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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Background
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Background
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Yang, S., Zhao, M., Lu, M., Feng, Y., Zhang, X., Wang, D., & Jiang, W.-W. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46060333 · Cited by 10
Cilostazol Attenuates Hepatic Steatosis and Intestinal Disorders in Nonalcoholic Fatty Liver Disease
Min, T., Qiu, S., Bai, Y., Cao, H., Guo, J., & Su, Z.-Q. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25116280 · Cited by 10
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“55 The AKT protein is a core downstream factor of insulin/PI3K/AKT signalling, 56,57 is widely expressed in insulin-sensitive tissues, and can regulate glucose metabolism by inducing downstream molecules such as Glut to enhance glucose uptake.”
Background
Genetic Factors Associated with the Development of Neuropathy in Type 2 Diabetes
Tordai, D. Z., Hajdú, N., Rácz, R., Istenes, I., Békeffy, M. Z., Vági, O. E., Kempler, M., Körei, A. E., Tóbiás, B., Illés, A., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031815 · Cited by 9
“RXRA also activates the PI3K/AKT pathway, which is known to be involved in the development of obesity and T2DM [39].”
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“Correspondingly, PI3K/AKT pathway has been reported to be identified as therapeutic targets of obesity and T2DM [31].”
Background
SIRT1 alleviates insulin resistance and respiratory distress in late preterm rats by activating QKI5-mediated PPARγ/PI3K/AKT pathway
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“Phosphatidylinositide 3-kinases (PI3K) is an intra-cellular phosphatidylinositol kinase, and AKT is a serine/threonine-specific protein kinase that plays a key role in various cell growth processes [19].”
Background
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Praeruptorin C alleviates cognitive impairment in type 2 diabetic mice through restoring PI3K / AKT / GSK3β pathway
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Exercise improves homeostasis of the intestinal epithelium by activation of apelin receptor–AMP‐activated protein kinase signalling
Chae, S. A., Du, ‬., Son, J. S., & Zhu, M. J. (2023) · The Journal of Physiology · doi:10.1113/jp284552 · Cited by 12
“…stimulates mitochondrial biogenesis (Herzig & Shaw, 2018) and browning adipogenesis (Daval et al., 2006; Desjardins & Steinberg, 2018); and (2) APJ-dependent Gαi activation (Nakano et al., 2017) in promoting lipolysis (Choi et al., 2010; Huang et al., 2018) and cell proliferation (Yu & Cui, 2016).”
Background
Antidiabetic potential of Chlorella pyrenoidosa functional formulations in streptozocin-induced type 2 diabetic mice
Huang, Z.-F., Chen, J., Wang, C., Xiao, M., Zhu, Y., Li, N., Huang, Z.-R., Liu, B., & Huang, Y. (2023) · Journal of Functional Foods · doi:10.1016/j.jff.2023.105489 · Cited by 10
Association between lipid peroxidation biomarkers and microRNA expression profiles
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Background
Short variation of the sheep PDGFD gene is correlated with litter size
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Harnessing Phytochemicals and Nanotechnology Synergy for Molecular, Epigenetic, and Microbiota-Driven Regulation in Type 2 Diabetes Mellitus
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“It has been shown that the PI3K-AKT signaling pathway [59, 60] is associated with numerous complications of T2DM, which is consistent with our study.”
Glabridin Alleviates Metabolic Disorders in Diet‐Induced Diabetic Mice
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“In metabolic tissues like the liver and muscle, AKT coordinates the balance between lipid synthesis and oxidation (Huang et al. 2018; Ma et al. 2024).”
Imo-induced changes in gut hormones and glucose metabolism: A key to improving insulin sensitivity in type 2 diabetes
Naseem, S., & Rizwan, M. (2025) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2025.112285 · Cited by 10
The Combined Effect of High-Intensity Interval Training and Time-Restricted Feeding on the AKT-IGF-1-mTOR Signaling Pathway in the Muscle Tissue of Type 2 Diabetic Rats
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“The AKT3-mTOR-IGF-1 signaling pathway plays a crucial role in regulating glucose uptake in muscle cells, acting as a key mechanism for insulin sensitivity and muscle metabolism [56].”
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FER1L6 ameliorates insulin resistance by regulating GLUT4 expression
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Background
BI-7273, a BRD9 inhibitor, reduces lipid accumulation by downregulating the AKT/mTOR/SREBP1 signaling pathway.
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Dietary butyrate promoted nutrient deposition by increasing carbohydrate utilization and energy supply in Scylla paramamosain
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Stilbenoids from fenugreek seeds alleviate insulin resistance by regulating the PI3K/AKT/mTOR signaling pathway in a type 2 diabetes zebrafish model
Gao, Y.-D., Wu, Y., Tie, F., & Wang, H.-L. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e32007 · Cited by 9
“The PI3K/AKT signaling pathway is necessary for normal metabolism due to its own characteristics, and its imbalance can lead to the development of obesity and T2DM [52].”
Background
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Background
Antidiabetic Effect of Urolithin A in Cultured L6 Myotubes and Type 2 Diabetic Model KK-Ay/Ta Mice with Glucose Intolerance
Kondo, S., Adachi, S.-I., Komatsu, W., Yoshizawa, F., & Yagasaki, K. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46020068 · Cited by 9
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Background
In vitro and in silico analysis proving DPP4 inhibition and diabetes-associated gene network modulation by a polyherbal formulation: Nisakathakadi Kashaya
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“The other critical markers were insulin signalling molecules like AKT1 and PI3K, demonstrating that these core pathways involved in diabetic pathogenesis can be regulated by the multitargeted action of NK (Huang et al., 2018).”
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Liu, G., Yang, L., Tang, Y.-F., Lin, J.-C., Wang, F., Shen, J., Chang, B., & Kong, X.-N. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.117330 · Cited by 9
Self-citation
In Silico Investigation of AKT2 Gene and Protein Abnormalities Reveals Potential Association with Insulin Resistance and Type 2 Diabetes
Elnageeb, M. E., Elfaki, I., Adam, M. I. E., Adam, K. M., Alameen, A. O., Elfadl, A. K., Albalawi, I. A., Almasoudi, K. S., Almotairi, R., Alsaedi, B. S. O., et al. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45090471 · Cited by 9
Chinese Sumac Fruits (Rhus chinesis Mill.) Alleviate Type 2 Diabetes in C57BL/6 Mice through Repairing Islet Cell Functions, Regulating IRS-1/PI3K/AKT Pathways and Promoting the Entry of Nrf2 into the Nucleus
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“Adjust Zang and arouse spirit” electroacupuncture ameliorates cognitive impairment by reducing endoplasmic reticulum stress in db/db mice
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“When the insulin signaling pathway is abnormal, the phosphorylation expression of PI3K and AKT is significantly reduced (24).”
Background
Current and future approaches for in vitro hit discovery in diabetes mellitus
Zhang, X., Kupczyk, E., Schmitt‐Kopplin, P., & Mueller, C. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.07.016 · Cited by 13
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Unraveling the Systems Biology of Curcumin: A Mini-review of its Anti-diabetic Potential through Network Pharmacology
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Mitochondrial Peroxiredoxins and Monoamine Oxidase-A: Dynamic Regulators of ROS Signaling in Cardioprotection
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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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