Mechanisms and consequencesAlbumin aka Human Serum Albumin (HSA) is the main protein in the blood. It is part of a superfamily that includes vitamin D-binding protein (VDP), alpha-fetoprotein and alpha-albumin (afamin). Recent seminal research (DOI https://doi.org/10.1186/s12967-024-05000-5) has also identified albumin as a glycoprotein. Because albumin is their primary distribution carrier, how compounds interact with albumin determines …

Mechanisms and consequencesThe body’s distribution system comprises a framework of local transporters, hubs, and systemic carriers. We see examples of this framework in operation in our social structures such as -the Postal Service. Designated sorting centres distribute to local hubs that then distribute by electric bike, truck etc, to the final destination;the suburban + interstate …

Mechanisms and consequencesDrug administration for dysphagia is a fraught issue. Many pharmaceutical manufacturers recommend their products not be crushed, chewed, dissolved … which is fine if swallow capability is uncompromised. However, approximately 8% of the global population has dysphagia, with the elderly and disability sectors being particularly well represented. How can we safely administer prescribed …

Mechanisms and consequences 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 …

AMPK mechanisms and consequencesAMPK (adenosine monophosphate-activated protein kinase) is an energy sensor in the cells. It rebalances adenosine triphosphate (ATP) levels in times of stress, and thus is important in a range of physiological functions. Our focus is on the various pathways that AMPK utilises to stimulate GLUT4 translocation. AMPK exerts multiple mechanisms of action to …

PKC mechanisms and consequencesPKC (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.PKCPKC 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 …

Mechanisms and consequencesGlucose 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 …

Mechanisms and consequencesThe glucose transporters SWEETs is a relatively recent discovery about which not much is known. The SWEETs are predominantly found in plants, and the only known human transporter is SWEET1.The primary function of glucose is as a key energy source for physiological function. Many organs can derive energy from fats and proteins in …

Mechanisms and consequencesGlucose transporters (GLUTs) and sodium–glucose linked transporters (SGLTs) are the regulatory pathways essential for glucose homeostasis. Glucose is important as -an energy source for most cells,a substrate in many biochemical reactions, andas precursors for cellular building blocks, including lipids and amino acids.This post focuses on the GLUTs.GLUTs -transport glucose, galactose, mannose, glucosamine, and …

Mechanisms and consequencesThe interdependence of copper-iron interactions, and their importance in health management, remains overlooked and under-researched. Deficiencies or excesses of either mineral alters the effect of the other, and may alter local and general physiological processes.Intake sourcesThree key sources of copper (Cu) and iron (Fe) availability include -Dietary intake – includes both volume of …

Mechanisms and consequencesDrug-induced tipping points and health management strategies are an unlikely combination and rarely considered. A common definition (https://global-tipping-points.org/what-is-a-tipping-point/) for a tipping point is –   – where a small change makes a big difference to a system (Gladwell [debut novel], 2000), or   – the point at which a series of small changes or incidents …

Mechanisms and consequencesOsmolality seems to be a rarely-considered contributor to a range of primarily gastro-intestinal side effects. It is probably overlooked because osmolality data is difficult to access. Further, there is no regulatory requirement for its inclusion in the Product Information document.Osmolality measures the number of solute particles per kilogram of solvent and is referred …

Mechanisms and consequencesNot to be crushed, chewed, broken or dissolved and its many variations are commonly included in most Product Information documents. If a medicine is crushed, chewed, broken or dissolved to ensure safe administration then there is non-compliance with manufacturer’s instructions. Further, crushing, chewing, breaking or dissolving a medicine means alteration to some aspects …

Mechanisms and consequencesExcipients are the ingredients that comprise about 90% of a medicine – they are added to optimise some aspect of the medicine’s administration and/or therapeutic benefit. Excipients seem to have 3 key roles, being -to negatively impact pathophysiology (injury- or disease-caused upset physiological processes),starting points for drug discovery projects,treatment enhancers as functional supplements.Functional …

Mechanisms and consequences“Not clinically relevant”, “inhibition unlikely at therapeutic interventions”, “clinical inhibition deemed minimal”, and similar other phrases typically refer to drug-transporter interactions; the phrases such as “at this dose” or similar, are also generally included and all relate to drug-drug interactions only. From a nutrition perspective, these phrases are red flags as indirect nutrition …

Mechanisms and consequencesThe side effects of many prescribed medicines include altered glycaemic status which is associated with physical harm to the body. Glycaemia (blood sugar levels) are variable and at times can be either too high (hyperglycaemia) or too low (hypoglycaemia). Both hyperglycaemia and hypoglycaemia are associated with oxidative stress which is considered a primary …

