Table 2.

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

Author, year	Diseases		Improvements	Underlying mechanisms
Gannon et al.93; Nuttall et al.94; Dashti et al.95; Hussain et al.96	T2DM		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	Obesity		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	NAFLD		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	PCOS		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	AD		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	PD		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	ALS		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	Epilepsy		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	Depression		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	Anxiety disorders		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