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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Figure 1 PI3K/AKT pathway. PI3K activates AKT, and AKT phosphorylates downstream substrates that are involved in the regulation of diverse cellular functions, including apoptotic, metabolism and cell cycle progression. As illustrated by these targets, a high degree of functional versatility and overlap exists amongst AKT substrates. Red and black line indicates inhibition and activation respectively. AKT, protein kinase B; AS160, Akt Substrate of 160 kDa; FoxO1, Forkhead box O1; GSK3, glycogen synthase kinase 3; GPCR, G-protein-coupled receptors; IRS-1/2,insulin receptor substrate-1/2; IKK, IkB-kinase; MAD1, MAX dimerization protein 1; MDM2, murine double minute 2; MLK3, mixed lineage kinase 3; mTORC1/2, mTOR complex 1/2; PDK1, phosphoinositide-dependent protein kinase 1; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-biphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, Phosphatase and tensin homologue; RTK, receptor tyrosine kinases; SREBP, sterol regulatory element-binding proteins; TSC1/2, tuberous sclerosis complex 1/2.CC BY-NC · PubMed Central

Figure 2 PI3K/AKT pathway in muscle tissue when normal state and insulin resistance. In normal sate, insulin mediates PI3K/AKT pathway and then regulates glucose transport through activating AS160, glycogen synthesis through inhibiting GSK3 and protein synthesis through activating S6K1 or inhibiting 4E-BP1. When the excess FFAs enters into skeletal muscle, FFAs forms LCACoAs, and then partitioned to the TAG or toward the mitochondria for oxidation fatty acid, which inhibits PI3K/AKT signalling and leads to skeletal muscle insulin resistance. Red and black line indicates inhibition and activation respectively. See text for detailed descriptions.CC BY-NC · PubMed Central

Figure 3 PI3K/AKT pathway in liver and other tissue mediate liver metabolism. PI3K/AKT signal increase DNL in four ways: activating S6K1 and SREBP, inhibiting Lipin1 and GSK3. And inhibits HGP through directly inhibiting FoxO1 or indirectly other tissue PI3K/AKT signaling including adipose, brain and pancreas. Red and black line indicates inhibition and activation respectively. See text for detailed descriptions.CC BY-NC · PubMed Central

Figure 4 PI3K/AKT pathway in normal state and insulin resistance. In normal state, ligand activates PI3K/AKT signalling which inhibits food intake in hypothalamus. And the signalling also inhibits HGP through regulate liver and inhibit lipolysis through regulate adipose tissue. And when the ligand can not pass through BBB, and the ER stress occurs, insulin resistance would occurs in brain, leading to damage PI3K/AKT pathway. Red and black line indicates inhibition and activation respectively. See text for detailed descriptions.CC BY-NC · PubMed Central

Figure 5 In chronic energy excessive conditions, the causes of insulin resistance. In chronic energy excessive conditions, lipid accumulation is saturated and results in an increase in lipolysis in adipose tissue, causing excess FFAs. Lipid ectopic accumulation in skeletal muscle causes reduce of glucose transport and glycogen synthesis; excess circulating FFAs also destroy β cell function and insulin secretion; and in liver, insulin action is normal, but inhibition of extra-hepatic insulin signalling and lipid ectopic accumulation causes increase of HGP and excess insulin causes increasing DNL; and in brain, excess FFAs causes glucose and lipid metabolism disorder. All those ultimately impair PI3K/AKT signal, causing insulin resistance, and insulin resistance further exacerbates PI3K/AKT signalling, forming a vicious circle. Black arrow indicates activation or augment. Red arrow indicates reduction.CC BY-NC · PubMed Central

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Self-citation
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The multifunctional role of bovine colostrum in managing diabetes: clinical insights and potential therapeutic effects
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Salacia Reticulata Extract Improves Insulin Sensitivity and Glucose Homeostasis by Activating Insulin Signaling and Glucagon-like Peptide-1 Modulation
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Effects of dechlorane plus on hepatic pathology, metabolic health and gut microbiota in male mice.
