Beneficial Effects Of Metformin Research Articles

Metformin enhances endogenous neural stem cells proliferation, neuronal differentiation, and inhibits ferroptosis through activating AMPK pathway after spinal cord injury

BackgroundInadequate nerve regeneration and an inhibitory local microenvironment are major obstacles to the repair of spinal cord injury (SCI). The activation and differentiation fate regulation of endogenous neural stem cells (NSCs) represent one of the most promising repair approaches. Metformin has been extensively studied for its antioxidative, anti-inflammatory, anti-aging, and autophagy-regulating properties in central nervous system diseases. However, the effects of metformin on endogenous NSCs remains to be elucidated.MethodsThe proliferation and differentiation abilities of NSCs were evaluated using CCK-8 assay, EdU/Ki67 staining and immunofluorescence staining. Changes in the expression of key proteins related to ferroptosis in NSCs were detected using Western Blot and immunofluorescence staining. The levels of reactive oxygen species, glutathione and tissue iron were measured using corresponding assay kits. Changes in mitochondrial morphology and membrane potential were observed using transmission electron microscopy and JC-1 fluorescence probe. Locomotor function recovery after SCI in rats was assessed through BBB score, LSS score, CatWalk gait analysis, and electrophysiological testing. The expression of the AMPK pathway was examined using Western Blot.ResultsMetformin promoted the proliferation and neuronal differentiation of NSCs both in vitro and in vivo. Furthermore, a ferroptosis model of NSCs using erastin treatment was established in vitro, and metformin treatment could reverse the changes in the expression of key ferroptosis-related proteins, increase glutathione synthesis, reduce reactive oxygen species production and improve mitochondrial membrane potential and morphology. Moreover, metformin administration improved locomotor function recovery and histological outcomes following SCI in rats. Notably, all the above beneficial effects of metformin were completely abolished upon addition of compound C, a specific inhibitor of AMP-activated protein kinase (AMPK).ConclusionMetformin, driven by canonical AMPK-dependent regulation, promotes proliferation and neuronal differentiation of endogenous NSCs while inhibiting ferroptosis, thereby facilitating recovery of locomotor function following SCI. Our study further elucidates the protective mechanism of metformin in SCI, providing new mechanistic insights for its candidacy as a therapeutic agent for SCI.

Beneficial effect of metformin on tolerance to analgesic effects of sodium salicylate in male rats.

Tolerance to the analgesic effects of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) is a major concern for relieving pain. Thus, it is highly valuable to find new pharmacological strategies for prolonged therapeutic procedures. Biguanide-type drugs such as metformin (MET) are effective for neuroprotection and can be beneficial for addressing opioid tolerance in the treatment of chronic pain. It has been proposed that analgesic tolerance to NSAIDs is mediated by the endogenous opioid system. According to the cross-tolerance between NSAIDs, especially sodium salicylate (SS), and opiates, especially morphine, the objective of this study was to investigate whether MET administration can reduce tolerance to the anti-nociceptive effects of SS. Fifty-six male Wistar rats were used in this research (weight 200-250 g). For induction of tolerance, SS (300 mg/kg) was injected intraperitoneally for 7 days. During the examination period, animals received MET at doses of 50, 75, or 100 mg/kg for 7 days to evaluate the development of tolerance to the analgesic effect of SS. The hot plate test was used to evaluate the drugs' anti-nociceptive properties. Salicylate injection significantly increased hot plate latency as compared to the control group, but the total analgesic effect of co-treatment with SS + Met50 was stronger than the SS group. Furthermore, the effect of this combination undergoes less analgesic tolerance over time. It can be concluded that MET can reduce the analgesic tolerance that is induced by repeated intraperitoneal injections of SS in Wister rats.

Prediabetes Increases the Risk of Frailty in Prefrail Older Adults With Hypertension: Beneficial Effects of Metformin.

