Cited by 1,673Metabolism, Diabetes, and CancerPI3K/AKT/mTOR signaling in cancerAdipokines, Inflammation, and Metabolic Diseases

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The PI3K/AKT pathway in obesity and type 2 diabetes

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Huang, Xingjun, Liu, Guihua, Guo, Jiao, Su, Zhengquan·2018·International Journal of Biological Sciences

DOI 10.7150/ijbs.27173PMC PMC6158718

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Abstract

Obesity and type 2 diabetes mellitus are complicated metabolic diseases that affect multiple organs and are characterized by hyperglycaemia. Currently, stable and effective treatments for obesity and type 2 diabetes mellitus are not available. Therefore, the mechanisms leading to obesity and diabetes and more effective ways to treat obesity and diabetes should be identified. Based on accumulated evidences, the PI3K/AKT signalling pathway is required for normal metabolism due to its characteristics, and its imbalance leads to the development of obesity and type 2 diabetes mellitus. This review focuses on the role of PI3K/AKT signalling in the skeletal muscle, adipose tissue, liver, brain and pancreas, and discusses how this signalling pathway affects the development of the aforementioned diseases. We also summarize evidences for recently identified therapeutic targets of the PI3K/AKT pathway as treatments for obesity and type 2 diabetes mellitus. PI3K/AKT pathway damaged in various tissues of the body leads to obesity and type 2 diabetes as the result of insulin resistance, and in turn, insulin resistance exacerbates the PI3K/AKT pathway, forming a vicious circle.

