Metformin: update on mechanisms of action and repurposing potential.

Currently, metformin is the first-line medication to treat type 2 diabetes mellitus (T2DM) in most guidelines and is used daily by >200 million patients. Surprisingly, the mechanisms underlying its therapeutic action are complex and are still not fully understood. Early evidence highlighted the liver as the major organ involved in the effect of metformin on reducing blood levels of glucose. However, increasing evidence points towards other sites of action that might also have an important role, including the gastrointestinal tract, the gut microbial communities and the tissue-resident immune cells. At the molecular level, it seems that the mechanisms of action vary depending on the dose of metformin used and duration of treatment. Initial studies have shown that metformin targets hepatic mitochondria; however, the identification of a novel target at low concentrations of metformin at the lysosome surface might reveal a new mechanism of action. Based on the efficacy and safety records in T2DM, attention has been given to the repurposing of metformin as part of adjunct therapy for the treatment of cancer, age-related diseases, inflammatory diseases and COVID-19. In this Review, we highlight the latest advances in our understanding of the mechanisms of action of metformin and discuss potential emerging novel therapeutic uses.

Metformin, a biological and synthetic overview.

Metformin is the most widely known anti-hyperglycemic, officially acquired by the USA government in 1995 and in 2001 it became the most prescribed treatment for type II diabetes. But how did it become the must-use drug for this disease in such a short period of time? it all started with traditional medicine, by using a plant known as "goat's rue" for the reduction of blood glucose levels. Its use arose in 1918 and evolved to the metformin synthesis in laboratories a couple of years later, using very rudimentary methods which involved melting and strong heating. Thus, a first synthetic route that allowed the preparation of the initial metformin derivates was established. Some of these resulted toxics, and others outperformed the metformin, reducing the blood glucose levels in such efficient way. Nevertheless, the risk and documented cases of lactic acidosis increased with metformin derivatives like buformin and phenformin. Recently, metformin has been widely studied, and it has been associated and tested in the treatment of type II diabetes, cancer, polycystic ovarian syndrome, cell differentiation to oligodendrocytes, reduction of oxidative stress in cells, weight reduction, as anti-inflammatory and even in the recent COVID-19 disease. Herein we briefly review and analyze the history, synthesis, and biological applications of metformin and its derivates.

Dipeptidyl Peptidase-4 Inhibitors, Glucagon-like Peptide-1 Receptor Agonists, and Sodium-Glucose Cotransporter-2 Inhibitors and COVID-19 Outcomes.

PURPOSE: It has been reported that dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have a role in modulation of inflammation associated with coronavirus disease 2019 (COVID-19). This study assessed the effect of these drug classes on COVID-19-related outcomes. METHODS: Using a COVID-19 linkable administrative database, we selected patients aged ≥40 years with at least 2 prescriptions of DPP-4i, GLP-1 RA, or SGLT-2i or any other antihyperglycemic drug and a diagnosis of COVID-19 from February 15, 2020, to March 15, 2021. Adjusted odds ratios (ORs) with 95% CIs were used to calculate the association between treatments and all-cause and in-hospital mortality and COVID-19-related hospitalization. A sensitivity analysis was performed by using inverse probability treatment weighting. FINDINGS: Overall, 32,853 subjects were included in the analysis. Multivariable models showed a reduction of the risk for COVID-19 outcomes for users of DPP-4i, GLP-1 RA, and SGLT-2i compared with nonusers, although statistical significance was reached only in DPP-4i users for total mortality (OR, 0.89; 95% CI, 0.82-0.97). The sensitivity analysis confirmed the main results reaching a significant reduction for hospital admission in GLP-1 RA users and in-hospital mortality in SGLT-2i users compared with nonusers. IMPLICATIONS: This study found a beneficial effect in the risk reduction of COVID-19 total mortality in DPP-4i users compared with nonusers. A positive trend was also observed in users of GLP-1 RA and SGLT-2i compared with nonusers. Randomized clinical trials are needed to confirm the effect of these drug classes as potential therapy for the treatment of COVID-19.