Prediabetes has garnered increasing attention due to its association with cardiovascular conditions, especially hypertension, which heightens the risk of prefrailty and frailty among older individuals. We screened elders with prefrail hypertension from March 2021 to January 2023. We assessed the correlation linking cognitive dysfunction (Montreal Cognitive Assessment score), insulin resistance (triglyceride-to-glucose index), and physical impairment (5-meter gait speed). Then, we measured the risk of developing frailty after a 1-year follow-up period, adjusting the outcome using multivariable Cox regression analysis. We also investigated the impact of administering 500 mg of metformin once daily to a subset of frail subjects for an additional 6 months. We assessed the relationship between the triglyceride-to-glucose index and the Montreal Cognitive Assessment score, observing a significant correlation (r, 0.880; P<0.0001). Similarly, we analyzed the association between the triglyceride-to-glucose index and 5-meter gait speed, uncovering a significant link between insulin resistance and physical impairment (r, 0.809; P<0.0001). Prediabetes was found to significantly (P<0.0001) elevate the risk of frailty development compared with individuals without prediabetes by the end of the 1-year follow-up, a finding confirmed via multivariable analysis with Cox regression. Furthermore, among the subgroup of subjects who developed frailty, those who received metformin exhibited a significant decrease in frailty levels (P<0.0001). Insulin resistance and prediabetes play substantial roles in the development of cognitive and physical impairments, highlighting their importance in managing hypertension, even before the onset of frank diabetes. Metformin, a well-established drug for the treatment of diabetes, has shown favorable effects in mitigating frailty.

Biochemical bases of the organoprotective properties of metformin

Metformin is recognized as the "gold standard" for the treatment of type 2 diabetes mellitus (DM2). Its hypoglycemic properties are realized by reducing insulin resistance, contributing to the utilization of glucose in liver cells, muscles and adipose tissue; suppression of gluconeogenesis in the liver. Due to the wide range of biochemical targets of its pharmacological action, the scientific community actively discusses the use of metformin as an organoprotective drug. Now, the beneficial effect of metformin on the course of neuropathy, diseases of the cardiovascular system, normalization of the composition and metabolic activity of the intestinal microbiota, the course of metabolically associated fatty liver disease has already been proven, the nephroprotective effect has also been proven, and the study of the anti-oncogenic properties of metformin continues. The number of publications devoted to research on the positive effects of metformin on various organs and systems is actively increasing, and data on the identification of new effects are regularly published. The purpose of this literature review is to analyze the pleiotropic effects of metformin at the level of biochemical interactions for a more detailed understanding of the principles of their implementation.

Is Metformin Use Associated with a More Favorable COVID-19 Course in People with Diabetes?

Background: Diabetes Mellitus (DM) has been associated with a higher Coronavirus disease-19 (COVID-19) mortality, both in hospitalized patients and in the general population. A possible beneficial effect of metformin on the prognosis of COVID-19 has been reported in some observational studies, whereas other studies disagree. Methods: To investigate the possible effect of metformin on COVID-19 in-hospital mortality, we performed a retrospective study that included all SARS-CoV-2-positive patients with DM who were admitted to two Italian hospitals. In order to adjust for possible confounders accounting for the observed reduction of mortality in metformin users, we adopted the COVID-19 Mortality Risk Score (COVID-19 MRS) as a covariate. Results: Out of the 524 included patients, 33.4% died. A binomial logistic regression showed that metformin use was associated with a significant reduction in case fatality (OR 0.67 [0.45-0.98], p = 0.039), with no significant effect on the need for ventilation (OR 0.75 [0.5-1.11], p = 0.146). After adjusting for COVID-19 MRS, metformin did not retain a significant association with in-hospital mortality [OR 0.795 (0.495-1.277), p = 0.342]. Conclusions: A beneficial effect of metformin on COVID-19 was not proven after adjusting for confounding factors. The use of validated tools to stratify the risk for COVID-19 severe disease and death, such as COVID-19 MRS, may be useful to better explore the potential association of medications and comorbidities with COVID-19 prognosis.