Mechanisms and consequencesMultidrug resistance proteins (MRPs) are efflux transporters and as such are responsible for the movement of a wide variety of both endobiotics (endogenous substances that influence the functioning of an organ or biological process. [Wiktionary]) and xenobiotics (foreign compounds not produced by an organism’s metabolism, or biological substances present in excessive concentrations), across …

Guest case studyGuest case study – hypercalcaemia is based on a question from a concerned clinician.Oral calcium intake – no evidence of excessive calcium intake in diet, and no high-dose calcium supplements prescribed.Pathology results -PTH (parathyroid hormone) normal;calcium ~ 2.7ish mmol/L (elevated), some degree of fluctuation.Prescribed medications – fluoxetine, olanzapine.Nutrient supplements – multivitamin, zinc.Fluid intake …

Mechanisms and consequencesOATs (Organic Anion Transporters) are primarily influx transporters albeit some are bidirectional. They can transport a wide variety of anionic and cationic substances into the kidney and then regulate their rate of excretion.OATP IsoformsThere are 11 known human isoforms as summarised -OAT1Included in drug discovery processes to minimise drug-drug interactionsRoleprefers hydrophilic compounds;important in …

Mechanisms and consequencesOATPs (Organic Anion Transporting Proteins) are influx transporters ie transport substrates from blood into organs and cells. OATPs can transport compounds that are relatively large and have a high degree of albumin binding under physiological conditions; they also mediate xenobiotic uptake.In conjunction with the Organic Anion Transporters (OATs), the OATPs are important in …

Mechanisms and consequencesPermeability-glycoprotein is known as P-glycoprotein or P-gp or multidrug resistance protein (MDR1/2); it has a large and versatile drug-binding region that encompasses multiple and overlapping binding sites inside a large and flexible binding pocket lined with aromatic residues that can accommodate a large range of smaller or larger molecules or several molecules simultaneously, …

Mechanisms and consequencesThe Sodium Vitamin C Transporters (SVCTs) regulate vitamin C homeostasis (system stability) such that excessive intakes result in reduced intestinal absorption and renal reabsorption, and inadequate intakes result in increased intestinal absorption and renal reabsorption.The SVCT1/2 substrate is the reduced form of vitamin C/ascorbic acid ie ascorbate.There are 3 identified SVCTs, being –SVCT1 …

Mechanisms and consequencesMATE1/2 (Multi drug and toxin exclusion transporters MATE1 and MATE2) are major efflux transporters involved in the hepatic and renal excretion of many cationic endogenous and xenobiotic substances. As efflux transporters they primarily move lipophobic substances -out of the liver ie hepatic biliary excretion – MATE1,out of the kidneys and into urine ie …

Mechanisms and consequencesBCRP (Breast Cancer Resistance Protein) seems to be an initial defence against environmental insults such as phototoxic skin lesions, and xenobiotic absorption, and seems to prefer to excrete toxic substances via the biliary pathway. P-glycoprotein (aka P-gp, or MDR1) overlaps with BCRP and to a lesser extent with MRP1 (Multi Resistance Protein). Whether …

Mechanisms and consequencesThe thiamine transporters Thiamine Transporter 1 (THTR1) and Thiamine Transporter 2 (THTR2) transfer thiamine and pyridoxine, and are associated with two transfer systems, being -THTR1 – the nutrient concentration is low and therefore uptake requires energy,THTR2 – the nutrient concentration is high (thiamine > 2 mmol/L), and therefore uptake involves passive nutrient diffusion.Thiamine …

Mechanisms and consequencesSMVT (Sodium Multivitamin Transporter) facilitates the uptake of biotin, pantothenic acid, lipoic acid, and iodine from the gut and across the Blood Brain Barrier. It is the only currently known intestinal biotin transporter. SMVT is present in the small and large intestines, liver, kidney, heart, lungs, brain, cornea, retina, and placenta tissues.Functions and …

Mechanisms and consequencesOCTs regulate the transfer of many essential organic cations across biological membranes and therefore have an essential role in many metabolic processes.The OCTs are known as being polyspecific transporters because they recognize and transport a broad range of substances such as the organic amines choline and carnitine, the neurotransmitters dopamine and serotonin, and …

Mechanisms and consequencesMembrane transporters enable substances to cross impermeable cell membranes. Whilst they primarily transfer endogenous substances such as nutrients, they can also transfer exogenous substances such as toxic metals, pharmaceuticals, and other toxic substances. Membrane transporters function similarly to shuttle buses in that they efficiently move substances from one area to another – some only …

Mechanisms and consequencesMetformin’s role in healthcare management is expanding and is now being considered as a treatment for some cancers, bone health, neurodegeneration, and probably others, as well as its long-recognised role in diabetes management.The mechanisms by which metformin exerts its effects are still not fully understood but it is currently accepted that metformin inhibits …