Changes in Glycolytic Pathway in SARS-COV 2 Infection and Their Importance in Understanding the Severity of COVID-19

COVID-19 is an infectious disease caused by Coronavirus 2 (SARS-CoV-2) that may lead to a severe acute respiratory syndrome. Such syndrome is thought to be related, at least in part, to a dysregulation of the immune system which involves three main components: hyperactivity of the innate immune system; decreased production of type 1 Interferons (IFN) by SARS-CoV-2-infected cells, namely respiratory epithelial cells and macrophages; and decreased numbers of both CD4+ and particularly CD8+ T cells. Herein, we describe how excessive activation of the innate immune system and the need for viral replication in several cells of the infected organism promote significant alterations in cells’ energy metabolism (glucose metabolism), which may underlie the poor prognosis of the disease in severe situations. When activated, cells of the innate immune system reprogram their metabolism, and increase glucose uptake to ensure secretion of pro-inflammatory cytokines. Changes in glucose metabolism are also observed in pulmonary epithelial cells, contributing to dysregulation of cytokine synthesis and inflammation of the pulmonary epithelium. Controlling hyperglycolysis in critically ill patients may help to reduce the exaggerated production of pro-inflammatory cytokines and optimise the actions of the adaptive immune system. In this review, we suggest that the administration of non-toxic concentrations of 2-deoxy-D-glucose, the use of GLUT 1 inhibitors, of antioxidants such as vitamin C in high doses, as well as the administration of N-acetylcysteine in high doses, may be useful complementary therapeutic strategies for these patients, as suggested by some clinical trials and/ or reports. Overall, understanding changes in the glycolytic pathway associated with COVID-19 infection can help to find new forms of treatment for this disease.

AZP-3404, a Peptide Analog of IGFBP-2, Induces Weight Loss and Improves Glucose Metabolism in Leptin-Resistant db/db Mice

Insulin-like growth factor binding protein-2 (IGFBP-2) has been demonstrated to be a key mediator of the peripheral metabolic actions of leptin. The metabolic activity of IGFBP-2 is independent of IGF1 binding, and can be localized to a unique heparin-binding domain (HBD-1) within its structure. AZP-3404 is a 9-amino acid analog of the IGFBP-2 HBD-1 that reproduces the activity of IGFBP-2 on adipocyte and osteoblast differentiation. In addition, AZP-3404 has been demonstrated to increase glucose uptake by differentiated mouse myotubes in vitro, and to increase glucose disposal following an intraperitoneal glucose tolerance test (IPGTT) in leptin-deficient ob/ob mice. In the present study, we hypothesized that AZP-3404 should be able to improve metabolic regulation in the db/db mouse, which is leptin-resistant due to a mutation in the leptin receptor, and, as a result, is also IGFBP-2 deficient. Following pre-treatment with vehicle for 1 week to establish a baseline, 9-week old male db/db mice were treated with either vehicle or AZP-3404 at doses of 1, 3 or 6 mg/kg, sc, bid (n=10/group) for 8 weeks. At the initiation of treatment, the mice weighed an average of 39.7 + 0.3 grams, and after 8 weeks, vehicle-treated mice had gained an average 8.2 + 1.6 grams of body weight. Mice treated with AZP-3404 displayed a progressive decrease in body weight gain that began after 2 weeks and that continued through the 8 weeks of treatment, ultimately resulting in less than 50% of the weight gain observed in the vehicle-treated mice, and without an apparent change in food intake. To assess the impact on glucose disposal, after both 4 and 8 weeks of treatment, and following an overnight fast, the mice were administered an IPGTT (blood glucose measured 0, 30, 60, 90, 120 and 240 minutes post-ip injection of 1 g glucose/kg). By 4 weeks of treatment, a significant increase in glucose disposal was observed in mice treated with the 6 mg/kg dose of AZP-3404 (AUC glucose decreased by 28.7%) versus vehicle-treated controls. By 8 weeks of treatment, all three doses produced similar increases in glucose disposal (AUC glucose decreased by 18.8, 21.4 and 23.1% with 1, 3 and 6 mg/kg AZP-3404, respectively) versus vehicle controls. Correspondingly, 4-hour fasted plasma insulin was decreased by 54, 48 and 52%, and the HOMA measure of insulin resistance was decreased by 55, 52 and 67%, in mice treated for 8 weeks with 1, 3 and 6 mg/kg AZP-3404, respectively, as compared with vehicle-treated mice. These results, demonstrating both improved glucose metabolism and decreased body weight gain in the leptin-resistant db/db mouse, further confirm the ability of AZP-3404 to reproduce the metabolic activity of IGFBP-2, and support the development of AZP-3404 as a novel therapy for disease states characterized by insulin resistance and/or obesity.