Beneficial Effect of Metformin, Quercetin, and Resveratrol Combination on High Glucose-Induced lipogenesis in HepG2 Cells

Objectives: It has been reported that Metformin (MET), Resveratrol (RSV), and Quercetin (QRS) possess anti-lipogenic effects. This study aimed to investigate the combined effects of these compounds on lipid accumulation in HepG2 cells treated with high glucose (HG).&#x0D; Methods: HepG2 cells were treated with HG (33 mM), and different concentrations of MET, QRS, and RSV. The cytotoxic effects of these compounds were determined by an MTT assay. Changes in total lipid content and triglyceride (TG) levels were measured using Oil Red O staining and a triglyceride assay kit, respectively. The expression of fatty acid synthetase (FAS) and sterol regulatory element-binding protein 1c (SREBP1c) was evaluated by quantitative real-time PCR.&#x0D; Results: MET at doses 1, 2, and 5 mM, QRS at doses 5, 10, and 20 µM, and RSV at doses 25 and 50 µM could decrease total lipid content and triglyceride levels in HepG2 cells. The EC50 (half maximal effective concentration) from Oil red O staining results were MET: 1.786 mM, QRS: 8.132 μM, and RSV: 10.9 μM. The combination of MET (mM), QRS (µM), and RSV (µM) at ratios of (2:20:50), (1:10:25), and (0.5:5:10), could reduce lipogenesis greater than that observed with each of the individual compounds of MET, QRS, or RSV or the double combinations of MET+QRS or MET+RSV. In addition, combined treatment of MET (0.5mM), QRS (5 µM), and RSV (10 µM) was able to decrease SREBP-1c and FAS genes expression in HG-treated cells.&#x0D; Conclusion: The combination of MET, QRS, and RSV could inhibit lipid accumulation in HepG2 cells by reducing total lipid content, triglyceride levels, and the expression of the genes involved in lipogenesis.

Metformin Reduces the Progression of Atherogenesis by Regulating the Sestrin2-mTOR Pathway in Obese and Diabetic Rats.

In previous research, we found that Sestrin2 has a strong association with plasma atherogenicity and combats the progression of atherogenesis by regulating the AMPK-mTOR pathway. Metformin, an activator of AMPK, is widely used as a first-line therapy for diabetes, but its role in preventing atherosclerosis and cardiac outcomes is unclear. Hence, we aimed to assess the effect of metformin on preventing atherosclerosis and its regulatory role in the Sestrin2-AMPK -mTOR pathway in obese/diabetic rats. Animals were fed a high-fat diet to induce obesity, administered streptozotocin to induce diabetes, and then treated with metformin (150 mg/kg body weight) for 14 weeks. Aorta and heart tissues were analyzed for Sestrin2 status by western blotting and immunohistochemistry, AMPK and mTOR activities were investigated using western blotting, and atherogenicity-related events were evaluated using reverse transcription quantitative polymerase chain reaction and histology. Obese and diabetic rats showed significant decrease in Sestrin2 levels and AMPK activity, accompanied by increased mTOR activity in the heart and aorta tissues. Metformin treatment significantly restored Sestrin2 and AMPK levels, reduced mTOR activity, and restored the altered expression of inflammatory markers and adhesion molecules in obese and diabetic rats to normal levels. A histological analysis of samples from obese and diabetic rats showed atherosclerotic lesions both in aorta and heart tissues. The metformin-treated rats showed a decrease in atherosclerotic lesions, cardiac hypertrophy, and cardiomyocyte degeneration. This study presents further insights into the beneficial effects of metformin and its protective role against atherosclerosis through regulation of the Sestrin2-AMPK-mTOR pathway.

Beneficial effects of metformin on mice female fertility after a high-fat diet intake

Female fertility is highly dependent on energy balance. High fat diet (HFD) intake entails a risk of infertility and ovulatory disorders. Considering the increase in the prevalence of overweight and obesity over the last decades, it is crucial to understand the mechanisms involved in overweight-associated infertility. In this study, we evaluated the reproductive performance of female mice fed with a HFD and the effects of metformin administration on ovarian function in these mice. We hypothesized that one of the mechanisms involved in subfertility due to a HFD intake is the alteration of ovarian blood vessel formation. We found that mice fed with HFD had altered estrous cycles and steroidogenesis, increased ovarian fibrosis, fewer pups per litter and require more time to achieve pregnancy. HFD-fed mice also presented dysregulated ovarian angiogenesis and an increase in nuclear DNA damage in ovarian cells. Ovulation rates were lower in these animals, as evidenced both in natural mating and after ovulation induction with gonadotropins. Metformin ameliorated ovarian angiogenesis, improved steroidogenesis, fibrosis, and ovulation, decreased the time to pregnancy and increased litter sizes in HFD-fed mice. We conclude that ovarian angiogenesis is one of the mechanisms detrimentally affected by HFD intake. Since metformin could improve ovarian microvasculature, it may be an interesting strategy to study in women to shed light on new targets for patients with metabolic disturbances.