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“This active Akt subsequently promotes glucose transporter type 4 translocation to the plasma membrane, markedly enhancing insulin-stimulated glucose uptake in obese subjects (21).”
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Shi, K., Pei, Z., Quan, S., Shi, Y., & Zhou, Y. (2025) · Medicine · doi:10.1097/md.0000000000046737
“Simultaneously, insulin resistance disrupts the signaling pathway, [33,34] leading to reduced secretion of the anti-inflammatory cytokine.”
Bioactive aporphines and flavonoids from a fermented beverage target metabolic inflammatory pathways in obesity and type 2 diabetes
Wu, X., Qiu, Y., Dai, R., Huang, Z., Wang, J.-H., Yan, X., Nie, X.-Z., & Liu, R. (2025) · Scientific Reports · doi:10.1038/s41598-025-30778-9
“…node, enhancing insulin sensitivity through the PI3K-Akt signaling by promoting glucose transporter type 4 (GLUT4)-mediated glucose uptake and inhibiting hepatic gluconeogenesis via forkhead box protein O1 (FOXO1) 56–58 , while also counteracting inflammation by suppressing TNF/NF-κB signaling 59 .”
miR-199a Knockdown Alleviates Insulin Resistance and Inflammation by Targeting DDIT4 via the PI3K/AKT Pathway in vitro and in vivo
Cai, Y.-W., Tang, L., Zhu, Y., Ye, S.-S., & Chen, T.-E. (2025) · Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy · doi:10.2147/dmso.s549884
“21,22 Dysregulation of the PI3K/AKT pathway is a hallmark of IR.”
Bioconverted Red Ginseng Protects Liver Functions and Alters Insulin Homeostasis-Associated Gut Microbiome Composition in Aged Mice
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Lee, Y.-J., Xu, Y., & Hyun, C. (2025) · Pharmaceuticals · doi:10.3390/ph18121780 · Cited by 1
“However, by inhibiting AKT phosphorylation, it is possible to discourage adipocyte differentiation and regulate lipid metabolism, thereby preventing lipid accumulation [31].”
Transgenic overexpression of miR-486 and sAnk1.5 does not alter glucose handling in mice.
Buonocore, S., Fiore, F., Rubino, E. M., Catallo, M. R., Raucci, L., Laurino, A., Rossi, D., Pierantozzi, E., & Sorrentino, V. (2025) · Biochimica et biophysica acta. Molecular cell research · doi:10.1016/j.bbamcr.2025.120087
Inhibition of Neuroinflammation by Costunolide Attenuates Hypoxic-Ischemic Brain Damage via the PI3K/AKT Pathway in Neonatal Rats
Hu, Y.-Y., Qian, R., He, Y.-F., Gao, Q.-Q., Wang, X., Lin, H.-L., Lin, W., Fang, Y., Zhu, J.-H., Wang, X.-Y., et al. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05372-9
“PI3K/AKT signaling plays a dominant role in neuronal survival, polarity, axon specificity, and synaptic plasticity, thereby influencing cerebral development and functions, which have been implicated in a variety of neurological impairments [45, 46].”
Network pharmacology and experiments verify the effect of triptolide on extraocular muscle fibrosis
Jiang, M., Wang, P., Yu, D.-D., Guo, P., Qu, Z., Zhao, J., & Yan, S. (2025) · PLoS ONE · doi:10.1371/journal.pone.0336487
“This recruits and activates AKT, which phosphorylates downstream targets by translocating to cellular compartments such as the nucleus, mitochondria, and endoplasmic reticulum [37].”
Bidirectional regulation of free fatty acid receptors and non-alcoholic fatty liver disease.
Lin, Y., Liu, Y., Liu, J., Wu, J., Wei, K.-H., Guo, J., & Su, Z.-Q. (2025) · Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2025.110180
Self-citation
Network pharmacology based study of TCM formulations for non-insulin dependent diabetes mellitus
Jha, A., Venkatesh, S. K. S., & Lakkaniga, N. R. (2025) · In Silico Pharmacology · doi:10.1007/s40203-025-00451-0
“…glycogen synthesis, TSC2 to stimulate mTORC1-driven protein and lipid synthesis, FoxOs to suppress glu - coneogenesis, and AS160 to enhance glucose uptake, while also inhibiting lipolysis in adipose tissue and supporting β-cell survival and insulin secretion in the pancreas (Huang et al. 2018).”
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Chander, R., Sharma, R., & Agnihotri, V. K. (2025) · Natural Product Research · doi:10.1080/14786419.2025.2572038
Proanthocyanidins from Chinese dwarf cherry [Cerasus humilis (Bge.) Sok.] pomace ameliorate hepatic glucose-lipid metabolism abnormalities in T2DM mice via PI3K/Akt/FoxO1 and AMPK/ACC signaling pathways
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“17 Critically, Akt phosphorylation is essential for regulating FoxO1 activity.”
Integrated network pharmacology and cellular assay revealed an anti-type 2 diabetes effect of Astaxanthin from Haematococcus pluvialis
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In silico of Secondary Metabolite Compounds in Garcinia mangostana as A Therapy for Type 2 Diabetes
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Discovery of placental microRNAs associated with maternal insulin sensitivity during pregnancy
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Dietary Potassium Synergistically Enhances Anti-Obesity Efficacy of Garcinia Cambogia Complex in High-Fat Diet-Induced Obese Mice
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“This pathway is central to insulin signaling and plays a crucial role in suppressing he-patic lipogenesis and promoting lipid oxidation (Boucher et al ., 2010; Huang et al ., 2018; Wang et al ., 2023).”
Antioxidant, Anti‐Proliferative and Porcine α‐Amylase Inhibitory Potential of Flavonoids From Hydnocarpus pentandrus (Buch.–Ham.) Oken (In Vitro and In Silico Studies)
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“PI3K protein plays a crucial role in both cancer and T2DM as the activation of this protein stimulates the responses of metabolism and proliferation along with tumour development and resistance to anticancer therapies [29].”
Transcriptomic analysis of the mechanism of male reproductive injuries caused by the mixture of three phthalates in rats.
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The mixture of Momordica charantia, Lagerstroemia speciosa and Jerusalem artichoke exert hypoglycemic effect in diabetic mice
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Fu-Fang-Qi-Di-Hua-Yu-Tang Improves Diabetic Macrovascular Disease via PI3K/AKT Pathway Regulation
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The novel role of Periploca laevigata Aiton extracts as antidiabetic and anti-inflammatory functions in pancreatic Β cells exposed to hyperglycaemia
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Akkermansia muciniphila: A Promising Next Generation Probiotic
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“Notably, PI3K-Akt signalling regulates metabolism, and its dysfunction leads to obesity and diabetes 39 .”
Ubiquitous expression of an activating mutation in the Pik3ca gene reprograms glucose and lipid metabolism in mice
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“While this data would seem to be in disagreement with the known role of PI3K to inhibit lipolysis through inhibition of protein kinase A (PKA) [10], Duncan and colleagues have previously shown that lipolysis is stimulated during fasting [19], providing a potential explanation for the increased…”
