PKC mechanisms and consequences
PKC (Protein Kinase C) is a second pathway that stimulates insulin-dependent glucose transporters to translocate.
Outlined below are the key factors in both the insulin/IR/IRS/PI3K/PDK/Akt/GLUT and insulin/IR/PKS/GLUT pathways.
PKC
PKC is present in every cell and is important in a range of physiological functions. The focus of this article is the role of PKC in stimulating insulin-dependent glucose transporter translocation.
PKC may be either a sole factor or one of several factors that influence the translocation stimulation for these insulin-dependent glucose transporters.
Transporter
PKC mechanism of action
GLUT1
for activation.
GLUT4
can stimulate translocation.
GLUT8
can stimulate translocation (bovine).
GLUT13
can stimulate translocation.
SGLT1
as a regulatory factor.
SGLT2
as a regulatory factor.
PKC’s activation and inhibition are dependent upon a range of normal and abnormal stressors, several of which seem to be related to DAG availability.
DAG (Diacylglyerol)
Either directly or indirectly, DAG is important in a range of functions that includes regulating the PKCs.
DAG is produced from either –
- phosphatidylinositol 4,5- bisphosphate [PIP2] and phosphatidylcholine; or
- dephosphorylation of phosphatidic acid (PA).
DGK (diacylglycerol kinase) regulates DAG levels. Decreased DGK activity means increased DAG and consequent PKC pathway stimulation.
One of DGK’s regulatory mechanisms is activation of the conversion of DAG to phosphatidic acid. This PA-DAG conversion reduces the availability of DAG and by default lowers PKC levels.
PKC activators
Phosphorylation of the tyrosine residues on IRS1 activates the PI3K/Akt/GLUT cascade. Phosphorylation of the serine 307 residues on IRS1 in skeletal muscle by PKC stimulates the insulin-dependent glucose transporters to translocate by an alternate pathway. Factors that activate PKC include –
Activators
PKC activation mechanisms of action
DAG
increased DAG levels.
high fat diets
increase DAG levels.
hyperglycaemia
increases the synthesis and accumulation of DAG from glucose.
Insulin resistance
stimulates the conversion of PIP2 to DAG (instead of converting PIP2 to PIP3).
Activated PKC inhibitors
Factors that inhibit activated PKC include –
Inhibitors
Activated PKC inhibition mechanisms of action
DGK
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Yvonne Coleman has 30+ years of experience in aged care as a dietitian. Her mission is to make information about interactions between medicines and nutrition easy to access for those working in the healthcare sector. She has created a comprehensive resource identifying drug-nutrient and drug-food interactions from a nutrition perspective.
Her areas of competency include food science & nutrition, dietetics and health education. You can find out more about her work on LinkedIn, AusMed, the Enlightened Pharmacist podcast, and The FX Medicine Podcast.