The PI3K/AKT Pathway in Obesity and Type 2 Diabetes

Huang, Xingjun; Liu, Guihua; Guo, Jiao; Su, Zhengquan

doi:10.7150/ijbs.27173

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

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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AKT activation leads to increased glucose transporter 4 (GLUT4) expression and translocation, ultimately leading to increased glucose uptake.
“AKT activation leads to increased glucose transporter 4 (GLUT4) expression and translocation, ultimately leading to increased glucose uptake.”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [48]
PI3K is an enzyme that activates protein kinase B (AKT), which regulates glucose metabolism.
“PI3K is an enzyme that activates protein kinase B (AKT), which regulates glucose metabolism, among other intracellular functions [48].”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [48]

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“In the hypothalamic arcuate nucleus (ARC), anorexigenic proopiomelanocortin (POMC) and orexigenic AgRP coordinately regulate food intake and energy expenditure, as well as peripheral tissue glucose homeostasis and energy partitioning through insulin, leptin and nutrients [111].”
Background
Dose-response curves for in vivo insulin sensitivity in individual tissues in rats
Kraegen, E. W., James, D. E., Jenkins, A. B., & Chisholm, D. J. (1985) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1985.248.3.e353 · Cited by 409 · cited 1× · see citing works
“Approximately 90% of insulin-stimulated glucose utilization occurs in skeletal muscle and plays an important role in regulating glucose metabolism and energy homeostasis [36].”
Background
Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid–induced insulin resistance
Schenk, S., & Horowitz, J. F. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30566 · Cited by 407 · cited 3× · see citing works
“In early studies, insulin resistance was thought to be accompanied by excessive intramyocellular lipid (IMCL) levels [49], and improved insulin sensitivity observed in subjects with T2DM by reduced IMCL levels [50].”
Background
Central nervous system control of metabolism
Myers, M. G., & Olson, D. P. (2012) · Nature · doi:10.1038/nature11705 · Cited by 399 · cited 2× · see citing works
“In the presence of persistent excess energy availability, leptin signalling activates other pathways, such as STAT3 or SH2-containing tyrosine phosphatase, to predominantly regulate food intake in POMC neurons [90, 113, 119].”
Background
Insulin resistance and impaired adipogenesis
Gustafson, B., Hedjazifar, S., Gogg, S., Hammarstedt, A., & Smith, U. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.01.006 · Cited by 398 · cited 2× · see citing works
“In the presence of adipose hypertrophy, insulin resistance also occurs because of the expansion of adipose tissues exceeds their storage capacity [45, 78, 79].”
Background
Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1
Lu, M., Wan, M., Leavens, K. F., Chu, Q., Monks, B. R., Fernandez, S., Ahima, R. S., Ueki, K., Kahn, C. R., & Birnbaum, M. J. (2012) · Nature Medicine · doi:10.1038/nm.2686 · Cited by 392 · cited 3× · see citing works
“Additionally, those mice still maintained the normal postprandial state, even in the absence of canonical liver insulin signalling [85, 87].”
BackgroundResult
Direct Insulin and Leptin Action on Pro-opiomelanocortin Neurons Is Required for Normal Glucose Homeostasis and Fertility
Hill, J. W., Elias, C. F., Fukuda, M., Williams, K. W., Berglund, E. D., Holland, W. L., Cho, Y.-R., Chuang, J.-C., Xu, Y., Choi, M., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.002 · Cited by 391 · cited 1× · see citing works
“The selective inactivation of IR in AgRP neurons in mice results in an inability to suppress HGP whereas only a deficiency in both leptin and IRs in POMC neurons resulted in systemic insulin resistance [45, 129].”
Background
PtdIns(3,4,5) P 3-Dependent Activation of the mTORC2 Kinase Complex
Liu, P., Gan, W., Chin, Y. R., Ogura, K., Guo, J., Zhang, J., Wang, B., Blenis, J., Cantley, L. C., Toker, A., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0460 · Cited by 385 · cited 1× · see citing works
“First, phosphorylation of the threonine 308 (AKT1) in the kinase domain by phosphoinositide-dependent protein kinase 1 (PDK1) initiates the activation process [19], subsequent phosphorylation at serine 473 (AKT1) in the carboxy-terminal regulatory domain through mTOR complex 2 (mTORC2)[17, 20], which is activated by a…”
BackgroundSelf-citation
The PI3K/AKT Pathway and Renal Cell Carcinoma
Guo, H., Germán, P., Bai, S., Barnes, S., Guo, W., Qi, X., Lou, H., Liang, J., Jonasch, E. W., Mills, G. B., et al. (2015) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2015.03.003 · Cited by 373 · cited 2× · see citing works
“Phosphoinositide 3-kinase (PI3K) was discovered in 1985 and identified as a previously unknown phosphoinositide kinase [7, 8].”
Background
Potential Role of Protein Kinase B in Insulin-induced Glucose Transport, Glycogen Synthesis, and Protein Synthesis
Ueki, K., Yamamoto‐Honda, R., Kaburagi, Y., Yamauchi, T., Tobe, K., Burgering, B. M. T., Coffer, P. J., Komuro, I., Akanuma, Y., Yazaki, Y., et al. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.9.5315 · Cited by 356 · see citing works
Irisin inhibits hepatic gluconeogenesis and increases glycogen synthesis via the PI3K/Akt pathway in type 2 diabetic mice and hepatocytes.
Liu, T.-Y., Shi, C.-X., Gao, R., Sun, H.-J., Xiong, X.-Q., Ding, L., Chen, Q., Li, Y.-H., Wang, J.-J., Kang, Y.-M., et al. (2015) · Clinical science · doi:10.1042/cs20150009 · Cited by 352 · see citing works
Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents
Benoit, S. C., Kemp, C. J., Elias, C. F., Abplanalp, W., Herman, J. P., Migrenne, S., Lefevre, A.-L., Cruciani-Guglielmacci, C., Magnan, C., Yu, F., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci36714 · Cited by 351 · cited 1× · see citing works
“Insulin signalling is blocked during insulin resistance in the brain due to increased protein kinase C (PKC) activity, ER stress and inflammation [134, 135], which blocks the ability of PI3K to generate PIP3.”
Background
Regulation of Glucose-6-phosphatase Gene Expression by Protein Kinase Bα and the Forkhead Transcription Factor FKHR
Schmoll, D., Walker, K. S., Alessi, D. R., Grempler, R., Burchell, A., Guo, S., Walther, R., & Unterman, T. G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003616200 · Cited by 349 · cited 1× · see citing works
“In previous studies, insulin suppressed PEPCK and G6PC expression, which are known to increase hepatic gluconeogenesis by activating the PI3K/AKT pathway [84-86].”
Background
Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice
Hill, J. W., Williams, K. W., Ye, C., Luo, J., Balthasar, N., Coppari, R., Cowley, M. A., Cantley, L. C., Lowell, B. B., & Elmquist, J. K. (2008) · Journal of Clinical Investigation · doi:10.1172/jci32964 · Cited by 348 · cited 2× · see citing works
“In the presence of persistent excess energy availability, leptin signalling activates other pathways, such as STAT3 or SH2-containing tyrosine phosphatase, to predominantly regulate food intake in POMC neurons [90, 113, 119].”
Background
The Akt-SREBP nexus: cell signaling meets lipid metabolism.
Krycer, J., Sharpe, L. J., Luu, W., & Brown, A. J. (2010) · Trends in endocrinology and metabolism · doi:10.1016/j.tem.2010.01.001 · Cited by 347 · cited 4× · see citing works
“AKT regulates lipid metabolism through sterol regulatory element-binding proteins (SREBP), which increases cholesterol and fatty acid accumulation, including SREBP-1c, SREBP-1a, and SREBP-2[18, 34].”
BackgroundInfluential
Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function
Kahn, S. E., Prigeon, R. L., McCulloch, D. K., Boyko, E. J., Bergman, R. N., Schwartz, M. W., Neifing, J. L., Ward, W. K., Beard, J. C., Palmer, J. P., et al. (1993) · Diabetes · doi:10.2337/diabetes.42.11.1663 · Cited by 328 · see citing works
PI3K/Akt signaling in osteosarcoma
Zhang, J., Yu, X., Yan, Y., Wang, C., & Wang, W. (2015) · Clinica Chimica Acta · doi:10.1016/j.cca.2014.12.041 · Cited by 328 · cited 6× · see citing works
“First, phosphorylation of the threonine 308 (AKT1) in the kinase domain by phosphoinositide-dependent protein kinase 1 (PDK1) initiates the activation process [19], subsequent phosphorylation at serine 473 (AKT1) in the carboxy-terminal regulatory domain through mTOR complex 2 (mTORC2)[17, 20], which is activated by a…”
BackgroundInfluential
Hypothalamic nutrient sensing in the control of energy homeostasis
Blouet, C., & Schwartz, G. J. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.12.024 · Cited by 321 · cited 1× · see citing works
“However, mTOR1 signalling is required for glucose homeostasis in the hypothalamus [126, 127].”
Background
Enzymatic Reduction of Oxysterols Impairs LXR Signaling in Cultured Cells and the Livers of Mice
Chen, W., Chen, G., Head, D. L., Mangelsdorf, D. J., & Russell, D. W. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2006.11.012 · Cited by 316 · cited 1× · see citing works
“In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nuclear SREBP-1c [65, 6…”
Background
Interplay between FOXO, TOR, and Akt
Hay, N. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.03.013 · Cited by 311 · cited 3× · see citing works
“AKT regulates lipid metabolism through sterol regulatory element-binding proteins (SREBP), which increases cholesterol and fatty acid accumulation, including SREBP-1c, SREBP-1a, and SREBP-2[18, 34].”