228-LB: Metformin Alleviates Aging-Associated Metabolic Disorders through Intestinal AMPK-Mediated Gut Microbiome Alteration

The biguanide drug metformin combats age-related disorders and improves health span and is currently the first FDA approved drug to be tested for its age-targeting effects in the large clinical trial. However, the underlying molecular mechanisms remain unclear. AMPK is a key nutrient sensor for maintaining cellular energy status and a known therapeutic target of metformin to treat T2D. Despite current understandings of its well-established roles in regulating glucose metabolism in various tissues, the functions of AMPK in the intestine remain largely unexplored. Our previous study uncovered a novel link between intestinal AMPK activation and energy metabolism through modulating the anti-microbial peptide (AMP)-controlled gut microbiota. We therefore ask whether intestinal AMPK also mediates metformin effects on aging-associated metabolic improvement. In this study, we showed that AMPKα1 deficiency in the intestine resulted in weight gain, impaired glucose tolerance and insulin resistance in aged mice. Interestingly, metformin administration ameliorated these aging-associated metabolic disorders in aged wild type but not intestinal AMPK α1 KO mice, which indicated that the beneficial effects of metformin were dependent on the intestinal AMPKα1 in aging animals. Moreover, we found that metformin treatment significantly altered the abundance of several gut bacterial genera in aged-AMPKα1fl/fl but not intestinal AMPK α1 KO mice. Mechanistically, we identified several key anti-microbial peptides were upregulated by metformin treatment in an intestinal AMPK-dependent manner in aged mice. In summary, our findings provide a new mechanistic underpinning by which intestinal AMPK regulates aging metabolism, which may shed light on not only the ongoing large clinical trials of metformin in aging patients, but also general drug discoveries utilizing enteral drug administration to treat aging-associated metabolic diseases. Disclosure E. Zhang: None. W. Huang: None.

Metformin for Overweight and Obese Children With Bipolar Spectrum Disorders Treated With Second-Generation Antipsychotics (MOBILITY): Protocol and Methodological Considerations for a Large Pragmatic Randomized Clinical Trial

Youth with bipolar spectrum disorders may experience improved mood stability when treated with second generation antipsychotics (SGAs); however, SGAs are associated with unhealthy weight gain and adverse metabolic effects. Metformin may mitigate this weight gain but is rarely prescribed by community mental health practitioners. Its long-term efficacy, safety, and acceptability in usual care, and factors that might moderate these effects, are unknown. The Metformin for Overweight and Obese Children and Adolescents with Bipolar Spectrum Disorders Treated with Second Generation Antipsychotics (MOBILITY) trial aims to fill these gaps. We present the design and analytic plan of this multi-site, open-label, randomized trial. Patients will be randomized to either metformin plus brief healthy diet and exercise education (MET+LIFE) or to LIFE alone. Up to 1637 patients will be followed for up to 2 years at 64 community and academic mental health treatment facilities. Patients may switch between treatment arms during follow-up. Pragmatic trials place few burdens and constraints on participating patients, families, and clinicians. This flexibility will allow MOBILITY to obtain long-term follow-up in a large, diverse sample, but produces analytic challenges. MOBILITY's flexible design has the potential to generate several novel methodological issues that we address. Some patients randomized to LIFE will fail to lose weight, and therefore metformin initiation contrary to the randomization may result from weight gain. Adherence to medications, SGAs, and lifestyle recommendations as well as satiety are potential time-varying mediators, moderators, or confounders of the effect of metformin. Adherence to metformin and SGAs may be positively correlated; therefore, a beneficial effect of metformin on weight could be obscured by the known SGA adverse effect on body weight. However, such correlation could facilitate causal inference by providing indirect information about unknown metformin adherence among patients who did not receive it. A perceived protective effect of metformin could potentially lead to risk compensation, with poorer diet and activity among those receiving metformin. We discuss limitations of traditional statistical approaches and summarize an advanced methodology ("Targeted Learning") that addresses some of these limitations. Metformin for Overweight & OBese ChILdren and Adolescents With BDS Treated With SGAs (MOBILITY); https://clinicaltrials.gov/; NCT02515773.

