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The cell biology of systemic insulin function
Open accessAbstract
Insulin is the paramount anabolic hormone, promoting carbon energy deposition in the body. Its synthesis, quality control, delivery, and action are exquisitely regulated by highly orchestrated intracellular mechanisms in different organs or “stations” of its bodily journey. In this Beyond the Cell review, we focus on these five stages of the journey of insulin through the body and the captivating cell biology that underlies the interaction of insulin with each organ. We first analyze insulin’s biosynthesis in and export from the β-cells of the pancreas. Next, we focus on its first pass and partial clearance in the liver with its temporality and periodicity linked to secretion. Continuing the journey, we briefly describe insulin’s action on the blood vasculature and its still-debated mechanisms of exit from the capillary beds. Once in the parenchymal interstitium of muscle and adipose tissue, insulin promotes glucose uptake into myofibers and adipocytes, and we elaborate on the intricate signaling and vesicle traffic mechanisms that underlie this fundamental function. Finally, we touch upon the renal degradation of insulin to end its action. Cellular discernment of insulin’s availability and action should prove critical to understanding its pivotal physiological functions and how their failure leads to diabetes.
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“An increase in circulating glucose levels is sensed by pancreatic β‐cells through the glucose transporter GLUT2.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [24]
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Central nervous system control of food intake
Schwartz, M. W., Woods, S. C., Porte, D., Seeley, R. J., & Baskin, D. G. (2000) · Nature · doi:10.1038/35007534 · Cited by 6,451 · cited 1×
“Insulin regulates appetite by reducing expression of neuropeptide Y and Agouti-related peptide (orexigenic) and, conversely, elevating expression of pro-opiomelanocortin (anorexigenic; Schwartz et al., 2000).”
BackgroundVascular endothelial cells synthesize nitric oxide from L-arginine
Palmer, R. M. J., Ashton, D., & Moncada, S. (1988) · Nature · doi:10.1038/333664a0 · Cited by 4,786 · cited 1×
“In turn, Akt activates endothelial NO synthase to catalyze the conversion of l-arginine to NO (Palmer et al., 1988; Zeng et al., 2000).”
BackgroundCritical nodes in signalling pathways: insights into insulin action
Taniguchi, C. M., Emanuelli, B., & Kahn, C. R. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1837 · Cited by 2,760 · cited 1×
“…of the hormone’s journey in the body have been correlated and often causally related to insulin resistance, hypertension, and type 2 diabetes (Taniguchi et al., 2006; Hoehn et al., 2008; Odegaard and Chawla, 2013; Boucher et al., 2014; DeFronzo et al., 2015; Samuel and Shulman, 2016;…”
BackgroundDeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.19 · Cited by 2,611 · cited 1×
“…2018) and CEA CAM1 expression (Lee, 2011) in obesity • Impaired vasoactive effects of insulin during insulin resistance, including capillary recruitment (de Jongh et al., 2004; Clerk et al., 2006; Keske et al., 2009); reduced insulin delivery to muscle in obesity and diabetes (Broussard et al.,…”
BackgroundMechanisms for Insulin Resistance: Common Threads and Missing Links
Samuel, V. T., & Shulman, G. I. (2012) · Cell · doi:10.1016/j.cell.2012.02.017 · Cited by 2,294 · cited 1×
“, 2013) as well as a number of proteins of the GLUT4 vesicle fusion machinery (Aslamy and Thurmond, 2017); the underlying defects include alterations in the maintenance of the storage compartment (Foley et al., 2011; Samuel and Shulman, 2012) and in the insulin-derived signals that trigger GLUT4 vesicle release from s…”
BackgroundRole of Brain Insulin Receptor in Control of Body Weight and Reproduction
Brüning, J. C., Gautam, D., Burks, D. J., Gillette, J., Schubert, M., Orban, P. C., Klein, R., Krone, W., Müller-Wieland, D., & Kahn, C. R. (2000) · Science · doi:10.1126/science.289.5487.2122 · Cited by 2,235
Insulin Receptor Signaling in Normal and Insulin-Resistant StatesPreprint
Boucher, J., Kleinridders, A., & Kahn, C. R. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a009191 · Cited by 1,550 · cited 1×
“…often causally related to insulin resistance, hypertension, and type 2 diabetes (Taniguchi et al., 2006; Hoehn et al., 2008; Odegaard and Chawla, 2013; Boucher et al., 2014; DeFronzo et al., 2015; Samuel and Shulman, 2016; Haeusler et al., 2018; also see other important highlights in the text box).”
