Glucose transporters SGLTs

Glucose transporters SGLTs (sodium-dependent glucose transporters) are one of the three identified families of glucose transporters in humans.

Being a large molecule glucose requires assistance from membrane transporters to cross the lipid bilayer of the plasma membranes. Each glucose transporter, excluding the ubiquitous GLUT1, has distinct cell- and tissue-specific expression patterns. Changes in the expression and/or function of any of these glucose transporters may lead to various physiological disorders.

This article will outline the fundamentals of the glucose transporters SGLT, and will focus on Group1 isoforms. Human SGLT family transporters can be defined into two main groups -

   - Group 1 – SGLT1-6. Transports sugars and myo-inositol, and

   - Group 2 – SMIT1, CHT, SMVT, SMCT1, SMCT2, NIS. Transports key metabolites such as monocarboxylates, iodide, choline, and biotin.

Articles on each of the Group 2 SGLTs will be written at various times ie much later.

SGLTs have become a popular focus of research as their roles and functions do not rely on insulin.

The gliflozin rage of drugs are based on SGLT1/2 inhibition, with their main mechanisms of action including -

   - increased urinary glucose excretion;

   - inhibited early proximal reabsorption of glucose, NaCl (salt), bicarbonate, and fluid;

Gliflozins are perceived to be a low risk for hypoglycaemia.

Clinical considerations

Inhibition of SGLT1/2 means increased excretion of glucose, and likely other substrates, from the kidneys.

Although glucose and vitamin C are molecularly similar, the evidence is minimal regarding the impact of SGLTs on vitamin C status.

Further, very limited evidence indicates SGLT2 likely negatively impacts thiamine status either directly or indirectly.

Key regulatory bodies currently do not require identification of effects on the glucose transporter systems during the drug discovery process. Omission of this regulatory requirement is a concern, especially given the commonality of the side effect altered glycaemia.

The evidence seems to be increasing that increased urinary glucose also increases the risk of Urinary Tract Infections (UTIs). Frequent UTIs in elderly typically negatively impact appetite with resultant weight loss and increased risk of loss of function.

Clinical questions

Even with the limited evidence available, what actions will you initiate as you a review a person whose prescribed medications include SGLT inhibitors, will you -

   - monitor thiamine and vitamin C levels on a regular basis ie at least 6-monthly?

   - suggest regular auditing of UTI frequency once an SGLT has been prescribed?

Conclusions

Glucose transporters SGLTs are attracting a lot of research interest, albeit minimal interest in impacts on nutritional factors.

Case study

These 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

Relatively recent available biochemistry indicates

   - low sodium - likely due to paroxetine. Hyponatraemia is associated with increased risk of falls, and poor appetite. Advisable to recheck status and if still low then advisable to exclude SIADH, and to consider strategies to increase sodium status - preferably not with a salt supplement.

   - elevated MCV - advisable to check B12 levels. Neuro-imaging research found increasing memory impairment as B12 levels dropped even whilst within currently defined acceptable ranges. The authors recommend B12 interventions once levels are less than 300 pmol/L.

Advisable to check plasma proteins (albumin, total proteins) as they are the primary transporters for 3 of the prescribed drugs and hypoproteinaemia may alter their effects.

Glycaemia

Currently prescribed 2 medications that alter glycaemia.

Pharmaconutrition

Currently prescribed -

   - 6 medications that include nausea as a side effect.

   - 5 medications that include vomiting and diarrhoea as side effects.

   - 4 medications that include altered anaemia and altered potassium status as side effects.

   - 3 medications that include, altered calcium status, altered appetite, dry mouth status side effects.

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 aspirin then advisable to administer vitamin C prior to drug as vitamin C does not impact drug absorption whereas the drug does.

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

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

Magnesium stearate, a common excipient (ingredient), has been found to inhibit the effectiveness of aspirin.

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

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

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

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

Regular monitoring sodium levels recommended whilst paroxetine prescribed.

Zincaps commenced one year ago. Zinc and copper share the same absorption mechanism, and sustained zinc supplementation will reduce copper absorption and ultimately there is a risk that copper deficiency will manifest - likely as a myeloneuropathy. Advisable to check zinc levels as pantoprazole also prescribed which decreases zinc (and copper) absorption.

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 ensure magnesium status is well within acceptable range.

Mag-sup provides 37.4 mg elemental magnesium/day therefore current intervention provides 74.8 mg elemental magnesium/day. Men require 420 mg magnesium per day; the Upper Limit for magnesium from non-food sources is 350 mg elemental magnesium per day. Advisable to recheck magnesium levels and if still marginal then review current magnesium intervention and consider one that provides about 300 mg elemental magnesium per day. Currently prescribed pantoprazole which is likely negatively impacting magnesium absorption.

The evidence is increasing that proton pump inhibitors such as pantoprazole significantly impair magnesium absorption - magnesium deficiency manifests as confusion, disorientation, personality changes, loss of appetite, depression, muscle cramps, tingling, numbness, hypertension, cardiac dysrhythmia, seizures. Magnesium is an intracellular ion therefore serum levels are unlikely to detect early depletion of status. Cellular magnesium status is unknown whilst magnesium levels within acceptable range however if magnesium levels are low then typically indicates significant cellular depletion and intervention recommended. Advisable to monitor magnesium status and ensure within acceptable range.

Bowel management

   Regular aperient prescribed.

   Oral PRN aperient prescribed: administered 4 x one recent month.

   No Nurse Initiated interventions administered.

Staff comments

Staff advise Mr ADC does not drink milkshakes and that he may or may not consume main course, preferentially enjoys desserts and is currently only given one serve (of dessert).

Observations

Mr ADC is a pale, thin man with an impressive beard and very dry, psoriasis-looking dry legs, and who was sitting in his room when I went to speak to him. He told me he eats well, does not feel upset in the tummy, and only goes outside to have a cigarette. Mr ADC also told me he likes apple juice, chocolate topping on his ice cream, and that he does not like milkshakes as they are too sweet.

Mr ADC's weight status is currently indeterminate as I am unable to ascertain whether he is losing weight or remaining weight stable.

Pharmaconutrition comments

Mr ADC is a smoker and smoking diminishes vitamin C availability. Benefit may be gained 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. The evidence is increasing evidence that longterm (3+ years) proton pump inhibitor prescription is associated with

    - increased risk of scurvy;

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

   - altered gut microbiome;

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

   - generalised malnutrition due to impaired absorption of a range of nutrients such as B12, vitamin C, magnesium, zinc, iron, etc;

   - 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. Being important in quenching reactive substances, if there is insufficient vitamin C then cell status becomes compromised and the cells typically die which also causes pain. 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.

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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.