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Review Open Access

β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review)

  • Authors:
    • Xianyi Ding
    • Jiabin Wu
    • Lian Wang
    • Ke Li
    • Haoyang Gao
    • Mingyu Wu
    • Qiuyu Zhang
    • Ruonan Han
    • Wenhong Wang
    • Weihua Xiao
  • View Affiliations / Copyright

    Affiliations: Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
    Copyright: © Ding et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 12
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    Published online on: November 3, 2025
       https://doi.org/10.3892/ijmm.2025.5683
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Abstract

Type 2 diabetes mellitus (T2DM) is a major metabolic disease that poses a threat to human health; therefore, the development of new pharmaceutical therapies for the treatment of T2DM is of great importance. β‑hydroxybutyric acid (β‑HB) is the primary ketone body present in the human body. β‑HB not only serves as an energy substrate to maintain the metabolic homeostasis of the body but also acts as a signaling molecule, exerting multiple biological functions both inside and outside cells. The present review summarizes the research progress and latest findings of β‑HB in T2DM models from the perspective of metabolism, physiological effects and potential as a therapeutic agent. Research indicates that β‑HB exerts protective effects against T2DM by regulating glucose and lipid metabolism, preserving the integrity of pancreatic β‑cells and improving insulin resistance (IR). Additionally, β‑HB can alleviate the core pathological conditions of T2DM and related complications by enhancing the stability of cellular proteins, reducing oxidative stress and controlling inflammatory responses and endoplasmic reticulum stress (ERS), while regulating mitochondrial biogenesis, autophagy and apoptosis. Furthermore, the present review also describes the application of β‑HB in clinical research on T2DM. Research indicates that regulating β‑HB levels through endogenous and exogenous ketogenesis approaches can influence body weight, fasting blood glucose levels, IR and memory ability in T2DM patients. These results suggest that β‑HB is a potential metabolite for T2DM treatment.
View Figures

Figure 1

Production of β-HB by the liver and
the breakdown of β-HB by extrahepatic tissues. β-HB is synthesized
through the following steps: i) The β-oxidation of FFAs results in
the production of a substantial amount of acetyl CoA
(CH3COSCoA) in the mitochondria of the liver; ii) the
condensation of two molecules of acetyl CoA (CH3COSCoA)
into acetoacetyl CoA (CH3COCH2COSCoA) is
catalyzed by HMGCS2 with the release of one molecule of CoASH; iii)
the condensation of acetoacetyl CoA
(CH3COCH2COSCoA) with another molecule of
acetyl CoA (CH3COSCoA) forms HMG-CoA, catalyzed by
HMGCL, releasing an additional molecule of CoASH; iv) HMG-CoA is
then cleaved by HMG-CoA lyase to produce ACAC
(CH3COCH2COOH) and acetyl CoA; and v) The
reduction of ACAC (CH3COCH2COOH) to β-HB is
mediated by BDH1, utilizing NADH as the hydrogen donor. A minor
fraction of ACAC is converted to acetone
(CH3COCH3). β-HB is transported by MCTs into
the vasculature into the circulatory system and eventually into
extrahepatic tissues. The catabolism of β-HB: i) β-HB is
dehydrogenated to ACAC (CH3COCH2COOH) in the
mitochondria of extrahepatic tissues, which is catalyzed by BDH1;
ii) ACAC (CH3COCH2COOH) is subsequently
converted to acetoacetyl CoA (CH3COCH2COSCoA)
by OXCT1; and iii) acetoacetyl CoA (CH3COCH2COSCoA) is catalyzed by
ACAT to become acetyl CoA, which then enters the TCA cycle for
complete oxidative decomposition to CO2, H2O
and release of ATP. FFA, free fatty acids; ACAT, acetyl-CoA
acetyltransferase; HMGCS2, 3-hydroxymethylglutaryl-CoA synthase 2;
HMGCL, 3-hydroxymethylglutaryl-CoA lyase; BDH1, β-hydroxybutyrate
dehydrogenase 1; NAD, nicotinamide adenine dinucleotide; β-HB,
β-hydroxybutyric acid; TCA, tricarboxylic acid; ATP, adenosine
triphosphate; OXCT1, 3-oxoacid CoA transferase 1; MCTs,
monocarboxylate transporters; ACAC, acetoacetate; CoA, coenzyme
A.