BackgroundFarris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E. A., Frosch, M. P., Eckman, C. B., Tanzi, R. E., Selkoe, D. J., & Guénette, S. Y. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0230450100 · Cited by 1,526 · cited 1×
“…the role of IDE in hepatic insulin clearance in vivo is controversial, as some studies report that loss of IDE results in hyperinsulinemia (Farris et al., 2003; Abdul-Hay et al., 2011), whereas others observed no changes in systemic circulating insulin in the absence of the enzyme…”
BackgroundThe pathogenesis of insulin resistance: integrating signaling pathways and substrate flux
Samuel, V. T., & Shulman, G. I. (2016) · Journal of Clinical Investigation · doi:10.1172/jci77812 · Cited by 1,484 · cited 1×
“…often causally related to insulin resistance, hypertension, and type 2 diabetes (Taniguchi et al., 2006; Hoehn et al., 2008; Odegaard and Chawla, 2013; Boucher et al., 2014; DeFronzo et al., 2015; Samuel and Shulman, 2016; Haeusler et al., 2018; also see other important highlights in the text box).”
BackgroundArnold, W. P., Mittal, C. K., Katsuki, S., & Murad, F. (1977) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.74.8.3203 · Cited by 1,459 · cited 1×
“NO is a potent vasodilator that rapidly diffuses to the vessels’ outer layer of smooth muscle cells, where it activates intracellular guanylate cyclase to increase cyclic guanosine monophosphate production (Arnold et al., 1977).”
Background
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Molecular Mechanisms Linking Oxidative Stress and Diabetes Mellitus
Yaribeygi, H., Sathyapalan, T., Atkin, S. L., & Sahebkar, A. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/8609213 · Cited by 749
“The normal process of glucose uptake via GLUT-4 is closely dependent on the physiological functioning of healthy mitochondria [134] that produce the energy needed for glucose uptake in peripheral tissues [134].”
BackgroundSchalkwijk, C., & Stehouwer, C. D. A. (2019) · Physiological Reviews · doi:10.1152/physrev.00001.2019 · Cited by 649
The Short-Chain Fatty Acid Acetate in Body Weight Control and Insulin Sensitivity
Hernández, M. A. G., Canfora, E. E., Jocken, J. W. E., & Blaak, E. E. (2019) · Nutrients · doi:10.3390/nu11081943 · Cited by 650
“Other acetate mediated signals may indirectly contribute to insulin secretion, such as via gut-derived GLP-1 and vagal activation of the parasympathetic nervous system [176].”
BackgroundSarcopenia – Molecular mechanisms and open questions
Wiedmer, P., Jung, T., Castro, J. P., Pomatto, L. C. D., Sun, P. Y., Davies, K. J. A., & Grune, T. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101200 · Cited by 524
“Insulin is another anabolic hormone acting on myocytes (Tokarz et al., 2018).”
The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia
Sylow, L., Tokarz, V. L., Richter, E. A., & Klip, A. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.03.020 · Cited by 366
Self-citationKlip, A., McGraw, T. E., & James, D. E. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.rev119.008351 · Cited by 365
Self-citationHyperinsulinemia in Obesity, Inflammation, and Cancer
Zhang, A. M. Y., Wellberg, E. A., Kopp, J. L., & Johnson, J. D. (2021) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2020.0250 · Cited by 344
“Hyperinsulinemia can manifest as an elevation in basal/fasting circulating insulin and/or as a potentiation of post-prandial insulin secretion [71,72], and can result from insulin hypersecretion or reduced systemic insulin clearance, or both [73-76].”
BackgroundJanssen, J. A. M. J. L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22157797 · Cited by 315
“Receptor-mediated insulin uptake followed by insulin degradation by hepatocytes is the basic mechanism of hepatic insulin clearance [53].”
BackgroundKostov, K. G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061351 · Cited by 280
“This occurs when the membrane potential reaches approximately −50 mV [20].”
BackgroundInfluentialHepatic Insulin Clearance: Mechanism and Physiology
Najjar, S. M., & Perdomo, G. (2019) · Physiology · doi:10.1152/physiol.00048.2018 · Cited by 271
“Receptor-mediated insulin uptake followed by insulin degradation in hepatocytes constitutes the basic mechanism of hepatic insulin clearance (204).”
BackgroundThe cell biology of the hepatocyte: A membrane trafficking machine
Schulze, R. J., Schott, M. B., Casey, C. A., Tuma, P. L., & McNiven, M. A. (2019) · The Journal of Cell Biology · doi:10.1083/jcb.201903090 · Cited by 281
Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes
Hogrebe, N. J., Ishahak, M., & Millman, J. R. (2023) · Cell Stem Cell · doi:10.1016/j.stem.2023.04.002 · Cited by 210
Yang, Y., Cai, J., Yang, X., Wang, K., Sun, K., Yang, Z., Zhang, L., Yang, L., Gu, C. P., Huang, X., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.02.021 · Cited by 198
Inter‐organ communication: a gatekeeper for metabolic health
Castillo‐Armengol, J., Fajas, L., & Lopez‐Mejia, I. C. (2019) · The EMBO Reports · doi:10.15252/embr.201947903 · Cited by 178
“Glucose sensing leads to a b -cell response that ultimately leads to insulin secretion [24].”
