Glucose transporters and insulin function

Glucose transporters and insulin function is rarely considered whilst “insulin and blood sugars” is integral to many care discussions.

Given glucose transporters are responsible for moving glucose into and out of cells, why is insulin important in glucose uptake?

Glucose transporters and insulin function

The resting location of glucose transporters seems to dictate insulin’s role. Most glucose transporters are insulin-independent which means that they are typically positioned for glucose uptake. Insulin stimulates the insulin-dependent transporters to translocate from the inner membrane wall into position on the outer membrane wall.

An analogy for glucose transporters and insulin function is the summoning of a lift in a tall building. Pushing a button in the wall sends a signal to the lift that then arrives in the fullness of time.

Similarly, by locking onto an insulin receptor (IR), insulin stimulates a signaling sequence via the phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt) pathway. This signaling activates translocation of insulin-dependent glucose transporters into their glucose uptake position.

Lack of nutrient availability at any point in the IRS/PI3K/Akt cascade means translocation of insulin-dependent glucose transporters will not proceed. The outcome is decreased glucose uptake, consequent hyperglycaemia and likely insulin resistance.

Insulin-dependent glucose transporters

The current status of GLUT3 is insulin-independence, however several authors also referred to (older) evidence of insulin-dependence.

IRS/PI3K/AKT signalling cascade issues

1. Vitamin C

Oxidative stress inhibits phosphorylation of insulin receptor substrate.

Vitamin C increases insulin signalling by increasing IRS-1 expression.

2. Vitamin D

Phosphorylation of the tyrosine residues on IRS1 actually activates the insulin-PI3K-Akt cascade. Protein kinase C (PKC) phosphorylates serine residues on IRS1 which means IRS/PI3K/Akt is not activated. Vitamin D reduces IRS1 phosphorylation of the serine residues.

Chronic hyperinsulinaemia causes increased insulin receptor degradation and desensitization. Vitamin D primarily impacts glucose homeostasis by upregulating insulin receptors, thus reversing hyperinsulinaemia. The insulin receptor gene that regulates insulin receptor expression is adjacent to the vitamin D response element (VDRE).

3. Magnesium

Magnesium impacts glucose transporters and insulin function both directly and indirectly –

• Directly - magnesium is essential for insulin-stimulated Akt activation;
• Indirectly – adequate magnesium availability is essential for activation of nutrients such as vitamin D and vitamin C.

4. Other

Inadequate intake of vitamins C+D contribute to impairment of the IRS/PI3K/Akt cascade, with consequent hyperglycaemia and insulin resistance. Does this mean some forms of insulin resistance are due to mal-nutrition and therefore reversible? Also, which other nutrients also contribute to insulin resistance via this pathway?

If all nutrients associated with this pathway only, were identified, monitored, and managed, then what would be the savings in physiological and financial benefits?

The consequences of nutrient interventions are unlikely to manifest overtly and therefore not be easily measured or monitored.

Clinical considerations and questions

The brain requires glucose specifically as its energy source, the remainder of the body can also derive and utilize energy from proteins and fats. Can and should dietary advice be structured to accommodate the differing insulin requirements of the glucose transporters?

No regulatory requirement exists for glucose transporters and insulin function to be included in drug discovery and Product Information documents. Further, there are no standard clinical management strategies, and identifying and initiating appropriate clinical interventions becomes very difficult.

Clinical Questions

As impairment to the IRS/PI3K/Akt cascade is considered a contributor to insulin resistance, what nutritional strategies will you initiate to optimize the cascade’s outcomes?

Will you initiate a regular monitoring schedule for known nutrients such as vitamin C, vitamin D and magnesium?

Conclusions

Glucose transporters and insulin function is steadily attracting research interest, albeit with limited interest in the role of nutritional factors.

Case study

The comments refer to the drug-nutrient, drug-food, and PharmacoNutrition effects only.

Data summary

Medical History with Nutritional Aspect

Biochemistry with Pharmaconutrition Consequences

Medications That May Adversely Affect Nutritional Status

Transporter-mediated interactions and nutrients

Biochemistry

Recent relevant available biochemistry indicates -

   - high folic acid – may be a consequence of the prescribed multivitamin or transporter inhibition.

