Impairment of the IR-IRS-PI3K-AKT signaling pathway in Insulin Resistance: New Insights into Insulin Resistance Mechanisms

Insulin is a master metabolic hormone that regulates the metabolism of glucose and fat. Obesity produces factors that increase insulin resistance, which is the leading cause of type 2 diabetes in the world. In insulin resistance, the main signaling pathway IR-IRS-PI3K-AKT pathway, is disrupted, which is the central cause of insulin resistance and T2DM. This review explains the molecular mechanism of the dysfunction of these signaling pathways. Focusing on receptor dysfunction, post-receptor alteration, and all other factors that decrease signaling accuracy. The importance of genetic modifiers and receptor–substrate dynamics is shown by the fact that combined IR and IRS-1 knockouts mimic human type 2 diabetes. IRS-1 serine phosphorylation disrupts IR–PI3K interaction, which reduces downstream signaling. We study different AKT isoforms. There is a role of AKT-2 in insulin resistance, but a little role of AKT-1and AKT-3. Furthermore, we study a rare form of mutation, PPAR-ℽ mutation (P115Q), which shows that despite severe obesity, there is insulin sensitivity and lower insulin resistance. TNF-α signaling inhibition, which raises receptor tyrosine kinase activity in muscle and fat, restores insulin sensitivity. This review shows that insulin resistance is not caused by a single factor, but rather by a combination of different proteins which is modified and unable to function properly, such as loss of Tyrosine Kinase activity, nuclear receptor modulation, IRS dysregulation, receptor dysfunction, PI3-K dysfunction, AKT protein disturbance, and inflammatory stress. Understanding these dysfunctions, various unknown factors, and processes enables the development of precision therapies that can restore metabolic balance and slow the progression of type 2 diabetes.