KLF5 Is Induced by FOXO1 and Causes Oxidative Stress and Diabetic Cardiomyopathy
Kyriazis, I. D., Hoffman, M., Gaignebet, L., Lucchese, A. M., Markopoulou, E., Palioura, D., Wang, C., Bannister, T. D., Christofidou‐Solomidou, M., Oka, S., et al. (2020) · Circulation Research · doi:10.1161/circresaha.120.316738 · Cited by 149
CD36 as a gatekeeper of myocardial lipid metabolism and therapeutic target for metabolic disease
Glatz, J. F. C., Heather, L. C., & Luiken, J. J. F. P. (2023) · Physiological Reviews · doi:10.1152/physrev.00011.2023 · Cited by 134
The Therapeutic Role of Ketogenic Diet in Neurological Disorders
Pietrzak, D., Kasperek, K., Rękawek, P., & Piątkowska‐Chmiel, I. (2022) · Nutrients · doi:10.3390/nu14091952 · Cited by 136
“Insulin is a hormone produced by pancreatic β cells that increases glucose uptake by the cells, thereby reducing blood glucose levels [60].”
BackgroundInsulin Resistance Exacerbates Alzheimer Disease via Multiple Mechanisms
Wei, Z.-H., Koya, J., & Reznik, S. E. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.687157 · Cited by 133
Microbe-mediated intestinal NOD2 stimulation improves linear growth of undernourished infant mice
Schwarzer, M., Gautam, U. K., Makki, K., Lambert, A., Brabec, T., Joly, A., Šrůtková, D., Poinsot, P., Novotná, T., Geoffroy, S., et al. (2023) · Science · doi:10.1126/science.ade9767 · Cited by 124
Insulin translates unfavourable lifestyle into obesity
Kolb, H., Stümvoll, M., Kramer, W., Kempf, K., & Martin, S. (2018) · BMC Medicine · doi:10.1186/s12916-018-1225-1 · Cited by 117
Rho GTPases—Emerging Regulators of Glucose Homeostasis and Metabolic Health
Møller, L. L. V., Klip, A., & Sylow, L. (2019) · Cells · doi:10.3390/cells8050434 · Cited by 82
“Under normal circumstances, Cdc42 and Rac1 activation is needed for this process [58,63,67].”
BackgroundSelf-citationA systematic review on gut microbiota in type 2 diabetes mellitus
Chong, S., Lin, M., Chong, D., Jensen, S. O., & Lau, N. S. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1486793 · Cited by 107
Fatty acids and their role in type‑2 diabetes (Review)
Shetty, S. S., & Kumari, S. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.10138 · Cited by 83
Chakraborty, R., & Roy, S. (2021) · Journal of Chinese Integrative Medicine · doi:10.1016/j.joim.2021.09.006 · Cited by 79
Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo
Batista, T. M., García-Martín, R., Cai, W., Konishi, M., O'Neill, B. T., Sakaguchi, M., Kim, J. H., Jung, D. Y., Kim, J. K., & Kahn, C. R. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.02.081 · Cited by 76
“This occurs through regulation of a range of physiological processes involved in metabolism, growth, differentiation, and cell survival (Boucher et al., 2014; Tokarz et al., 2018).”
BackgroundRosenstock, J., Juneja, R., Beals, J. M., Moyers, J. S., Ilag, L. L., & McCrimmon, R. J. (2024) · Endocrine Reviews · doi:10.1210/endrev/bnad037 · Cited by 83
“…diameter and account for approximately 0.2% of the total surface area of the capillary endothelium and, to a lesser extent, large paracellular gaps, which are estimated to be 25 to 30 nm in diameter and account for 0.002% to 0.02% of the total surface area of the capillary endothelium (19, 29, 45).”