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Effect of Single Session of Swedish Massage on Circulating Levels of Interleukin-6 and Insulin-like Growth Factor 1
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“…functions that relate to the development of obesity and diabetes mellitus by affecting the translocation of GLUT 4 transporter and lipid metabolism via Forkhead box protein O1 (FoxO1), mammalian target of rapamycin complex 1 (mTORC1), and sterol regulatory element-binding proteins (SREBPs) [24,28].”
Background
Modeling sex-specific whole-body metabolic responses to feeding and fasting
Abo, S. M. C., & Layton, A. T. (2024) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2024.109024 · Cited by 5
Cardioprotective Effects of ‘Vasant Kusumakar Rasa,’ a Herbo-metallic Formulation, in Type 2 Diabetic Cardiomyopathy in Rats
Singh, A. D., Chawda, M. B., & Kulkarni, Y. A. (2024) · Cardiovascular Toxicology · doi:10.1007/s12012-024-09891-0 · Cited by 4
“The proper functioning of the PI3K/Akt pathway is necessary for the insulin-dependent regulation of both systemic and cellular metabolism [12, 13].”
Metabolomic and lipidomic profiling of the spinal cord in type 2 diabetes mellitus rats with painful neuropathy
Yu, Z., Yang, J., Jiang, Y., Wei, M., Lyu, Y., Yang, D., Shen, S., Han, Y., & Li, M. (2024) · Metabolic Brain Disease · doi:10.1007/s11011-024-01376-x · Cited by 4
The role and mechanism of VDAC1 in type 2 diabetes: An underestimated target of environmental pollutants
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Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations
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“Specifically, the Pi3k/Akt pathway is dysregulated in T2DM and is also a promising target for NAFLD due to its regulation of downstream Mtor and Srebpc , which induce lipogenesis in the liver (Feng et al., 2022; Huang et al., 2018).”
Background
Landscape of transcriptome‐wide m6A modification in diabetic liver reveals rewiring of PI3K‐Akt signaling after physical exercise
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“8 Proper activation of this pathway is necessary for insulin to work properly, but kinase inhibitors directly targeting PI3K-Akt and its downstream effectors might disrupt the metabolic balance.”
Background
Diverse effects of a Cyperus rotundus extract on glucose uptake in myotubes and adipocytes and its suppression on adipocyte maturation
Pichetkun, V., Khine, H., Srifa, S., Nukulkit, S., Nuengchamnong, N., Hansapaiboon, S., Saenmuangchin, R., Chaotham, C., & Chansriniyom, C. (2024) · Scientific Reports · doi:10.1038/s41598-024-59357-0 · Cited by 4
“Approximately 90% and 10% of postprandial glucose uptake is by skeletal muscle and adipose tissue, respectively 22 .”
High Fat Diet–Wheat Gliadin Interaction and its Implication for Obesity and Celiac Disease Onset: In Vivo Studies
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Sex-based differences in growth-related IGF1 signaling in response to PAPP-A2 deficiency: comparative effects of rhGH, rhIGF1 and rhPAPP-A2 treatments
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“IGF1 elicits transient insulin-like activation of the PI3K p85 subunit, leading to AKT phosphorylation and GSK3 inactivation, and thereby facilitating glycogen synthesis, fatty acid synthesis for storage, cell apoptosis protection and cell cycle progression [64].”
Coconut (Cocos nucifera (L.)) Water Improves Glucose Uptake with Concomitant Modulation of Antioxidant and Purinergic Activities in Isolated Rat Psoas Muscles
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“PI-3 kinase has been reported for its role in insulin signaling and insulin-mediated translocation of GLUT4, thereby driving muscle glucose uptake [46,47].”
