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

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.

Unveiling the presence of epigenetic mark by Lactobacillus supplementation in high-fat diet-induced metabolic disorder in Sprague-Dawley rats.

Gut dysbiosis, particularly bacteria from Firmicutes and Bacteroidetes phyla, plays a fundamental role in the progression of metabolic disorders. Probiotics have shown to restore the gut microbiota composition in metabolic disorders with subsequent beneficial effects. Recent studies have reported that several species of Lactobacillus as probiotic supplementation improve insulin sensitivity and glucose metabolism. Nonetheless, whether Lactobacillus could influence the epigenetic modifications that underlie insulin-resistant conditions is still unexplored. Therefore, the current study examined the therapeutic effects and underlying epigenetic mechanisms of three different species of Lactobacillus in the high-fat diet (HFD)-induced insulin-resistant rats. Three different species of Lactobacillus; Lactobacillus casei, Lactobacillus gasseri, and Lactobacillus rhamnosus were individually supplemented orally (109 CFU/mL) to insulin-resistant SD rats for 12 weeks. Lactobacillus supplementation led to a significant reduction in the hyperglycemia, hyperinsulinemia, and hyperlipidemia associated with HFD-induced insulin resistance. Histopathological examination also indicated the protective effects of Lactobacillus supplementation against the hepatic and intestinal damage caused by the high-fat diet. Lactobacillus supplementation also down-regulated the expression of FOXO1, a major transcription factor of insulin signaling. In addition, at the epigenetic level, Lactobacillus supplementation predominantly prevented methylation and demethylation of H3K79me2 and H3K27me3, respectively. Chromatin Immunoprecipitation (ChIP) coupled with quantitative PCR (ChIP-qPCR) assay revealed the presence of cross-talk between these two histone modifications at the promoter region of FOXO1. Taken together, this is the first report to observe that the effects of Lactobacillus supplementation involve alteration in FOXO1 expression via cross-talking between H3K79me2 and H3K27me3 histone modifications.

The effects of curcumin supplementation on glycemic status, lipid profile and hs-CRP levels in overweight/obese women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVE: The aim of the current study was to assess the effects of curcumin supplementation on glycemic status, lipid profile and high sensitivity C-reactive protein (hs-CRP) serum levels in women with polycystic ovary syndrome (PCOS). DESIGN: This randomized double-blind placebo-controlled clinical trial was conducted on 60 women who were randomly assigned to the intervention or control groups using block randomization. SETTING: Infertility referral center. INTERVENTIONS: Curcumin (500 mg/d) or placebo twice daily for 6 weeks. MAIN OUTCOME MEASURES: Serum evaluation of lipid profile (triglycerides (TG), low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol concentrations, LDL/HDL-C and TG/HDL-C ratios), glycemic index (fasting blood sugar (FBS), insulin concentrations, homeostasis model of assessment insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI)) and hs-CRP levels. RESULTS: Glycemic index, lipid profile and hs-CRP serum levels were measured at first and at the end of trial. Serum insulin (p = 0.020) and Quantitative Insulin Sensitivity Check Index (QUICKI) (p = 0.003) were improved significantly, while Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (p = 0.067) improved marginally in curcumin treated group (within group analysis). CONCLUSIONS: Curcumin supplementation might be beneficial for improving serum insulin and QUICKI, however, future investigations are suggested in order to draw a firm link between curcumin and glycemia control.

High-Dose, Diazoxide-Mediated Insulin Suppression Boosts Weight Loss Induced by Lifestyle Intervention.

