Prolonged exposure to insulin might cause epigenetic alteration leading to insulin resistance
Glucose homeostasis is maintained by insulin. Insulin resistance is caused by multiple factors including hereditary factors and diet. The molecular mechanism underlying insulin resistance (IR) is not completely understood. Hyperinsulinemia often precedes insulin resistance and Type 2 diabetes. We ha...
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| Format: | Article |
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Wiley
2025-01-01
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| Series: | FEBS Open Bio |
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| Online Access: | https://doi.org/10.1002/2211-5463.13891 |
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| author | Shehnaz Bano Shyam More Dattatray S. Mongad Abdul Khalique Dhiraj P. Dhotre Manoj K. Bhat Vasudevan Seshadri |
| author_facet | Shehnaz Bano Shyam More Dattatray S. Mongad Abdul Khalique Dhiraj P. Dhotre Manoj K. Bhat Vasudevan Seshadri |
| author_sort | Shehnaz Bano |
| collection | DOAJ |
| description | Glucose homeostasis is maintained by insulin. Insulin resistance is caused by multiple factors including hereditary factors and diet. The molecular mechanism underlying insulin resistance (IR) is not completely understood. Hyperinsulinemia often precedes insulin resistance and Type 2 diabetes. We had previously shown that prolonged exposure of insulin‐responsive cells to insulin in the absence of high levels of glucose led to insulin resistance. In the present study, we show that the underlying cause for the impaired insulin signalling is the defective PI3K/AKT pathway. The observed insulin resistance is likely due to epigenetic alterations, as it can be maintained for several generations even when insulin is not provided, and epigenetic modifiers can reverse it. We also show that liver cell line (BRL‐3A) developed impaired insulin signalling upon prolonged exposure to insulin in the absence of high levels of glucose. Transcriptomic analysis of the insulin‐sensitive and resistance cells uncover altered signalling networks involved in chromatin remodelling, Rho GTPases, and ubiquitination. Furthermore, trimethylation of histone H3 at lysine 4 (H3K4me3) is increased in insulin‐resistant cells. We extended these studies to mice, and show that mice injected with low doses of insulin when fasting develop insulin resistance with impaired glucose tolerance and increased HOMA‐IR index. Altogether, these findings suggest that dysregulated synthesis of insulin in the absence of glucose stimulus could lead to epigenetic alterations that may ultimately result in insulin resistance. |
| format | Article |
| id | doaj-art-ef3fbca7cd81478bb407a594a68f7c7d |
| institution | Kabale University |
| issn | 2211-5463 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | FEBS Open Bio |
| spelling | doaj-art-ef3fbca7cd81478bb407a594a68f7c7d2025-01-07T02:27:34ZengWileyFEBS Open Bio2211-54632025-01-01151819310.1002/2211-5463.13891Prolonged exposure to insulin might cause epigenetic alteration leading to insulin resistanceShehnaz Bano0Shyam More1Dattatray S. Mongad2Abdul Khalique3Dhiraj P. Dhotre4Manoj K. Bhat5Vasudevan Seshadri6National Centre for Cell Science Pune IndiaNational Centre for Cell Science Pune IndiaNational Centre for Cell Science Pune IndiaNational Centre for Cell Science Pune IndiaNational Centre for Cell Science Pune IndiaNational Centre for Cell Science Pune IndiaNational Centre for Cell Science Pune IndiaGlucose homeostasis is maintained by insulin. Insulin resistance is caused by multiple factors including hereditary factors and diet. The molecular mechanism underlying insulin resistance (IR) is not completely understood. Hyperinsulinemia often precedes insulin resistance and Type 2 diabetes. We had previously shown that prolonged exposure of insulin‐responsive cells to insulin in the absence of high levels of glucose led to insulin resistance. In the present study, we show that the underlying cause for the impaired insulin signalling is the defective PI3K/AKT pathway. The observed insulin resistance is likely due to epigenetic alterations, as it can be maintained for several generations even when insulin is not provided, and epigenetic modifiers can reverse it. We also show that liver cell line (BRL‐3A) developed impaired insulin signalling upon prolonged exposure to insulin in the absence of high levels of glucose. Transcriptomic analysis of the insulin‐sensitive and resistance cells uncover altered signalling networks involved in chromatin remodelling, Rho GTPases, and ubiquitination. Furthermore, trimethylation of histone H3 at lysine 4 (H3K4me3) is increased in insulin‐resistant cells. We extended these studies to mice, and show that mice injected with low doses of insulin when fasting develop insulin resistance with impaired glucose tolerance and increased HOMA‐IR index. Altogether, these findings suggest that dysregulated synthesis of insulin in the absence of glucose stimulus could lead to epigenetic alterations that may ultimately result in insulin resistance.https://doi.org/10.1002/2211-5463.13891epigenetic modifiershistone methylationinsulin resistancemouse modelRNA‐sequencing |
| spellingShingle | Shehnaz Bano Shyam More Dattatray S. Mongad Abdul Khalique Dhiraj P. Dhotre Manoj K. Bhat Vasudevan Seshadri Prolonged exposure to insulin might cause epigenetic alteration leading to insulin resistance FEBS Open Bio epigenetic modifiers histone methylation insulin resistance mouse model RNA‐sequencing |
| title | Prolonged exposure to insulin might cause epigenetic alteration leading to insulin resistance |
| title_full | Prolonged exposure to insulin might cause epigenetic alteration leading to insulin resistance |
| title_fullStr | Prolonged exposure to insulin might cause epigenetic alteration leading to insulin resistance |
| title_full_unstemmed | Prolonged exposure to insulin might cause epigenetic alteration leading to insulin resistance |
| title_short | Prolonged exposure to insulin might cause epigenetic alteration leading to insulin resistance |
| title_sort | prolonged exposure to insulin might cause epigenetic alteration leading to insulin resistance |
| topic | epigenetic modifiers histone methylation insulin resistance mouse model RNA‐sequencing |
| url | https://doi.org/10.1002/2211-5463.13891 |
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