Glucometabolic Perturbations in Type 2 Diabetes Mellitus and Coronavirus Disease 2019: Causes, Consequences, and How to Counter Them Using Novel Antidiabetic Drugs - The CAPISCO International Expert Panel.

The growing amount of evidence suggests the existence of a bidirectional relation between coronavirus disease 2019 (COVID-19) and type 2 diabetes mellitus (T2DM), as these two conditions exacerbate each other, causing a significant healthcare and socioeconomic burden. The alterations in innate and adaptive cellular immunity, adipose tissue, alveolar and endothelial dysfunction, hypercoagulation, the propensity to an increased viral load, and chronic diabetic complications are all associated with glucometabolic perturbations of T2DM patients that predispose them to severe forms of COVID-19 and mortality. Severe acute respiratory syndrome coronavirus 2 infection negatively impacts glucose homeostasis due to its effects on insulin sensitivity and ß-cell function, further aggravating the preexisting glucometabolic perturbations in individuals with T2DM. Thus, the most effective ways are urgently needed for countering these glucometabolic disturbances occurring during acute COVID-19 illness in T2DM patients. The novel classes of antidiabetic medications (dipeptidyl peptidase 4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are considered candidate drugs for this purpose. This review article summarizes current knowledge regarding glucometabolic disturbances during acute COVID-19 illness in T2DM patients and the potential ways to tackle them using novel antidiabetic medications. Recent observational data suggest that preadmission use of GLP-1 RAs and SGLT-2is are associated with decreased patient mortality, while DPP-4is is associated with increased in-hospital mortality of T2DM patients with COVID-19. Although these results provide further evidence for the widespread use of these two classes of medications in this COVID-19 era, dedicated randomized controlled trials analyzing the effects of in-hospital use of novel antidiabetic agents in T2DM patients with COVID-19 are needed.

A clinical trial on anti-diabetic efficacy of submerged culture medium of Ceriporia lacerata mycelium.

BACKGROUND: Increased glucose level and insulin resistance are major factors in Type 2 diabetes mellitus (T2M), which is chronic and debilitating disease worldwide. Submerged culture medium of Ceriporia lacerata mycelium (CLM) is known to have glucose lowering effects and improving insulin resistance in a mouse model in our previous studies. The main purpose of this clinical trial was to evaluate the functional efficacy and safety of CLM in enrolled participants with impaired fasting blood sugar or mild T2D for 12 weeks. METHODS: A total of 72 participants with impaired fasting blood sugar or mild T2D were participated in a randomized, double-blind, placebo-controlled clinical trial. All participants were randomly assigned into the CLM group or placebo group. Fasting blood glucose (FBG), HbA1c, insulin, C-peptide, HOMA-IR, and HOMA-IR by C-peptide were used to assess the anti-diabetic efficacy of CLM for 12 weeks. RESULTS: In this study, the effectiveness of CLM on lowering the anti-diabetic indicators (C-peptide levels, insulin, and FBG) was confirmed. CLM significantly elicited anti-diabetic effects after 12 weeks of ingestion without showing any side effects in both groups of participants. After the CLM treatment, FBG levels were effectively dropped by 63.9% (ITT), while HOMA-IR level in the CLM group with FBG > 110 mg/dL showed a marked decrease by 34% up to 12 weeks. Remarkably, the effect of improving insulin resistance was significantly increased in the subgroup of participants with insulin resistance, exhibiting effective reduction at 6 weeks (42.5%) and 12 weeks (61%), without observing a recurrence or hypoglycemia. HbA1c levels were also decreased by 50% in the participants with reduced indicators (FBG, insulin, C-peptide, HOMA-IR, and HOMA-IR). Additionally, it is noteworthy that the levels of insulin and C-peptide were significantly reduced despite the CLM group with FBG > 110 mg/dL. No significant differences were detected in the other parameters (lipids, blood tests, and blood pressure) after 12 weeks. CONCLUSION: The submerged culture medium of CLM showed clinical efficacy in the improvement of FBG, insulin, C-peptide, HbAc1, and HOMA-index. The microbiome-based medium could benefit patients with T2D, FBG disorders, or pre-diabetes, which could guide a new therapeutic pathway in surging the global diabetes epidemic.

