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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“3D), which are implicated in insulin secretion and cell differentiation [38–40].”
Lactiplantibacillus plantarum Ln4 attenuates streptozotocin and high-fat diet-induced Type-2 diabetes
Sood, R., Kritika, Sanjay, & Lee, H. (2026) · Journal of Functional Foods · doi:10.1016/j.jff.2026.107219 · Cited by 1
Biologically active compounds of Shan yao: Molecular mechanisms and implications for gestational diabetes mellitus through network pharmacology and metabolic profiling
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The role of PAQR3 in cancer progression—Molecular regulation, signaling pathways, and clinical implications: A review
Lv, Y., Li, D., Ren, X.-F., Guo, Q., & Ren, Q. (2026) · Biomolecules & biomedicine · doi:10.17305/bb.2026.13696 · Cited by 1
“Table 6 presents indicators related to the prognosis and patho-logicalfeaturesassociatedwith PAQR3 overexpressionincancer patients.”
Donepezil enhances the testicular protective effect of metformin in diabetic rats by modulating steroidogenic signaling and Bax/Bcl-2/Caspase-3 pathway.
Akhigbe, R., Chimezie, J., Odeyemi, A. A., Oyesode, S. O., Adesogan, F., Oladipo, A. A., Ashonibare, P. J., Akhigbe, T., Ashamu, E., & Olamoyegun, M. (2026) · Steroids · doi:10.1016/j.steroids.2026.109748 · Cited by 1
Effect of Astragalus sinicus Ethanol Extract on Menopausal Symptoms in an Ovariectomized (OVX) Mouse Model
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Macrophage immunometabolic reprogramming impairs tissue regeneration in type 2 diabetes zebrafish model
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“The correlation matrix revealing strong relationships between mitochondrial dysfunction parameters and glycolytic markers provides mechanistic insight into how hyperglycemia drives immunometabolic reprogramming in macrophages (21).”
Role of neddylation in diabetes metabolism: potential therapeutic target
Li, H., Zeng, R., Liu, J., & Wang, H. (2026) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-025-01837-9 · Cited by 1
“The activation of PI3K further leads to the phosphorylation of Akt (also known as PKB), which is a core molecule in the insulin signaling pathway and participates in the regulation of a variety of cellular physiological processes [28, 29].”
Parameria laevigata (Juss.) Moldenke Healing Wound via PI3K/AKT/MAPK Pathway.
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Renalase deficiency suppresses hepatic triglyceride accumulation in the progression to MASLD/MASH by GAN diet in male mice
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Influential
Enhanced Effects of Complex Tea Extract and the Postbiotic BPL1® HT on Ameliorating the Cardiometabolic Alterations Associated with Metabolic Syndrome in Mice
de la Fuente-Muñoz, M., Román-Carmena, M., Amor, S., González-Hedström, D., Martínez-Ríos, V., Guilera-Bermell, S., Canet, F., Lamelas, A., García-Villalón, Á., Martorell, P., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27020680 · Cited by 1
“…pathogenesis of MetS is insulin resistance, a condition characterized by the disruption of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, a critical mediator of insulin’s metabolic actions in key metabolic tissues such as liver, muscle, and adipose tissue [2,3].”
