| Literature link | GPT Summary | Evidence category | Disease type |
|---|---|---|---|
| 7969452 | Insulin receptor substrate-1 (IRS-1) is a key mediator of insulin and insulin-like growth factor (IGF) signaling, serving as the primary substrate for their receptor tyrosine kinases. With a molecular weight of 160–190 kDa, IRS-1 undergoes tyrosine phosphorylation, enabling its interaction with signaling proteins such as the p85 subunit of phosphatidylinositol 3-kinase (PI3K), which facilitates glucose transporter translocation, and ASH/Grb2, which activates the Ras/MAPK cascade. Additionally, IRS-1 contains binding sites for other SH2-domain proteins, including Syp and Nck, contributing to diverse intracellular signaling events. To elucidate the physiological role of IRS-1 in vivo, mice with targeted disruption of the IRS-1 gene were generated. Homozygous knockout mice were viable but exhibited significant growth retardation during both embryonic and postnatal development. Furthermore, these mice demonstrated resistance to insulin, IGF-1, and IGF-2, indicating impaired glucose metabolism. These findings highlight the critical role of IRS-1 in insulin and IGF signaling while also suggesting the presence of IRS-1-independent pathways that compensate for metabolic regulation. |
Mechanism |
Insulin resistance |
| 14560023 | Ceramide, a lipid mediator produced in response to stress, plays a critical role in regulating cellular processes such as cell death, differentiation, and insulin sensitivity. This study reveals that ceramide inhibits protein kinase B (PKB/Akt) activation via atypical protein kinase C zeta (PKCζ). In unstimulated cells, PKB and PKCζ form a complex, which dissociates upon insulin stimulation, allowing PKB activation. However, ceramide prevents this dissociation by activating PKCζ, leading to phosphorylation of the PKB-PH domain at Thr34. This modification blocks phosphatidylinositol 3,4,5-trisphosphate (PIP3) binding, thereby inhibiting PKB activation. A T34A-mutated PKB-PH domain, which retains PIP3 binding ability, remains resistant to ceramide-induced inhibition. Inhibition of PKCζ restores PKB activity, underscoring its role in this regulatory pathway. As PKB is essential for cell survival and insulin signaling, ceramide-mediated PKCζ activation represents a potential mechanism contributing to insulin resistance and apoptosis. |
Mechanism |
Insulin resistance |
| 16176208 | This study investigated whether elevated serum insulin levels in early pregnancy (before 16 weeks) could predict gestational diabetes mellitus (GDM) in high-risk women. Among 71 participants, fasting and 120-min post-OGTT insulin levels were strong predictors of GDM. At gestation weeks 24-28, fasting and 120-min insulin levels had sensitivities of 69.2% and 92.3% and specificities of 96.4% and 85.7%, respectively. Their negative predictive values were 0.87 and 0.96, while their odds ratios for predicting GDM at weeks 32-34 were 16.6 and 13.3, respectively. The study concludes that early pregnancy serum insulin determination is an effective and reliable method for predicting GDM in high-risk women. Even with a negative OGTT, elevated insulin levels warrant GDM management, while normal levels may justify delaying OGTT to later gestation. |
Risk factor |
GDM |
| 9335553 | This study investigates the role of protein kinase C (PKC) activation in modulating insulin signaling in human kidney fibroblast (293) cells. The findings reveal that PKC activation inhibits insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), a critical step in insulin signaling. This inhibition was observed both in vivo and in vitro when IRS-1 and the insulin receptor were isolated from PKC-activated cells. To determine whether serine phosphorylation contributes to this effect, researchers mutated serine 612 (S612) to alanine (S612A). Unlike the wild-type IRS-1, the mutant retained its ability to undergo insulin-induced tyrosine phosphorylation and associate with phosphatidylinositol 3-kinase (PI3K) even after PKC activation. Further analysis confirmed that PKC promotes the phosphorylation of IRS-1 at serine 612, which reduces its susceptibility to insulin receptor-mediated tyrosine phosphorylation. Notably, cytosolic extracts from the livers of obese (ob/ob) mice exhibited an eightfold increase in kinase activity targeting this phosphorylation site compared to lean littermates. These findings suggest that PKC-mediated serine phosphorylation of IRS-1 disrupts insulin signaling, providing a potential mechanistic link between PKC activation and insulin resistance in obesity-related metabolic dysfunction. | Mechanism | Insulin resistance |
| 16176208 | This study investigated whether elevated serum insulin levels in early pregnancy (before 16 weeks) could predict gestational diabetes mellitus (GDM) in high-risk women. Among 71 participants, fasting and 120-min post-OGTT insulin levels were strong predictors of GDM. At gestation weeks 24-28, fasting and 120-min insulin levels had sensitivities of 69.2% and 92.3% and specificities of 96.4% and 85.7%, respectively. Their negative predictive values were 0.87 and 0.96, while their odds ratios for predicting GDM at weeks 32-34 were 16.6 and 13.3, respectively. The study concludes that early pregnancy serum insulin determination is an effective and reliable method for predicting GDM in high-risk women. Even with a negative OGTT, elevated insulin levels warrant GDM management, while normal levels may justify delaying OGTT to later gestation. | Risk factor | GDM |
| 30170598 | Cardiovascular disease (CVD) has long been the leading cause of death globally, often accompanied by comorbidities like obesity, abnormal lipid profiles, and insulin resistance. Insulin, a key regulator of cellular metabolism, is impaired in insulin resistance, characterized by defects in glucose uptake, oxidation, and glycogen synthesis, with a lesser effect on lipid oxidation. While free fatty acids are the primary substrate for ATP production in the myocardium, other substrates, such as glucose and lactate, can also be used. Insulin resistance induces metabolic alterations that contribute to CVD, including chronic hyperglycemia, oxidative stress, and inflammation. Additionally, insulin resistance disrupts lipid metabolism, leading to dyslipidemia and the lipid triad: elevated plasma triglycerides, low HDL, and small dense LDL, which together, along with endothelial dysfunction, promote atherosclerotic plaque formation. Insulin resistance in the myocardium generates damage through three mechanisms: altered signal transduction, impaired substrate metabolism regulation, and disrupted substrate delivery to the heart. This review aims to explore the mechanisms linking insulin resistance to CVD, highlighting the potential for therapies targeting insulin resistance to reduce CVD and atherosclerotic plaque formation. | Mechanism | Cardiovascular |
| KEGG pathway |
|---|
| Insulin signaling pathway, Insulin secretion, Type II diabetes mellitus |
RF's name
Insulin
RF's type
Pancreatic function indicator