Insulin Resistance | Basics and Mechanism | Basic Science Series

Insulin Resistance | Basics and Mechanism | Basic Science Series

Insulin resistance, a hallmark of type 2 diabetes, stems from a complex interplay of molecular mechanisms within cells. At the cellular level, insulin binds to its receptor, initiating a cascade of events crucial for glucose uptake. The insulin receptor substrate (IRS) proteins are phosphorylated upon insulin binding, facilitating the activation of downstream signaling pathways. One of the key pathways affected by insulin resistance is the phosphoinositide 3-kinase (PI3K)/Akt pathway. Activation of PI3K leads to the production of phosphatidylinositol-3,4,5-trisphosphate (PIP3), which in turn recruits Akt to the plasma membrane. Akt activation promotes the translocation of glucose transporter proteins, such as GLUT4, to the cell membrane, facilitating glucose uptake. In type 2 diabetes, insulin resistance disrupts this pathway at multiple levels. Increased serine phosphorylation of IRS proteins by various kinases, such as c-Jun N-terminal kinase (JNK) and inhibitor of nuclear factor kappa-B kinase subunit beta (IKK-β), leads to their degradation and inhibits downstream signaling. Furthermore, elevated levels of circulating free fatty acids, characteristic of obesity and insulin resistance, activate protein kinase C (PKC) isoforms. PKC activation impairs insulin signaling by phosphorylating IRS proteins and interfering with Akt activation. Additionally, the mammalian target of rapamycin complex 1 (mTORC1) pathway, which integrates nutrient and hormonal signals to regulate cell growth and metabolism, has been implicated in insulin resistance. Hyperactivation of mTORC1 in obesity disrupts insulin signaling and promotes insulin resistance by inhibiting IRS-1 function and impairing Akt activation. Moreover, dysregulation of mitogen-activated protein kinase (MAPK) pathways, particularly the extracellular signal-regulated kinase (ERK) pathway, contributes to insulin resistance. Chronic activation of ERK signaling in obesity leads to serine phosphorylation of IRS proteins, inhibiting their function and impairing insulin signaling. Collectively, these molecular alterations in cellular signaling pathways contribute to insulin resistance in type 2 diabetes. Understanding these intricate mechanisms provides insights into potential therapeutic targets for the prevention and management of the disease. Keywords: insulin resistance, type 2 diabetes, molecular mechanisms, cellular level, insulin receptor, insulin receptor substrate (IRS), phosphoinositide 3-kinase (PI3K), Akt pathway, glucose uptake, phosphatidylinositol-3,4,5-trisphosphate (PIP3), GLUT4, serine phosphorylation, c-Jun N-terminal kinase (JNK), inhibitor of nuclear factor kappa-B kinase subunit beta (IKK-β), free fatty acids, protein kinase C (PKC), mammalian target of rapamycin complex 1 (mTORC1), mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), obesity, therapeutic targets WhatsApp group: https://chat.whatsapp.com/HTXQC1Ax2qfKYa3MrZiMeD Twitter: https://twitter.com/basic_series Facebook Group: https://www.facebook.com/groups/742235929758671 LinkedIn: https://www.linkedin.com/in/basic-science-series-a54439208/ Instagram: https://www.instagram.com/basic_science_series/ Support my work at https://www.patreon.com/user?u=37177596

Disclaimer: The information provided is for educational purposes only. The content of this channel should not be considered as medical advice of any kind. Use this information at your own risk. We hold no responsibility for any issue, concerns, or damage arising from the content of the video. Under no circumstances this channel be responsible or liable in any way for any content, including but not limited to, any errors or omissions in the content, any loss, any damage of any kind incurred as a result of any content communicated in this video, whether by this channel or a third party. In no event shall this channel be liable for any special indirect or consequential damages of any damages whatsoever resulting from the content of the channel. ... https://www.youtube.com/watch?v=pfbYP-9qof8