Glycaemia

BSLS

   - reportable limits: < 3 and > 28 on drug chart and < 4.0 and > 20 on Care Plan.

   - tested monthly.

   - advisable to check HbA1c and clarify overall glycaemic control.

Mr ADD’s glycaemia management was changed from metformin and weekly BSLs to no drugs and monthly BSLs further to his hospitalisation. Advisable to check BSLs bd for 3 consecutive days and clarify overall glycaemic control.

Mr ADD’s BSL reportable limits range is quite broad - to the point of concern. Advisable to review current limits and consider ranges that are more in line with current practice.

Currently prescribed 3 medications that alter glycaemia.

Pharmaconutrition

Side effects profile from the currently prescribed medicines –

- 7 medications that includes nausea.

- 6 medications that include vomiting and diarrhoea.

- 5 medications that includes altered taste.

- 4 medications that include anaemia, altered potassium, dry mouth, and altered appetite.

- 3 medications that include constipation and sweating.

- 2 medications that include hyperuricaemia, hyponatraemia, altered weight status, tremor, altered iron status, altered zinc status, and altered riboflavin status.

- 1 medications that includes hypothyroidism.

Vitamin C (960 mg/day) attenuates aspirin-induced gastric injury.

Caffeine increases aspirin absorption by altering gastric pH

Aspirin inhibits vitamin C absorption by either inhibiting vitamin C binding to albumin, or by inhibiting/regulating/modulating GLUT1 (glucose transporter 1) uptake of vitamin C as DHA (dehydroascorbic acid).

If there is concurrent administration of a vitamin C intervention and the drug then advisable to administer vitamin C prior to drug as vitamin C does not impact drug absorption whereas the drug does.

Aspirin has a negative impact on folate status - the mechanism of action remains speculative.

Coffee inhibits vitamin D uptake by inhibiting the osteoblasts (bone builders) vitamin D receptors, consequently decreasing calcium and zinc absorption.

Chronic use of coloxyl + senna may promote excessive loss of water and electrolytes, especially potassium, and their regular monitoring recommended.

Mirtazepine decreases sodium levels and hyponatraemia is associated with increased risk of falls and reduced appetite therefore advisable to monitor sodium status.

Mirtazepine 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.

Pantoprazole decreases B12, vitamin C, magnesium, zinc and iron absorption, may decrease calcium absorption, and decreases thiamine availability.

Perindopril impairs zinc status.

Currently prescribed vitamin D (1 tab/day). Advisable to check vitamin D levels and if still low then review current vitamin D management strategy.

Currently prescribed thiamine and vitamin D on a daily basis; both thiamine and vitamin D require magnesium in order to be activated therefore advisable to consider a magnesium intervention to optimise the effectiveness of these interventions. Men require 420 mg elemental magnesium per day, however there are side effects if non-food magnesium of 350+ mg elemental magnesium is administered therefore advisable to consider a magnesium intervention that provides about 300 mg elemental magnesium per day.

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 ADD’s prescribed medications include -

• substrates - thiamine, riboflavin, niacin, pantothenate, pyridoxine, biotin, folate, B12, DHA (vitamin C), vitamin D, carnitine, choline, iodide, and vit K;
• inhibitors – pantothenate, biotin, vitamin A, vitamin D.

The duration of drug inhibition of transporters currently remains unknown.

Bowel management 

-   - regular aperient prescribed.

   - no PRN interventions prescribed.

   - no Nurse Initiated interventions administered.

Staff comments

Staff advise Mr ADD eats well, and is sometimes assisted with his meals.

Observations

Mr ADD is a well-built man who was in his room when I went to speak to him - he told me he eats well and eats enough.

Mr ADD has been weight stable for the last 9 months.

Pharmaconutrition comments

Mr ADC is a smoker and as smoking diminishes vitamin C availability, he may benefit from a vitamin C intervention especially since he is prescribed 2 drugs that also decrease vitamin C availability, being aspirin and pantoprazole.