Background
Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3
Lee, J. H., Budanov, A. V., Talukdar, S., Park, E. J., Park, H. L., Park, H.-W., Bandyopadhyay, G., Li, N., Aghajan, M., Jang, I., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.08.004 · Cited by 295 · cited 1× · see citing works
“MCF7-tet OFF Sesn2F cells Sestrins (Sesn1/2/3) through activation of AMPK and mTORC2, which is necessary for activation of AKT Regulate both glucose and lipid metabolism [164, 165]”
Background
AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue
Steculorum, S. M., Ruud, J., Karakasilioti, I., Backes, H., Engström, L., Timper, K., Hess, M. E., Tsaousidou, E., Mauer, J., Vogt, M. C., et al. (2016) · Cell · doi:10.1016/j.cell.2016.02.044 · Cited by 284 · see citing works
Leptin signalling pathways in hypothalamic neurons
Kwon, O., Kim, K. W., & Kim, M. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2133-1 · Cited by 283 · cited 1× · see citing works
“Leptin is the most important hormone reported to date that regulates food intake and energy balance [110].”
Background
Direct Hepatocyte Insulin Signaling Is Required for Lipogenesis but Is Dispensable for the Suppression of Glucose Production
Titchenell, P. M., Quinn, W. J., Lu, M., Chu, Q., Lu, W., Li, C., Chen, H., Monks, B. R., Chen, J., Rabinowitz, J. D., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.022 · Cited by 281 · see citing works
Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase
Owen, J., Zhang, Y., Bae, S., Farooqi, M., Liang, G., Hammer, R., Goldstein, J., & Brown, M. S. (2012) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1213343109 · Cited by 276 · cited 1× · see citing works
“In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nuclear SREBP-1c [65, 6…”
Background
Brain Insulin Controls Adipose Tissue Lipolysis and Lipogenesis
Scherer, T., O’Hare, J., Diggs‐Andrews, K. A., Schweiger, M., Cheng, B., Lindtner, C., Zieliński, E., Vempati, P., Su, K., Dighe, S. V., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.01.008 · Cited by 262 · see citing works
Dynamic Functional Relay between Insulin Receptor Substrate 1 and 2 in Hepatic Insulin Signaling during Fasting and Feeding
Kubota, N., Kubota, T., Itoh, S., Kumagai, H., Kozono, H., Takamoto, I., Mineyama, T., Ogata, H., Tokuyama, K., Ohsugi, M., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.05.007 · Cited by 244 · cited 1× · see citing works
“increases glycogen synthesis and the synthesis of fatty acids for storage and subsequent utilization by other tissues [82, 83].”
Background
GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI3K/Akt pathway.
Anitha, M., Gondha, C., Sutliff, R., Parsadanian, A., Mwangi, S., Sitaraman, S., & Srinivasan, S. (2006) · Journal of Clinical Investigation · doi:10.1172/jci26295 · Cited by 243 · cited 1× · see citing works
“Pancreatic beta-cell glial cell line-derived neurotrophic factor (GDNF) Activates phosphorylation of AKT improves glucose tolerance and β cell mass [157, 158]”
Background
Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus
Hesselink, M. K. C., Schrauwen-Hinderling, V., & Schrauwen, P. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.104 · Cited by 242 · cited 1× · see citing works
“Excessive fatty acid oxidation in the mitochondria via the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) increases the production of fatty acid metabolites and reactive oxygen species (ROS), subsequently activated intracellular stress kinases to inhibit IRS-1 and possibly exerting effects on in…”
Background
FoxO1, the transcriptional chief of staff of energy metabolism
Kousteni, S. (2011) · Bone · doi:10.1016/j.bone.2011.06.034 · Cited by 240 · cited 2× · see citing works
“AKT directly inhibits FoxO1, reducing glucose levels [31], FoxO1”
Background
PI3K‐independent AKT activation in cancers: A treasure trove for novel therapeutics
Mahajan, K. N., & Mahajan, N. P. (2012) · Journal of Cellular Physiology · doi:10.1002/jcp.24065 · Cited by 229 · cited 1× · see citing works
“Although several studies have reported an absolute requirement for PI3K in AKT activation, AKT activation has also been suggested to be mediated by a PI3K-independent mechanism [27].”
Background
S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction
Yang, L., Calay, E. S., Fan, J., Arduini, A., Kunz, R. C., Gygi, S. P., Yalçın, A., Fu, S., & Hotamışlıgil, G. S. (2015) · Science · doi:10.1126/science.aaa0079 · Cited by 229 · cited 1× · see citing works
“Chronic metabolic inflammation and endoplasmic reticulum (ER) stress also impair hepatic insulin-AKT signalling and subsequently causes insulin resistance [106, 107].”
Background
FoxO1 Controls Insulin-dependent Adipose Triglyceride Lipase (ATGL) Expression and Lipolysis in Adipocytes*
Chakrabarti, P., & Kandror, K. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.c800241200 · Cited by 226 · cited 4× · see citing works
“The substrate SREBP, which regulates fatty acid synthase and cholesterol-related genes [18, 61], and FOXO1, which regulates lipolysis by controlling the expression of adipose triglyceride lipase (ATGL) [62], are primary substrates for AKT-mediated lipid metabolism [63].”
BackgroundInfluential
Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced Akt activity in pancreatic islet β cells
Bernal‐Mizrachi, E., Fátrai, S., Johnson, J. D., Ohsugi, M., Otani, K., Han, Z., Polonsky, K. S., & Permutt, M. A. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20016 · Cited by 223 · cited 1× · see citing works
“In contrast, overexpression of a kinase dead mutant in β cells, which reduced AKT activity by 80%, results in a lack of insulin secretion [145].”
Background
Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling
Peng, M., Yin, N., & Li, M. O. (2014) · Cell · doi:10.1016/j.cell.2014.08.038 · Cited by 220 · cited 1× · see citing works
“MCF7-tet OFF Sesn2F cells Sestrins (Sesn1/2/3) through activation of AMPK and mTORC2, which is necessary for activation of AKT Regulate both glucose and lipid metabolism [164, 165]”
Background
From chronic overnutrition to insulin resistance: The role of fat-storing capacity and inflammation
Lionetti, L., Mollica, M. P., Lombardi, A., Cavaliere, G., Gifuni, G., & Barletta, A. (2009) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2008.10.010 · Cited by 217 · cited 1× · see citing works
“However, this process triggers the ectopic accumulation of lipids and subsequently causes lipotoxicity and insulin resistance [75].”
Background
Synergy in activating class I PI3Ks
Burke, J. E., & Williams, R. L. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.12.003 · Cited by 216 · cited 1× · see citing works
“RTKs recruit class I PI3Ks to the plasma membrane, which relieves the inactivation function of p85 and p110 to activate the protein [12, 13].”
Background
Insulin Regulates Adipocyte Lipolysis via an Akt-Independent Signaling Pathway
Choi, S. M., Tucker, D. F., Gross, D. N., Easton, R., DiPilato, L. M., Dean, A. S., Monks, B. R., & Birnbaum, M. J. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00797-10 · Cited by 211 · cited 5× · see citing works
“In the fed state, PI3K/AKT inhibits protein kinase A (PKA) and thus suppresses lipolysis.”
BackgroundInfluential
Leptin inhibits hypothalamic Npy and Agrp gene expression via a mechanism that requires phosphatidylinositol 3-OH-kinase signaling
Morrison, C. D., Morton, G. J., Niswender, K. D., Gelling, R. W., & Schwartz, M. W. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00094.2005 · Cited by 210 · cited 1× · see citing works
“Leptin requires intact PI3K signalling to promote hypothalamic expression of POMC genes and inhibit expression of the NPY and AgRP genes [113, 114].”
Background
Hepatic Insulin Signaling Is Required for Obesity-Dependent Expression of SREBP-1c mRNA but Not for Feeding-Dependent Expression
Haas, J. T., Miao, J., Chanda, D., Wang, Y., Zhao, E., Haas, M. E., Hirschey, M. D., Vaitheesvaran, B., Farese, R. V., Kurland, I. J., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.05.002 · Cited by 207 · cited 2× · see citing works
“In normal physiology, feeding is able to activate synthesis of SREBP-1c via insulin-dependent pathway (mTORC1) or insulin-independent pathway (carbohydrate response element binding protein (ChREBP)) [59, 60].”
Background
Free fatty acids and skeletal muscle insulin resistance
Kraegen, E. W., & Cooney, G. J. (2008) · Current Opinion in Lipidology · doi:10.1097/01.mol.0000319118.44995.9a · Cited by 206 · cited 3× · see citing works
“Excessive fatty acid oxidation in the mitochondria via the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) increases the production of fatty acid metabolites and reactive oxygen species (ROS), subsequently activated intracellular stress kinases to inhibit IRS-1 and possibly exerting effects on in…”
Background
ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver
Denechaud, P., Bossard, P., Lobaccaro, J. A., Millatt, L. J., Staels, B., Girard, J. R., & Postic, C. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34314 · Cited by 205 · cited 1× · see citing works
“In normal physiology, feeding is able to activate synthesis of SREBP-1c via insulin-dependent pathway (mTORC1) or insulin-independent pathway (carbohydrate response element binding protein (ChREBP)) [59, 60].”
Background
Rapid activation of Akt2 is sufficient to stimulate GLUT4 translocation in 3T3-L1 adipocytes.
Ng, Y., Ramm, G., Lopez, J., & James, D. E. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.02.008 · Cited by 204 · cited 1× · see citing works
“Previous research has found knockout or knockdown of AKT or IRS adaptor proteins obviously reduce insulin-induced glucose uptake, whereas overexpression of AKT increases glucose uptake [37].”