The Impact of COVID-19 Lockdown on Patients with Type 2 Diabetes Mellitus: A Brief Report.

BACKGROUND: The Italian population's habits changed dramatically during the "COVID- 19 lockdown" due to physical distancing and self-isolation. Moreover, medical consultations of patients with chronic diseases, such as type 2 diabetes (T2D), were suspended or postponed, unless urgent or semi-urgent, for several consecutive months. Thus, it is expected that the lockdown could have affected glucometabolic control in T2D. v Purpose: The aim of the study was to assess changes in glucometabolic control in a cohort of T2D patients before (T1) and after (T2) the COVID-19 lockdown (March-May 2020). METHODS: The study was approved by the Ethics Committee of the University of Bari, and all patients provided informed written consent to participate. Medical history, complete physical examination, and laboratory assessment were conducted as real-life clinical practice. Changes in clinical and laboratory variables between T1 and T2 were calculated. RESULTS: In detail, 13 patients were on metformin as monotherapy, 36 on GLP-1RA, 12 on sodiumglucose transporter 2 inhibitors (SGLT-2i), and 2 on dipeptidyl-peptidase 4 inhibitors (DPP4i). The mean age was 65.3 years (43-83). Study participants were mainly men (73%). The body weight (BW) ranged from 56 to 145 kg, and the waist circumference ranged from 88 to 146 cm. The mean HbA1c was 51.0 mmol/mol. At T2, no statistically significant changes were observed frombaseline except for BW [-1.6 (-2.60 to -0.62)] and HbA1c [-2.90 (-4.69; -1.12)]. CONCLUSION: We evaluated the effects of the COVID-19 lockdown on glucometabolic control in patients with background well-controlled T2D. We found that the lockdown had no adverse effects on metabolic profile regardless of background clinical characteristics and antihyperglycemic management. Despite limitations due to the nature of this study (sample size, retrospective observation, lack of data on lifestyle changes in our patients' everyday lives), T2D patients managed in our Diabetes Centers faced the lockdown-related restrictions without any detrimental consequence.

Pre-admission use of sodium glucose transporter-2 inhibitor (SGLT-2i) may significantly improves Covid-19 outcomes in patients with diabetes: A systematic review, meta-analysis, and meta-regression.

AIMS: This study aims to examine the effectiveness of using sodium glucose transporter-2 inhibitor (SGLT-2i) before hospital admission on Covid-19 outcomes in diabetic patients. METHODS: A literature search was conducted using specific keywords until October 24th, 2022 on 4 databases: Medline, Scopus, Cochrane Library, and ClinicalTrials.gov. All articles regarding SGLT-2i in diabetic patients with Covid-19 were included in the study. Outcomes in this study were calculated using random-effect models to generate pooled odds ratio (OR) with 95% confidence intervals (CI). RESULTS: A total of 17 studies were included in the analysis. Our meta-analysis showed that pre-admission use of SGLT-2i was associated with reduced mortality (OR 0.69; 95 %CI: 0.56 - 0.87, p = 0.001, I2 = 91 %) and severity of Covid-19 (OR 0.88; 95 %CI: 0.80 - 0.97, p = 0.008, I2 = 13 %). This benefit of SGLT-2i on Covid-19 mortality was not significantly affected by patient's factors such as age (p = 0.2335), sex (p = 0.2742), hypertension (p = 0.2165), heart failure (p = 0.1616), HbA1c levels (p = 0.4924), metformin use (p = 0.6617), duration of diabetes (p = 0.7233), and BMI (p = 0.1797). CONCLUSIONS: This study suggests that SGLT-2i as glucose lowering treatment in patients with diabetes has a positive effect on Covid-19 outcomes, therefore can be considered as an antidiabetic drug of choice, especially during the Covid-19 pandemic. Short Title: SGLT-2i in diabetes and Covid-19. REGISTRATION DETAILS: CRD42022369784.

Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms.

Caloric restriction promotes longevity in multiple animal models. Compounds modulating nutrient-sensing pathways have been suggested to reproduce part of the beneficial effect of caloric restriction on aging. However, none of the commonly studied caloric restriction mimetics actually produce a decrease in calories. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) are a class of drugs which lower glucose by promoting its elimination through urine, thus inducing a net loss of calories. This effect promotes a metabolic shift at the systemic level, fostering ketones and fatty acids utilization as glucose-alternative substrates, and is accompanied by a modulation of major nutrient-sensing pathways held to drive aging, e.g., mTOR and the inflammasome, overall resembling major features of caloric restriction. In addition, preliminary experimental data suggest that SGLT-2i might also have intrinsic activities independent of their systemic effects, such as the inhibition of cellular senescence. Consistently, evidence from both preclinical and clinical studies have also suggested a marked ability of SGLT-2i to ameliorate low-grade inflammation in humans, a relevant driver of aging commonly referred to as inflammaging. Considering also the amount of data from clinical trials, observational studies, and meta-analyses suggesting a tangible effect on age-related outcomes, such as cardiovascular diseases, heart failure, kidney disease, and all-cause mortality also in patients without diabetes, here we propose a framework where at least part of the benefit provided by SGLT-2i is mediated by their ability to blunt the drivers of aging. To support this postulate, we synthesize available data relative to the effect of this class on: 1- animal models of healthspan and lifespan; 2- selected molecular pillars of aging in preclinical models; 3- biomarkers of aging and especially inflammaging in humans; and 4- COVID-19-related outcomes. The burden of evidence might prompt the design of studies testing the potential employment of this class as anti-aging drugs.

Brassica Genus Seeds: A Review on Phytochemical Screening and Pharmacological Properties.

Traditionally, Brassica species are widely used in traditional medicine, human food, and animal feed. Recently, special attention has been dedicated to Brassica seeds as source of health-promoting phytochemicals. This review provides a summary of recent research on the Brassica seed phytochemistry, bioactivity, dietary importance, and toxicity by screening the major online scientific database sources and papers published in recent decades by Elsevier, Springer, and John Wiley. The search was conducted covering the period from January 1964 to July 2022. Phytochemically, polyphenols, glucosinolates, and their degradation products were the predominant secondary metabolites in seeds. Different extracts and their purified constituents from seeds of Brassica species have been found to possess a wide range of biological properties including antioxidant, anticancer, antimicrobial, anti-inflammatory, antidiabetic, and neuroprotective activities. These valuable functional properties of Brassica seeds are related to their richness in active compounds responsible for the prevention and treatment of various chronic diseases such as obesity, diabetes, cancer, and COVID-19. Currently, the potential properties of Brassica seeds and their components are the main focus of research, but their toxicity and health risks must also be accounted for.

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases.

Metformin can suppress gluconeogenesis and reduce blood sugar by activating adenosine monophosphate-activated protein kinase (AMPK) and inducing small heterodimer partner (SHP) expression in the liver cells. The main mechanism of metformin's action is related to its activation of the AMPK enzyme and regulation of the energy balance. AMPK is a heterothermic serine/threonine kinase made of a catalytic alpha subunit and two subunits of beta and a gamma regulator. This enzyme can measure the intracellular ratio of AMP/ATP. If this ratio is high, the amino acid threonine 172 available in its alpha chain would be activated by the phosphorylated liver kinase B1 (LKB1), leading to AMPK activation. Several studies have indicated that apart from its significant role in the reduction of blood glucose level, metformin activates the AMPK enzyme that in turn has various efficient impacts on the regulation of various processes, including controlling inflammatory conditions, altering the differentiation pathway of immune and non-immune cell pathways, and the amelioration of various cancers, liver diseases, inflammatory bowel disease (IBD), kidney diseases, neurological disorders, etc. Metformin's activation of AMPK enables it to control inflammatory conditions, improve oxidative status, regulate the differentiation pathways of various cells, change the pathological process in various diseases, and finally have positive therapeutic effects on them. Due to the activation of AMPK and its role in regulating several subcellular signalling pathways, metformin can be effective in altering the cells' proliferation and differentiation pathways and eventually in the prevention and treatment of certain diseases.