PolyMet-HA nanocomplexs regulates glucose uptake by inhibiting SHIP2 activity

Metformin, the first-line drug to treat type 2 diabetes, inhibits mitochondrial glycerolphosphate dehydrogenase in the liver to suppress gluconeogenesis. The major adverse effects caused by metformin were lactic acidosis and gastrointestinal discomfort. Therefore, there is need to develop a strategy with excellent permeability and appropriate retention effects.In this study, we synthesized a simple and biocompatible PolyMetformin (denoted as PolyMet) through conjugation of PEI1.8K with dicyandiamide, and then formed PolyMet-hyaluronic acid (HA) nanocomplexs by electrostatic self-assembly of the polycationic PolyMet and polyanionic hyaluronic acid (HA). Similar to metformin, the PolyMet-HA nanocomplexs could reduce the catalytic activity of the recombinant SHIP2 phosphatase domain in vitro. In SHIP2-overexpressing myotubes, PolyMet-HA nanocomplexes ameliorated glucose uptake by downregulating glucose transporter 4 endocytosis. PolyMet-HA nanocomplexes also could restore Akt signaling and protect the podocyte from apoptosis induced by SHIP2 overexpression. In essence, the PolyMet-HA nanocomplexes act similarly to metformin and increase glucose uptake, and maybe have a potential role in the treatment of type 2 diabetes.

Imeglimin, a novel, first in-class, blood glucose-lowering agent: a systematic review and meta-analysis of clinical evidence

Imeglimin is a novel, first in-class, blood glucose-lowering agent which acts via a mitochondrial mechanism to enhance glucose-induced insulin secretion, decrease hepatic glucose output and increase glucose uptake by skeletal muscle. A systematic review and meta-analysis of randomised controlled clinical trials (RCTs) with imeglimin in adults with type 2 diabetes was undertaken. Of 45 articles identified, five were RCTs but, due to the format of the data, only three could be combined in a meta-analysis (total n=180 participants). A random-effects model found that imeglimin 1500 mg twice daily as monotherapy and add-on to metformin or sitagliptin was associated with reductions of HbA1c by −0.63% (95% CI −0.84 to −0.42) (−6.6 mmol/mol, 95% CI −8.8 to −4.4) and reductions of fasting plasma glucose by −0.52 mmol/L (95% CI −0.80 to −0.24) compared with placebo. Adverse events were minimal, mostly gastrointestinal, and without hypoglycaemia. It is concluded that imeglimin displays promising improvements in HbA1c and fasting plasma glucose and is generally well tolerated.

The role of group I p21-activated kinases in contraction-stimulated skeletal muscle glucose transport