Background
FoxO1 Target Gpr17 Activates AgRP Neurons to Regulate Food Intake
Ren, H., Orozco, I. J., Su, Y., Suyama, S., Juárez, R. G., Horváth, T. L., Wardlaw, S. L., Plum, L., Arancio, O., & Accili, D. (2012) · Cell · doi:10.1016/j.cell.2012.04.032 · Cited by 201 · cited 1× · see citing works
“Recently, Gpr17, the target of FoxO1, was shown to regulate feeding and sensitivity through insulin and leptin in AgRP neurons [117, 118].”
Background
Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors
Haeusler, R. A., Hartil, K., Vaitheesvaran, B., Arrieta‐Cruz, I., Knight, C. M., Cook, J. R., Kammoun, H. L., Febbraio, M. A., Juárez, R. G., Kurland, I. J., et al. (2014) · Nature Communications · doi:10.1038/ncomms6190 · Cited by 192 · cited 1× · see citing works
“The role of FoxO1 in liver lipid metabolism is less well studied; some studies have shown that FoxO1 is directly associated with insulin-promoted expression of fat genes in the liver, whereas others have reported a permissive role for FoxO1 in these processes [100-102].”
Background
Leptin at the Intersection of Neuroendocrinology and Metabolism: Current Evidence and Therapeutic Perspectives
Dalamaga, Μ., Chou, S. H.-H., Shields, K. S., Papageorgiou, P., Pοlyzos, S. A., & Mantzoros, C. S. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.05.010 · Cited by 191 · cited 1× · see citing works
“As shown in a previous study, acute activation of mTOR1 promotes the ability of hypothalamic neural circuits to sense the nutritional milieu and regulate feeding [122, 123].”
Background
PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K
Malek, M., Kielkowska, A., Chessa, T., Anderson, K. E., Barneda, D., Pir, P., Nakanishi, H., Eguchi, S., Koizumi, A., Sasaki, J., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.09.024 · Cited by 190 · see citing works
Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes
Scheen, A. J., & Gaal, L. F. V. (2014) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(14)70004-x · Cited by 190 · cited 1× · see citing works
“Both obesity and T2DM are associated with insulin resistance [6].”
Background
Critical Role for Hypothalamic mTOR Activity in Energy Balance
Mori, H., Inoki, K., Münzberg, H., Opland, D. M., Faouzi, M., Villanueva, E. C., Ikenoue, T., Kwiatkowski, D. J., MacDougald, O. A., Myers, M. G., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.03.005 · Cited by 188 · cited 1× · see citing works
“As shown in a previous study, acute activation of mTOR1 promotes the ability of hypothalamic neural circuits to sense the nutritional milieu and regulate feeding [122, 123].”
Background
Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats
Carvalheira, J. B. C., Ribeiro, E. B., Ara�jo, E. P., Guimar�es, R. B., Telles, M. M., Torsoni, M., Gontijo, J. A. R., Velloso, L. A., & Saad, M. J. A. (2003) · Diabetologia · doi:10.1007/s00125-003-1246-x · Cited by 176 · cited 1× · see citing works
“Leptin and insulin-mediate PI3K/AKT signalling is impaired in the brains of obese subjects with insulin resistance [132].”
Background
Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats
Ono, H., Pocai, A., Wang, Y., Sakoda, H., Asano, T., Backer, J., Schwartz, G. J., & Rossetti, L. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34277 · Cited by 175 · see citing works
PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling
Braccini, L., Ciraolo, E., Campa, C. C., Perino, A., Longo, D. L., Tibolla, G., Pregnolato, M., Cao, Y., Tassone, B., Damilano, F., et al. (2015) · Nature Communications · doi:10.1038/ncomms8400 · Cited by 175 · cited 1× · see citing works
“Recently, endomembranes that contain PIP3 and PIP2 have also been shown to directly contribute to AKT activation [25, 26].”
Background
Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo
Titchenell, P. M., Chu, Q., Monks, B. R., & Birnbaum, M. J. (2015) · Nature Communications · doi:10.1038/ncomms8078 · Cited by 169 · cited 3× · see citing works
“Additionally, those mice still maintained the normal postprandial state, even in the absence of canonical liver insulin signalling [85, 87].”
BackgroundResult
Imbalanced Insulin Actions in Obesity and Type 2 Diabetes: Key Mouse Models of Insulin Signaling Pathway
Kubota, T., Kubota, N., & Kadowaki, T. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.03.004 · Cited by 169 · cited 1× · see citing works
“including protecting tissues and organs from cold and hot, thermogenesis and the production of various hormones/cytokines that are collectively referred to as cytokines [56, 57].”
Background
The Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance
Pagel-Langenickel, I., Bao, J., Pang, L., & Sack, M. N. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0003 · Cited by 154 · cited 1× · see citing works
“Excessive lipid production and impaired disposal may promote the development of insulin resistance and diabetes in the skeletal muscle [47, 48].”
Background
High-fat diet, muscular lipotoxicity and insulin resistance
Schrauwen, P. (2007) · Proceedings of the Nutrition Society · doi:10.1017/s0029665107005277 · Cited by 153 · cited 1× · see citing works
“In early studies, insulin resistance was thought to be accompanied by excessive intramyocellular lipid (IMCL) levels [49], and improved insulin sensitivity observed in subjects with T2DM by reduced IMCL levels [50].”
Background
Lipid Mediators of Insulin Resistance
Holland, W. L., Knotts, T. A., Chavez, J. A., Wang, L.-P., Hoehn, K. L., & Summers, S. A. (2008) · Nutrition Reviews · doi:10.1111/j.1753-4887.2007.tb00327.x · Cited by 147 · cited 1× · see citing works
“In the presence of insulin resistance, the level of free fatty acids increases in the body resulting in the accumulation of intramyocellular lipids, such as DAG and ceramides [52].”
Background
FoxO1 Inhibits Sterol Regulatory Element-binding Protein-1c (SREBP-1c) Gene Expression via Transcription Factors Sp1 and SREBP-1c
Deng, X., Zhang, W., O‐Sullivan, I., Williams, J. B., Dong, Q., Park, E. A., Raghow, R., Unterman, T. G., & Elam, M. B. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.347211 · Cited by 147 · cited 1× · see citing works
“The role of FoxO1 in liver lipid metabolism is less well studied; some studies have shown that FoxO1 is directly associated with insulin-promoted expression of fat genes in the liver, whereas others have reported a permissive role for FoxO1 in these processes [100-102].”
Background
A Phosphorylation Cascade Controls the Degradation of Active SREBP1*
Bengoechea-Alonso, M., & Ericsson, J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m807906200 · Cited by 144 · cited 9× · see citing works
“In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nuclear SREBP-1c [65, 6…”
BackgroundInfluential
Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity
Kubota, N., Kubota, T., Kajiwara, E., Iwamura, T., Kumagai, H., Watanabe, T., Inoue, M., Takamoto, I., Sasako, T., Kumagai, K., et al. (2016) · Nature Communications · doi:10.1038/ncomms12977 · Cited by 143 · cited 1× · see citing works
“And recent study finds Irs2-knockout mice develop ‘selective insulin resistance’, whereas mice lacking in Irs1, or both Irs1 and Irs2, develop ‘total insulin resistance’, which indicates the IRS 1/2 are the cause of insulin selective resistance [109]; in the second, hepatic insulin signalling remains intact but the ce…”
Background
Postprandial Hepatic Lipid Metabolism Requires Signaling though Akt2 Independent of the Transcription Factors FoxA2, FoxO1 and SREBP1c
Wan, M., Leavens, K. F., Saleh, D., Easton, R., Guertin, D., Peterson, T. R., Kaestner, K., Sabatini, D., & Birnbaum, M. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.09.001 · Cited by 138 · cited 1× · see citing works
“However, in the absence of AKT2, the activation of mTORC1 and SREBP-1c is not sufficient to drive postprandial lipid generation [99].”
Background
FOXO1 in the ventromedial hypothalamus regulates energy balance
Kim, K. W., Donato, J., Berglund, E. D., Choi, Y., Kohno, D., Elias, C. F., DePinho, R. A., & Elmquist, J. K. (2012) · Journal of Clinical Investigation · doi:10.1172/jci62848 · Cited by 137 · cited 1× · see citing works
“In a subsequent study, leptin and insulin were shown to coordinately regulate FoxO1 activity, increasing the expression of NPY and AgRP and suppressing POMC expression [115, 116].”
Background
Targeting glycogen synthase kinase-3 (GSK-3) in the treatment of Type 2 diabetes
Macaulay, K., & Woodgett, J. (2008) · Expert opinion on therapeutic targets · doi:10.1517/14728222.12.10.1265 · Cited by 127 · see citing works
PHLPP-1 Negatively Regulates Akt Activity and Survival in the Heart
Miyamoto, S., Purcell, N. H., Smith, J. M., Gao, T., Whittaker, R., Huang, K., Castillo, R., Glembotski, C. C., Sussman, M. A., Newton, A. C., et al. (2010) · Circulation Research · doi:10.1161/circresaha.109.215020 · Cited by 127 · see citing works
Tissue and isoform-selective activation of protein kinase C in insulin-resistant obese Zucker rats - effects of feeding.
Qu, X.-Q., Seale, J., & Donnelly, R. (1999) · Journal of Endocrinology · doi:10.1677/joe.0.1620207 · Cited by 123 · cited 1× · see citing works
“Meanwhile, excessive oxidation of FFAs increases the hepatic acetyl-CoA content and thus activates pyruvate carboxylase, which is required for gluconeogenesis [45], and increases DAG levels, which impair PI3K/AKT pathway and exacerbate insulin resistance [48, 105].”
Background
Electrical Stimuli Release ATP to Increase GLUT4 Translocation and Glucose Uptake via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells
Osorio‐Fuentealba, C., Contreras‐Ferrat, A. E., Altamirano, F. J., Espinosa, A., Li, Q., Niu, W., Lavandero, S., Klip, A., & Jaimovich, E. (2012) · Diabetes · doi:10.2337/db12-1066 · Cited by 121 · cited 1× · see citing works
“AKT directly phosphorylates AS160, inducing GLUT4 translocation, which translocated to the plasma membrane from storage vesicles and transports glucose in skeletal muscle following stimulation of insulin and AKT [38, 39].”