Novel hit of DPP-4Is as promising antihyperglycemic agents with dual antioxidant/anti-inflammatory effects for type 2 diabetes with/without COVID-19.

DPP-4Is are well recognized therapy for type 2 diabetes. In spite of sharing a common mode of action, the chemical diversity among members of DPP-4Is raised the question whether structural differences may result in distinguished activities. DPP-4Is were recently explored as drug repurposing means for treatment of SARS-CoV-2 due to the urgent need for small molecule drugs for controlling infections. The use of DPP-4Is was not correlated with adverse COVID-19-related consequences among patients with type 2 diabetes. Inspired by these reasons and the importance of pyrimidinone ring as DPP-4I with both antioxidant and anti-inflammatory activities, we succeeded to prepare some novel pyrimidinone and thio-pyrimidinone derivatives, which were then screened for their antidiabetic activity and DPP-4 inhibition. In addition, their anti-inflammatory effect on LPS-stimulated RAW 264.7 cells were evaluated. Furthermore, their antioxidant activities were also tested.

Cucumis melo var. momordica as a Potent Antidiabetic, Antioxidant and Possible Anticovid Alternative: Investigation through Experimental and Computational Methods.

Diabetes mellitus is a typical life threatening of disease, which generate due to the dysfunction of ß cells of pancreas. In 2014, WHO stated that 422 million people were infected with DM. The current pattern of management of diabetes included synthetic or plant based oral hypoglycemic drugs and insulin but drug resentence is become a very big issues in antidiabetic therapy. Thus, it's very earnest to discover now medication for this disease. Now the days, it is well acknowledged that diabetic patients are more prone towards covid and related complications. Thus, medical practitioners reformed the methodology of prescribing medication for covid infected antidiabetic therapy and encouraging the medication contains dual pharmacological properties. It is also well know that polyphenols specifically hold a significant role in oxidative stress and reduced the severity of many inflammatory diseases. Cucumis melo has rich history as ethano-pharmacological use in Indian subcontinent. The fruit and seed are well-known for the treatment of various diseases due to the presence of phenolics. Therefore, in this study, the combined mixture of flower and seeds were used for the extraction of polyphenolic rich extract and tested for antidiabetic activity through the antioxidant and in vivo experiments. The antioxidant potential measurement exhibited that the selected plant extract has the significant competence to down-regulate oxidative stress (DPPH scavenging IC50 at 60.7±1.05 µg/mL, ABTS IC50 at 62.15±0.50 µg/mL). Furthermore, the major polyphenolic phyto-compounds derived from the Cucumis melo were used for in silico anticovid activity, docking, and complementarity studies. The anticovid activity prognosis reflected that selected phyto-compounds amentoflavone and vanillic acid have optimal possibility to interact with 3C-like protease and through this moderate anticovid activity can be exhibit. The docking experiments established that the selected compounds have propensity to interact with protein tyrosine phosphatase 1B, 11ß-Hydroxysteroid dehydrogenase, superoxide dismutase, glutathione peroxidase, and catalase ß-glucuronidase receptor. In vivo experiments showed that 500 mg/kg, Cucumis melo extract ominously amplified body weight, plasma insulin, high-density lipoprotein levels, and biochemical markers. Furthermore, extract significantly downregulate the blood glucose, total cholesterol, triglycerides, low-density lipoprotein, and very low-density lipoprotein.

Metformin: Is it a drug for all reasons and diseases?