Background
Yangyinghuoxue decoction exerts a treatment effect on hepatic fibrosis by PI3K/AKT pathway in rat model: based on the network pharmacology and molecular docking
Bai, Y.-M., Liang, S., & Zhou, B. (2024) · Aging · doi:10.18632/aging.205559 · Cited by 4
Molecular Insights of Nonalcoholic Fatty Liver Disease Pathogenesis
Dawood, R. M., Salum, G. M., El-Meguid, M. A., & Fotouh, B. E.-S. (2024) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2023.0162 · Cited by 4
“Glucose and lipid metabolism are regulated through binding the insulin with insulin receptors that elicit tyrosine phosphorylation and then activate phosphatidylinositol-3-kinase (PI3K/AKT) pathway (Huang et al., 2018).”
Progesterone Receptor Membrane Component 1 Regulates Cellular Stress Responses and Inflammatory Pathways in Chronic Neuroinflammatory Conditions
Jo, S.-L., & Hong, E. (2024) · Antioxidants · doi:10.3390/antiox13020230 · Cited by 6
“However, in insulin-resistant brains, ER stress occurs, leading to impairment of the PI3K/AKT pathway [77,78].”
Background
E4orf1: The triple agent of adenovirus – Unraveling its roles in oncogenesis, infectious obesity and immune responses in virus replication and vector therapy
Göttig, L., & Schreiner, S. (2024) · Tumour Virus Research · doi:10.1016/j.tvr.2024.200277 · Cited by 4
“Insulin resistance in adipose tissue can lead to abnormal glucose metabolism [210,211], causing adipose tissue to become dysfunctional and often enlarged, fostering a pro-inflammatory and hyperlipidemic environment that ultimately promotes adipose hypertrophy and obesity [212].”
Background
The Safety and Efficacy of Combining Saxagliptin and Pioglitazone Therapy in Streptozocin-Induced Diabetic Rats
Othman, A. M., Ibrahim, I. A., Saleh, S. M., Abo–Elmatty, D. M., Mesbah, N. M., & Abdel-Hamed, A. R. (2023) · Biomedicines · doi:10.3390/biomedicines11123300 · Cited by 4
“It mediates growth factor signals and essential cellular processes such as glucose homeostasis, lipid metabolism, protein synthesis, and cell proliferation and survival [17].”
Background
Influence of metabolic stress and metformin on synaptic protein profile in SH‐SY5Y‐derived neurons
Yang, A. J. T., Mohammad, A., Finch, M. S., Tsiani, E., Spencer, G. E., Necakov, A., & MacPherson, R. E. K. (2023) · Physiological Reports · doi:10.14814/phy2.15852 · Cited by 3
“Impairments in Akt action are observed with brain IR and AD, and Akt signaling impairments in the brain play a comparative role in dysregulated insulin action with that seen with T2D and peripheral IR (Huang et al., 2018).”
Background
Functional analysis of differentially expressed circular RNAs in sheep subcutaneous fat
Liu, T., Feng, H., Yousuf, S., Xie, L., & Miao, X. (2023) · BMC Genomics · doi:10.1186/s12864-023-09401-6 · Cited by 4
“PI3K/Akt signaling pathway can reduce liver glucose production and glycogen decomposition, increase the synthesis of glycogen and fatty acids, and store energy for other tissues [61].”
Background
The ameliorating effects of mesenchymal stem cells compared to α‐tocopherol on apoptosis and autophagy in streptozotocin‐induced diabetic rats: Implication of PI3K/Akt signaling pathway and entero‐insular axis
Mubarak, H. A., Kamal, M. M., Mahmoud, Y., Abd-Elsamea, F. S., Abdelbary, E. R., Gamea, M. G., & El-Mahdy, R. I. (2023) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30482 · Cited by 4
“11,45 Therefore, enhanced expression of PI3K, Akt, and PDX ‐ 1 is closely linked to the normal β ‐ cells physiology, whereas reduced activity is related to the dysfunction in insulin biosynthesis and secretion.”