Background
Regulation of angiogenesis by PI3K signaling networks
Graupera, M., & Potente, M. (2013) · Experimental Cell Research · doi:10.1016/j.yexcr.2013.02.021 · Cited by 116 · cited 1× · see citing works
“Class I PI3K is a heterodimer and is divided into class IA and class IB, according to differences in the molecular structure [11].”
Background
FAM3A Activates PI3K p110α/Akt Signaling to Ameliorate Hepatic Gluconeogenesis and Lipogenesis
Wang, C., Chi, Y., Li, J., Miao, Y., Li, S., Su, W., Shi, J., Chen, Z., Du, S., Zhang, X., et al. (2013) · Hepatology · doi:10.1002/hep.26945 · Cited by 115 · see citing works
Emerging evidence of signalling roles for PI(3,4)P2 in Class I and II PI3K-regulated pathways
Hawkins, P. T., & Stephens, L. (2016) · Biochemical Society Transactions · doi:10.1042/bst20150248 · Cited by 110 · cited 1× · see citing works
“PIP2 is synthesized by class II PI3Ks using PIP as substrate [16].”
Method
Influence of mTOR in energy and metabolic homeostasis
Haissaguerre, M., Saucisse, N., & Cota, D. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.07.015 · Cited by 108 · cited 1× · see citing works
“However, mTOR1 signalling is required for glucose homeostasis in the hypothalamus [126, 127].”
Background
Central GLP-2 Enhances Hepatic Insulin Sensitivity via Activating PI3K Signaling in POMC Neurons
Shi, X., Zhou, F., Li, X., Chang, B. H.-J., Li, D., Wang, Y., Tong, Q., Xu, Y., Fukuda, M., Zhao, J. J., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.06.014 · Cited by 104 · cited 1× · see citing works
“Recently, Another ligand, glucagon-like peptide (GLP-2), it was recently shown to play a key role in the control of HGP through the PI3K/AKT pathway[131], suggesting that in addition to insulin and leptin, GLP-2 also regulates HGP through PI3K/AKT signalling.”
Background
NFE2 Induces miR-423-5p to Promote Gluconeogenesis and Hyperglycemia by Repressing the Hepatic FAM3A-ATP-Akt Pathway
Yang, W., Wang, J., Chen, Z., Chen, J., Meng, Y., Chen, L., Chang, Y., Geng, B., Sun, L., Dou, L., et al. (2017) · Diabetes · doi:10.2337/db16-1172 · Cited by 101 · see citing works
Tissue‐specific insulin signaling in the regulation of metabolism and aging
Zhang, J., & Liu, F. (2014) · IUBMB Life · doi:10.1002/iub.1293 · Cited by 100 · cited 3× · see citing works
“The pancreas is mainly composed of four types of cells, of which pancreatic β cells are vitally important in maintaining glucose homeostasis by producing and secreting insulin in response to the blood glucose concentration [58].”
BackgroundInfluential
Pharmacological Inhibition of PI3K Reduces Adiposity and Metabolic Syndrome in Obese Mice and Rhesus Monkeys
Ortega-Molina, A., Lopez-Guadamillas, E., Mattison, J. A., Mitchell, S. J., Muñoz‐Martín, M., Iglesias, G., Gutierrez, V. M., Vaughan, K. L., Szarowicz, M. D., González‐García, I., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.02.017 · Cited by 99 · cited 1× · see citing works
“At this point, the pharmacological inhibition of PI3K is an effective and safe anti-obesity and anti-cancer intervention that can reverse the negative effects of human diseases [152].”
Background
Hypothalamic Insulin Resistance in Obesity: Effects on Glucose Homeostasis
Chen, W., Balland, É., & Cowley, M. A. (2017) · Neuroendocrinology · doi:10.1159/000455865 · Cited by 99 · cited 5× · see citing works
“There are two reasons for this: first, the transport of insulin through the blood brain barrier is impaired in obese subjects [45].”
BackgroundInfluential
Influence of Insulin in the Ventromedial Hypothalamus on Pancreatic Glucagon Secretion In Vivo
Paranjape, S., Chan, O. T. M., Zhu, W., Horblitt, A. M., McNay, E. C., Cresswell, J. A., Bogan, J. S., McCrimmon, R. J., & Sherwin, R. S. (2010) · Diabetes · doi:10.2337/db10-0014 · Cited by 94 · see citing works
Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs
Ramnanan, C. J., Saraswathi, V., Smith, M. S., Donahue, E. P., Farmer, B., Farmer, T. D., Neal, D. W., Williams, P. E., Lautz, M., Mari, A., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci45472 · Cited by 94 · cited 1× · see citing works
“However, further studies should be carried on because the action of insulin in brain may not common in all species [92, 93].”
Background
Role of S6K1 in regulation of SREBP1c expression in the liver.
Li, S., Ogawa, W., Emi, A., Hayashi, K., Senga, Y., Nomura, K., Hara, K., Yu, D., & Kasuga, M. (2011) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2011.07.038 · Cited by 87 · cited 1× · see citing works
“AKT has been reported to modulate the mTORC1-S6K1 pathway to regulate SREBP-1c expression in the liver [97].”
Background
Mitochondrial dysfunction and type 2 diabetes
Parish, R., & Petersen, K. F. (2005) · Current Diabetes Reports · doi:10.1007/s11892-005-0006-3 · Cited by 83 · cited 4× · see citing works
“Excessive fatty acid oxidation in the mitochondria via the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) increases the production of fatty acid metabolites and reactive oxygen species (ROS), subsequently activated intracellular stress kinases to inhibit IRS-1 and possibly exerting effects on in…”
BackgroundInfluential
Molecular Mechanisms of Human Disease Mediated by Oncogenic and Primary Immunodeficiency Mutations in Class IA Phosphoinositide 3-Kinases
Dornan, G. L., & Burke, J. E. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00575 · Cited by 83 · see citing works
Lipid Sensing and Insulin Resistance in the Brain
Yue, J. T. Y., & Lam, T. K. T. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.01.013 · Cited by 82 · cited 2× · see citing works
“second, brain insulin action is attenuated or even diminished in response to both endogenous and exogenous insulin stimulation [133], which impairs hypothalamic AKT activation due to ER stress and the activation of inflammatory pathways [134].”
Background
Pancreatic deletion of insulin receptor substrate 2 reduces beta and alpha cell mass and impairs glucose homeostasis in mice
Cantley, J., Choudhury, A. I., Asare‐Anane, H., Selman, C., Lingard, S. J., Heffron, H., Herrera, P. L., Persaud, S. J., & Withers, D. J. (2007) · Diabetologia · doi:10.1007/s00125-007-0637-9 · Cited by 79 · cited 1× · see citing works
“β cell-specific knockout of IRS2 or the IR, which disrupts of insulin signalling in pancreatic β cells, reduces the pancreatic insulin content, β cell mass and glucose-stimulated insulin secretion, followed by the development of a phenotype similar to T2DM [140, 141].”
A Noncanonical, GSK3-Independent Pathway Controls Postprandial Hepatic Glycogen Deposition
Wan, M., Leavens, K. F., Hunter, R. W., Koren, S., von Wilamowitz-Moellendorff, A., Lu, M., Satapati, S., Chu, Q., Sakamoto, K., Burgess, S. C., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.06.001 · Cited by 79 · cited 3× · see citing works
“[161] C57BL/6 mice HepG2 cell glycerol kinase (Gyk) Decreases the expression of FoxO1 reduced expression of G6Pase and PEPCK [162] C57BL/6 mice NPC1L1 Regulates the AKT-FOXO1-PEPCK/G6Pase pathway reduced expression of G6Pase and PEPCK [163] MCF7-tet OFF Sesn2F cells Sestrins (Sesn1/2/3) through activation of AMPK and…”
BackgroundInfluential
Cellular Regulation of Glucose Uptake by Glucose Transporter GLUT4
Govers, R. (2014) · Advances in clinical chemistry · doi:10.1016/b978-0-12-801401-1.00006-2 · Cited by 76 · cited 1× · see citing works
“And the direct target of AKT is a substrate of 160 kDa (AS160), also known as TBC1D1 [29].”
Background
Liver-specific p70 S6 Kinase Depletion Protects against Hepatic Steatosis and Systemic Insulin Resistance*
Bae, E., Xu, J., Oh, D., Bandyopadhyay, G., Lagakos, W., Keshwani, M. M., & Olefsky, J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.365544 · Cited by 75 · cited 1× · see citing works
“In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nuclear SREBP-1c [65, 6…”
Background
Loss of 50% of excess weight using a very low energy diet improves insulin-stimulated glucose disposal and skeletal muscle insulin signalling in obese insulin-treated type 2 diabetic patients
Jazet, I. M., Schaart, G., Gastaldelli, A., Ferrannini, E., Hesselink, M. K. C., Schrauwen, P., Romijn, J. A., Maassen, J. A., Pijl, H., Ouwens, D. M., et al. (2007) · Diabetologia · doi:10.1007/s00125-007-0862-2 · Cited by 73 · cited 1× · see citing works
“In early studies, insulin resistance was thought to be accompanied by excessive intramyocellular lipid (IMCL) levels [49], and improved insulin sensitivity observed in subjects with T2DM by reduced IMCL levels [50].”