InfluentialContribution of muscle satellite cells to sarcopenia
Huo, F., Liu, Q., & Liu, H. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.892749 · Cited by 74
Nutrient Metabolism, Subcellular Redox State, and Oxidative Stress in Pancreatic Islets and β-Cells
Roma, L. P., & Jonas, J. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.10.012 · Cited by 77
Mitochondrial dysfunction in the fetoplacental unit in gestational diabetes mellitus
Sobrevía, L., Valero, P., Grismaldo, A., Villalobos-Labra, R., Pardo, F., Subiabre, M., Armstrong, G. A., Toledo, F., Vega, S., Cornejo, M., et al. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165948 · Cited by 75
Starvation in the Midst of Plenty: Reflections on the History and Biology of Insulin and Leptin
Flier, J. S. (2018) · Endocrine Reviews · doi:10.1210/er.2018-00179 · Cited by 72
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 76
Antidiabetic Properties of Chitosan and Its Derivatives
Tzeng, H.-P., Liu, S., & Chiang, M. (2022) · Marine Drugs · doi:10.3390/md20120784 · Cited by 67
“Thus, defects of GLUT4 may lead to insulin resistance and glucose intolerance [53,54].”
BackgroundInsulin: Trigger and Target of Renal Functions
Pina, A. F., Borges, D. O., Meneses, M. J., Branco, P. Q., Birne, R., Vilasi, A. D., & Macedo, M. P. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00519 · Cited by 67
Ponce-Lopez, T. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26094209 · Cited by 75
“By maintaining blood sugar levels and interacting with hormones like glucagon, insulin ensures a balanced regulation of energy storage and utilization across the body [56].”
Cdc42: A Novel Regulator of Insulin Secretion and Diabetes-Associated Diseases
Huang, Q.-Y., Lai, X., Qian, X., Lv, L., Li, J., Duan, J., Xiao, X., & Xiong, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20010179 · Cited by 67
“Second-phase insulin secretion requires the continual mobilization of insulin granules from synthetic parts to the plasma membrane, and this process mainly relies on filamentous actin (F-actin) remodelling regulated by Cdc42 and its downstream factors [34].”
BackgroundFrendo‐Cumbo, S., Tokarz, V. L., Bilan, P. J., Brumell, J. H., & Klip, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.708431 · Cited by 66
Self-citationThe evolving view of thermogenic fat and its implications in cancer and metabolic diseases
Yin, X., Chen, Y., Ruze, R., Xu, R., Song, J., Wang, C., & Xu, Q. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01178-6 · Cited by 72
“In this process, thermogenic adipocytes serve as a cellular ‘rheostat’ that senses the glucose status and contributes significantly to whole-body energy homeostasis.(65,66) Given that brown and beige adipocytes can take up glucose positively, (18)F-fluorodeoxyglucose positron emission tomography combined with computed…”
MethodChanges in Cells Associated with Insulin Resistance
Szablewski, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25042397 · Cited by 78
“Insulin action begins after the hormone binds to INSR, which activates IRS-1 [2,37].”
BackgroundInfluentialMartinou, E., Stefanova, I., Iosif, E., & Angelidi, A. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063339 · Cited by 64
“Insulin is a peptide hormone that is expressed by the β-pancreatic cells in response to blood glucose [335].”
BackgroundPreclinical Characterization of LY3209590, a Novel Weekly Basal Insulin Fc-Fusion Protein
Moyers, J. S., Hansen, R. J., Day, J. W., Dickinson, C. D., Zhang, C., Ruan, X., Ding, L., Brown, R. M., Baker, H. E., & Beals, J. M. (2022) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.122.001105 · Cited by 61
“…(PK) profile must be balanced with the receptor engagement; thus, the strategy requires attenuating IR binding to decrease clearance by receptor mediated endocytosis (RME) (Tokarz et al., 2018), as well as mitigating renal filtration (Ferrannini et al., 1983; Henriksen et al., 1987).”
BackgroundInfluentialRichter, E. A., Bilan, P. J., & Klip, A. (2025) · Physiological Reviews · doi:10.1152/physrev.00033.2024 · Cited by 64
Self-citationKim, T. H., Yang, Y. M., Han, C. Y., Koo, J. H., Oh, H., Kim, S. S., You, B. H., Choi, Y. H., Park, T., Lee, C. H., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci97831 · Cited by 64
Walker, J. T., Haliyur, R., Nelson, H. A., Ishahak, M., Poffenberger, G., Aramandla, R., Reihsmann, C., Luchsinger, J. R., Saunders, D. C., Wang, P., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.137017 · Cited by 65
“This shift closes ATP-sensitive potassium channels, depolarizing the cell membrane and opening voltage-dependent calcium channels where calcium influx is a trigger of insulin granule exocytosis (12).”
BackgroundExosomes and Obesity-Related Insulin Resistance
Lei, L.-M., Lin, X., Xu, F., Shan, S., Guo, B., Li, F., Zheng, M.-H., Wang, Y., Xu, Q.-S., & Yuan, L. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.651996 · Cited by 55
“Indeed, the actions of insulin mainly contribute to glucose uptake by skeletal muscle and adipose tissue and reduce liver gluconeogenesis and glycogenolysis (Titchenell et al., 2017; Tokarz et al., 2018).”
