4.3 Flashcards
(10 cards)
- What is the primary role of the insulin signalling pathway in cellular metabolism?
The insulin signalling pathway regulates glucose uptake, glycogen synthesis, lipogenesis, and overall energy homeostasis. Upon insulin binding to its receptor—a tyrosine kinase—it activates PI3K and subsequently AKT, which then orchestrate metabolic and growth-related processes.
- Which key molecules are involved in the insulin signalling cascade, and what are their functions?
The cascade begins with the insulin receptor, which phosphorylates and activates phosphatidylinositol 3-kinase (PI3K). PI3K produces PIP3, recruiting and activating AKT. Activated AKT phosphorylates targets such as FOXO transcription factors, mediating processes like glucose uptake and suppression of gluconeogenesis.
- How does insulin/IGF-1 signalling control gene expression, particularly regarding FOXO transcription factors?
When insulin/IGF-1 signalling activates AKT, FOXO transcription factors are phosphorylated and sequestered in the cytoplasm instead of translocating to the nucleus. This prevents expression of genes involved in gluconeogenesis, stress responses, and apoptosis, thereby shifting cellular metabolism toward anabolic processes.
- What are some downstream transcriptional effects of insulin signalling in the liver?
Insulin signalling leads to reduced expression of gluconeogenic genes (such as G6PC and PCK1) through the inhibition of FOXO activity, while concurrently promoting glycogen synthesis and lipid storage genes that help lower blood glucose and store energy.
- Why is Caenorhabditis elegans a valuable model organism for longevity studies in relation to insulin signalling?
C. elegans has a short lifespan and a well-characterized insulin/IGF-1 signalling pathway (involving DAF-2 and DAF-16). Mutations in these genes show dramatic lifespan extension, establishing a clear genetic link between reduced insulin signalling and longevity.
- How do mammalian models, such as mice, contribute to our understanding of the insulin/IGF-1 pathway in ageing?
Mice share many physiological similarities with humans, and studies in these animals have shown that lower insulin/IGF-1 signalling or downstream modifications—like increased FOXO activity—correlate with improved stress resistance and longer lifespan. However, their longer lifespan and cost pose challenges for large-scale longevity screens.
- What role do non-human primates and large animal models serve in longevity research related to insulin signalling?
Non-human primates, with approximately 99% genetic similarity to humans, offer translational insights into insulin signalling and ageing. Large animal models (e.g., pigs) provide structural and metabolic parallels to human physiology. They are especially useful for assessing the impact of interventions on complex traits, despite higher costs and ethical considerations.
- How does reduced insulin/IGF-1 signalling affect lifespan in model organisms?
In multiple models, such as C. elegans and Drosophila, reduced insulin/IGF-1 signalling activates FOXO transcription factors, leading to enhanced stress resistance and metabolic adjustments that extend lifespan. Similar, though more nuanced, relationships have been observed in mammalian systems.
- How does mTOR interact with the insulin/IGF-1 signalling pathway to influence ageing?
mTOR is a nutrient-sensing kinase activated downstream of AKT and by amino acids (such as leucine and arginine). While active mTOR promotes cellular growth and anabolic processes, its chronic activation is associated with accelerated ageing. Inhibition of mTOR—with agents like rapamycin—has been shown to extend lifespan in mice.
- What evidence supports the role of targeting the insulin/IGF-1 and mTOR pathways to extend lifespan?
Studies in several model organisms, notably mice treated with rapamycin, show significant lifespan extension. These findings suggest that modulating insulin/IGF-1 signalling (thereby reducing mTOR activity) promotes cellular maintenance, stress resistance, and longevity. This has been further supported by genetic studies in invertebrates linking reduced signalling through these pathways to increased lifespan.
