁹

Higher energy cost

Increased energy consumption in gluconeogenesis and the thermic effect of protein digestion

Paoli et al.¹¹⁸

Increased fat oxidation and reduced lipogenesis

Decreased insulin level

Shimazu et al.¹⁴⁵

Increased oxidative stress resistance

β-HB increases histone acetylation of genes encoding oxidative stress resistance factors

Taggart et al.¹⁰⁹; Graff et al.¹⁴⁶; Youm et al.¹⁴⁷

Reduction in hepatic inflammation

Activation of GPR109A and inhibition of NLRP3

Mardinoglu et al.⁵⁴

Increased folate production

Microbial alteration of the gut microbiota

Mavropoulos et al.¹⁴⁹; Gower et al.¹⁵⁰; Paoli et al.¹⁵¹

Reduction of LH/FSH ratio

Unclear; AMPK may be involved

Reduction of testosterone level

Reduction of blood insulin level

Broom et al.¹⁵⁹; Kashiwaya et al.¹⁶⁰

Reduces amyloid plaques, and reverses Aβ toxicity

Increased neurite number and length

Hughes et al.¹⁶⁸; Kim et al.¹⁶⁹; Bough et al.¹⁷⁰

Improved mitochondrial function and elevated ATP levels

Improves the number and function of mitochondria; modulates the calcium-induced membrane permeability transition (mPT)

Lu et al.¹⁷¹

Attenuated oxidative stress

Nrf2 activation

Cullingford et al.⁷⁷; Rahman et al.¹⁷²; Dupuis et al.¹⁷³

Reduction of inflammation

Reduction of pro-inflammatory cytokines, such as IL-1β and TNF-α, inhibited the activation of NF-κB in activated B cells and downregulated COX2 expression

Joniec-Maciejak et al.¹⁸⁶

Inhibition of neurodegenerative processes increased metabolic activity in striatal mitochondria

Yang & Cheng¹⁹⁰

Anti-inflammatory effects

Decreased pro-inflammatory cytokine expression, including IL-1β, IL-6, and TNF-α, in the substantia nigra

Cheng et al.¹⁹¹

Inhibition of dopaminergic cell apoptosis

Upregulation of the Bcl-2/Bax ratio

Kong et al.²⁰⁰

Attenuation of oxidative stress

Suppression of Class I histone deacetylases

Zhao et al.²⁰²

Regulated mitochondrial dysfunction

Restores the activity of Complex II of the electron chain

Improved motor functions

Weinshenker et al.²⁰⁸; Dahlin et al.²⁰⁹; Calderón et al.²¹⁰

Prioritizes inhibitory over excitatory neurotransmitters

Increased norepinephrine and orexigenic neuropeptides, galanin metabolites of dopamine and serotonin, GABA, and agmatine

Yellen et al.²¹⁴

Reduced brain glucose utilization and glycolytic ATP production

Induces potassium channels sensitive to ATP opening

Andrews et al.²¹⁵

Limited the ROS generation

Increased polyunsaturated fatty acid levels and induced the expression of neuronal uncoupling proteins

Nagpal et al.²²³

Changed cerebrospinal fluid AD biomarkers

Modulated gut microbiome and short-chain fatty acids

Sussman et al.²²⁴

Exhibited reduced susceptibility to anxiety and depression

Programed the offspring neuro-anatomy and influences their behavior in adulthood

Campbell et al.²²⁶; DM et al.²²⁷

Ameliorated social defeat and lipopolysaccharide-induced depressive-like behaviors

Restoration of the microglial activation and the neuronal excitability in the lateral habenula

Forte et al.²²⁹; Erecińska et al.²³⁰ Sussman et al.²²⁴

Decreased affective disorders, and improved social and physical activity levels

Enhances the synthesis and transmission of GABA at the synapse, decreases the content of aspartic acid and the excitability of neurons

Rawat et al.²³¹; Cheng et al.²³²; Youm et al.¹⁴⁷

Regulated the abundance of intestinal microbiota, and improved intestinal barrier function

Bound G protein-coupled receptors, inhibit histone deacetylases (HDACs) and reduced the production of ROS and free radicals

Hao et al.²³⁷; Vallejo et al.²⁸⁵

Cancer

Colon adenocarcinoma, glioblastoma

Affected glucose metabolism

Suppresses the lactate/pyruvate cycle, inhibits neovascularization and activates hypoxia-induced vascular epidermal growth factor and angiogenesis

Shang et al.²³⁸; Ristic et al.²³⁹; Elangovan et al.²⁴⁰

Glioblastoma, colon carcinoma, breast cancer

Inhibited inflammation

Inhibits NLRP3 inflammasome, GPR109A, which is a receptor for β-HB, which is downregulated in cancer

Hopkins et al.²⁴¹; Xia et al.²⁴²

Pancreatic, bladder, endometrial, breast cancer, acute myeloid leukemia

Overcomes drug resistance

Decreased hyperglycemia and insulin secretion, reduced intratumoral mTORC1 signaling, selectively increased activation of BRAF V600E-mutant-dependent MEK1 signaling

Morscher et al.²⁴³; Allen et al.²⁴⁴; Abdelwahab et al.²⁴⁵; Zahra et al.²⁴⁶; Ferrere et al.²⁴⁸; Dai et al.²⁴⁹

Neuroblastoma, glioma, lung cancer

Improved the efficacy of classical chemotherapy or radiotherapy, anti-PD1/PD-L1 immunotherapy, and anti-CTLA-4 immunotherapy

Anti-angiogenic efficacy prevented the upregulation of PD-L1, promoted the expansion of CXCR3 + T cells and consequent T cell-mediated tumor immunosurveillance, decreased PD-L1 protein levels, and increased the expression of type-I interferon and antigen-presentation genes

Poff et al.²⁵⁰; Magee et al.²⁵¹; Poff et al.²⁵²

Acute myeloid leukemia, melanoma

Inhibited tumor metastasis

Induction of ROS production in tumor cells