AimMuscle contraction stimulates skeletal muscle glucose transport. Since it occurs independently of insulin, it is an important alternative pathway to increase glucose uptake in insulin-resistant states, but the intracellular signalling mechanisms are not fully understood. Muscle contraction activates group I p21-activated kinases (PAKs) in mouse and human skeletal muscle. PAK1 and PAK2 are downstream targets of Rac1, which is a key regulator of contraction-stimulated glucose transport. Thus, PAK1 and PAK2 could be downstream effectors of Rac1 in contraction-stimulated glucose transport. The current study aimed to test the hypothesis that PAK1 and/or PAK2 regulate contraction-induced glucose transport.MethodsGlucose transport was measured in isolated soleus and extensor digitorum longus (EDL) mouse skeletal muscle incubated either in the presence or absence of a pharmacological inhibitor (IPA-3) of group I PAKs or originating from whole-body PAK1 knockout (KO), muscle-specific PAK2 (m)KO or double whole-body PAK1 and muscle-specific PAK2 knockout mice.ResultsIPA-3 attenuated (−22%) the increase in muscle glucose transport in response to electrically-stimulated contraction. PAK1 was dispensable for contraction-stimulated glucose uptake in both soleus and EDL muscle. Lack of PAK2, either alone (−13%) or in combination with PAK1 (−14%), reduced contraction-stimulated glucose transport compared to control littermates in EDL, but not soleus muscle.ConclusionContraction-stimulated glucose transport in isolated glycolytic mouse EDL muscle is partly dependent on PAK2, but not PAK1.

Effect of Phyllanthus emblica L. fruit on improving regulation of methylglyoxal-induced insulin resistance in 3T3-L1 cells

The increasing methylglyoxal (MG) level of body has been found in people with obesity and insulin resistance, resulting from their dietary style and abnormal metabolic functions. MG promotes inflammation, oxidative stress, glycation, and all of which are closely related to insulin resistance and chronic diseases. Phyllanthus emblica L. fruit has various bioactivities such as anti-inflammation, anti-diabetes, anti-nonalcoholic fatty liver, and anti-dyslipidemia. Therefore, this study was aimed to investigate the effects of water extract of P. emblica (WEPE) and its enriched compound, ellagic acid, on MG-induced inflammation, insulin resistance, and lipogenesis in 3T3-L1 cells. The results showed that MG activated the peroxisome proliferator activated receptor-gamma (PPARγ) and CCAAT/ enhancer-binding protein alpha (C/EBPα), which can increase adipogenesis in adipocytes. In addition, MG enhanced pro-inflammatory cytokine IL-6 protein expression and release through the activation of MAPK and NF-κB signaling pathway, as well as increasing the monocyte chemoattractant protein-1 expression to cause macrophage infiltration. MG also significantly reduced glucose uptake, indicating that insulin resistance in obese patients may be related to MG generation. WEPE and ellagic acid effectively decreased IL-6 protein expression and cytokine release through inactivation of JNK and p65 pathways. WEPE and ellagic acid significantly increased glucose uptake and reduced insulin resistance by MG treatment. WEPE also decreased the protein-tyrosine phosphatase 1B to reduce insulin resistance and inhibited MG-induced fat accumulation related proteins such as PPARγ, C/EBPα, FAS, and p-ACC. Therefore, WEPE may have the potential to ameliorate MG-induced inflammation, increase glucose uptake, and decrease fat accumulation.

Theaflavins Improve Insulin Sensitivity through Regulating Mitochondrial Biosynthesis in Palmitic Acid-Induced HepG2 Cells

Theaflavins, the characteristic and bioactive polyphenols in black tea, possess the potential improvement effects on insulin resistance-associated metabolic abnormalities including obesity and type 2 diebetes. However, the molecular mechanisms of theaflavins improving insulin sensitivity are still not clear. In this study, we investigated the protective effects and mechanisms of theaflavins on palmitic acid-induced insulin resistance in HepG2 cells. Theaflavins could significantly increase glucose uptake of insulin-resistant cells at noncytotoxic doses. This activity was mediated by upregulating the glucose transporter 4 protein expression, increasing the phosphorylation of IRS-1 at Ser307, and reduced the phosphor-Akt (Ser473) level. Moreover, theaflavins were found to enhance mitochondrial DNA copy number through down-regulate the PGC-1β mRNA level and up-regulate PRC mRNA expression in insulin-resistant HepG2 cells. These results indicated that theaflavins could improve free fatty acid-induced hepatic insulin resistance by promoting mitochondrial biogenesis, and were promising functional food and medicines for insulin resistance-related disorders.