From the Guidelines
Lack of insulin decreases PFK2 stimulation by preventing the activation of signaling pathways that normally promote PFK2 activity, ultimately leading to reduced glycolytic flux and contributing to hyperglycemia in insulin deficiency states. The relationship between insulin and PFK2 stimulation is crucial in understanding the metabolic changes that occur in insulin deficiency states, such as type 1 diabetes, as discussed in the study by 1. In this context, the absence of insulin prevents the activation of the PI3K/Akt pathway, which is necessary for the phosphorylation and activation of PFK2. Key points to consider include:
- Insulin activates the PI3K/Akt pathway, leading to PFK2 phosphorylation and activation
- PFK2 produces fructose-2,6-bisphosphate, a potent allosteric activator of PFK1, the rate-limiting enzyme in glycolysis
- Without adequate PFK2 stimulation, less fructose-2,6-bisphosphate is produced, resulting in decreased PFK1 activity and reduced glycolytic flux
- This metabolic shift is part of the body's response to low insulin states, such as fasting or diabetes, where glucose utilization is decreased in favor of gluconeogenesis and fatty acid oxidation, as noted in the study by 1. The decreased glycolysis in insulin-sensitive tissues like liver and muscle contributes to the hyperglycemia observed in insulin deficiency states, highlighting the importance of insulin in regulating PFK2 activity and glycolytic flux.
From the Research
Lack of Insulin and PFK2 Stimulation
- The relationship between lack of insulin and PFK2 stimulation is complex and involves various metabolic pathways.
- According to a study published in the European Journal of Biochemistry 2, insulin activates phosphofructokinase 2 (PFK 2) in cultured hepatocytes without accompanying changes in effector levels or cAMP-stimulated protein kinase activity ratios.
- Another study published in the Journal of the American Heart Association 3 found that cardiac insulin signaling regulates glycolysis through phosphofructokinase 2 content and activity, and that decreased insulin signaling leads to a decrease in cardiac PFK-2 protein content.
Mechanisms of PFK2 Regulation
- The study by 2 suggests that insulin may act via activation of PFK 2 phosphatase, rather than through changes in cAMP and effector levels or through inhibition of cAMP-dependent protein kinase dissociation.
- The study by 3 found that decreased insulin signaling leads to rapid degradation of PFK-2 via both proteasomal- and chaperone-mediated autophagy in cardiomyocytes.
Effects of Lack of Insulin on PFK2 Stimulation
- The lack of insulin leads to a decrease in PFK-2 content and activity, which impairs the capacity to dynamically regulate glycolysis and elevates the levels of early glycolytic intermediates 3.
- This impairment may be beneficial in the fasted state to conserve systemic glucose, but it represents a pathological impairment in diabetes mellitus 3.