Integrating Bulk and Single‐Cell RNA‐Seq Reveals Glycolysis‐Associated Macrophages and Its Related Tumor Subgroup Signatures to Predict Prognosis and Therapy in Clear Cell Renal Cell Carcinoma
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Cell models to probe the biological bases of antipsychotic-induced metabolic Syndrome: towards an individual specific approach
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Role of Dietary Catalpol Supplementation in Regulating Reproductive Development of Harmonia axyridis
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Sex differences in the association between fatty liver index and biological aging: A mediation analysis of insulin resistance in a cross-sectional study
Yang, J., Liu, H.-F., Zhao, W.-M., & Liu, T.-J. (2025) · Medicine · doi:10.1097/md.0000000000046152 · Cited by 1
“[43] Fourthly, hyperinsulinemia activates renin-angiotensin-aldosterone system, promoting vascular calcification, endothelial dysfunction, reduced cardiac output, and systemic ischemia-hypoxia; reduced insulin sensitivity significantly increases accelerated aging risk, partly mediated by arterial…”
Cross-Study Meta-Analysis of Blood Transcriptomes in Type 2 Diabetes
Tkachenko, A. A., Tonyan, Z. N., Nasykhova, Y. A., Barbitoff, Y. A., Renev, I. N., Danilova, M. M., Basipova, A. A., Glavnova, O. B., Polev, D. E., Chepanov, S. V., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262412046 · Cited by 1
“A double knockout of Shank1 and Shank2 in mice has shown a significant reduction in the activation levels of the Akt signaling pathway [44], which is one of the primary signaling pathways involved in the pathogenesis of T2D and associated obesity [45].”
Masking macrophage injury sensing via poly I sustained release system reduces inflammation and fibrosis
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Serine Supplementation Attenuates High-Selenium-Induced Insulin Resistance via Feedback Inhibition of PHGDH in Mice.
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Comparative proteomics and micro-RNA analysis of skeletal muscle cell small extracellular vesicles - Unique profiles in cells from severely obese individuals with type 2 diabetes versus normal glucose tolerance
Christiansen, S. F., Haug, K. B. F., Hussain, M., Hussein, A., Brusletto, B. S., Øvstebø, R., Witczak, O., & Aas, V. (2025) · Frontiers in Physiology · doi:10.3389/fphys.2025.1696916 · Cited by 3
“Interestingly, the top metabolic pathways in the T2D group were all inositol-phosphate related, molecules vital for insulin signaling in skeletal muscle, as well as insulin secretion and apoptotic protection in β-cells (Huang et al., 2018).”
Effect of lithium on glucose homeostasis: Role of protein kinase B (AKT) in rats
Ghamry, M., Ibrahim, I. A., Elshazly, S., & Fahmy, A. (2025) · Open Veterinary Journal · doi:10.5455/ovj.2025.v15.i11.15 · Cited by 1
“To be more specific, β-arrestin-2 has the ability to interact with the insulin receptor and Akt, which can either enhance or modulate the activation of Akt (Huang et al. , 2018).”
A Global Transcriptomic Analysis Reveals Body Weight‐Specific Molecular Responses to Chronic Orange Juice Consumption in Healthy Individuals
Fraga, L. N., Milenkovic, D., Duarte, I. D. A. E., Nuthikattu, S., Coutinho, C. P., Lajolo, F. M., & Hassimotto, N. (2025) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.70299 · Cited by 1
“Bioinformatic analyses also revealed that differentially expressed genes following OJ intake are involved in the PI3K-Akt signaling pathway, whose dysregulation has been associated with the diseases such as obesity and diabetes [40].”
Small extracellular vesicles produced from canine adipose-derived mesenchymal stem cells mitigate diabetes mellitus in streptozotocin-induced mice via β-cell revitalization
Siriarchavatana, P., Oontawee, S., Rodprasert, W., Thongsit, A., Somparn, P., Nan, D. N., Nedumpun, T., Osathanon, T., Egusa, H., Srisuwatanasagul, S., et al. (2025) · BMC Veterinary Research · doi:10.1186/s12917-025-05042-x
“At the same time, normalization of QUICKI and substantial reduction in HOMA-IR in sEV-treated groups suggest enhanced insulin sensitivity, likely mediated by activation of signaling pathways such as PI3K/Akt and AMPK and increased GLUT4 expression in muscle and adipose tissue [70, 71].”