Unraveling Early Molecular Signatures of Type 2 Diabetes: A Multi-Omics Integration Using MOFA+
Omran, M. M., Alhfnawy, A. M., Gamaleldin, M., Abushady, A. M., Khalil, H., Demerdash, H., Elattar, M., & El-Hadidi, M. S. (2025) · International Conference on Machine Intelligence and Smart Innovation (ICMISI) · doi:10.1109/icmisi65108.2025.11115188
Beyond Base Camp: Promise and Pitfalls of PI3K/mTOR Inhibition in Pediatric High- Grade GliomasPreprint
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“PI3K/Akt signaling, particularly downregulating AKT2, facilitates insulin-driven glucose uptake in muscle, liver, and fat cells by promoting the glucose transporters translation to the plasma membrane [45].”
Meta-analysis and network pharmacology study of Xiaoke Pill in the treatment of type 2 diabetes mellitus
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Novel therapeutic targets for metabolism-related diseases: proteomic Mendelian randomization and colocalization analyses
Zhang, Y., Wang, B., Chen, B., & Wan, Q. (2025) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/20420188251343140
“46 This study has several significant strengths.”
LPI (a compound liquid preparation) regulates type II diabetes by targeting AMPK and ISR1 signaling pathways
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The Physiological Role of GABA in Fine-Tuning Control of Blood Glucose and Diabetes Treatment
Davari, M., Sohrabipour, S., & Golkari, A. (2024) · Disease and Diagnosis · doi:10.34172/ddj.1595
“GABA improves glucose tolerance and insulin resistance by increasing GLUT4.”
Influential
Neurological Impact of Diabetes, and Stem Cell as a Course of Action
Noor, R., Varkey, J., Torremocha, V., & Kethar, J. (2024) · Journal of Student Research · doi:10.47611/jsrhs.v13i4.8432
“When Akt receives insulin, it begins the process of metabolizing substances such as proteins and glucose (Huang et al., 2018).”
Integrated network pharmacology, molecular docking analysis and experimental validation to reveal the mechanisms of Jinglian Hexiao formula in the treatment of adenoid hypertrophy
Li, N., Li, X., Guo, Y., Gu, J., Zhang, B., Zheng, F. Y., Pi, Z., & Yue, H. (2024) · International Conference on Public Health and Data Science (ICPHDS) · doi:10.1145/3718677.3718702
“The PI3K/AKT signaling pathway, integral to cell growth, proliferation, metabolism, survival, and cell cycle regulation [ 28 – 30 ] , and is closely related to cellular oxidative stress [ 31 , 32 ] , inflammation [ 33 , 34 ] , apoptosis [ 35 ] , autophagy [ 36 ] and so on.”
THE ROLE OF PYRUVATE IN ENERGY TURNOVER OF RATS WITH ALLOXAN DIABETES UNDER THE CONDITIONS OF MELATONIN INJECTIONS
Kushnir, О. Y., Kushnir, О. Y., Yaremii, І. М., & Yaremii, K. M. (2024) · Biolohichni systemy · doi:10.31861/biosystems2024.02.215
Huatan Qushi formula alleviates non-alcoholic fatty liver disease via PI3K/Akt signaling and gut microbiota modulation
Zhang, X., Zhu, L.-H., Ma, J., Zheng, Y., Yang, X.-J., Yang, L., Dong, Y., Zhang, Y., Liu, B., & Li, L.-R. (2024) · Journal of Traditional Chinese Medical Sciences · doi:10.1016/j.jtcms.2024.08.004
Akt1 deficiency does not affect fiber type composition or mitochondrial protein expression in skeletal muscle of male mice
Miyaji, T., Kasuya, R., Sawada, A., Sawamura, D., Kitaoka, Y., & Miyazaki, M. (2024) · Physiological Reports · doi:10.14814/phy2.70048
Long-term GABA Supplementation Regulates Diabetic Gastroenteropathy through GABA Receptor/trypsin-1/PARs/Akt/COX-2 Axis
Yazdanimoghaddam, F., Rezazadeh, H., Soltani, N., Mehranfard, N., Dastgerdi, A. H., Rad, M. G., & Ghasemi, M. (2024) · Doklady Biochemistry and Biophysics · doi:10.1134/s1607672924600386 · Cited by 1
RNA-Seq transcriptome profiling of Nile rat livers reveals novel insights on the anti-diabetic mechanisms of Water-Soluble Palm Fruit Extract
Leow, S.-S., Khoo, J., Lee, W.-K., Hoh, C.-C., Fairus, S., Sambanthamurthi, R., & Hayes, K. C. (2024) · Journal of Applied Genetics · doi:10.1007/s13353-024-00880-1
“It also inhibited cell migration and invasion by suppressing epithelial-mesenchymal transition (Liu et al. 2018).”
The impact of MIR196A2 and MIR423 genes polymorphisms on the development of type 2 diabetes mellitus in a sample of the Iraqi population
Jubair, S., Hadi, S. M., Farhan, N. H., & Dhefer, I. H. (2024) · Human Gene · doi:10.1016/j.humgen.2024.201271
Identification of potential molecular mechanism related to craniofacial dysmorphism caused by FOXI3 deficiency
Xing, X., Zeng, Z., Wang, Y., Pan, B., & Huang, X. (2024) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.2411
“…have been reported to be associated with almost all diseases, such as cancer (Noorolyai et al., 2019; Xue et al., 2021), cardiovascular diseases (Qin et al., 2021; Zhang et al., 2018), nervous system diseases (Gabbouj et al., 2019; Sharma & Mehan, 2021), and metabolic diseases (Huang et al., 2018).”
BackgroundSelf-citation
Bioinformatic analysis and construction of competitive endogenous RNA network reveals protective effect of Jiangtang Sanhao Formula on the liver of diabetic mice
Mo, F., An, T., Yang, N., Zhao, D.-D., Zhang, D.-W., Jiang, G., & Gao, S.-H. (2024) · Pharmacological Research - Modern Chinese Medicine · doi:10.1016/j.prmcm.2024.100408
Distinctive genes and signaling pathways associated with type 2 diabetes-related periodontitis: Preliminary study
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“…various stimuli (e.g., cytokines, growth factors, cellular stresses, and insulin) and regulates several biological processes (e.g., cellular survival, apoptosis, autophagy, proliferation, growth, motility, transcription, and translation) involved in periodontitis and other diseases [29, 30].”
Background
Inverse relationship between platelet Akt activity and hippocampal atrophy: A pilot case-control study in patients with diabetes mellitus
Tokuda, H., Hori, T., Mizutani, D., Hioki, T., Kojima, K., Onuma, T., Enomoto, Y., Doi, T., Matsushima-Nishiwaki, R., Ogura, S., et al. (2024) · World Journal of Clinical Cases · doi:10.12998/wjcc.v12.i2.302
“Akt is known to play an important role in human platelet activation[6,9-14], and impairment of Akt signalling is closely related to insulin resistance, a central pathology of T2DM[16,17].”
Effects of Voluntary Exercise on Liver and Adipose Tissue Dysfunction in Both Young and Middle‐Aged Mice Fed a High‐Fat Diet Combined with Dietary Advanced Glycation End Products
Liu, R., Ma, T., He, Z., Chen, G., Gu, H., & Wan, Z. (2024) · Journal of Food Biochemistry · doi:10.1155/2024/5226432
PATHOGENIC MECHANISMS OF HEART FAILURE IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
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Bioactive Compounds from Momordica charantia, Nigella sativa, and Anethum graveolens against Metabolic Syndrome: Untangling the Complex Relationship
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“44 In both normal and abnormal cardiac hypertrophy, several studies have shown that the PI3K-AKT pathway regulates cardiomyocyte size, survival, angiogenesis, and inflammation.”