Background
Promotion of Hair Regrowth in Androgenetic Alopecia with Supplemented Erzhi Wan: Exploring Its Mechanism Using Network Pharmacology and Molecular Docking
Ji, C., Ma, J., Feng, C., Zhu, H., Gao, Y., Huang, J. C., Shen, H., & Wei, Y. (2023) · Clinical Cosmetic and Investigational Dermatology · doi:10.2147/ccid.s425295 · Cited by 5
Nε-(Carboxymethyl)lysine (CML) Promotes Disorders of Glucose and Lipid Metabolism in Human Hepatic LO2 Cells
Wu, Y., Wu, Y.-T., Zhang, Z., Cai, J., Zong, M.-H., Li, L., Zhang, X., Wu, H.-C., & Li, B. (2023) · ACS Food Science & Technology · doi:10.1021/acsfoodscitech.3c00176 · Cited by 4
miRDM-rfGA: Genetic algorithm-based identification of a miRNA set for detecting type 2 diabetes
Park, A., & Nam, S. (2023) · BMC Medical Genomics · doi:10.1186/s12920-023-01636-2 · Cited by 4
“Insulin resistance occurs when PI3K signaling is inhibited [59, 60] and has been observed in adipocytes [61, 62], muscle cells [57], the liver [63], and blood [56].”
Background
Exploring the Underlying Mechanism of Alpinia officinarum Hance Ameliorating Diabetic Gastroparesis through Combining Network Pharmacology, Molecular Docking, and in Vivo Experimental Verification.
Zheng, X.-W., Zhang, Y., Xu, J., Li, X.-Y., Wen, H., Zhang, X.-G., Liu, A., & Zhang, J. (2023) · Frontiers in Bioscience · doi:10.31083/j.fbl2808164 · Cited by 4
“Furthermore, a related study has proved that the PI3K-AKT signaling pathway is one of the key insulin signaling pathways involved in the regulation of glucose and lipid metabolism [73].”
Background
Olanzapine manipulates neuroactive signals and may onset metabolic disturbances
Khanal, P., Zargari, F., Dey, Y. N., & Nikfarjam, Z. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2023.2235617 · Cited by 5
“PI3K-Akt signaling pathway has been well documented for the upregulation of the lipid biosynthesis and downregulation of lipolysis which is regulated by SREBP; regulator of fatty acid synthase and FOXO1; regulates the expression of the adipose triglyceride lipase, are considered as the substrates for AKT-metabolism (H…”
A diabetes-like biochemical and behavioural phenotype of Drosophila induced by predator stress
Krama, T., Bahhir, D., Ots, L., Popovs, S., Bartkevičs, V., Pugajeva, I., Krams, R., Merivee, E., Must, A., Rantala, M. J., et al. (2023) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2023.0442 · Cited by 4
“via GLUT4-dependent pathway in muscles), and defects in this pathway are therefore closely associated with the development of diabetes [46].”
Background
Omentin-1 and diabetes: more evidence but far from enough
Xu, J., Li, M., Jiang, X., Wang, Y., Ma, H., Zhou, Y., Tian, M., & Liu, Y. (2023) · Archives of Physiology and Biochemistry · doi:10.1080/13813455.2023.2230380 · Cited by 10
“Pi3K/Akt is a traditional signalling pathway that exerts profound effects on diverse processes, including cell proliferation, survival, and energy metabolism. impaired Pi3K/Akt signalling pathway may lead to insulin resistance, metabolic disorders, and diabetes (Huang et al. 2018).”
Subchronic co-exposure to particulate matter and fructose-rich-diet induces insulin resistance in male Sprague Dawley rats
Jiménez-Chávez, A., Morales-Rubio, R. A., Sánchez-Gasca, E., Rivera-Rosas, M., Uribe-Ramírez, M., Amador-Muñóz, O., Martínez-Domínguez, Y. M., Rosas‐Pérez, I., Choy, E. H. Y., Herman, D. A., et al. (2023) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2023.104115 · Cited by 4
Prognosis and Characterization of Microenvironment in Cervical Cancer Influenced by Fatty Acid Metabolism-Related Genes
Zhou, Y., Zhu, J., Gu, M., & Gu, K. (2023) · Journal of Oncology · doi:10.1155/2023/6851036 · Cited by 4
Neuroprotective effect of Hibiscus sabdariffa extract against high glucose-induced toxicity in Neuro-2a cells and Caenorhabditis elegans
Malar, D. S., Prasanth, M. I., Brimson, J. M., Verma, K., Prasansuklab, A., & Tencomnao, T. (2023) · Nutrition and Healthy Aging · doi:10.3233/nha-220177 · Cited by 7
“Down-regulation of the AKT signaling pathway has been observed under hyperglycemic conditions in cellular models [76, 77].”