Background
Regulation of fat specific protein 27 by isoproterenol and TNF-α to control lipolysis in murine adipocytes
Ranjit, S., Boutet, E., Gandhi, P., Prot, M., Tamori, Y., Chawla, A., Greenberg, A. S., Puri, V., & Czech, M. (2010) · Journal of Lipid Research · doi:10.1194/jlr.m008771 · Cited by 73 · cited 1× · see citing works
“How does insulin resistance occur in adipose tissues? The synthesis and secretion of adiponectin, tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6), which enhance lipolysis by reducing perilipin and fat-specific protein 27 levels [76].”
Background
Ribosomal S6K1 in POMC and AgRP Neurons Regulates Glucose Homeostasis but Not Feeding Behavior in Mice
Smith, M. A., Katsouri, L., Irvine, E. E., Hankir, M. K., Pedroni, S. M. A., Voshol, P. J., Gordon, M. W., Choudhury, A. I., Woods, A., Vidal‐Puig, A., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.03.029 · Cited by 69 · cited 1× · see citing works
“One way to regulate HGP is that S6K1, a downstream molecule of mTOR1, regulates HGP, modulates neuronal excitability and peripheral lipid metabolism in POMC neurons, regulates the insulin sensitivity of skeletal muscle via AgRP neurons [128].”
Background
Endomembrane PtdIns(3,4,5)P3 activates the PI3K-Akt pathway
Jethwa, N., Chung, G. H. C., Lete, M. G., Alonso, A., Byrne, R. D., Calleja, V., & Larijani, B. (2015) · Journal of Cell Science · doi:10.1242/jcs.172775 · Cited by 68 · cited 1× · see citing works
“Recently, endomembranes that contain PIP3 and PIP2 have also been shown to directly contribute to AKT activation [25, 26].”
Background
Dissociation of the Glucose and Lipid Regulatory Functions of FoxO1 by Targeted Knockin of Acetylation-Defective Alleles in Mice
Banks, A. S., Kim-Muller, J. Y., Mastracci, T. L., Kofler, N. M., Qiang, L., Haeusler, R. A., Jurczak, M. J., Laznik, D., Heinrich, G., Samuel, V. T., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.09.012 · Cited by 67 · cited 1× · see citing works
“The role of FoxO1 in liver lipid metabolism is less well studied; some studies have shown that FoxO1 is directly associated with insulin-promoted expression of fat genes in the liver, whereas others have reported a permissive role for FoxO1 in these processes [100-102].”
Background
PDK-1/FoxO1 pathway in POMC neurons regulatesPomcexpression and food intake
Iskandar, K., Cao, Y., Hayashi, Y., Nakata, M., Takano, E., Yada, T., Zhang, C., Ogawa, W., Oki, M., Chua, S. C., et al. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00512.2009 · Cited by 67 · cited 1× · see citing works
“In response to insulin resistance in the brain, overexpression of FoxO1 in POMC neurons leads to obesity and hyperphagia [136].”
Background
MicroRNA-451 Negatively Regulates Hepatic Glucose Production and Glucose Homeostasis by Targeting Glycerol Kinase–Mediated Gluconeogenesis
Zhuo, S., Yang, M., Zhao, Y., Chen, X., Zhang, F., Li, N., Yao, P., Zhu, T., Mei, H., Wang, S., et al. (2016) · Diabetes · doi:10.2337/db16-0166 · Cited by 67 · see citing works
Insulin fails to stimulate muscle protein synthesis in sepsis despite unimpaired signaling to 4E-BP1 and S6K1.
Vary, T., Jefferson, L., & Kimball, S. (2001) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.281.5.e1045 · Cited by 64 · cited 1×
“In skeletal muscle, insulin stimulates protein synthesis and accelerates mRNA translation by regulating the initiation steps of protein translation [42].”
Background
ROS acts as a double-edged sword in the pathogenesis of type 2 diabetes mellitus: is Nrf2 a potential target for the treatment?
Wang, X., & Hai, C. (2011) · Mini-Reviews in Medical Chemistry · doi:10.2174/138955711797247761 · Cited by 63 · see citing works
Hepatic Overexpression of ATP Synthase β Subunit Activates PI3K/Akt Pathway to Ameliorate Hyperglycemia of Diabetic Mice
Wang, C., Chen, Z., Li, S., Zhang, Y., Shi, J., Li, J., Chi, Y., Miao, Y., Guan, Y., & Yang, J. (2013) · Diabetes · doi:10.2337/db13-1096 · Cited by 62 · see citing works
Bone morphogenetic protein‐7 (BMP‐7) augments insulin sensitivity in mice with type II diabetes mellitus by potentiating PI3K/AKT pathway
Chattopadhyay, T., Singh, R. R., Gupta, S., & Surolia, A. (2017) · BioFactors · doi:10.1002/biof.1334 · Cited by 56 · cited 1× · see citing works
“promotes peripheral insulin resistance [156]”
Evidence against a Physiologic Role for Acute Changes in CNS Insulin Action in the Rapid Regulation of Hepatic Glucose Production
Ramnanan, C. J., Edgerton, D. S., & Cherrington, A. D. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.03.006 · Cited by 56 · cited 2× · see citing works
“Third, insulin functions through the AKT pathway suppress α-cell glucagon secretion in the brain, which reducing HGP levels in the liver [92, 95, 96].”
Background
Disruption of Adipose Rab10-Dependent Insulin Signaling Causes Hepatic Insulin Resistance
Vazirani, R. P., Verma, A., Sadacca, L. A., Buckman, M. S., Picatoste, B., Beg, M., Torsitano, C., Bruno, J., Patel, R. T., Šimonytė, K., et al. (2016) · Diabetes · doi:10.2337/db15-1128 · Cited by 55 · cited 1× · see citing works
“For example, specifically knockdown of GLUT4 in adipose tissues resulted in insulin resistance in skeletal muscle and liver instead of adipose tissues [74].”
Background
Mammalian target of rapamycin-independent S6K1 and 4E-BP1 phosphorylation during contraction in rat skeletal muscle
Liu, Y., Vertommen, D., Rider, M. H., & Lai, Y. (2013) · Cellular Signalling · doi:10.1016/j.cellsig.2013.05.005 · Cited by 53 · cited 1× · see citing works
“AKT-mediated mTORC1 activation regulates a number of downstream effectors proteins through phosphorylation, including the well-characterized effectors p70 ribosomal S6 protein kinase-1 (S6K1) and eukaryotic translation initiation factor-4E (eIF4E)binding protein-1 (4E-BP1), to increase protein synthesis [43, 44].”
Background
Glial cell line-derived neurotrophic factor increases beta-cell mass and improves glucose tolerance.
Mwangi, S., Anitha, M., Mallikarjun, C., Ding, X.-K., Hara, M., Parsadanian, A., Larsen, C., Thulé, P., Sitaraman, S., Anania, F., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2007.12.033 · Cited by 51 · see citing works
Gpr17 in AgRP Neurons Regulates Feeding and Sensitivity to Insulin and Leptin
Ren, H., Cook, J. R., Kon, N., & Accili, D. (2015) · Diabetes · doi:10.2337/db15-0390 · Cited by 51 · see citing works
Differential regulation of adipocyte PDE3B in distinct membrane compartments by insulin and the β3-adrenergic receptor agonist CL316243: effects of caveolin-1 knockdown on formation/maintenance of macromolecular signalling complexes
Ahmad, F., Lindh, R., Tang, Y., Ruishalme, I., Öst, A., Sahachartsiri, B., Strålfors, P., Degerman, E., & Manganiello, V. (2009) · Biochemical Journal · doi:10.1042/bj20090842 · Cited by 50 · cited 1× · see citing works
“AKT-independent, PI3K-dependent pathway also regulates adipocyte lipolysis by directly regulating PKA [72], AKT regulate FoxO1 through three pathway: reducing the expression of the rate-limiting lipolytic enzyme (ATGL), which is responsible for triacylglycerol hydrolase activity (ATGL) [62]; reducing the expression of…”
Background
Inhibiting or antagonizing glucagon: making progress in diabetes care
Lefébvre, P., Paquot, N., & Scheen, A. (2015) · Diabetes, obesity and metabolism · doi:10.1111/dom.12480 · Cited by 41 · cited 1× · see citing works
“Third, insulin functions through the AKT pathway suppress α-cell glucagon secretion in the brain, which reducing HGP levels in the liver [92, 95, 96].”
Background
Targeting type 2 diabetes: lessons from a knockout model of insulin receptor substrate 2
Oliveira, J. M., Rebuffat, S. A., Gasa, R., & Gomis, R. (2014) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2014-0114 · Cited by 41 · see citing works
Interleukin-1 effect on glycemia in the non-obese diabetic mouse at the pre-diabetic stage.
Amrani, A., Jafarian-Tehrani, M., Morméde, P., Durant, S., Pléau, J., Haour, F., Dardenne, M., & Homo-Delarche, F. (1996) · Journal of Endocrinology · doi:10.1677/joe.0.1480139 · Cited by 40 · cited 1× · see citing works
“The increased in subjects with obesity-induced inflammation, aggravating insulin resistance [77].”
Background
Rapamycin does not improve insulin sensitivity despite elevated mammalian target of rapamycin complex 1 activity in muscles ofob/obmice
Miller, A. M., Brestoff, J. R., Phelps, C. B., Berk, E. Z., & Reynolds, T. (2008) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90428.2008 · Cited by 36 · cited 1× · see citing works
“According to a recent study, mTOR1 is dispensable for the regulation of feeding behaviour and energy metabolism [124], and chronic activation of mTOR1 interferes with the hypothalamic neurons that regulate feeding and energy balance [125].”
Background
PHLPP: a putative cellular target during insulin resistance and type 2 diabetes.