BackgroundInsulin Resistance in Pediatric Obesity: From Mechanisms to Treatment Strategies
Luo, Y., Luo, D., Li, M., & Tang, B. (2024) · Pediatric Diabetes · doi:10.1155/2024/2298306 · Cited by 78
“Insulin resistance arises when peripheral tissues, such as skeletal muscle, liver, and adipose tissue exhibit decreased sensitivity to insulin, resulting in impaired uptake and utilization of glucose [10].”
Li, X., Li, L., Lei, W., Chua, H. Z., Li, Z., Huang, X., Wang, Q., Li, N., & Zhang, H. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111979 · Cited by 55
Wang, S., Li, Q., Peng, J., & Niu, H. (2023) · Animals · doi:10.3390/ani13101619 · Cited by 54
“The hormones involved in stress regulation include INS, GH, GC, thyroid hormones, etc. INS has the effect of enhancing anabolism and promoting energy deposition in the body [41].”
BackgroundWiedemann, P., Sorgente, N., Bekhor, C., Patterson, R., Tran, T., & Ryan, S. J. (1985) · PubMed · Cited by 53
Ghadieh, H. E., Russo, L., Muturi, H. T., Ghanem, S. S., Manaserh, I. H., Noh, H. L., Suk, S., Kim, J. K., Hill, J. W., & Najjar, S. M. (2019) · Metabolism · doi:10.1016/j.metabol.2019.01.008 · Cited by 58
“This phosphorylates other substrates and delivers insulin to early/late endosomes for degradation before the receptor recycles back to the surface membrane [5].”
BackgroundNagy, T., Fisi, V., Frank, D., Kátai, E., Nagy, Z., & Miseta, A. (2019) · Cells · doi:10.3390/cells8090999 · Cited by 54
“It is caused by decreased uptake of glucose by insulin sensitive cells (hepatocytes, myocytes, adipocytes) [20].”
BackgroundČater, M., & Bombek, L. K. (2022) · Antioxidants · doi:10.3390/antiox11081473 · Cited by 55
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Gołacki, J., Matuszek, M., & Matyjaszek‐Matuszek, B. (2022) · Diagnostics · doi:10.3390/diagnostics12071681 · Cited by 61
“Insulin signaling also plays an important role in nitric oxide production, which is considered a strong vasodilator and a substance with anti-atherosclerosis properties [7].”
BackgroundEndosomal trafficking in metabolic homeostasis and diseases
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Patel, B. M., & Goyal, R. K. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172657 · Cited by 51
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Kurtzhals, P., Nishimura, E., Haahr, H. L., Høeg-Jensen, T., Johansson, E., Madsen, P., Sturis, J., & Kjeldsen, T. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.05.005 · Cited by 51
Janssen, J. A. M. J. L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25105488 · Cited by 70
“Unprocessed insulin passes the liver and is delivered into the systemic (post-hepatic) circulation to exert its actions in peripheral tissues (such as muscles and fat cells) [89].”
BackgroundVerbascoside Protects Pancreatic β-Cells against ER-Stress
Galli, A., Marciani, P., Marku, A., Ghislanzoni, S., Bertuzzi, F., Rossi, R., Giancamillo, A. D., Castagna, M., & Perego, C. (2020) · Biomedicines · doi:10.3390/biomedicines8120582 · Cited by 48
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Yang, W., Lyu, Y., Xiang, R., & Yang, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232416054 · Cited by 44
“Rab10 then interacts with RAS-like oncoprotein A and membrane-to-cortex linker Myosin-Ic to stimulate the translocation of GLUT4 from cytoplasm to membrane, enhancing glucose uptake [181].”
BackgroundThe physiology of MASLD: molecular pathways between liver and adipose tissues
Lee, W., Kipp, Z. A., Bates, E. A., Pauss, S. N., Martinez, G. J., & Hinds, T. D. (2025) · Clinical Science · doi:10.1042/cs20257571 · Cited by 52
“Both have been demonstrated to participate in insulin receptor-dependent endocytosis [143,144] and insulin-degrading processes [145,146], which ultimately mediate circulating insulin levels.”
Okada, J., Yamada, E., Saito, T., Yokoo, H., Osaki, A., Shimoda, Y., Ozawa, A., Nakajima, Y., Pessin, J., Okada, S., et al. (2020) · Molecules · doi:10.3390/molecules25030495 · Cited by 40
“The first family contains glucose transporter (GLUT) proteins, which are stereospecific facilitative glucose transporters, with net transport driven by the concentration gradient of glucose across the membrane [1].”
