Control of diabetic hyperglycaemia and insulin resistance through TSC22D4
Open accessAbstract
Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes. Efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications Here, we identify transforming growth factor beta-like stimulated clone (TSC) 22 D4 as a molecular determinant of insulin signalling and glucose handling. Hepatic TSC22D4 inhibition both prevents and reverses hyperglycaemia, glucose intolerance and insulin resistance in diabetes mouse models. TSC22D4 exerts its effects on systemic glucose homeostasis-at least in part-through the direct transcriptional regulation of the small secretory protein lipocalin 13 (LCN13). Human diabetic patients display elevated hepatic TSC22D4 expression, which correlates with decreased insulin sensitivity, hyperglycaemia and LCN13 serum levels. Our results establish TSC22D4 as a checkpoint in systemic glucose metabolism in both mice and humans, and propose TSC22D4 inhibition as an insulin sensitizing option in diabetes therapy.
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Both mRNA and plasma levels of LCN13 are low in mice with genetic or high-fat diet-induced obesity.
“both mRNA and plasma levels of LCN13 are low in mice with genetic or high-fat diet-induced obesity [254,257].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [257]
Plasma levels of LCN13 decrease in patients with obesity and type 2 diabetes.
“Plasma levels of LCN13 decrease in patients with obesity and type 2 diabetes [257]”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [257]
Knockdown of LCN13 or administration of recombinant LCN13 protein in mice have no significant effects on body weight or adipose tissue mass compared with control animals.
“Interestingly, knockdown of LCN13 or administration of recombinant LCN13 protein in mice have no significant effects on body weight or adipose tissue mass compared with control animals [257].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [257]
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Cites
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216 · see citing works
AKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115 · see citing works
Mechanisms 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 · see citing works
Chen, H., Charlat, O., Tartaglia, L. A., Woolf, E. A., Weng, X., Ellis, S. J., Lakey, N. D., Culpepper, J., More, K. J., Breitbart, R. E., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81294-5 · Cited by 2,214 · see citing works
Understanding the mechanisms and treatment options in cancer cachexia
Fearon, K. C. H., Arends, J., & Baracos, V. E. (2012) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2012.209 · Cited by 937 · see citing works
Klöting, N., Fasshauer, M., Dietrich, A., Kovacs, P., Schön, M. R., Kern, M., Stumvoll, M., & Blüher, M. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00586.2009 · Cited by 856 · see citing works
Self-citationDifferentiation Stage-Specific Inhibition of the Raf-MEK-ERK Pathway by Akt
Rommel, C., Clarke, B. A., Zimmermann, S., Nuñez, L., Rossman, R., Reid, K., Moelling, K., Yancopoulos, G. D., & Glass, D. J. (1999) · Science · doi:10.1126/science.286.5445.1738 · Cited by 759 · see citing works
New Perspectives into the Molecular Pathogenesis and Treatment of Type 2 Diabetes
Saltiel, A. R. (2001) · Cell · doi:10.1016/s0092-8674(01)00239-2 · Cited by 684 · see citing works
Insulin signaling pathways in time and space
Saltiel, A. R., & Pessin, J. E. (2002) · Trends in Cell Biology · doi:10.1016/s0962-8924(01)02207-3 · Cited by 628 · see citing works
Lipodystrophies: Genetic and Acquired Body Fat Disorders
Garg, A. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1159 · Cited by 556 · see citing works
Tissue–Specific Insulin Signaling, Metabolic Syndrome, and Cardiovascular Disease
Rask‐Madsen, C., & Kahn, C. R. (2012) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.111.241919 · Cited by 376 · see citing works
CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ
Herzig, S., Hedrick, S. A., Morantte, I. G., Koo, S., Galimi, F., & Montminy, M. (2003) · Nature · doi:10.1038/nature02110 · Cited by 321 · see citing works
Self-citationPIKKing on PKB: regulation of PKB activity by phosphorylation
Bozulic, L., & Hemmings, B. A. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.02.002 · Cited by 208 · see citing works
Herzig, R. P., Scacco, S., & Scarpulla, R. C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.17.13134 · Cited by 197 · see citing works
Blüher, M., UNGER, R. H., Rassoul, F., Richter, V., & Paschke, R. (2002) · Diabetologia · doi:10.1007/s00125-001-0723-3 · Cited by 152 · see citing works
Self-citationMetabolic control through glucocorticoid hormones: An update
Rose, A. J., & Herzig, S. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.03.007 · Cited by 133 · see citing works
Self-citationKlingmüller, U., Bauer, A., Bohl, S., Nickel, P. J., Breitkopf, K., Dooley, S., Zellmer, S., Kern, C., Merfort, I., Sparna, T., et al. (2006) · IEE Proceedings - Systems Biology · doi:10.1049/ip-syb:20050067 · Cited by 127 · see citing works
Insulin Resistance in the Defense against Obesity
Saltiel, A. R. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.03.001 · Cited by 101 · see citing works
Differential Levels of Diabetogenic Stress in Two New Mouse Models of Obesity and Type 2 Diabetes
Leiter, E. H., & Reifsnyder, P. C. (2004) · Diabetes · doi:10.2337/diabetes.53.2007.s4 · Cited by 99 · see citing works
Molecular Control of Systemic Bile Acid Homeostasis by the Liver Glucocorticoid Receptor
Rose, A. J., Díaz, M. B., Reimann, A., Klement, J., Walcher, T., Krones, A., Strobel, O., Werner, J. M., Peters, A., Kleyman, A., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.04.010 · Cited by 94 · see citing works
Self-citationYoon, S. H., Han, E. J., Sung, J. H., & Chung, S. H. (2007) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.30.2196 · Cited by 88 · see citing works
TSC22D4 is a molecular output of hepatic wasting metabolism
Jones, A., Friedrich, K., Rohm, M., Schäfer, M., Algire, C., Kulozik, P., Seibert, O., Müller‐Decker, K., Sijmonsma, T., Strzoda, D., et al. (2013) · EMBO Molecular Medicine · doi:10.1002/emmm.201201869 · Cited by 63 · see citing works
Self-citationKulozik, P., Jones, A., Mattijssen, F., Rose, A. J., Reimann, A., Strzoda, D., Kleinsorg, S., Raupp, C., Kleinschmidt, J. A., Müller‐Decker, K., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.02.011 · Cited by 60 · see citing works
Self-citationHerzig, S., FÜZESI, L., & Knepel, W. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003345200 · Cited by 60 · see citing works
Self-citationDíaz, M. B., Krones, A., Metzger, D., Ziegler, A., Vegiopoulos, A., Klingenspor, M., Müller‐Decker, K., & Herzig, S. (2008) · Hepatology · doi:10.1002/hep.22383 · Cited by 57 · see citing works
Self-citationNarvekar, P., Díaz, M. B., Krones, A., Hardeland, U., Strzoda, D., Stöhr, S., Frohme, M., & Herzig, S. (2009) · Diabetes · doi:10.2337/db08-1184 · Cited by 55 · see citing works
Self-citationMetabolic Disease Drug Discovery— “Hitting the Target” Is Easier Said Than Done
Moller, D. E. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2011.10.012 · Cited by 43 · see citing works
Cho, K. W., Zhou, Y., Sheng, L., & Rui, L. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.00459-10 · Cited by 42 · see citing works
Nakamura, M., Kitaura, J., Enomoto, Y., Yang, L., Nishimura, K., Isobe, M., Ozaki, K., Komeno, Y., Nakahara, F., Oki, T., et al. (2011) · Cancer Science · doi:10.1111/j.1349-7006.2011.02108.x · Cited by 37 · see citing works
Lipocalin 13 regulation of glucose and lipid metabolism in obesity
Zhou, Y., & Rui, L. (2013) · Vitamins & Hormones · doi:10.1016/b978-0-12-407766-9.00015-8 · Cited by 28 · see citing works
Canterini, S., Bosco, A., Carletti, V., Fuso, A., Curci, A., Mangia, F., & Fiorenza, M. T. (2010) · The Cerebellum · doi:10.1007/s12311-010-0211-8 · Cited by 27 · see citing works
Flagged first, then by citations
1 of the 32 references couldn’t be matched to a known paper.