Metformin was first used to treat type 2 diabetes in the late 1950s and in 2022 remains the first-choice drug used daily by approximately 150 million people. An accumulation of positive pre-clinical and clinical data has stimulated interest in re-purposing metformin to treat a variety of diseases including COVID-19. In polycystic ovary syndrome metformin improves insulin sensitivity. In type 1 diabetes metformin may help reduce the insulin dose. Meta-analysis and data from pre-clinical and clinical studies link metformin to a reduction in the incidence of cancer. Clinical trials, including MILES (Metformin In Longevity Study), and TAME (Targeting Aging with Metformin), have been designed to determine if metformin can offset aging and extend lifespan. Pre-clinical and clinical data suggest that metformin, via suppression of pro-inflammatory pathways, protection of mitochondria and vascular function, and direct actions on neuronal stem cells, may protect against neurodegenerative diseases. Metformin has also been studied for its anti-bacterial, -viral, -malaria efficacy. Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an anti-hyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct anti-viral actions. Clarification is also sought as to whether data from ex vivo studies based on the use of high concentrations of metformin can be translated into clinical benefits, or whether they reflect a 'Paracelsus' effect. The environmental impact of metformin, a drug with no known metabolites, is another emerging issue that has been linked to endocrine disruption in fish, and extensive use in T2D has also raised concerns over effects on human reproduction. The objectives for this review are to: 1) evaluate the putative mechanism(s) of action of metformin; 2) analyze the controversial evidence for metformin's effectiveness in the treatment of diseases other than type 2 diabetes; 3) assess the reproducibility of the data, and finally 4) reach an informed conclusion as to whether metformin is a drug for all diseases and reasons. We conclude that the primary clinical benefits of metformin result from its insulin-sensitizing and antihyperglycaemic effects that secondarily contribute to a reduced risk of a number of diseases and thereby enhancing healthspan. However, benefits like improving vascular endothelial function that are independent of effects on glucose homeostasis add to metformin's therapeutic actions.

Preadmission use of antidiabetic medications and mortality among patients with COVID-19 having type 2 diabetes: A meta-analysis.

BACKGROUND: Diabetes is an independent predictor of poor outcomes in patients with COVID-19. We compared the effects of the preadmission use of antidiabetic medications on the in-hospital mortality of patients with COVID-19 having type 2 diabetes. METHODS: A systematic search of PubMed, EMBASE, Scopus and Web of Science databases was performed to include studies (except case reports and review articles) published until November 30, 2021. We excluded papers regarding in-hospital use of antidiabetic medications. We used a random-effects meta-analysis to calculate the pooled OR (95% CI) and performed a sensitivity analysis to confirm the robustness of the meta-analyses. MAIN FINDINGS: We included 61 studies (3,061,584 individuals), which were rated as having low risk of bias. The OR (95% CI) indicated some medications protective against COVID-related death, including metformin [0.54 (0.47-0.62), I2 86%], glucagon-like peptide-1 receptor agonist (GLP-1RA) [0.51 (0.37-0.69), I2 85%], and sodium-glucose transporter-2 inhibitor (SGLT-2i) [0.60 (0.40-0.88), I2 91%]. Dipeptidyl peptidase-4 inhibitor (DPP-4i) [1.23 (1.07-1.42), I2 82%] and insulin [1.70 (1.33-2.19), I2 97%] users were more likely to die during hospitalization. Sulfonylurea, thiazolidinedione, and alpha-glucosidase inhibitor were mortality neutral [0.92 (95% CI 0.83-1.01, I2 44%), 0.90 (95% CI 0.71-1.14, I2 46%), and 0.61 (95% CI 0.26-1.45, I2 77%), respectively]. The sensitivity analysis indicated that our findings were robust. CONCLUSIONS: Metformin, GLP-1RA, and SGLT-2i were associated with lower mortality rate in patients with COVID-19 having type 2 diabetes. DPP-4i and insulin were linked to increased mortality. Sulfonylurea, thiazolidinedione, and alpha-glucosidase inhibitors were mortality neutral. These findings can have a large impact on the clinicians' decisions amid the COVID-19 pandemic.

Potential role of Drug Repositioning Strategy (DRS) for management of tauopathy.