Context: Obesity-related hyperinsulinism may impede lifestyle-initiated weight loss. Objective: Proof-of-concept study to investigate the amplifying effects of diazoxide (DZX)-mediated insulin suppression on lifestyle-induced weight loss in nondiabetic, hyperinsulinemic, obese men. Design: Twelve-month study comprising an initial 6-month, double-blind trial, followed by a partially de-blinded 6-month extension in men with obesity with a body mass index of 30 to 37.5 kg/m2 and a fasting serum C-peptide level >1.00 nM. Patients were randomized into three treatment groups: DZX + placebo (DZX + PL), DZX + metformin (DZX + MTF), and double PL (PL + PL). Results: At 6 months, DZX treatment was associated with a 6.1-kg PL-subtracted decline in fat mass (FM), and at 12 months, FM had decreased by a total of 15.7 ± 2.5 kg. Twelve months of DZX treatment was also associated with a significant decline in systolic (-6.6%) and diastolic (-8.6%) blood pressure and low-density lipoprotein-cholesterol (-18%) and triglycerides (-43%) and a 39% rise in high-density lipoprotein-cholesterol. These effects were achieved at the cost of a small rise in fasting glucose (95% CI: 0.2 to 1.0 mM) and hemoglobin A1c (95% CI: -0.08% to 0.44%). There were no differences between DZX monotherapy and the combination of DZX + MTF. Conclusion: High-dose DZX treatment of 1 year resulted in a substantial decrease in FM, blood pressure, and lipid levels at the cost of a small rise in blood glucose levels.

Management of calcium channel blocker overdoses.

Calcium channel blockers (CCBs) are some of the most commonly used medications in clinical practice to treat hypertension, angina, cardiac arrhythmias, and some cases of heart failure. Recent data show that CCBs are the most common of the cardiovascular medications noted in intentional or unintentional overdoses.(1) Novel treatment approaches in the form of glucagon, high-dose insulin therapy, and intravenous lipid emulsion therapies have been tried and have been successful. However, the evidence for these are limited to case reports and case series. We take this opportunity to review the various treatment options in the management of CCB overdoses with a special focus on high-dose insulin therapy as the emerging choice for initial therapy in severe overdoses.

Potential treatments for insulin resistance in the horse: a comparative multi-species review.

Insulin resistance and hyperinsulinaemia increase the risk of laminitis and horse owners and veterinarians should attempt to enhance insulin sensitivity in at-risk groups. In obese animals this may be achieved, in part, by promoting weight loss and increasing exercise, but such intervention may not be appropriate in non-obese insulin-resistant animals, or where exercise is contra-indicated for clinical reasons. An alternative approach to controlling insulin sensitivity in obese and non-obese horses may be the use of certain herbal compounds that have shown promise in humans and laboratory animals, although little is known of the effects of these compounds in horses. The herbs can be grouped according to their primary mechanism of action, including activators of the peroxisome proliferator-activated receptors, anti-obesity compounds, anti-oxidants, compounds that slow carbohydrate absorption, insulin receptor activators and stimulators of glucose uptake, with some herbs active in more than one pathway. Certain herbs have been prioritised for this review according to the quality and quantity of published studies, the reported (or extrapolated) safety profile, as well as potential for efficacy, all of which will hopefully motivate further research in this field.

HSP72 protects against obesity-induced insulin resistance.

Patients with type 2 diabetes have reduced gene expression of heat shock protein (HSP) 72, which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of kappaB kinase, and tumor necrosis factor-alpha, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.

Additive benefits of long-chain n-3 polyunsaturated fatty acids and weight-loss in the management of cardiovascular disease risk in overweight hyperinsulinaemic women.

BACKGROUND: Obesity, inflammation, insulin resistance and cardiovascular disease (CVD) risk are inter-related. Both weight-loss and long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) are independently known to reduce metabolic risk, but the combined effects are unclear. OBJECTIVE: This study examines whether addition of LC n-3 PUFA to a low fat/high carbohydrate weight-loss programme results in greater improvements in inflammation, insulin sensitivity and CVD risk, than weight-loss alone. DESIGN: One hundred and sixteen overweight insulin-resistant women entered a 24-week randomised intervention study. Thirty-nine women were randomised to a weight-loss programme, with LC n-3 PUFA (WLFO), 38 to a weight-loss programme with placebo oil (WLPO), and 39 to receive placebo oil, with no weight-loss programme (control). RESULTS: Ninety-three women completed the study (35 WLFO, 32 WLPO and 26 control), with significant weight-loss in WLFO (10.8+/-1.0%) and WLPO (12.4+/-1.0%) compared to the control group (P<0.0001). The WLFO, but not WLPO or control group, showed significant increases in adipose tissue LC n-3 PUFA (0.34+/-0.20 vs 0.17+/-0.10 and 0.16+/-0.10 %DHA, P<0.0001). Weight-loss showed significant improvements in insulin sensitivity (P<0.001), lipid profile (triglycerides P<0.05) and inflammation (sialic acid P<0.05). Time*group effects showed significant decreases in triglycerides (P<0.05) and increases in adiponectin (P<0.01) with LC n-3 PUFA, in the WLFO vs WLPO groups. CONCLUSIONS: Weight-loss improved risk factors associated with CVD, with some additional benefits of LC n-3 PUFA on triglycerides and adiponectin. Given the current low dietary intake of LC n-3 PUFA, greater attention should be given to increase these fatty acids in the treatment of obesity.

