Irisin Ameliorates Glucolipotoxicity-Associated β-Cell Dysfunction and Apoptosis via AMPK Signaling and Anti-Inflammatory Actions
Open accessAbstract
Background/Aims: Islet metabolic disorder and inflammation contribute to the pathogenesis and progression of type 2 diabetes mellitus (T2DM). Irisin is a recently identified adipomyokine with protective effects on metabolic homeostasis and inflammation-suppressing effects in hepatic and vascular cells. The present study examined the effects of irisin on lipid metabolism and inflammation in β cells under glucolipotoxic conditions. Methods: Rat INS-1E β cells and islets isolated from C57BL/6 mice were incubated in glucolipotoxic conditions with or without irisin. Intracellular lipid contents and lipogenic gene expression were determined by enzymatic colorimetric assays and real-time PCR, respectively. Inflammatory status was evidenced by Western blot analysis for the phosphorylation of nuclear factor-κB (NF-κB) p65 and real-time PCR analysis for the expression of pro-inflammatory genes. Results: Irisin reversed glucolipotoxicity-induced intracellular non-esterified fatty acid (NEFA) and triglyceride accumulation, suppressed associated elevations in lipogenic gene expression, and phosphorylated acetyl-CoA-carboxylase (ACC) in INS-1E cells. These demonstrated effects were dependent on irisin-activated adenosine monophosphate-activated protein kinase (AMPK). Meanwhile, AMPK signaling mediated the protective effects of irisin on INS-1E cell insulin secretory ability and survival as well. Additionally, irisin inhibited phosphorylation of NF-κB p65 while decreasing the expression of pro-inflammatory genes in INS-1E cells under glucolipotoxic conditions. Moreover, irisin also improved insulin secretion, inhibited apoptosis, and restored β-cell function-related gene expression in isolated mouse islets under glucolipotoxic conditions. Conclusion: Irisin attenuated excessive lipogenesis in INS-1E cells under glucolipotoxic state through activation of AMPK. Irisin also suppressed overnutrition-induced inflammation in INS-1E cells. Our findings implicate irisin as a promising therapeutic target for the treatment of islet lipid metabolic disorder and islet inflammation in T2DM.
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Other exercise-induced factors, such as irisin, follistatin, and OCN, directly protect β-cells from damage, further potentiating their beneficial metabolic properties.
“Concurrently, other exercise-induced factors, such as irisin [66], follistatin [183], and OCN [209], directly protect β-cells from damage, further potentiating their beneficial metabolic properties.”
In vitro, irisin prevented excessive lipogenesis of mouse islets under glucolipotoxic conditions, improving insulin secretion, inhibiting apoptosis and restoring β-cell function-related gene expression.
“In vitro, irisin prevented excessive lipogenesis of mouse islets under glucolipotoxic conditions, resulting in improved insulin secretion, inhibition of apoptosis and restored β-cell function-related gene expression117.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [117]
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“Visfatin stimulates insulin secretion and inhibits beta cell apoptosis through the MAPK and phosphatidylinositol 3-kinase pathway (PI3K)/protein kinase B (AKT) pathway (24), whereas irisin improves glucolipotoxicity associated with beta cell dysfunction through adenosine monophosphate- activated protein kinase (AMPK)…”
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“Some anti-inflammatory and anti-apoptotic effect of irisin have been postulated (9), and, because of this, irisin has been suggested as a therapeutic target in cardiovascular diseases (10).”
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“Silencing of circANKRD36 targets miR-145 via XBP1 to restrain STZ-caused insulin resistance and inflammation in diabetic rats [23].”
BackgroundIrisin—A Pancreatic Islet Hormone
Norman, D., Drott, C., Carlsson, P., & Espes, D. (2022) · Biomedicines · doi:10.3390/biomedicines10020258 · Cited by 12 · see citing works
“Considering that other studies have found that irisin improves GSIS under glucolipotoxic conditions [12,33] and that irisin is antiapoptotic for INS-1 cells [11,12,33], it could be that the increased GSIS is an indirect effect through antiapoptotic effects—i.”