Exploring the Mechanisms of n-Butanol Extract from Tibetan Medicine Biebersteinia heterostemon in Improving Type 2 Diabetes Based on Network Pharmacology and Cellular Experiments
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Computational Modeling of PI3K/AKT Pathway in Bipolar Disorder and Type 2 Diabetes: Implications for Lithium Treatment and Curcumin as a Potential Alternative
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“Many diterpenes have been proved to elicit their antihyperglycemic activity by facilitating the enhanced cellular glucose uptake and glycogen synthesis by the activation of PI3K/Akt pathway [98].”
Modulation Effect of Muntingia calabura Leaves Extracts Supplementation in High Fat Diet-Administrated BALB/c Mouse
Putra, W. E., Shofiyah, I. N., Rahim, A., Hidayatullah, A., & Rifa'i, M. (2025) · Iraqi Journal of Science · doi:10.24996/ijs.2025.66.8.3 · Cited by 1
“Activating PI3K/Akt pathway by TNF-α synthesized by Th1 cells could also induce insulin resistance in essential tissues [82].”
miR-221-3p Exacerbates Obesity-Induced Insulin Resistance by Targeting SOCS1 in Adipocytes
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Antidiabetic potential of Gynura procumbens (Lour.) Merr.: a review of in vitro and in vivo studies
Nor, N. M. M., Jaffar, F., Kashim, M., & Mokhtar, M. H. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1646591 · Cited by 1
“In addition, PI3K/Akt also plays an important role in cell physiology by regulating the transmission of growth factor signals during important cellular processes and organismal growth, including glucose homeostasis and metabolism (Huang et al., 2018; Savova et al., 2023).”
Osteoking Ameliorates Type 2 Diabetes Osteoporosis by Enhancing Osteoblast Differentiation via PI3K/AKT/GSK‐3β Pathway Activation
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Cetacean-specific GPR12 mutation is functionally associated with blubber thickening
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Bifidobacterium longum TISTR 2893 Regulates Glycemic Homeostasis by Modulating the Hepatic Carbohydrate Metabolism in High-Fat Diet and Streptozotocin-Induced Type 2 Diabetic Rats.
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Mapping the microRNA-mediated crosstalk between insulin resistance and Alzheimer’s disease: A computational genomic insight
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Fermented Lentinus edodes improves insulin sensitivity in dam and offspring mice via activation of the hepatic PI3K/AKT signaling pathway
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Timing of glucose intake drives distinct hepatic outcomes: Divergent glucose and lipid metabolism
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In-silico guided identification and in-vitro studies of potential FFAR4 agonists for type 2 diabetes mellitus therapy
Jhinjharia, D., Juneja, P., Srivastava, G., Lokhande, K. B., Sharma, A., Rathore, J. S., Kaur, S., & Sahi, S. (2025) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2025.2522896 · Cited by 2
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Nature’s blueprint for sugar metabolism: translating bee and ant strategies into human diabetes therapies
Nurkolis, F., Romano, R., & Santini, A. (2025) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-025-01755-z · Cited by 1
“In contrast, disruptions in the PI3 K/ Akt pathway in humans are closely linked to the development of insulin resistance and type 2 diabetes [83–85].”
Diet–Gene Interaction Between Fruit Intake and CMIP rs2925979 Polymorphism in Relation to Type 2 Diabetes: A Family-Based Study in Northern China
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Triglyceride-glucose index in predicting gastric cancer prognosis: A need for caution
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Validating the antidiabetic potential of Nakima (Tupistra clarkei Hook.f.), a traditional food from eastern Himalayan region, through network pharmacology and in vivo experimentation
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Metabolites associated with type 2 diabetes and Alzheimer’s disease trigger differential intracellular signaling responses in mouse primary neurons
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“Likewise, the Akt signaling mechanism in both T2D 54 and AD 55 is disrupted by insulin resistance, resulting in subsequent alterations to the Akt pathway.”