A Beneficial Effect of Metformin in Improving Survival Among Obese and Diabetic Patients Affected with COVID-19: Findings of A Meta-Analysis

A Beneficial Effect of Metformin in Improving Survival Among Obese and Diabetic Patients Affected with COVID-19: Findings of A Meta-Analysis

Metformin attenuates symptoms of osteoarthritis: role of genetic diversity of Bcl2 and CXCL16 in OA

ObjectiveThis study aimed to evaluate the effectiveness of metformin versus placebo in overweight patients with knee osteoarthritis (OA). In addition, to assess the effects of inflammatory mediators and apoptotic proteins in the pathogenesis of OA, the genetic polymorphisms of two genes, one related to apoptosis (rs2279115 of Bcl-2) and the other related to inflammation (rs2277680 of CXCL-16), were investigated.MethodsIn this double-blind placebo-controlled clinical trial, patients were randomly divided to two groups, one group receiving metformin (n = 44) and the other one receiving an identical inert placebo (n = 44) for 4 consecutive months (starting dose 0.5 g/day for the first week, increase to 1 g/day for the second week, and further increase to 1.5 g/day for the remaining period). Another group of healthy individuals (n = 92) with no history and diagnosis of OA were included in this study in order to evaluate the role of genetics in OA. The outcome of treatment regimen was evaluated using the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. The frequency of variants of rs2277680 (A181V) and rs2279115 (938C>A) were determined in extracted DNAs using PCR-RFLP method.ResultsOur results indicated an increase in scores of pain (P ≤ 0.0001), activity of daily living (ADL) (P ≤ 0.0001), sport and recreation (Sport/Rec) (P ≤ 0.0001), and quality of life (QOL) (P = 0.003) and total scores of the KOOS questionnaire in the metformin group compared to the placebo group. Susceptibility to OA was associated with age, gender, family history, CC genotype of 938C>A (Pa = 0.001; OR = 5.2; 95% CI = 2.0–13.7), and GG+GA genotypes of A181V (Pa = 0.04; OR = 2.1; 95% CI = 1.1–10.5). The C allele of 938C>A (Pa = 0.04; OR = 2.2; 95% CI = 1.1–9.8) and G allele of A181V (Pa = 0.02; OR = 2.2; 95% CI = 1.1–4.8) were also associated with OA.ConclusionOur findings support the possible beneficial effects of metformin on improving pain, ADL, Sport/Rec, and QOL in OA patients. Our findings support the association between the CC genotype of Bcl-2 and GG+GA genotypes of CXCL-16 and OA.

Anti-Obesity Effects of Metformin: A Scoping Review Evaluating the Feasibility of Brown Adipose Tissue as a Therapeutic Target.

Brown adipose tissue (BAT) is increasingly recognized as the major therapeutic target to promote energy expenditure and ameliorate diverse metabolic complications. There is a general interest in understanding the pleiotropic effects of metformin against metabolic complications. Major electronic databases and search engines such as PubMed/MEDLINE, Google Scholar, and the Cochrane library were used to retrieve and critically discuss evidence reporting on the impact of metformin on regulating BAT thermogenic activity to ameliorate complications linked with obesity. The summarized evidence suggests that metformin can reduce body weight, enhance insulin sensitivity, and improve glucose metabolism by promoting BAT thermogenic activity in preclinical models of obesity. Notably, this anti-diabetic agent can affect the expression of major thermogenic transcriptional factors such as uncoupling protein 1 (UCP1), nuclear respiratory factor 1 (NRF1), and peroxisome-proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) to improve BAT mitochondrial function and promote energy expenditure. Interestingly, vital molecular markers involved in glucose metabolism and energy regulation such as AMP-activated protein kinase (AMPK) and fibroblast growth factor 21 (FGF21) are similarly upregulated by metformin treatment in preclinical models of obesity. The current review also discusses the clinical relevance of BAT and thermogenesis as therapeutic targets. This review explored critical components including effective dosage and appropriate intervention period, consistent with the beneficial effects of metformin against obesity-associated complications.