BackgroundFrom Single- to Multi-organ-on-a-Chip System for Studying Metabolic Diseases
Jang, M., & Kim, H. N. (2023) · BioChip Journal · doi:10.1007/s13206-023-00098-z · Cited by 44
“Abnormal blood glucose levels, called hypo- or hyperglycemia, stimulate pancreatic insulin secretion and glucagon [50].”
BackgroundGut microbiota impairs insulin clearance in obese mice
Foley, K. P., Zlitni, S., Duggan, B. M., Barra, N. G., Anhê, F. F., Cavallari, J. F., Henriksbo, B. D., Chen, C. Y., Huang, M., Lau, T. C., et al. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101067 · Cited by 42
“Approximately 50 e 80% of insulin may be depleted from the blood by hepatic uptake and degradation during fi rst-pass insulin clearance [9,10].”
Melnik, B. C. (2021) · Biomolecules · doi:10.3390/biom11030404 · Cited by 47
Ortega, R., Liu, B., & Persaud, S. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310777 · Cited by 45
“These effects are achieved by insulin binding to the heterotetrameric insulin receptor, which has intrinsic tyrosine kinase activity [29].”
BackgroundLow-Density Lipoprotein Cholesterol Is Associated With Insulin Secretion
Dannecker, C., Wagner, R. J., Peter, A., Hummel, J., Vosseler, A., Häring, H., Fritsche, A., Birkenfeld, A. L., Stefan, N., & Heni, M. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab147 · Cited by 41
“As insulin and C-peptide undergo different elimination mechanisms with a high hepatic first-pass clearance of insulin (31), we next investigated possible links between LDL cholesterol and insulin clearance that could potentially explain these contrary results.”
ResultTargeting the Zinc Transporter ZIP7 in the Treatment of Insulin Resistance and Type 2 Diabetes
Adulcikas, J., Sonda, S., Norouzi, S., Sohal, S. S., & Myers, S. (2019) · Nutrients · doi:10.3390/nu11020408 · Cited by 40
Insulin Action in the Hypothalamus Increases Second-Phase Insulin Secretion in Humans
Heni, M., Wagner, R., Willmann, C., Jaghutriz, B. A., Vosseler, A., Kübler, C., Hund, V., Scheffler, K., Peter, A., Häring, H.-U., et al. (2020) · Neuroendocrinology · doi:10.1159/000504551 · Cited by 36
Agonist-Biased Signaling via Matrix Metalloproteinase-9 Promotes Extracellular Matrix Remodeling
Qorri, B., Kalaydina, R.-V., Velickovic, A., Kaplya, Y., DeCarlo, A., & Szewczuk, M. R. (2018) · Cells · doi:10.3390/cells7090117 · Cited by 36
“Insulin resistance as a result of decreased sensitivity to the ligand and decreased ligand availability presents as a significant problem in many pathological conditions [118].”
BackgroundGenetic, epigenetic, and environmental mechanisms govern allele-specific gene expressionPreprint
Pierre, C. L. S., Macias-Velasco, J. F., Wayhart, J. P., Li, Y., Semenkovich, C. F., & Lawson, H. A. (2022) · Genome Research · doi:10.1101/gr.276193.121 · Cited by 39
“The liver plays an important role in regulating homeostatic insulin levels and removing it from the bloodstream (Tokarz et al. 2018).”
Barriers to Type 1 Diabetes Adherence in Adolescents
Azar, S., Jaoude, N. M. A., Kędzia, A. W., & Niechciał, E. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13195669 · Cited by 47
“Insulin plays a vital role in the fate of macronutrients, mainly carbohydrates, to achieve optimal energy usage while regulating glucose levels within the bloodstream to a set threshold of approximately 70 mg/dL (3.9 mmol/L) [1,2].”
BackgroundInfluentialHormonal Contribution to Liver Regeneration
Rmilah, A. A. A., Zhou, W., & Nyberg, S. L. (2020) · Mayo Clinic Proceedings Innovations Quality & Outcomes · doi:10.1016/j.mayocpiqo.2020.02.001 · Cited by 37
“To decrease the blood glucose concentration back to normal, insulin promotes cellular uptake of glucose and synthesis of glycogen, fat, and protein.(36) The following sections review insulin as a hepatic mitogen.”
BackgroundDynamic Uni- and Multicellular Patterns Encode Biphasic Activity in Pancreatic Islets
Jaffredo, M., Bertin, É., Pirog, A., Puginier, E., Gaitan, J., Ouchérif, S., Lebreton, F., Bosco, D., Catargi, B., Cattaert, D., et al. (2021) · Diabetes · doi:10.2337/db20-0214 · Cited by 32
Minerals and the Menstrual Cycle: Impacts on Ovulation and Endometrial Health
Kapper, C., Oppelt, P., Ganhör, C., Gyunesh, A. A., Arbeithuber, B., Stelzl, P., & Rezk, M. (2024) · Nutrients · doi:10.3390/nu16071008 · Cited by 51
Extracellular vesicles in metabolic perspective: mechanism and targeted therapy
Sheng, Q., Wu, Z., Li, W., Wang, L., Xu, H., Wang, W., Yan, Z., Ge, G., Xu, Y., & Geng, D. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03763-7 · Cited by 36
“Elements like insulin promote glucose uptake after binding to cellular receptors [5].”
