Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: rationale for clinical management

Abstract

Risk factors for COVID-19 patients with poorer outcomes include pre-existing conditions: obesity, type 2 diabetes mellitus, cardiovascular disease (CVD), heart failure, hypertension, low oxygen saturation capacity, cancer, elevated: ferritin, C reactive protein (CRP) and D-dimer. A common denominator, hyperinsulinaemia, provides a plausible mechanism of action, underlying CVD, hypertension and strokes, all conditions typified with thrombi. The underlying science provides a theoretical management algorithm for the frontline practitioners.Vitamin D activation requires magnesium. Hyperinsulinaemia promotes: magnesium depletion via increased renal excretion, reduced intracellular levels, lowers vitamin D status via sequestration into adipocytes and hydroxylation activation inhibition. Hyperinsulinaemia mediates thrombi development via: fibrinolysis inhibition, anticoagulation production dysregulation, increasing reactive oxygen species, decreased antioxidant capacity via nicotinamide adenine dinucleotide depletion, haem oxidation and catabolism, producing carbon monoxide, increasing deep vein thrombosis risk and pulmonary emboli. Increased haem-synthesis demand upregulates carbon dioxide production, decreasing oxygen saturation capacity. Hyperinsulinaemia decreases cholesterol sulfurylation to cholesterol sulfate, as low vitamin D regulation due to magnesium depletion and/or vitamin D sequestration and/or diminished activation capacity decreases sulfotransferase enzyme SULT2B1b activity, consequently decreasing plasma membrane negative charge between red blood cells, platelets and endothelial cells, thus increasing agglutination and thrombosis.Patients with COVID-19 admitted with hyperglycaemia and/or hyperinsulinaemia should be placed on a restricted refined carbohydrate diet, with limited use of intravenous dextrose solutions. Degree/level of restriction is determined by serial testing of blood glucose, insulin and ketones. Supplemental magnesium, vitamin D and zinc should be administered. By implementing refined carbohydrate restriction, three primary risk factors, hyperinsulinaemia, hyperglycaemia and hypertension, that increase inflammation, coagulation and thrombosis risk are rapidly managed.

Keywords: cytokines; deep vein thrombosis; inflammation; oxidative stress; venous thromboembol.

Figure 1

Schematic representation of the role of hyperinsulinaemia in endothelial/vascular inflammation, red blood cell (RBC) and platelet coagulation, sequestration and/or inhibition of vitamin D activation and its downstream consequences, such as decreased cholesterol sulfate (Ch-S), heparan sulfate proteoglycans (HSPG) and cathelicidin synthesis. Carbon dioxide (CO₂), carbon monoxide (CO), deep vein thrombosis (DVT), endothelial nitric oxide synthase (eNOS), reduced glutathione (GSH), oxidised glutathione (GSSG), haemoglobin A1c (HbA1c), haem-oxygenase (HO), manganese superoxide dismutase 2 (MnSOD2), nicotinamide adenine dinucleotide (NAD+), plasma membrane (PM), plasminogen activator inhibitor type 1 (PAI-1), pulmonary embolism (PE), reactive oxygen species (ROS), oxygen saturation (SpO2), sirtuin 3 (SIRT3) and type 2 diabetes mellitus (T2DM).

Figure 2

Clinical management schematic. Beta-hydroxybutyrate (BHB), high-density lipoprotein (HDL), low carbohydrate healthy fat diet (LCHF), low glycaemic load diet (LG), sodium–glucose cotransporter 2 (SGLT2), well-formulated ketogenic diet (WFKD) and upper tolerable limit (UTL).