BackgroundCirculating Irisin and esRAGE as Early Biomarkers of Decline of Metabolic Health
Dozio, E., Vianello, E., Sitzia, C., Ambrogi, F., Benedini, S., Gorini, S., Rampoldi, B., Rigolini, R., Tacchini, L., & Romanelli, M. M. C. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9020454 · Cited by 13 · see citing works
Exercise and inactivity as modifiers of β cell function and type 2 diabetes risk
Hall, L. G., Thyfault, J. P., & Johnson, J. D. (2023) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00472.2022 · Cited by 14 · see citing works
Resistance Training Reduces Blood Pressure: Putative Molecular Mechanisms
Mendes, B. F., Caria, A. C. I., Magalhães, C. O. D. E., Dias‐Peixoto, M. F., Cassilhas, R. C., de Oliveira, E. M., & Sousa, R. A. L. D. (2024) · Current Hypertension Reviews · doi:10.2174/0115734021277791240102041632 · Cited by 11 · see citing works
Lai, T. P., Park, S. Y., Nguyen, G. T. H., Pham, P. N. H., Kang, S. M., Hong, J., Lee, J., Im, S., Choi, D. H., & Cho, E.-H. (2024) · Endocrinology and Metabolism · doi:10.3803/enm.2024.1984 · Cited by 11 · see citing works
Irisin protects female mice with LPS-induced endometritis through the AMPK/NF-κB pathway.
Jiang, X., Hu, Y., Zhou, Y., Chen, J., Sun, C., Chen, Z., Jing, C., Xu, L., Liu, F., Ni, W.-J., et al. (2021) · PubMed Central · doi:10.22038/ijbms.2021.56781.12678 · Cited by 11 · see citing works
“Numerous studies found irisin’s beneficial effect was achieved via regulation of the AMPK pathway (12, 26).”
BackgroundMyokines in Acromegaly: An Altered Irisin Profile
Mizera, Ł., Halupczok-Żyła, J., Kolačkov, K., Zembska, A., Grzegrzółka, J., Jędrzejuk, D., Bolanowski, M., & Daroszewski, J. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.728734 · Cited by 9 · see citing works
Irisin Regulates Hepatic Glucose Metabolism via AMPK and PI3K/Akt Activation
Zhi, S.-Y., Yang, L., Yang, G.-K., Qin, C.-B., Yan, X., Niu, M.-M., Zhang, W., Liu, M., Zhao, M., & Nie, G. (2022) · Aquaculture Nutrition · doi:10.1155/2022/1946960 · Cited by 8 · see citing works
“Studies have shown that irisin can, through the AMPK (5′- AMP-activated protein kinase) and PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B), regulate body metabolism [9, 10].”
BackgroundHorwitz, A., & Birk, R. Z. (2024) · Biomolecules · doi:10.3390/biom14060643 · Cited by 9 · see citing works
“For example, the supplementation of exogenous irisin suppressed the expression of pro-inflammatory genes and reduced cellular apoptosis in rat INS-1E β cells [67].”
BackgroundRole of irisin in metabolic and cardiovascular disorders and its therapeutic potential
Khalil, R. G., Atia, T. A., Yousef, A. I., Sakr, H. I., & Ahmed, O. M. (2025) · Beni-Suef University Journal of Basic and Applied Sciences · doi:10.1186/s43088-025-00643-9 · Cited by 8 · see citing works
Research progress on the role of FGF21 in insulin resistance
Zhang, H., Zhu, R., Sun, Q., & Du, L. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1619462 · Cited by 10 · see citing works
Yang, J., Tan, A., Li, T., et al. (2024) · IUBMB Life · doi:10.1002/iub.2907 · Cited by 7 · see citing works
“19,20 Furthermore, irisin is found to show a protective property on the heart by suppressing the NLRP3-mediated pyroptosis.”
Does irisin has neuroprotective effect against diabetes induced neuropathy in male rats?
Kalkan, Ö. F., Aktaş, O., Sürmeneli, Y. E., Alver, A., Özcan, M., & Şahin, Z. (2020) · Archives of Physiology and Biochemistry · doi:10.1080/13813455.2020.1835985 · Cited by 5 · see citing works
“In recent studies, they showed that increased exercise intensity leads to higher serum irisin concentrations (Tsuchiya et al. 2014, Zhang et al. 2018).”