Background
Quantitative Proteomic Analysis of Serum Reveals MST1 as a Potential Candidate Biomarker in Spontaneously Diabetic Cynomolgus Monkeys
Tian, C., Qiu, M., Lv, H.-Z., Yue, F., & Zhou, F.-F. (2022) · ACS Omega · doi:10.1021/acsomega.2c05663 · Cited by 4
Sleeve gastrectomy attenuated diabetes-related cognitive decline in diabetic rats
Ding, H., Liu, C., Zhang, S., Li, B., Xu, Q., Shi, B., Li, S., Dong, S., Ma, X., Zhang, Y., et al. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1015819 · Cited by 5
“PI3K was activated by direct interaction with insulin receptor substrate 1 (IRS-1), and then the Akt was phosphorylated, which in turn induced the phosphorylation of GSK3b and ultimately promoted the balance of blood glucose (53).”
Background
IL-25 directly modulates adipocyte function and inflammation through the regulation of adiponectin
Jeerawattanawart, S., Siripurkpong, P., Roytrakul, S., & Angkasekwinai, P. (2022) · Inflammation Research · doi:10.1007/s00011-022-01606-x · Cited by 4
“PI3K/AKT signaling pathway involved in the regulation of metabolic function in adipocytes [46].”
Background
Gypenoside, the main active compound of Gynostemma pentaphyllum, mitigates the Diabetic Nephropathy through down-regulating mTOR
Chen, C., Fu, D., Wu, Y., Huang, C.-H., & Huang, P. (2022) · Clinical Complementary Medicine and Pharmacology · doi:10.1016/j.ccmp.2022.100060 · Cited by 4
Molecular Mechanisms Underlying Reproductive Dysfunction in Polycystic Ovary Syndrome
Kobayashi, H., Shigetomi, H., Nishio, M., Umetani, M., Imanaka, S., & Hashimoto, H. (2026) · Reproductive Sciences · doi:10.1007/s43032-026-02097-5 · Cited by 3
“…PI3K–AKT and subsequently mTORC1, which phosphorylates S6K1 and Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 (4E-BP1) downstream, thereby integratively regulating glucose and lipid metabolism, protein metabolism, cell proliferation, survival, apoptosis, and autophagy [133].”
Metabolic Myokines and Adipokines in the Follicular Microenvironment: Implications for Oocyte Competence and IVF Outcomes
Voros, C., Chatzinikolaou, F. G., Papadimas, G. K., Papapanagiotou, I., Karpouzos, A., Koulakmanidis, A.-M., Athanasiou, D., Bananis, K., Athanasiou, A. I., Athanasiou, A. V., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27083344 · Cited by 3
Glucolipid metabolic disorders and ferroptosis in diabetic ulcers: pathogenic crossroads and therapeutic opportunities
Yeerbao, Z., Li, X., Zhang, L., Du, G., Tang, J., Jiang, S., Ru, X., Li, D.-L., Abulimiti, D., Chen, L., et al. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1760943 · Cited by 3
“…involves a series of key molecules, including the insulin receptor (IR), insulin receptor substrates (IRS), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt) (41), which collectively regulate a broad spectrum of genes and protein functions related to anabolism and cell survival.”
1,1-Diethoxyethane increases insulin sensitivity and ameliorates obesity and dyslipidemia in mice fed high-fat diet
Huu, T. N., Thanh, H. D., Kim, M.-K., Sah, D. K., Trinh, V. H., Yoon, H. J., Choi, J. M., Lee, G.-H., Kim, S., & Lee, S.-R. (2026) · npj Metabolic Health and Disease · doi:10.1038/s44324-025-00094-x · Cited by 3

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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