Chromium is very important in enhancing the signalling cascade that stimulates insulin-dependent glucose transporters such as GLUT4 to translocate.
A key chromium function is to activate tyrosine kinases to phosphorylate tyrosine residues in the insulin receptors.
The binding of insulin to its receptor enables some glucose to enter the cell. When chromium also binds to the insulin receptor, the receptor remains in the active position which means increased glucose entry into the cell.
Chromium’s stimulation of tyrosine kinase is insulin-dependent ie chromium has no effect if insulin is not present. If insulin is present, then chromium significantly (eightfold) increases tyrosine kinase activity. Tyrosine kinase activity is reduced if there is a lack of chromium.
Ultimately, chromium availability is the rate limiter for insulin receptor tyrosine kinase activity and subsequent insulin activity and effect.
Chromium transportation
Chromium is primarily transported in the blood by transferrin likely as a chromium-iron mix, and possibly also transported by albumin.
Chromodulin aka LMWCr (low molecular weight-chromium-binding substance) is chromium’s within-cell transporter.
The transferrin receptor (TfrR) requires insulin stimulation to translocate to the outer cell membrane surface. The chromium-iron-transferrin complex binds to the transferrin receptor which enables chromium and iron to enter the cell and be released.
Chromium binds to chromodulin which then binds to the insulin receptor completing the activation process that enables stimulation of GLUT4 translocation to proceed.
Once chromium has activated tyrosine kinase then it is rapidly excreted from both cells and the body. Chromium’s urinary excretion from time of glucose intake is quite fast. Hyperglycaemia also induces chromium loss.
By binding to transferrin, chromium reduces the amount of iron being transported. By altering transferrin’s structure, hyperglycaemia decreases transferrin’s capacity to transport chromium.
Mechanism of action
Seminal work by Wang et al (2021) [https://doi.org/10.1038/s41467-023-37351-w] has established much of chromium’s mechanism of action in activating the chromium/AMPK/GLUT cascade.
During hyperglycaemia chromium suppresses ATP Synthase activity by displacing a magnesium in ATP5B, the core unit in ATP Synthase. Suppressed ATP Synthase activity results in increased AMP:ATP which activates the LKB1/AMPK cascade and consequently GLUT4 translocation. Chromium inhibition of ATP synthase activity does not induce hypoglycaemia.
During normoglycaemia, chromium has limited effect on ATP synthase activity.
AMPK is an energy-status sensor important in maintaining cellular energy homoeostasis as per our article Glucose transporters and AMPK.
Chromium has a capacity to activate AMPK however that mechanism of action remains elusive.
Potential chromium substitution
Chromodulin binding sites - are protected from substitution by metal cations such as iron, magnesium and zinc.
ATP Synthase binding sites - theoretically metal cations such as zinc, manganese, copper, cobalt, nickel, and iron could bind to the magnesium sites. However, in reality their bindings are not strong enough.
Clinical issues
Copper is integral to transferrin availability and therefore also impacts chromium effect. (MedNut Mail article The interdependence of copper-iron interactions).
Statistically significant evidence indicates an inverse correlation between HbA1c and serum chromium levels.
Early evidence indicates the pharmaceuticals clozapine, doxepin and imipramine both increase food intake and chromium loss ultimately causing a nett negative chromium balance.
Drug-induced hyperglycaemia is a very common side effect. Further, we typically don’t know if each prescribed medicine negatively impacts chromium status. Given the importance of chromium’s insulin amplification effect, then there seem to be a three management options to consider –
Clinical Questions
Impairment to the insulin/glucose transporter signaling cascade is considered a contributor to insulin resistance. Evidence indicates chromium can be a significant moderator of insulin resistance.
What actions will you initiate as you a review a person whose prescribed medications profile includes hyperglycaemia, will you -
- recommend regular monitoring of chromium, iron, copper and magnesium?
- recommend a prophylactic chromium intervention if their prescribed medications side effects profile includes hyperglycaemia?
Conclusions
Chromium’s key role in the insulin signalling cascade to stimulate insulin-dependent glucose transporters to translocate has been identified.
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
No recent relevant results available.
Prescribed medications side effects profile - biochemistry
Medications that may adversely affect nutritional status
Transporter-mediated interactions and nutrients matrix
Biochemistry
No recent relevant available biochemistry. Advisable to check plasma proteins (albumin, total proteins) as they are the primary transporters for three of the prescribed drugs and hypoproteinaemia may alter their effects.
Glycaemia
Currently prescribed 3 medications that alter glycaemic status.
Pharmaconutrition
Side effects profile from the currently prescribed medicines include –
- 5 medications that include altered bowel status;
- 3 medications that include altered potassium, dry mouth and altered appetite.
Indoxyl combi impairs zinc status.
Chronic use of coloxyl + senna may promote excessive loss of water and electrolytes, especially potassium, and their regular monitoring recommended.
Frusemide increases urinary excretion of calcium, magnesium, zinc, potassium, sodium and thiamine.
Olanzapine is a CYP1A2 substrate (can be carried by the transporter). CYP1A2 substrates include caffeine, retinol, melatonin, phosphatidylcholine, inhibitors include grapefruit juice and inducers include coffee; drug’s metabolism inhibited by caffeine therefore drug will remain active in the body for longer.
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 Mrs ADG’s prescribed medications include -
- substrates - thiamine, riboflavin, niacin, pantothenate, pyridoxine, biotin, folate, B12, vitamin C, carnitine and choline;
- inhibitors – niacin.
The duration of drug inhibition of transporters currently remains unknown.
Bowel management
- regular aperient prescribed;
- oral PRN aperient prescribed;
- no Nurse Initiated interventions administered.
Staff comments
Staff advise Mrs ADG has a good appetite and is served large meals, and loves desserts
Observations
Mrs ADG is a small, pale, frail, very deaf lady who was sitting in the Day Room when I went to speak to her - she told me she does not eat animals and so will not eat meat, fish, chicken, but will eat eggs (mixed into foodstuffs), milk, yoghurt, cheese, and seemed unfamiliar with dried beans, lentils, legumes, chick peas. She also told me several times she loves potatoes and loves cheese.
Mrs ADG has been losing weight for the last 6 months.
PharmacoNutrition comments
Nutritional interventions that support to wound healing include -
- plasma proteins within acceptable range - status currently unknown, and currently prescribed 3 drugs that are transported by them;
- ensure adequate status of B12, magnesium, zinc and iron;
zinc - inadequate zinc status has been associated with impaired hearing. Currently prescribed furosemide therefore advisable to check zinc status and if low then intervention recommended;
- thiamine – associated with bilateral hearing loss and proposed mechanism of action is that thiamine transporter OCT2 is expressed in the hair cells of the cochlea therefore interruptions to thiamine accessibility are likely to impact hair cell function. Currently prescribed furosemide and indoxyl combi which decrease thiamine availability both directly and indirectly.
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 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.