Malnutrition

Mr ADC’s diagnoses include malnutrition, and he is prescribed a general multivitamin supplement and several individual supplements to resolve his malnutrition. However, Mr ADC has also been prescribed pantoprazole for 15+ months, which negatively impacts the absorption of three of the key nutrients being supplemented. Further, the degree of positive effect of the supplements is likely to be minimal due to pantoprazole changing the gastric acidity to a much less acidic pH. Mr ADC is in the difficult position of being prescribed a proton pump inhibitor and having a malnutrition that is unlikely to resolve properly whilst the proton pump inhibitor is prescribed. Advisable to consider -

   - whether proton pump inhibitor prescription is still required;

   - if suppression of gastric acidity is still required then could it be managed with an H2 antagonist such as ranitidine (there is a general belief that they cause less nutritional harm than proton pump inhibitors);

   - if the proton pump inhibitor intervention can be ceased until the malnutrition is resolved.

PPI prescription

Mr ADC has been prescribed a proton pump inhibitor since admission (15 months ago) and likely before then. There is increasing evidence that longterm (3+ years) proton pump inhibitor prescription is associated with

   - increased risk of food sensitivities at a level of peanut allergy, due to partial protein digestion;

   - increased risk of coeliac disease due to partial protein digestion;

   - altered gut microbiome;

   - increased risk of scurvy;

   - altered gastric pH which reduces absorption dynamics of a range of drugs and nutrients. Altered drug availability is relatively easily identified however reduced nutrient absorption is rarely identified due to the non-specific nature of their signs and symptoms.

Chronic pain

Mr ADC 's diagnoses include chronic pain - nutritional factors that may be useful to consider in pain management include

   - vitamin D - current intervention may not be adequate to attain adequate range, especially since levetiracetam prescribed. Evidence indicates increasingly brittle pain control with decreasing vitamin D levels.

   - vitamin C - pain increases the reactive substances (formerly Reactive Oxygen Species) within cells. Vitamin C is important in quenching reactive substances and if there is insufficient vitamin C then cell status becomes compromised and the cells typically die which also causes pain. Whilst vitamin C is not considered part of the pain management armament however it won't cause harm and evidence suggests it may confer benefit. Currently prescribed pantoprazole which decreases conversion of vitamin C to its active form and aspirin which inhibits its transfer to the albumin carrier.

   - low B12 exacerbates elevated TNF- α which is an inflammatory response marker; elevation of the inflammatory response can include a pain response and currently prescribed pantoprazole therefore advisable to check B12 status.

   - magnesium – proposed mechanism magnesium blocks the NMDA receptor channels in the spinal cord and thus limits the influx of calcium ie reduces the risk of excitotoxicity and consequent exacerbation of pain. Currently prescribed both pantoprazole which decreases magnesium absorption and a magnesium intervention – advisable to clarify current magnesium status.

Falls

Mr ADC’s diagnoses include falls - nutritional factors that may be useful to ensure within acceptable ranges include –

 - potassium - important in muscle function, currently prescribed pantoprazole therefore advisable to clarify status;

 - calcium - more likely to be low if potassium or magnesium low; important in muscle function, currently prescribed pantoprazole therefore advisable to clarify status;

 - vitamin D – increasing vitamin D intake increases muscle strength and decreases falls; currently prescribed colecalciferol and levetiracetam therefore advisable to clarify vitamin D status;

 - B12 - is important in the righting reflex when a person stumbles; prescribed pantoprazole therefore advisable to check status;

- iron – currently prescribed pantoprazole therefore advisable to check status;

 - zinc – can decrease food intake through altered sense of taste and poor appetite, and consequently reduced muscle mass; currently prescribed pantoprazole which significantly decreases zinc absorption, and the zinc supplement Zinvit therefore advisable to check status;

 - magnesium - magnesium is important in vitamin D activation, de novo carnitine production, and muscle function, amongst other functions. Also currently prescribed pantoprazole which significantly decreases magnesium absorption, and the magnesium supplement Mag-sup. Magnesium is an intracellular ion therefore serum levels are unlikely to detect early depletion of status Advisable to clarify magnesium status;

 - thiamine –is important in balance and position sense. Currently prescribed pantoprazole and also a thiamine intervention therefore advisable to monitor status.

What else would you include?

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