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Emerging Targets in Type 2 Diabetes and Diabetic Complications
Demir, S., Nawroth, P. P., Herzig, S., & Üstünel, B. E. (2021) · Advanced Science · doi:10.1002/advs.202100275 · Cited by 544 · see citing works
Self-citationThe role of hepatokines in NAFLD
Stefan, N., Schick, F., Birkenfeld, A. L., Häring, H., & White, M. F. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.01.006 · Cited by 282 · see citing works
Hepatokines and metabolism: Deciphering communication from the liver
Jensen-Cody, S. O., & Potthoff, M. J. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101138 · Cited by 252 · see citing works
Cancer Cachexia: More Than Skeletal Muscle Wasting
Schmidt, S. F., Rohm, M., Herzig, S., & Díaz, M. B. (2018) · Trends in cancer · doi:10.1016/j.trecan.2018.10.001 · Cited by 219 · see citing works
Self-citationAdvances in Research on Type 2 Diabetes Mellitus Targets and Therapeutic Agents
Su, J., Luo, Y., Hu, S., Tang, L., & Ouyang, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713381 · Cited by 104 · see citing works
Altamura, S., Müdder, K., Schlotterer, A., Fleming, T., Heidenreich, E., Qiu, R., Hammes, H., Nawroth, P. P., & Muckenthaler, M. U. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101235 · Cited by 94 · see citing works
Self-citationWang, K., Zhang, R., Yue, X., Zhou, Z., Bai, L., Tong, Y., Wang, B., Gu, D., Wang, S., Qiao, Y., et al. (2021) · ACS Sensors · doi:10.1021/acssensors.0c02217 · Cited by 51 · see citing works
Hushpulian, D. M., Kaidery, N. A., Ahuja, M., Poloznikov, A. A., Sharma, S. M., Gazaryan, I. G., & Thomas, B. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.673205 · Cited by 41 · see citing works
Carbon dot enhanced peroxidase-like activity of platinum nanozymes
Liu, C., Hu, J., Yang, W., Shi, J., Chen, Y., Fan, X., Gao, W., Cheng, L., Luo, Q.-Y., & Zhang, M. (2024) · Nanoscale · doi:10.1039/d3nr04964g · Cited by 35 · see citing works
Miao, X., Alidadipour, A., Saed, V., Sayyadi, F., Jadidi, Y., Davoudi, M., Amraee, F., Jadidi, N., & Afrisham, R. (2024) · Acta Diabetologica · doi:10.1007/s00592-024-02335-9 · Cited by 34 · see citing works
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Demir, S., Wolff, G., Wieder, A., Maida, A., Bühler, L., Brune, M., Hautzinger, O., Feuchtinger, A., Poth, T., Szendroedi, J., et al. (2022) · Science Advances · doi:10.1126/sciadv.abo5555 · Cited by 26 · see citing works
Self-citationXiao, Y.-X., Lee, S. Y., Aguilera-Uribe, M., Samson, R., Au, A., Khanna, Y., Liu, Z., Cheng, R., Aulakh, K., Wei, J., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114417 · Cited by 18 · see citing works
Zhang, W., Zhang, D., Cheng, Y., Liang, X., & Wang, J. (2022) · Experimental Eye Research · doi:10.1016/j.exer.2022.108969 · Cited by 16 · see citing works
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Stefanaki, K., Ilias, Ι., Paschou, S. Α., & Karagiannakis, D. S. (2023) · HORMONES · doi:10.1007/s42000-023-00487-x · Cited by 15 · see citing works
Hwang, J., Haque, M. A., Suzuki, H., ten Dijke, P., & Kato, M. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.11.149 · Cited by 14 · see citing works
Roy, P., Saha, S., & Chakraborty, J. (2021) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2021.102830 · Cited by 13 · see citing works
Wolff, G., Sakurai, M., Mhamane, A., Troullinaki, M., Maida, A., Deligiannis, I. K., Yin, K., Weber, P., Morgenstern, J., Wieder, A., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101487 · Cited by 12 · see citing works
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Hu, J., Wang, L., Wang, F., Chi, G., Liu, G., & Sun, L. (2019) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2019.110914 · Cited by 12 · see citing works
Brie, B., Sarmento‐Cabral, A., Pascual, F. L., Córdoba‐Chacón, J., Kineman, R. D., & Becú‐Villalobos, D. (2024) · Journal of the Endocrine Society · doi:10.1210/jendso/bvae015 · Cited by 10 · see citing works
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Sakurai, M., Weber, P., Wolff, G., Wieder, A., Szendroedi, J., Herzig, S., & Üstünel, B. E. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.05.100 · Cited by 9 · see citing works
