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
normalises abnormal PKC activity during hyperglycaemia.
indirect PKC inhibitor.
tyrosine phosphorylation
regulates DGKα activation and therefore DAG availability.
indirect PKC inhibitor.
EGCG
Epigallocatechin gallate
regulates DGKα activation and therefore DAG availability.
indirect PKC inhibitor.
vitamin E
activates DGK through tyrosine phosphorylation.
indirect PKC inhibitor.
(400 IU vit E/day ineffective; 1800 IU vit E /day effective).
vitamin D
inhibits IRS1 serine phosphorylation.
indirect PKC inhibitor.
vitamin C
increases IRS-1 expression
essential for activation of nutrients such as vitamins C+D.
indirect PKC inhibitor.
magnesium
essential in the production of phosphatidylcholine.
essential for activation of nutrients such as vitamins C+D.
indirect PKC inhibitor.
Slightly increased glycaemic and insulin levels after food intake is a normal response.
Sustained hyperglycaemia and/or hyperinsulinaemia is an abnormal response.
Clinical issues
The IR/IRS/PI3K/PDK/Akt/GLUT and IR/PKC/GLUT pathways facilitate insulin-dependent glucose transporter translocation. Inadequacies in nutrients associated with either or both of these pathways will have profound effects. Perhaps we are already seeing these effects and not fully recognising them.
The IR/PKC/GLUT translocation pathway remains opaque and therefore difficulties arise in trying to identify important nutrients in this cascade.
A key question seems to be what determines the phosphorylation site in the insulin/GLUT pathway? That PKC activators include excessive glycaemia and lipaemia, and that activated PKC inhibitors include vitamins C, D, E and (indirectly) magnesium, suggests mal-nutrition may be a key determinant of the phosphorylation site.
If mal-nutrition is a key phosphorylation-site determinant then is PKC activation the body’s “Plan B” management strategy for excessive macronutrient and inadequate micronutrient intakes?
PKC-inhibitor drugs are in the developmental pipeline. Given PKC is a multi-function intermediary, what are the nutritional benefits and costs of drug-induced PKC inhibition?
Identification of drug impact on PKC function and its inclusion in the Product Information documents is not a regulatory requirement.
Are some prescribed medicines already inhibiting aspects of PKC function?
What is the impact of PKC inhibition on these identified (below), and other not-yet-identified nutrients? And how should we manage this issue until we have answers? … and the answers might take a very long time to be found.
Transporter
Vitamin substrates
GLUT1
Vitamin C
GLUT4
Vitamin C
SGLT1
Vitamin C, thiamine
Clinical Questions
Should interventions with vitamins C, D, E and magnesium be integral components in the management strategies for insulin resistance?
Conclusion
PKC is an essential pathway that stimulates insulin-dependent glucose transporters to translocate in the presence of normal and abnormal physiological stressors.
Case study
The comments refer to the drug-nutrient, drug-food, and PharmacoNutrition effects only.
Data summary
Medical history with nutritional aspect
Biochemistry with nutritional aspect
Medications that may adversely affect nutritional status
Transporter-mediated interactions and nutrients matrix
Biochemistry
Recent relevant available biochemistry indicates -
- low albumin + total proteins – currently prescribed duodart therefore advisable to recheck status;
- marginal vit D - current intervention provides 50000 IU/month. Advisable to check vitamin D levels and if still low then review current vitamin D management strategy.
Glycaemia
Currently prescribed 1 medication that alters glycaemia.
Pharmaconutrition
Side effects profile from the currently prescribed medicines include –
- 3 medications that include vomiting and diarrhoea as side effects.
Coffee inhibits vitamin D uptake by inhibiting the osteoblasts (bone builders) vitamin D receptors, consequently decreasing calcium and zinc absorption
Membrane transporters
Some of the identified membrane transporters alter the absorption and/or organ and cellular uptake of a range of nutrients. Inhibition of membrane transporters means blood test results may be unreliable. To clarify nutrient status advisable to conduct blood tests at least one hour before administration of relevant prescribed medicines. A concurrent detailed Diet History is also essential to corroborate adequacy of intake of all affected nutrients. Further, all affected nutrients to be monitored on a regular basis ie at least annually. Unreliable blood test results due to inhibition of transporters by prescribed medications, is raising concern in some clinical publications.
Nutrients that are affected by Mr ADE’s prescribed medications include -
- substrates - carnitine, choline;
- inhibitors –vitamin D, choline.
Bowel management
- regular aperient prescribed;
- oral PRN aperient prescribed;
- no Nurse Initiated interventions administered.
Staff comments
Staff advise Mr ADE eats well - consuming a large breakfast and evening meal, snack-style midday meal, afternoon tea, and large supper and that he is given large serves.
Observations
Mr ADE is a tall, slender charming man with a lovely smile and bony shoulders, and who was lying in bed when I went to speak to him - he told me he eats well and can manage more! Mr ADE specifically asked for 3 slices toast instead of 2 slices, 2 eggs at breakfast instead of one, and a definite morning tea. Mr ADE also said he was mistakenly given a meal at midday yesterday instead of sandwiches and enjoyed it so much that he would like the midday meal every day instead of sandwiches. Mr ADE told me eating sandwiches at midday was a well-established habit from his work days.
Mr ADE has remained weight stable about 60-62 kg since admission ie 3 months ago.
Pharmaconutrition comments
Currently prescribed vitamin D on a monthly basis. Vitamin D requires magnesium in order to be activated therefore advisable to monitor magnesium status on a regular basis ie at least annually.
What else would you include?
Please read this as it is important …
The information in this article is provided to support Health Professionals. It is not an exhaustive protocol and Health Professionals are advised that adequate professional supervision is accessed to ensure that Duty of Care obligations with respect to safe administration of medicines is met for each consumer.
Yvonne Coleman is an accomplished dietitian with 30+ years of experience in aged care. Her mission is to make information concerning the interactions between medication and nutrition public and easy to access, having created the most comprehensive resource on the matter.
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.