Insulin resistance and vessel endothelial function.

IRS is a complex disease consisting of a clustering of metabolic disorders, of which hyperglycaemia, hyper-insulinaemia and dyslipidaemia are the most important. Endothelial dysfunction plays an important role in the pathogenesis of atherosclerosis. The effects of hyperinsulinaemia seem to depend on lipidaemia and glycaemia. Hyperglycaemia and hyperlipidaemia have detrimental effects on endothelial function in the fasting as well as the postprandial states. In both situations, the generation of ROS and vasoactive molecules plays a major role in interfering with the atheroprotective endothelium-dependent NO system. Treatment of IRS in regard to endothelial function should be focused initially on lifestyle improvement, such as stopping smoking and eating a balanced diet containing antioxidant vitamins, folic-acid, L-arginine and long-chain omega-3 unsaturated FA. Strict glucose control has shown to improve endothelial function and decrease microvascular complications. However, macrovascular complications, in line with endothelial functional improvement, have so far been reduced only when treatment was focused on other characteristics of the IRS syndrome, in particular dyslipidaemia. Other relevant treatments include ACE inhibitors and thiazolidinediones, and probably tetrahydrobiopterin and folic acid supplementation. Future studies should address the effects of therapeutic neovascularization on endothelial dysfunction.

Long-term suppression of weight gain, adiposity, and serum insulin by central leptin gene therapy in prepubertal rats: effects on serum ghrelin and appetite-regulating genes.

Intracerebroventricular administration of recombinant adeno-associated virus (rAAV) encoding the rat leptin gene (rAAV-lep) to 24-d-old female and male rats suppressed postpubertal weight gain for extended periods by decreasing food consumption and adiposity, as reflected by lowered serum leptin, insulin, and FFA. Serum ghrelin levels were increased in young but not older rats. Central rAAV-lep therapy also increased energy expenditure through nonshivering thermogenesis in younger rats as shown by expression of uncoupling protein mRNA in brown adipose tissue. The sustained decrease in appetite seemingly resulted from attenuation of appetite-stimulating neuropeptide Y and enhancement of appetite-inhibiting melanocortin signalings in the hypothalamus. Neither the onset of pubertal sexual maturation nor reproductive cyclicity in adult female rats was affected by the sustained reduction in energy consumption and weight gain. These findings demonstrate that central leptin gene therapy in prepubertal rats is a novel therapy to control postpubertal weight gain, adiposity, and hyperinsulinemia for extended periods.

Enhancing the anti-dumping effect of Roux gastrojejunostomy with intestinal pacing.

We wondered whether Roux gastrojejunostomy alone or with intestinal pacing would slow gastric emptying and ameliorate the dumping syndrome after truncal vagotomy and subtotal distal gastrectomy. In five conscious dogs with vagotomy and distal gastrectomy, the Roux loop alone slowed gastric emptying of 100 ml 5% glucose instillates, but not of 100 ml 25% glucose instillates, while pacing the loop backwards slowed emptying of both. Pacing also decreased the postcibal hemoconcentration and hyperglycemia found after the 25% instillates. However, pacing did not alter the postprandial hyper-GIP-emia (gastric inhibitory peptide) and hyperinsulinemia found in Roux gastrectomy dogs, suggesting that pacing worked by slowing emptying of glucose rather than by releasing enteric hormones. Although pacing did not stimulate jejunal action potentials (contractions), the greater the number of action potentials occurring during pacing, the more the slowing (r = .738, p less than .001). We concluded that the combination of Roux gastrojejunostomy and pacing ameliorated postgastrectomy dumping in dogs. The tests provide a basis for treating humans with postgastrectomy dumping.