BackgroundMicrobiota and Glucidic Metabolism: A Link with Multiple Aspects and Perspectives
Ciarambino, T., Crispino, P., Leto, G., Minervini, G., Para, O., & Giordano, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241210409 · Cited by 4 · see citing works
“Furthermore, adipsin [29], visfatin [30], irisin [31], omentin [32], and apelin [33] have been shown to have a protective effect on beta cells.”
BackgroundObesity, Myokines, and Metabolic Health
Malandrino, N., & Ahima, R. S. (2023) · Springer eBooks · doi:10.1007/978-3-031-40116-9_56 · Cited by 2 · see citing works
Yang, Y., Pullisaar, H., Reseland, J. E., & Ma, J. (2025) · Journal of Molecular Medicine · doi:10.1007/s00109-025-02623-z · Cited by 1 · see citing works
Marrano, N., Borrelli, A., Biondi, G., Rella, M., D’Oria, R., Genchi, V. A., Caccioppoli, C., Galasso, V., Galluzzi, G., Roberto, L., et al. (2026) · Science Advances · doi:10.1126/sciadv.aee4804 · Cited by 1 · see citing works
“…and then exposed to glucolipotoxic conditions, irisin enhances the expression of genes related to β cell survival and function via AMP-activated protein kinase (AMPK)– mediated suppression of lipogenic gene expression and the consequent reduction in intracellular fatty acids/triglycerides ( 25 ).”
InfluentialChou, T.-J., Lin, L.-Y., Lu, C., Hsu, Y.-J., Huang, C., & Huang, K. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4162348
Obesity, Myokines, and Metabolic Health
Malandrino, N., & Ahima, R. S. (2023) · Springer eBooks · doi:10.1007/978-3-319-12125-3_56-1
Ajao, F. O., Ajiroba, O. S., Iyedupe, M. O., et al. (2024) · Medical Research Journal · doi:10.5603/mrj.102180
“The anti-diabetic medications used to manage diabetes display many harmful complications and are ineffective in curing the adverse effects [7].”
Gao, R., Zhang, Y., & Quan, L. (2026) · Comprehensive physiology · doi:10.1002/cph4.70248
Osiak-Wicha, C., Manastyrska-Stolarczyk, M., Muszyński, S., Kras, K., Dajnowska, A., Hiżewska, L., Woźniak, K., Tomaszewska, E., Słowik, T., Dobrowolski, P., et al. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48090967
“The decrease in PCNA-IR cell percentage in both sexes contrasts with previous findings from stressed β -cell models, in which irisin increased β -cell proliferation and reduced apoptosis under high-glucose or glucolipotoxic conditions [8,9].”
- Authors
- Zhang, D., Xie, T., & Leung, P. S.
- Affiliations
- Chinese University of Hong Kong (HK)
- Venue
- Cellular Physiology and Biochemistry
- Publisher
- S. Karger AG
- Published
- 2018
- Volume
- 51
- Issue
- 2
- Pages
- 924-937
- ISSN
- 1015-8987 (ISSN-L)
- 1421-9778
- OpenAlex
- W2901472381
- Cited by
- 65
- References
- 42
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 9 · 2023: 7 · 2022: 13 · 2021: 11 · 2020: 10 · 2019: 9
- FWCI
- 7.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cellular Physiology and Biochemistry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- irisin, glucolipotoxicity, beta-cell dysfunction, beta-cell apoptosis, AMPK signaling, NF-κB p65, insulitis, lipogenesis, free fatty acids, triglyceride accumulation, acetyl-CoA carboxylase, insulin secretion, type 2 diabetes, INS-1E cells
- MeSH terms
- Insulin Secretion, Acetyl-CoA Carboxylase, Animals, Anti-Inflammatory Agents, Fatty Acids, Nonesterified, Fibronectins, Glucose, Mice, Inbred C57BL, Phosphorylation, Triglycerides, Signal Transduction, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Palmitic Acid, Insulin-Secreting Cells, Glucose Transporter Type 2, Mice, Rats, Transcription Factor RelA, AMP-Activated Protein Kinases
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