Figure 2

Biological functions of β-HB. β-HB
acts as an energy substrate to regulate metabolic reactions as a
signaling molecule that binds to the ligand of the GPCR to modulate
downstream signaling molecules and inhibits NLRP3. As an epigenetic
regulator, β-HB inhibits HDAC, promotes Kbhb and controls
K+ channels. HDAC, histone deacetylase; Kbhb, lysine
β-hydroxybutyrylation; GPCRs, G protein-coupled receptors; NF-κB:
nuclear factor κB; ERK, extracellular regulated protein kinase;
TCA, tricarboxylic acid; ATP, adenosine triphosphate; NLRP3,
NOD-like receptor family pyrin domain containing 3; β-HB,
β-hydroxybutyric acid.

Figure 3

Possible mechanisms of β-HB against
T2DM. β-HB acts as a signaling molecule to regulate IR,
inflammation, oxidative stress, mitochondrial function and cell
apoptosis to improve T2DM. GPR, G protein-coupled receptor; AC,
adenylyl cyclase; PKA, protein kinase A; Raf1, Raf-1
proto-oncogene, serine/threonine-protein kinase; ERK, extracellular
regulated protein kinase; PPARγ, peroxisome proliferator-activated
receptor γ; GLP-1, glucagon-like peptide-1; P13K,
phosphatidylinositol-3-kinase; NF-κB: nuclear factor-κB; CHOP,
C/EBP-homologous protein; PES1, pescadillo 1; SREBP1c, sterol
regulatory element binding protein 1c; FASN, fatty acid synthase;
SCD1, stearoyl-CoA desaturase 1; TG, triglyceride; Caspase-1,
cysteinyl aspartate specific proteinase 1; NLRP3, NOD-like receptor
family pyrin domain-containing 3; TNF-α, tumor necrosis factor-α;
MCP1, monocyte chemoattractant protein 1; BDH1, β-hydroxybutyrate
dehydrogenase 1; ACAC, acetoacetate; TCA, tricarboxylic acid; MFN2,
mitofusin 2; Nrf2, nuclear factor-erythroid 2-related factor 2;
GSK3-β, glycogen synthase kinase 3-β; SOD, superoxide dismutase;
GPX4, glutathione peroxidase 4; ROS, reactive oxygen species;
β-hydroxybutyric acid; T2DM, type 2 diabetes mellitus.
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Copy and paste a formatted citation
Spandidos Publications style
Ding X, Wu J, Wang L, Li K, Gao H, Wu M, Zhang Q, Han R, Wang W, Xiao W, Xiao W, et al: β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review). Int J Mol Med 57: 12, 2026.
APA
Ding, X., Wu, J., Wang, L., Li, K., Gao, H., Wu, M. ... Xiao, W. (2026). β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review). International Journal of Molecular Medicine, 57, 12. https://doi.org/10.3892/ijmm.2025.5683
MLA
Ding, X., Wu, J., Wang, L., Li, K., Gao, H., Wu, M., Zhang, Q., Han, R., Wang, W., Xiao, W."β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review)". International Journal of Molecular Medicine 57.1 (2026): 12.
Chicago
Ding, X., Wu, J., Wang, L., Li, K., Gao, H., Wu, M., Zhang, Q., Han, R., Wang, W., Xiao, W."β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 12. https://doi.org/10.3892/ijmm.2025.5683
Copy and paste a formatted citation
x
Spandidos Publications style
Ding X, Wu J, Wang L, Li K, Gao H, Wu M, Zhang Q, Han R, Wang W, Xiao W, Xiao W, et al: β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review). Int J Mol Med 57: 12, 2026.
APA
Ding, X., Wu, J., Wang, L., Li, K., Gao, H., Wu, M. ... Xiao, W. (2026). β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review). International Journal of Molecular Medicine, 57, 12. https://doi.org/10.3892/ijmm.2025.5683
MLA
Ding, X., Wu, J., Wang, L., Li, K., Gao, H., Wu, M., Zhang, Q., Han, R., Wang, W., Xiao, W."β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review)". International Journal of Molecular Medicine 57.1 (2026): 12.
Chicago
Ding, X., Wu, J., Wang, L., Li, K., Gao, H., Wu, M., Zhang, Q., Han, R., Wang, W., Xiao, W."β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 12. https://doi.org/10.3892/ijmm.2025.5683
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