Deciphering the Mechanism of Usnic Acid in Type 2 Diabetes Treatment: A Network Pharmacology and Molecular Docking Approach
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Advanced glycation end products and human diseases
Zahra, H. A. (2025) · Journal of Biological Research - Bollettino della Società Italiana di Biologia Sperimentale · doi:10.4081/jbr.2025.12656
Network pharmacology and molecular docking technology-based predictive study and potential targets analysis of icariin for the treatment of diabetic nephropathy.
Chen, M., Zhou, Y.-J., Yang, J., & Yuan, H.-X. (2025) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2025.151434 · Cited by 1
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Identifying semaphorin 3C as a biomarker for sarcopenia and coronary artery disease via bioinformatics and machine learning
Ran, S., Li, Z., Lin, X., & Liu, B. (2025) · Archives of Gerontology and Geriatrics · doi:10.1016/j.archger.2025.105762 · Cited by 2
THE ROLE OF INTRACELLULAR SIGNALING PATHWAYS IN THE DEVELOPMENT OF TROPHIC PATHOLOGIES OF THE LOWER EXTREMITIES AND THEIR REGENERATION UNDER TYPE 2 DIABETES (PART 1)
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“Результати сучасної наукової літератури проде-монстрували, що даний сигнальний шлях конт-ролює не лише процеси метаболізму та клітин-Актуальні ний ріст, але й відіграє важливу роль у розвитку патологічних процесів в організмі, зокрема, ожи-рінні та при ЦД 2 типу [25].”
Promising Directions for Regulating Signaling Pathways Involved in the Type 2 Diabetes Mellitus Development
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Targeting serum response factor (SRF) deactivates ΔFosB and mitigates Levodopa-induced dyskinesia in a mouse model of Parkinson’s disease
Kambey, P. A., Wu, J., Liu, W., Su, M., Buberwa, W., & Tang, C. (2024) · Gene Therapy · doi:10.1038/s41434-024-00492-8
Potentilla fulgens Wall. Ex sims. Upregulates insulin receptor substrate 1 and Akt in alloxan-induced diabetic mice
Sunn, S. E., Pakyntein, C. L., Thabah, D., Kharshiing, C. E., Banerjee, S., Rai, A. K., Bhattacharjee, A., & Syiem, D. (2024) · Clinical Phytoscience · doi:10.1186/s40816-024-00382-x · Cited by 1
Investigating the altered expression of miR ‐486‐5p and miR ‐novel‐chr1_40444 in dysglycemia in a South African population
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“Moreover, these mediators are downstream targets of miR-486-5p 27,28 .”
Background
Unraveling the molecular genetic basis of type 2 diabetes
Nameghi, S. M. (2024) · Gene Reports · doi:10.1016/j.genrep.2024.101993 · Cited by 3
Diabetic Ketoacidosis With the Use of Alpelisib in a Patient With Metastatic Breast Cancer Without Diabetes
Polisetty, L., Selvin, S. T., & Tan, J.-W. (2024) · JCEM Case Reports · doi:10.1210/jcemcr/luae023 · Cited by 1
“Activated AKT regulates glucose levels by promoting the translocation of glucose transporter 4 receptors to the cell surface and enhancing glycogenesis in insulin-responsive tissues (9).”
Background
Antidiabetic potency and molecular insights of natural products bearing indole moiety: A systematic bioinformatics investigation targeting AKT1
Tanty, D. K., Sahu, P., Mohapatra, R., & Sahu, S. K. (2024) · Comput. Biol. Chem. · doi:10.1016/j.compbiolchem.2024.108059 · Cited by 1
Manipulation of Sonic Hedgehog Signaling Pathway in Maintenance, Differentiation, and Endocrine Activity of Insulin-Producing Cells: A Systematic Review
Dayer, D., Bayati, V., & Ebrahimi, M. (2024) · Iranian Journal of Medical Sciences · doi:10.30476/ijms.2023.95425.2678 · Cited by 1
“43 Qin and colleagues reported that administrating the Shh pathway receptor agonist improved neovascularization in diabetes.”
Background

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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