Gene Expression Profiling of Type 2 Diabetes Mellitus by Bioinformatics Analysis
Zhu, H., Zhu, X., Liu, Y., Jiang, F., Chen, M., Cheng, L., & Cheng, X. (2020) · Computational and Mathematical Methods in Medicine · doi:10.1155/2020/9602016 · Cited by 33
Senoo, H., Murata, D., Wai, M., Arai, K., Iwata, W., Sesaki, H., & Iijima, M. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.09.001 · Cited by 34
Beta cell dysfunction occurs independently of insulitis in type 1 diabetes pathogenesis
Huber, M. K., Widener, A. E., Cuaycal, A. E., Smurlick, D., Butterworth, E. A., Lenchik, N. I., Chen, J., Beery, M. L., Hiller, H., Verney, E., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116174 · Cited by 30
“52 To investigate this dysfunction further, we investigated changes in both RNA and protein expression involved in different facets of beta cell glucose metabolism from fixed pancreatic samples.”
Restoration of insulin receptor improves diabetic phenotype in T2DM mice
Wang, Y., Zhou, H. H., Palyha, O. C., & Mu, J. (2019) · JCI Insight · doi:10.1172/jci.insight.124945 · Cited by 36
Immunometabolism and the modulation of immune responses and host defense: A role for methylglyoxal?
Zhang, X., Schalkwijk, C. G., & Wouters, K. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2022.166425 · Cited by 31
Jaworski, M., Lorenc, A., Leszczyński, R., & Mrukwa–Kominek, E. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics16010015 · Cited by 31
Stožer, A., Šterk, M., Leitgeb, E. P., Markovič, R., Klemen, M. S., Ellis, C. E., Bombek, L. K., Dolenšek, J., MacDonald, P. E., & Gosak, M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.922640 · Cited by 37
Self-citationThe Role of Heme and Copper in Alzheimer’s Disease and Type 2 Diabetes Mellitus
Pal, I., & Dey, S. G. (2023) · JACS Au · doi:10.1021/jacsau.2c00572 · Cited by 32
The Relationship Between 5-Hydroxytryptamine and Its Metabolite Changes With Post-stroke Depression
Gu, S., He, Z., Xu, Q., Dong, J., Xiao, T., Liang, F., Ma, X., Wang, F., & Huang, J. H. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.871754 · Cited by 31
Research progress on drugs for diabetes based on insulin receptor/insulin receptor substrate
Su, J., Tang, L., Luo, Y., Xu, J., & Ouyang, S. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115830 · Cited by 32
From lipids to glucose: Investigating the role of dyslipidemia in the risk of insulin resistance
Jahdkaran, M., & Sistanizad, M. (2025) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2025.106744 · Cited by 36
Yao, Q., Liu, J., Xiao, L., & Wang, N. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.004411 · Cited by 29
“Adipose tissue receives insulin signals and is responsible for plasma glucose clearance by stimulating its uptake and utilization (1).”
BackgroundUçar, S., Özdemir, N., Koca, İ., & Altun, E. (2020) · The European Physical Journal Plus · doi:10.1140/epjp/s13360-020-00420-w · Cited by 29
Induction of Brain Insulin Resistance and Alzheimer’s Molecular Changes by Western Diet
Mietelska‐Porowska, A., Domańska, J. M., Want, A., Więckowska‐Gacek, A., Chutorański, D., Koperski, M., & Wojda, U. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094744 · Cited by 29
Lower insulin clearance is associated with increased risk of type 2 diabetes in Native Americans
Shah, M. H., Piaggi, P., Looker, H. C., Paddock, E., Krakoff, J. A., & Chang, D. C. (2021) · Diabetologia · doi:10.1007/s00125-020-05348-5 · Cited by 38
Zeng, M., Xu, J., Zhang, Z., Zou, X., Wang, X., Cao, K. J., Lv, W., Cui, Y., Long, J., Feng, Z., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101948 · Cited by 28
“Adipocytes are well acknowledged for actively responding to insulin signal for regulating systemic glucose and lipid homeostasis with the involvement of classic Akt phosphorylation and Glut4 translocation [3].”