Impact of Metformin on Periodontal and Peri-Implant Soft and Hard Tissue.

Periodontal and peri-implant soft and hard tissue in diabetic patients have always been a topic of interest for researchers and clinicians alike. Among which, a subtopic that has attracted more attention is the beneficial effect of metformin (MF) on periodontal and peri-implant soft and hard tissue. This review aimed to assess the impact of MF on the periodontal and peri-implant soft- and hard-tissue healing among diabetic patients. Research was conducted using the keywords 'metformin', 'diabetes', 'periodontitis', 'implant', and 'peri-implantitis' via the Medline (PubMed) and Google Scholar databases. Selected articles were reviewed. A total of 21 articles, discussing the impact on periodontal health (six animal studies, seven clinical studies, and three systematic reviews) and five studies on peri-implant health (four animal studies and one clinical study) were included. All have reported a positive impact of MF on decreasing the inflammatory response, oxidative stress, and ultimate bone loss. Similarly, human studies reported a positive effect of MF on clinical and radiographic parameters compared with controls. Despite systematic reviews reporting heterogeneity among the included studies, MF has shown a positive impact on periodontal health. In animal, clinical studies, and systematic reviews, MF showed a protective impact on periodontal and peri-implant health.

Influence of metformin on age-related macular degeneration

Metformin is the most commonly prescribed antihyperglycemic drug as first-line therapy in type II diabetic patients. In recent years, evidence is increasing that metformin has beneficial effects beyond its classical antihyperglycemic way of action. Those effects include anti-inflammation, anti-oxidation, anti-aging, anti-angiogenesis, anti-neoplasia, anti-apoptosis, and neuroprotection. The complex pathophysiology of age-related macular degeneration (AMD) includes age-related changes in the retinal pigment epithelium (RPE) and Bruch’s membrane. An inflammatory and oxidative damage component has also been described. The dry form of late AMD is especially characterized by degeneration of the RPE, Bruch’s membrane, the choriocapillaris and finally, loss of the photoreceptors (geographic atrophy), and the wet form of late AMD is characterized by pathological neovascularization. An increasing number of reports about the beneficial effects of metformin on AMD have been published in the last few years. Several effects of metformin could be linked to the AMPK pathway. A first prospective trial investigating the effect of metformin on dry AMD is ongoing with estimated results by the end of 2024. In this review, the current knowledge about the association between metformin and AMD is summarized. Keywords: Metformin, age-related macular degeneration retina, insulin, diabetes, aging, drug therapy, AMPK pathway

Abstract 10414: Sesn2/AMPK Signaling Medicates Metformin's Pharmacological Action on Cardiac Mitochondrial Functional Integrity in Response to Ischemic Insults

Introduction: Metformin activates AMP-activated protein kinase (AMPK) to limit cardiac damage caused by ischemia and reperfusion (I/R). We found that a stress inducible protein Sesn2 is associated with AMPK to maintain mitochondrial oxidative phosphorylation (OXPHOS) during I/R. But the role of Sesn2/AMPK complex in the beneficial effects of metformin on ischemic insults remain unknown. Hypothesis: Metformin modulates Sesn2/AMPK signaling cascade to maintain mitochondrial integrity and respiration functions during I/R stress. Methods: Cardiomyocyte specific Sesn2 knock out (cSesn2 -/- ) and wildtype littermates (Sesn2 f/f ) C57BL/6J mice were subjected to in vivo regional ischemia of 45 min followed by injection of metformin (2 mM, i.v.) 5 min before 24 hr of reperfusion. Mitochondrial functions were determined by a Seahorse XF24 Analyzer. The sarcomere shortening and calcium transients of cardiomyocytes were measured with IonOptix Calcium and Contractility System. Results: Echocardiography data showed that I/R versus sham operations significantly reduced ejection fraction (EF) and fractional shortening (FS) in both Sesn2 f/f and cSesn2 -/- mice. Metformin treatment improved cardiac function under I/R and reduced myocardial infarct size by I/R in Sesn2 f/f but not cSesn2 -/- mice. Immunoblotting data showed metformin activated AMPK signaling and augmented mitochondrial OXPHOS Complex II levels in Sesn2 f/f but not cSesn2 -/- hearts under I/R stress conditions. Transmission electronic microscopy with immuno-gold labeling showed that Sesn2 is primarily located in the mitochondrial membrane and metformin treatment stabilized mitochondrial Sesn2 in Sesn2 f/f versus cSesn2 -/- hearts under I/R conditions. IonOptix measurements showed that metformin rescues contractile dysfunctions and impaired calcium flux by I/R in Sens2 f/f but not cSesn2 -/- cardiomyocytes. In addition, metformin treatment reduced reactive oxygen species (ROS) levels and improved mitochondrial respiration rate under I/R conditions in Sesn2 f/f but not cSesn2 -/- hearts. Conclusions: Administration of metformin benefits cardiac functions under I/R stress. Sesn2/AMPK signaling mediates mitochondrial functional integrity during I/R with metformin treatment.