Mathur, A., Pandey, V., & Kakkar, P. (2017) · Journal of Endocrinology · doi:10.1530/joe-17-0081 · Cited by 31 · see citing works
Inhibition of Foxo1 mediates protective effects of ghrelin against lipotoxicity in MIN6 pancreatic β-cells
Wang, W., Liu, Y., Chen, Y., Cao, C.-P., Xiang, Y., Zhang, D., Han, L., Zhao, H., & Liu, G. (2009) · Peptides · doi:10.1016/j.peptides.2009.11.011 · Cited by 27 · cited 1× · see citing works
“In addition, the PI3K/AKT pathway prevents lipotoxicity in pancreatic β cells by inhibiting FoxO1, which is abundantly expressed in pancreatic β cells and promotes FFA-induced β cell apoptosis [146, 147].”
BackgroundSelf-citation
Apelin 13: a novel approach to enhance efficacy of hypoxic preconditioned mesenchymal stem cells for cell therapy of diabetes.
Mottaghi, S., Larijani, B., & Sharifi, A. (2012) · Medical Hypotheses · doi:10.1016/j.mehy.2012.08.007 · Cited by 25
Phosphoinositide 3‐kinase: a new kid on the block in vascular anomalies
Castillo, S. D., Vanhaesebroeck, B., & Sebire, N. J. (2016) · The Journal of Pathology · doi:10.1002/path.4802 · Cited by 24 · cited 1× · see citing works
“RTKs recruit class I PI3Ks to the plasma membrane, which relieves the inactivation function of p85 and p110 to activate the protein [12, 13].”
Background
mTORC1 signaling in Agrp neurons mediates circadian expression of Agrp and NPY but is dispensable for regulation of feeding behavior.
Albert, V., Cornu, M., & Hall, M. (2015) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2015.06.161 · Cited by 20 · see citing works
Dapper1 attenuates hepatic gluconeogenesis and lipogenesis by activating PI3K/Akt signaling
Kuang, J.-R., Zhang, Z., Leng, W., Lei, X., & Liang, Z. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.02.028 · Cited by 20 · see citing works
Hepatic NPC1L1 overexpression ameliorates glucose metabolism in diabetic mice via suppression of gluconeogenesis.
Kurano, M., Hara, M., Satoh, H., & Tsukamoto, K. (2015) · Metabolism: Clinical and Experimental · doi:10.1016/j.metabol.2015.01.011 · Cited by 14 · see citing works

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[142]Yuval Dor JB Olga I Martinez & Douglas A. Melton. Adult pancreatic b-cells are formed by self-duplication rather than stem-cell differentiation nature 2004 429 6 41 6 15129273
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[147]Wang HW Mizuta M Saitoh Y Noma K Ueno H Nakazato M Glucagon-like peptide-1 and candesartan additively improve glucolipotoxicity in pancreatic beta-cells Metabolism 2011 60 8 1081 9 21255808
[161]Villani V Milanesi A Sedrakyan S Da Sacco S Angelow S Conconi MT Amniotic fluid stem cells prevent beta-cell injury Cytotherapy 2014 16 1 41 55 24210784 PMC4374982

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Signaling pathways in obesity: mechanisms and therapeutic interventions
Wen, X., Zhang, B., Wu, B., Xiao, H., Li, Z., Li, R., Xu, X., & Li, T. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01149-x · Cited by 456 · see citing works
The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis
Xu, D., Wang, Z., Xia, Y., Shao, F., Xia, W., Wei, Y., Li, X., Qian, X., Lee, J.-H., Du, L., et al. (2020) · Nature · doi:10.1038/s41586-020-2183-2 · Cited by 360 · see citing works
Targeting PI3K/AKT signaling pathway in obesity
Savova, M. S., Mihaylova, L. V., Tews, D., Wabitsch, M., & Georgiev, M. I. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114244 · Cited by 288 · see citing works
The PI3K/Akt Pathway in Meta-Inflammation
Acosta‐Martínez, M., & Cabail, M. Z. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315330 · Cited by 252 · see citing works
“Akt1 is ubiquitously expressed, whereas Akt2 is mainly expressed in insulin-sensitive tissues, such as AT, liver and skeletal muscle, and Akt3 is expressed in the brain and the testes [25].”
Background
Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation‑mediating treatment options (Review)
Varra, F., Varras, M. N., Varra, V., & Theodosis‐Nobelos, P. (2024) · Molecular Medicine Reports · doi:10.3892/mmr.2024.13219 · Cited by 194 · see citing works
“The PI3K‑AKT signaling pathway regulates the metabolic insulin actions by promoting glucose utilization, protein synthesis and lipogenesis (228).”
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Flavonoids as Antiobesity Agents: A Review
Rufino, A. T., Costa, V. M., Carvalho, F., & Fernandes, E. (2021) · Medicinal Research Reviews · doi:10.1002/med.21740 · Cited by 174 · see citing works
Insulin resistance, autophagy and apoptosis in patients with polycystic ovary syndrome: Association with PI3K signaling pathway
Tong, C., Wu, Y., Zhang, L., & Yu, Y. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1091147 · Cited by 157 · see citing works
“In addition to endocrine metabolic abnormalities (30), disorders of this pathway are also associated with various malignancies, leukemia, schizophrenia, coronary heart disease, heart failure, osteoarthritis and other diseases (31–36).”
Background
Deficiency of gluconeogenic enzyme PCK1 promotes metabolic-associated fatty liver disease through PI3K/AKT/PDGF axis activation in male mice
Ye, Q., Liu, Y., Zhang, G., Deng, H., Wang, X., Tuo, L., Chen, C., Pan, X., Wu, K., Fan, J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37142-3 · Cited by 172 · see citing works
Mechanisms and therapeutic opportunities in metabolic aberrations of diabetic wounds: a narrative review
Xiong, Y., Knoedler, S. A., Alfertshofer, M. G., Kim, B., Jiang, D., Liu, G., Rinkevich, Y., & Mi, B. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07583-3 · Cited by 140 · see citing works
“The in ﬂ ammation-induced interference with IRS proteins blocks downstream activation of the phosphatidylinositol 3-kinase (PI3K) and AKT pathway, which is essential for glucose uptake in muscle and fat cells, thus leading to reduced cellular sensitivity to insulin [41].”
Self-citation
Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions
Huang, J., Chen, L., Wu, J., Ai, D., Zhang, J., Chen, T., & Wang, L. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01070 · Cited by 153 · see citing works
Understanding chronic inflammation: couplings between cytokines, ROS, NO, Cai2+, HIF-1α, Nrf2 and autophagy
Michalak, K. P., & Michalak, A. Z. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1558263 · Cited by 132 · see citing works
“In metabolic disorders such as obesity and type 2 diabetes, chronic inhibition of the PI3K/Akt pathway in adipose tissue and other organs is associated with insulin resistance and low-grade systemic in ﬂ ammation (81, 82).”
Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects
Stanciu, S., Radu, F. I., Ștefani, C., Miricescu, D., Stănescu-Spînu, I.-I., Greabu, M., Totan, A., & Jinga, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231710132 · Cited by 144 · see citing works
Insight into the Role of the PI3K/Akt Pathway in Ischemic Injury and Post-Infarct Left Ventricular Remodeling in Normal and Diabetic Heart
Walkowski, B., Kleibert, M., Majka, M., & Wojciechowska, M. (2022) · Cells · doi:10.3390/cells11091553 · Cited by 117 · see citing works
Mechanism of action of the bile acid receptor TGR5 in obesity
Lun, W., Yan, Q., Guo, X., Zhou, M., Bai, Y., He, J., Cao, H., Che, Q., Guo, J., & Su, Z. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.11.011 · Cited by 117 · see citing works
“Insulin resistance is another hazard of obesity 162 .”
BackgroundSelf-citation
Targeting Metabolic Diseases: The Role of Nutraceuticals in Modulating Oxidative Stress and Inflammation
Dama, A., Shpati, K., Daliu, P., Dümür, Ş., Gorica, E., & Santini, A. (2024) · Nutrients · doi:10.3390/nu16040507 · Cited by 122 · see citing works
“The impairment of glucose metabolism is often a result of alterations in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, a critical route for maintaining normal metabolic functions [19].”
Background
Gender Differences in Insulin Resistance: New Knowledge and Perspectives
Ciarambino, T., Crispino, P., Guarisco, G., & Giordano, M. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45100496 · Cited by 103 · see citing works
“Any defect in the PI3K/Akt/AS160 signaling will eventually reduce the glucose uptake in insulin-sensitive tissues and lead to insulin resistance [35].”
Background
Oxidative stress in alcoholic liver disease, focusing on proteins, nucleic acids, and lipids: A review
Lai, W., Zhang, J., Sun, J., Min, T., Bai, Y., He, J., Cao, H., Che, Q., Guo, J., & Su, Z. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.134809 · Cited by 87 · see citing works
Self-citation
Evidence of Flavonoids on Disease Prevention
Li, M., Qian, M., Jiang, Q., Tan, B., Yin, Y., & Han, X. (2023) · Antioxidants · doi:10.3390/antiox12020527 · Cited by 100 · see citing works
“In the liver, the defective PI3K/Akt pathway promotes gluconeogenesis by increasing the expression of PEPCK and G6P and inhibits glycogen synthesis by suppressing GK and GSK [56,58].”
BackgroundInfluential
A Review on the Antidiabetic Properties of Moringa oleifera Extracts: Focusing on Oxidative Stress and Inflammation as Main Therapeutic Targets
Mthiyane, F. T., Dludla, P. V., Ziqubu, K., Mthembu, S. X. H., Muvhulawa, N., Hlengwa, N., Nkambule, B. B., & Mazibuko-Mbeje, S. E. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.940572 · Cited by 82 · see citing works
“Literature suggests that effective modulation of energy metabolism and insulin signaling through the regulation of AMP-activated protein kinase (AMPK) or phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathways appears to reverse some devastating outcomes of diabetes (Long and Zierath, 2006; Huang et al., 2018;…”
Background
Antioxidant-Rich Functional Foods and Exercise: Unlocking Metabolic Health Through Nrf2 and Related Pathways
Tkaczenko, H., & Kurhaluk, N. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26031098 · Cited by 80 · see citing works
“In metabolic tissues, such as the muscle and liver, the PI3K/Akt pathway improves insulin sensitivity and enhances mitochondrial function, both of which are essential for maintaining metabolic balance [153].”