Tauopathy is a term that has been used to represent a pathological condition in which hyperphosphorylated tau protein aggregates in neurons and glia which results in neurodegeneration, synapse loss and dysfunction and cognitive impairments. Recently, drug repositioning strategy (DRS) becomes a promising field and an alternative approach to advancing new treatments from actually developed and FDA approved drugs for an indication other than the indication it was originally intended for. This paradigm provides an advantage because the safety of the candidate compound has already been established, which abolishes the need for further preclinical safety testing and thus substantially reduces the time and cost involved in progressing of clinical trials. In the present review, we focused on correlation between tauopathy and common diseases as type 2 diabetes mellitus and the global virus COVID-19 and how tau pathology can aggravate development of these diseases in addition to how these diseases can be a risk factor for development of tauopathy. Moreover, correlation between COVID-19 and type 2 diabetes mellitus was also discussed. Therefore, repositioning of a drug in the daily clinical practice of patients to manage or prevent two or more diseases at the same time with lower side effects and drug-drug interactions is a promising idea. This review concluded the results of pre-clinical and clinical studies applied on antidiabetics, COVID-19 medications, antihypertensives, antidepressants and cholesterol lowering drugs for possible drug repositioning for management of tauopathy.

Possible Involvement of Adipose Tissue in Patients With Older Age, Obesity, and Diabetes With SARS-CoV-2 Infection (COVID-19) via GRP78 (BIP/HSPA5): Significance of Hyperinsulinemia Management in COVID-19.

Aging, obesity, and diabetes are major risk factors for the severe progression and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019 [COVID-19]), but the underlying mechanism is not yet fully understood. In this study, we found that the SARS-CoV-2 spike protein physically interacts with cell surface GRP78, which promotes the binding to and accumulation in ACE2-expressing cells. GRP78 was highly expressed in adipose tissue and increased in humans and mice with older age, obesity, and diabetes. The overexpression of GRP78 was attributed to hyperinsulinemia in adipocytes, which was in part mediated by the stress-responsive transcription factor XBP-1s. Management of hyperinsulinemia by pharmacological approaches, including metformin, sodium-glucose cotransporter 2 inhibitor, or ß3-adrenergic receptor agonist, decreased GRP78 gene expression in adipose tissue. Environmental interventions, including exercise, calorie restriction, fasting, or cold exposure, reduced the gene expression of GRP78 in adipose tissue. This study provides scientific evidence for the role of GRP78 as a binding partner of the SARS-CoV-2 spike protein and ACE2, which might be related to the severe progression and outcome of COVID-19 in patients with older age, obesity, and diabetes. The management of hyperinsulinemia and the related GRP78 expression could be a therapeutic or preventative target.

Metformin to decrease COVID-19 severity and mortality: Molecular mechanisms and therapeutic potential.

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has become a serious challenge for medicine and science. Analysis of the molecular mechanisms associated with the clinical manifestations and severity of COVID-19 has identified several key points of immune dysregulation observed in SARS-CoV-2 infection. For diabetic patients, factors including higher binding affinity and virus penetration, decreased virus clearance and decreased T cell function, increased susceptibility to hyperinflammation, and cytokine storm may make these patients susceptible to a more severe course of COVID-19 disease. Metabolic changes induced by diabetes, especially hyperglycemia, can directly affect the immunometabolism of lymphocytes in part by affecting the activity of the mTOR protein kinase signaling pathway. High mTOR activity can enhance the progression of diabetes due to the activation of effector proinflammatory subpopulations of lymphocytes and, conversely, low activity promotes the differentiation of T-regulatory cells. Interestingly, metformin, an extensively used antidiabetic drug, inhibits mTOR by affecting the activity of AMPK. Therefore, activation of AMPK and/or inhibition of the mTOR-mediated signaling pathway may be an important new target for drug therapy in COVID-19 cases mostly by reducing the level of pro-inflammatory signaling and cytokine storm. These suggestions have been partially confirmed by several retrospective analyzes of patients with diabetes mellitus hospitalized for severe COVID-19.