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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“IRS-1 phosphorylated at the serine site (especially Ser307) can trigger its conformational alternation, becoming an unsuitable substrate to interact with insulin receptors and successively retarding the insulin signal cascade (Huang et al. 2018).”
Background
Influence and treatment of insulin receptor substrate/PI3K/Akt-mediated insulin resistance in diabetes mellitus (Review)
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“Therefore, effective control of insulin resistance is important for the prevention and treat‑ ment of diabetes (86).”

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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