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Bühler, L., Maida, A., Vogl, E. S., Georgiadi, A., Takacs, A., Kluth, O., Schürmann, A., Feuchtinger, A., von Toerne, C., Tsokanos, F., et al. (2021) · Life Science Alliance · doi:10.26508/lsa.202000898 · Cited by 8 · see citing works
Self-citationJung, J., Kim, G. W., Lee, W., Mok, C.-S., Chung, S. H., & Jang, W. (2018) · Scientific Reports · doi:10.1038/s41598-017-18082-7 · Cited by 8 · see citing works
Wang, L., Ma, S., Hu, Z., McGuire, T. F., & Xie, X.-Q. S. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2018.5757 · Cited by 8 · see citing works
Qin, X., Tan, Y., Ren, W., Zhou, W., Niu, R., Liang, L., Li, J., Cao, K., Wei, G., Zhu, X., et al. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.111812 · Cited by 7 · see citing works
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Xu, H., Jin, J., Li, Y., Wu, Y., Cheng, Z., Wang, M., Ye, X., Lai, M., & Zhang, D. (2025) · Marine Biotechnology · doi:10.1007/s10126-025-10516-y · Cited by 5 · see citing works
Schenk, M., Mörl, K., Herzig, S., & Beck‐Sickinger, A. G. (2024) · Journal of Peptide Science · doi:10.1002/psc.3611 · Cited by 5 · see citing works
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Yıldırım, S., Mhamane, A., Lösch, S., Wieder, A., Ermiş, E., König, A., Yilmaz, S., Hauck, S. M., Kocabaş, F., Szendroedi, J., et al. (2025) · FEBS Journal · doi:10.1111/febs.70194 · Cited by 3 · see citing works
Self-citationAfsharian, Y. P., Rahimnejad, M., Rabiee, S. M., Feizi, F., & Seitz, H. (2025) · Advanced Therapeutics · doi:10.1002/adtp.202400400 · Cited by 2 · see citing works
Identification, characterization and expression analysis of rLcn13, an epididymal lipocalin in rats
Yao, G., Xie, S., Wan, X., Zhang, L., Liu, Q., & Hu, S. (2023) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2023008 · Cited by 2 · see citing works
Vastrad, B. M., Pattanashetti, S., & Vastrad, C. M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.05.570305 · Cited by 2 · see citing works
Novel Insights into TSC22D Family Genes in Metabolic Diseases and Cancer
Shen, W., Shen, C., Jiao, Y., Deng, X., Jia, J., & YUAN, G. (2026) · Biomolecules · doi:10.3390/biom16010179 · Cited by 1 · see citing works
TSC22D4 interacts with Akt1 in response to metabolic and stress signalsPreprint
Demir, S., Wolff, G., Wieder, A., Maida, A., Rahm, M., Schnölzer, M., Hauck, S. M., Szendrödi, J., Herzig, S., & Üstünel, B. E. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.12.20.473554 · Cited by 1 · see citing works
Self-citationSun, J., Wang, H., 夏新方, Zhang, W., Chen, Y., Wang, Q., & Fang, Z. (2026) · Journal of Chromatography B · doi:10.1016/j.jchromb.2026.125224
Qin, X., Hong, Y., Ren, W., Lei, G., Zhou, W., Wu, S., Lin, Z., Tan, Y., Cao, K., Wei, Z., et al. (2026) · Liver International · doi:10.1111/liv.70858
- Authors
- Ekim Üstünel, B., Friedrich, K., Maida, A., Wang, X., Krones-Herzig, A., Seibert, O., Sommerfeld, A., Jones, A., Sijmonsma, T. P., Sticht, C., Gretz, N., Fleming, T., Nawroth, P. P., Stremmel, W., Rose, A. J., Berriel-Diaz, M., Blüher, M., & Herzig, S.
- Affiliations
- University Hospital Heidelberg (DE)
- Helmholtz Munich (DE)
- Medizinische Fakultät Mannheim (DE)
- Heidelberg University (DE)
- Leipzig University (DE)
- Corresponding author
- Herzig, Stephan
- ORCID
- Venue
- Nature Communications
- Published
- 2016-11-09
- Volume
- 7
- Issue
- 1
- Pages
- 13267-13267
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5105165
- OpenAlex
- W2551870514
- Cited by
- 36
- References
- 32
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 7 · 2023: 5 · 2022: 4 · 2021: 7 · 2020: 1 · 2019: 2 · 2018: 3
- FWCI
- 1.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Site cant be reached (submittedVersion, cc-by)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
- Funders
- European Foundation for the Study of Diabetes
- Deutsche Forschungsgemeinschaft (SFB1118)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- insulin resistance, hyperglycemia, type 2 diabetes, glucose homeostasis, insulin signaling, hepatic insulin sensitivity, impaired glucose tolerance, metabolic syndrome, insulin sensitization
- MeSH terms
- Animals, Blood Glucose, Cell Line, Diabetes Mellitus, Type 2, Female, Gene Expression Regulation, Humans, Hyperglycemia, Insulin Resistance, Liver, Male, Mice, Inbred C57BL, Transcription Factors, Mice, Knockout, Lipocalins
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