Authors: Huang, X., Liu, G., Guo, J., & Su, Z.
Affiliations: Guangdong Pharmaceutical University (CN)
Shenzhen Center for Disease Control and Prevention (CN)
Corresponding author: Guo, Jiao
Su, Zhengquan
ORCID: Liu, Guihua
Guo, Jiao
Su, Zhengquan
Venue: International Journal of Biological Sciences
Publisher: Ivyspring International Publisher
Published: 2018
Volume: 14
Issue: 11
Pages: 1483-1496
ISSN: 1449-2288 (ISSN-L)
DOI: 10.7150/ijbs.27173
PMC: PMC6158718
OpenAlex: W2886504687
Cited by: 1,673
References: 171
Citations by year: 2026: 197 · 2025: 296 · 2024: 282 · 2023: 258 · 2022: 246 · 2021: 211 · 2020: 136 · 2019: 44 · 2018: 3
FWCI: 9.71
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc
Locations: International Journal of Biological Sciences (publishedVersion, cc-by-nc)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Funders: National Natural Science Foundation of China (2017-02, 81173107)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Keywords: PI3K/Akt signaling, obesity, type 2 diabetes, insulin resistance, hyperglycemia, skeletal muscle, adipose tissue, liver, pancreas, therapeutic target, metabolic disorders
MeSH terms: Animals, Diabetes Mellitus, Type 2, Humans, Insulin Resistance, Obesity, Signal Transduction, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt

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The PI3K/AKT pathway in obesity and type 2 diabetes

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