Oxidative stress in hair follicle development and hair growth: Signalling pathways, intervening mechanisms and potential of natural antioxidants
Du, F., Li, J., Zhang, S., Zeng, X., Nie, J., & Li, Z. (2024) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.18486 · Cited by 75 · see citing works
“80 As mentioned earlier, activation of the PI3K/Akt signalling pathway can exert antioxidant effects, and whether OS mediated by the intervention of this pathway during HF development can affect HF anagen requires further investigation.”
Background
Function of Akkermansia muciniphila in type 2 diabetes and related diseases
Li, J., Yang, G., Zhang, Q., Liu, Z., Jiang, X. M., & Xin, Y. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1172400 · Cited by 71 · see citing works
“Notably, PI3K-Akt signaling plays an important role in glucose and lipid metabolism (Huang et al., 2018).”
Background
A Comprehensive Review of Biological Properties of Flavonoids and Their Role in the Prevention of Metabolic, Cancer and Neurodegenerative Diseases
Stachelska, M. A., Karpiński, P., & Kruszewski, B. (2025) · Applied Sciences · doi:10.3390/app151910840 · Cited by 75 · see citing works
Signaling pathways and intervention for therapy of type 2 diabetes mellitus
Cao, R. Y., Tian, H., Zhang, Y., Liu, G., Xu, H., Rao, G., Tian, Y., & Fu, X. (2023) · MedComm · doi:10.1002/mco2.283 · Cited by 92 · see citing works
Self-citation
In Vitro Insulin Resistance Model: A Recent Update
Yudhani, R., Sari, Y., Nugrahaningsih, D., Sholikhah, E. N., Rochmanti, M., Purba, A., Khotimah, H., Nugrahenny, D., & Mustofa, M. (2023) · Journal of Obesity · doi:10.1155/2023/1964732 · Cited by 73 · see citing works
Metabolites of traditional Chinese medicine targeting PI3K/AKT signaling pathway for hypoglycemic effect in type 2 diabetes
Feng, Y., Ren, Y., Zhang, X., Yang, S., Jiao, Q., Li, Q., & Jiang, W. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1373711 · Cited by 73 · see citing works
“As a serine/threonine kinase, AKT (protein kinase B) is one of the main effectors of the downstream signal network of PI3K (Huang et al., 2018).”
Background
Ultrasmall Coordination Polymer Nanodots Fe‐Quer Nanozymes for Preventing and Delaying the Development and Progression of Diabetic Retinopathy
Gui, S.-Y., Tang, W.-W., Huang, Z., Wang, X.-C., Gui, S.-Y., Gao, X., Xiao, D., Tao, L.-M., Jiang, Z.-X., & Wang, X.-W. (2023) · Advanced Functional Materials · doi:10.1002/adfm.202300261 · Cited by 71 · see citing works
Artesunate improves glucose and lipid metabolism in db/db mice by regulating the metabolic profile and the MAPK/PI3K/Akt signalling pathway
Chen, L., Wang, J., Ren, Y., Ma, Y., Liu, J., Jiang, H., & Liu, C. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155382 · Cited by 70 · see citing works
Hepatic insulin receptor: new views on the mechanisms of liver disease
Lee, W., Najjar, S. M., Kahn, C. R., & Hinds, T. D. (2023) · Metabolism · doi:10.1016/j.metabol.2023.155607 · Cited by 74 · see citing works
Modulation of the PI3K/Akt signaling pathway by resveratrol in cancer: molecular mechanisms and therapeutic opportunity
Hedayati, N., Safari, M. H., Milasi, Y. E., Kahkesh, S., Farahani, N., Khoshnazar, S. M., Dorostgou, Z., Alaei, E., Alimohammadi, M., Rahimzadeh, P., et al. (2025) · Discover Oncology · doi:10.1007/s12672-025-02471-w · Cited by 68 · see citing works
“AKT, also recognized as protein kinase B (PKB), belongs to the AGC-family of serine/threonine kinases [96, 97].”
Fucoidan’s Molecular Targets: A Comprehensive Review of Its Unique and Multiple Targets Accounting for Promising Bioactivities Supported by In Silico Studies
Zayed, A., Al-Saedi, D. A., Mensah, E. O., Kanwugu, O. N., Adadi, P., & Ulber, R. (2023) · Marine Drugs · doi:10.3390/md22010029 · Cited by 77 · see citing works
“In diabetes, fucoidan has been shown to upregulate the Nrf2 pathway together with its respective downstream targets, thus delaying the pathological damage to the kidneys [99].”
Background
Mitochondrial Fission as a Therapeutic Target for Metabolic Diseases: Insights into Antioxidant Strategies
Yu, T., Wang, L., Zhang, L., & Deuster, P. A. (2023) · Antioxidants · doi:10.3390/antiox12061163 · Cited by 71 · see citing works
Metabolic crossroads in insulin resistance: exploring lipid dysregulation and inflammation
Saadati, S., Godini, R., Reddy, A. J., Teede, H. J., & Mousa, A. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1692742 · Cited by 62 · see citing works
“…of this pathway alters nutrient handling, promotes fat storage and ectopic lipid deposition, reduces fatty acid oxidation, and impairs glucose disposal, collectively driving the development and progression of metabolic disorders including obesity, T2D, MASLD, PCOS, and metabolic syndrome (30 – 32).”
Therapeutic applications and challenges in myostatin inhibition for enhanced skeletal muscle mass and functions
Wetzlich, B., Nyakundi, B. B., & Yang, J. (2024) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-024-05120-y · Cited by 70 · see citing works
“MSTN inhibition upregulates the PI3K/Akt pathway, leading to an increase expression of GLUT4 [132, 133].”
Obesity, non-alcoholic fatty liver disease and hepatocellular carcinoma: current status and therapeutic targets
Chen, Y.-S., Wang, W., Morgan, M., Robson, T., & Annett, S. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1148934 · Cited by 63 · see citing works
“In patients with T2DM and NAFLD, inhibition of SGLT2 by dapagliflozin attenuates liver fibrosis and steatosis, and decreases the serum level of DDP4.”
BackgroundInfluential
Recent advances in the effect of adipose tissue inflammation on insulin resistance
Yan, K. (2024) · Cellular Signalling · doi:10.1016/j.cellsig.2024.111229 · Cited by 62 · see citing works
Protein tyrosine phosphatase 1B ( PTP1B ) function, structure, and inhibition strategies to develop antidiabetic drugs
Coronell‐Tovar, A., Pardo, J. P., Rodríguez‐Romero, A., Sosa‐Peinado, A., Vásquez-Bochm, L. X., Cano‐Sánchez, P., Álvarez‐Añorve, L. I., & González‐Andrade, M. (2024) · FEBS Letters · doi:10.1002/1873-3468.14901 · Cited by 70 · see citing works
“This transport process requires GLUT4 exocytosis by trans-locating GLUT4 storage vesicles (GSVs) from the cell’s interior to the plasma membrane, thus promoting glucose uptake in adjacent tissues and lowering plasma glucose levels [87,90].”
Obesity, diabetes mellitus, and cardiometabolic risk: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2023
Bays, H. E., Bindlish, S., & Clayton, T. L. (2023) · Obesity Pillars · doi:10.1016/j.obpill.2023.100056 · Cited by 65 · see citing works
“Speci ﬁ cally, obesity may result in adiposopathic increases in in ﬂ ammatory factors (e.g., cytokines such as tumor necrosis factor and interleukins) and free fatty acids that may impair PI3K/AKT signaling, potentially contributing to post-receptor insulin resistance, prediabetes, and/or T2DM [46].”
Background
In silico network pharmacology and in vivo analysis of berberine-related mechanisms against type 2 diabetes mellitus and its complications
Di, S., Han, L., An, X., Kong, R., Gao, Z., Yang, Y., Wang, X., Zhang, P., Ding, Q., Wu, H., et al. (2021) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2021.114180 · Cited by 57 · see citing works
The effect and a mechanistic evaluation of polystyrene nanoplastics on a mouse model of type 2 diabetes.
Wang, Y., Wei, Z.-L., Xu, K., Wang, X., Gao, X.-P., Han, Q., Wang, S., & Chen, M.-Q. (2023) · Food and Chemical Toxicology · doi:10.1016/j.fct.2023.113642 · Cited by 58 · see citing works
Metformin coordinates with mesenchymal cells to promote VEGF-mediated angiogenesis in diabetic wound healing through Akt/mTOR activation
Du, F., Liu, M., Wang, J., Hu, L., Zeng, D., Zhou, S., Zhang, L., Wang, M., Xu, X., Li, C., et al. (2023) · Metabolism · doi:10.1016/j.metabol.2023.155398 · Cited by 63 · see citing works
Progression of the PI3K/Akt signaling pathway in chronic obstructive pulmonary disease
Liu, Y., Kong, H., Cai, H., Chen, G., Chen, H., & Ruan, W. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1238782 · Cited by 54 · see citing works
“, 2019), diabetes (Huang et al., 2018), and osteoarthritis (Sun et al.”