BackgroundFatty liver diseases, mechanisms, and potential therapeutic plant medicines
Zhu, J., Yi, H., Huang, W., Pang, T., Zhou, H., & Wu, X. (2020) · Chinese Journal of Natural Medicines · doi:10.1016/s1875-5364(20)30017-0 · Cited by 24
HOMA-IR for predicting clinical pregnancy rate during IVF
Song, H., Yu, Z., Li, P., Wang, Y., & Shi, Y. (2021) · Gynecological Endocrinology · doi:10.1080/09513590.2021.1952976 · Cited by 26
Dietary curcumin restores insulin homeostasis in diet-induced obese aged mice
Lee, S., Chandrasekran, P., Mazucanti, C. H., O’Connell, J. F., Egan, J. M., & Kim, Y. (2022) · Aging · doi:10.18632/aging.203821 · Cited by 26
“improving two key components: β -cell functional integrity and hepatic insulin sensitivity [5].”
BackgroundGhosh, S., Leng, W., Wilsch‐Bräuninger, M., Barrera-Velázquez, M., Léopold, P., & Eaton, S. (2022) · Current Biology · doi:10.1016/j.cub.2022.02.068 · Cited by 25
Insulin: A connection between pancreatic β cells and the hypothalamus
de la Cruz-Concepción, B., Flores-Cortez, Y. A., Barragán-Bonilla, M. I., Mendoza-Bello, J. M., & Espinoza-Rojo, M. (2023) · World Journal of Diabetes · doi:10.4239/wjd.v14.i2.76 · Cited by 28
Insulin and the kidneys: a contemporary view on the molecular basis
Daza-Arnedo, R., Rico-Fontalvo, J. E., Aroca, G., Yánez, T. R., Martínez‐Ávila, M. C., Hurtado, A. J. A., Cardona-Blanco, M., Henao-Velásquez, C., Franco, J. A., Unigarro-Palacios, M., et al. (2023) · Frontiers in Nephrology · doi:10.3389/fneph.2023.1133352 · Cited by 25
“Furthermore, they run in parallel with the Ras-MAPK pathway (mitogen-activated proteins kinases such as MEK, MAPK/KRE), with some crossover (7, 12).”
BackgroundInfluentialFrom diabetic hyperglycemia to cerebrovascular Damage: A narrative review
Machado, R. S., Mathias, K., Joaquim, L. D. S., de Quadros, R. W., Petronilho, F. C., & Rezin, G. T. (2023) · Brain Research · doi:10.1016/j.brainres.2023.148611 · Cited by 25
Pujimulyani, D., Yulianto, W. A., Setyowati, A., Arumwardana, S., Kusuma, H. S. W., Sholihah, I. A., Rizal, R., Widowati, W., & Maruf, A. (2020) · Journal of Experimental Pharmacology · doi:10.2147/jep.s267912 · Cited by 25
Bhujle, R. R., Nayak, N., Gowda, N. A. N., Pandiselvam, R., & Sunil, C. K. (2024) · Critical Reviews in Biotechnology · doi:10.1080/07388551.2024.2423153 · Cited by 28
“The maintenance of normal glucose tolerance depends on a delicate balance between insulin action in peripheral tissues and insulin secretion [30].”
Experimental cell models of insulin resistance: overview and appraisal
Yang, Y., Wang, T., Xie, H.-A., Hu, P. P., & Pan, L. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1469565 · Cited by 29
“Furthermore, under physiological conditions, insulin secretion is meticulously regulated, dynamically adjusting in response to various factors such as blood glucose levels (134, 135).”
Metadata
- Authors
- Tokarz, V. L., MacDonald, P. E., & Klip, A.
- Affiliations
- University of Toronto (CA)
- University of Alberta (CA)
- Corresponding author
- Klip, Amira
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2018-04-05
- Volume
- 217
- Issue
- 7
- Pages
- 2273-2289
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC6028526
- OpenAlex
- W2796003794
- Cited by
- 471
- References
- 223
- Citations by year
- 2026: 37 · 2025: 63 · 2024: 46 · 2023: 64 · 2022: 80 · 2021: 88 · 2020: 41 · 2019: 41 · 2018: 10
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (FRN 148451, FRN: FND-143203)
- University of Toronto
- The Hospital for Sick Children
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- insulin, insulin biosynthesis, pancreatic beta cells, insulin secretion, hepatic insulin clearance, muscle glucose uptake, adipocyte glucose uptake, insulin signaling, vesicle trafficking, diabetes mellitus
- MeSH terms
- Adipose Tissue, Diabetes Mellitus, Glucose, Humans, Insulin, Insulin Resistance, Adipocytes, Muscle, Skeletal, Testosterone Congeners, Insulin-Secreting Cells
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