Background
Anthocyanins as Promising Molecules Affecting Energy Homeostasis, Inflammation, and Gut Microbiota in Type 2 Diabetes with Special Reference to Impact of Acylation
Chen, K., Kortesniemi, M. K., Linderborg, K. M., & Yang, B. (2022) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.2c05879 · Cited by 61 · see citing works
Post‐translational regulation of muscle growth, muscle aging and sarcopenia
Zhong, Q., Zheng, K., Li, W., An, K., Liu, Y., Xiao, X., Hai, S., Dong, B., Li, S., An, Z., et al. (2023) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13241 · Cited by 54 · see citing works
“inhibit its activity, which promotes skeletal muscle glycogen synthesis and produces ATP to enhance muscle strength.(13)”
Background
Ameliorative effects of mangiferin derivative TPX on insulin resistance via PI3K/AKT and AMPK signaling pathways in human HepG2 and HL-7702 hepatocytes
Fan, X., Jiao, G., Pang, T., Wen, T., He, Z., Han, J., Zhang, F., & Chen, W. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154740 · Cited by 50 · see citing works
A review on phytochemical and pharmacological facets of tropical ethnomedicinal plants as reformed DPP-IV inhibitors to regulate incretin activity
Chhabria, S., Mathur, S., Vadakan, S., Sahoo, D. K., Mishra, P., & Paital, B. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1027237 · Cited by 58 · see citing works
“Frontiers in Endocrinology 02 leading to compensatory hyperinsulinemia to maintain euglycemia which ultimately causes insulin resistance (4, 5).”
Background
Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice
Stec, D. E., Gordon, D. M., Nestor-Kalinoski, A. L., Donald, M. C., Mitchell, Z. L., Creeden, J. F., & Hinds, T. D. (2020) · Biomolecules · doi:10.3390/biom10030387 · Cited by 50 · see citing works
Magnoflorine Prevent the Skeletal Muscle Atrophy Via Akt/mTOR/FoxO Signal Pathway and Increase Slow-MyHC Production in Streptozotocin-Induced Diabetic Rats
Yadav, A., Singh, A., Phogat, J., Dahuja, A., & Dabur, R. (2021) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2020.113510 · Cited by 49 · see citing works
A stepwise activation model for the insulin receptor
Yunn, N.-O., Kim, J., Ryu, S. H., & Cho, Y. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01101-1 · Cited by 54 · see citing works
“The insulin-activated PI3K/AKT pathway is responsible for the majority of the metabolic effects mediated by insulin in peripheral tissues 43 .”
Background
Advances of phytotherapy in ischemic stroke targeting PI3K/Akt signaling
Liu, T., Wang, W.-J., Li, X.-L., Chen, Y.-D., Mu, F., Wen, A., Liu, M.-N., & Ding, Y. (2023) · Phytotherapy Research · doi:10.1002/ptr.7994 · Cited by 49
“Under the action of 3-phosphatidylinositol dependent kinase (PDK), thr308 and ser473 are phosphorylated so that AKT is fully activated (Huang et al., 2018).”
Background
The impact of dietary fructose on gut permeability, microbiota, abdominal adiposity, insulin signaling and reproductive function
Güney, C., Bal, N. B., & Akar, F. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e18896 · Cited by 51 · see citing works
“This resistant circumstance could be the consequence of a defect in insulin activation at the levels of IR, IRS1, PI3K, and AKT which are key effectors of insulin signaling thus diminishing glucose entry into the tissues due to disruption of GLUT4 translocation [148].”
Background
Association between Organophosphate Ester Exposure and Insulin Resistance with Glycometabolic Disorders among Older Chinese Adults 60–69 Years of Age: Evidence from the China BAPE Study
Ding, E., Deng, F., Fang, J., Li, T., Hou, M., Liu, J., Miao, K., Yan, W., Fang, K., Shi, W., et al. (2023) · Environmental Health Perspectives · doi:10.1289/ehp11896 · Cited by 61 · see citing works
Insulin Signaling in Arthritis
Tripolino, C., Ciaffi, J., Pucino, V., Ruscitti, P., van Leeuwen, N., Borghi, C., Giacomelli, R., Meliconi, R., & Ursini, F. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.672519 · Cited by 46 · see citing works
Diabetic Cardiomyopathy: 2023 Update by the International Multidisciplinary Board of Experts
Арманович, А. А., Fogacci, F., Вачиковна, П. Н., Kakrurskiy, L., Коган, Е. А., Urazova, O. I., Kobalava, Z. D., Михалева, Л. М., Vandysheva, R. A., Zarina, G., et al. (2023) · Current Problems in Cardiology · doi:10.1016/j.cpcardiol.2023.102052 · Cited by 52 · see citing works
RING-finger E3 ligases regulatory network in PI3K/AKT-mediated glucose metabolism
Wang, W., Shi, B., Cong, R., Hao, M., Peng, Y., Yang, H., Song, J., Feng, D., Zhang, N., & Li, D. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-01162-7 · Cited by 51 · see citing works
“PI3K/AKT signaling, as a well-known pathway, is activated among many diseases, especially cancer [11] and diabetes mellitus [12].”
Background
Impact of Diet Composition on Insulin Resistance
Martins, F. O., & Conde, S. V. (2022) · Nutrients · doi:10.3390/nu14183716 · Cited by 49 · see citing works
“Peripheral insulin resistance consists of an impaired biologic response to insulin stimulation of peripheral target tissues, namely the liver, muscle and fat tissue [1].”
Background
Berberine exerts antidepressant effects in vivo and in vitro through the PI3K/AKT/CREB/BDNF signaling pathway
Tang, Y., Su, H., Nie, K., Wang, H., Gao, Y., Shen, C., Lu, F., & Dong, H. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.116012 · Cited by 49 · see citing works
Polystyrene microplastics disturb maternal glucose homeostasis and induce adverse pregnancy outcomes
Zhang, R., Feng, Y., Nie, P., Wang, W., Wu, H., Wan, X., Xu, H., & Fu, F. (2024) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2024.116492 · Cited by 45 · see citing works
A framework towards digital twins for type 2 diabetes
Zhang, Y., Qin, G., Aguilar, B. H., Rappaport, N., Yurkovich, J. T., Pflieger, L. T., Huang, S., Hood, L., & Shmulevich, I. (2024) · Frontiers in Digital Health · doi:10.3389/fdgth.2024.1336050 · Cited by 46 · see citing works
Insulin resistance, metabolic syndrome and polycystic ovaries: an intriguing conundrum
Prosperi, S., & Chiarelli, F. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1669716 · Cited by 38 · see citing works
“During past decades, several mechanisms have been proposed and include post-receptor insulin signaling abnormalities, particularly in the PI3K/Akt pathway (in ﬂ uencing the expression of glucose transporter-4, GLUT-4) (22), increased serine phosphorylation of insulin receptor substrate-1 (IRS-1) (23), adipocyte dysfun…”
BPS‐induced ovarian dysfunction: Protective actions of melatonin via modulation of SIRT‐1/Nrf2/NFĸB and IR/PI3K/pAkt/GLUT‐4 expressions in adult golden hamster
Pal, S., Sahu, A., Verma, R., & Haldar, C. (2023) · Journal of Pineal Research · doi:10.1111/jpi.12869 · Cited by 43 · see citing works
“Stimulation of this highly integrated complex pathway enhances glucose uptake by stimulating insulin‐sensitive glucose uptake transporter‐4 (GLUT‐4) vesicle translocation to the plasma membrane.(31) Although recent 2 of 15 | PAL ET AL.”
Background
Aerobic Exercise Prevents Chronic Inflammation and Insulin Resistance in Skeletal Muscle of High-Fat Diet Mice
Li, N., Shi, H., Guo, Q., Gan, Y., Zhang, Y., Jia, J., Zhang, L., & Zhou, Y. (2022) · Nutrients · doi:10.3390/nu14183730 · Cited by 52 · see citing works
“The IRS-1/PI3K/AKT pathway is one of the main regulatory pathways of IR and has integrative roles in glucose and lipid metabolism [31].”
Background
Network pharmacology analysis revealed the mechanism and active compounds of jiao tai wan in the treatment of type 2 diabetes mellitus via SRC/PI3K/AKT signaling
Ye, C., Li, Y., Shi, J., He, L., Shi, X., Yang, W., Lei, W., Quan, S., Lan, X., & Liu, S. (2024) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2024.118898 · Cited by 39 · see citing works
Advancing the understanding of diabetic encephalopathy through unravelling pathogenesis and exploring future treatment perspectives
Nagayach, A., Bhaskar, R., Ghosh, S., Singh, D. K. K., Han, S. S., & Sinha, J. K. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102450 · Cited by 46 · see citing works
An insight into PI3k/Akt pathway and associated protein–protein interactions in metabolic syndrome: A recent update
Verma, K., Jaiswal, R., Paliwal, S., Dwivedi, J., & Sharma, S. K. (2023) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30433 · Cited by 48 · see citing works
Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy
Liu, H.-T., Stepicheva, N., Ghosh, S., Shang, P., Chowdhury, O., Daley, R. A., Yazdankhah, M., Gupta, U., Hose, S., Valapala, M., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33773-0 · Cited by 42 · see citing works
3D printing of reduced glutathione grafted gelatine methacrylate hydrogel scaffold promotes diabetic bone regeneration by activating PI3K/Akt signaling pathway
Wang, L., Shen, M., Hou, Q., Wu, Z., Xu, J., & Wang, L. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.09.236 · Cited by 45 · see citing works
DEHP and DBP, common phthalates, induce glucose metabolism disorders in rats via oxidative damage of PI3K/Akt/GLUT4 signaling
Li, L., Huang, L., Lei, R., Zhang, P., Yang, Y., Liu, H., & Zhang, Y. (2023) · Environmental Pollution · doi:10.1016/j.envpol.2023.122948 · Cited by 45 · see citing works
Therapeutic targeting of white adipose tissue metabolic dysfunction in obesity: mechanisms and opportunities
Yang, Z., Chen, F., Zhang, Y., Ou, M., Tan, P., Xu, X., Li, Q., & Zhou, S. (2024) · MedComm · doi:10.1002/mco2.560 · Cited by 35 · see citing works
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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 › Epidemiology › 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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