A brief insight into the etiology, genetics, and immunology of polycystic ovarian syndrome (PCOS).

Polycystic ovarian syndrome (PCOS) is a prevailing endocrine and metabolic disorder occurring in about 6-20% of females in reproductive age. Most symptoms of PCOS arise early during puberty. Since PCOS involves a combination of signs and symptoms, thus it is considered as a heterogeneous disorderliness. The most accepted diagnostic criteria is Rotterdam criteria which involves two of the latter three features: (a) hyperandrogenism, (b) oligo- or an-ovulation, and (c) polycystic ovaries. The persistent hormonal imbalance leads to multiple small antral follicles formation and irregular menstrual cycle, ultimately causing infertility among females. Insulin resistance, cardiovascular diseases, abdominal obesity, psychological disorders, infertility, and cancer are also related to PCOS. These pathophysiologies associated with PCOS are interrelated with each other. Hyperandrogenism causes insulin resistance and hyperglycemia, leading to ROS formation, oxidative stress, and abdominal adiposity. In consequence, inflammation, ROS production, insulin resistance, and hyperandrogenemia also increase. Elevation of AGEs in the body either produced endogenously or consumed from diet exaggerates PCOS symptoms and is also related to ovarian dysfunction. This review summarizes how AGE formation, inflammation, and oxidative stress are significantly essential in PCOS progression. Alterations during prenatal development like exposure to excess AMH, androgens, or toxins (bisphenol-A, endocrine disruptors, etc.) may also be the etiologic mechanism behind PCOS. Although the etiology of this disorder is unclear, environmental and genetic factors are primarily involved. Physical inactivity, as well as unhealthy eating habits, has a vital role in the progression of PCOS. This review outlines a collection of specific genes phenotypically linked with PCOS. Furthermore, beneficial effect of metformin in maintaining endocrine abnormalities and ovarian function is also mentioned. Kisspeptin is a protein which helps in onset of puberty and increases GnRH pulsatile release during ovulation as well as role of KNDy neurons in GnRH pulsatile signal required for reproduction are also elaborated. This review also focuses on the immunology related to PCOS involving chronic low-grade inflammation, and how the alterations within the follicular microenvironment are intricated in the development of infertility in PCOS patients. How PCOS develops following antiepileptic and psychiatric medication is also expanded in this review. Initiation of antiandrogen treatment in early age (≤ 25years) might be helpful in spontaneous conception in PCOS women. The role of BMP (bone morphogenetic proteins) in folliculogenesis and their expression in oocytes and granulosa cells are also explained. GDF8 and SERPINE1 expression in PCOS is given in detail.

Tauroursodeoxycholic acid functions as a critical effector mediating insulin sensitization of metformin in obese mice

Metformin is widely used to surmount insulin resistance (IR) and type 2 diabetes. Accumulating evidence suggests that metformin may improve IR through regulating gut microbiota and bile acids. However, the underlying mechanisms remain unclear. Our metabolomic analysis showed that metformin significantly increased the accumulation of tauroursodeoxycholic acid (TUDCA) in intestine and liver from high-fat diet (HFD)-induced IR mice. TUDCA also alleviated IR, and reduced oxidative stress and intestinal inflammation in ob/ob mice. TUDCA blocked KEAP1 to bind with Nrf2, resulting in Nrf2 translocation into nuclear and initiating the transcription of antioxidant genes, which eventually reduced intracellular ROS accumulation and improved insulin signaling. Analysis of gut microbiota further revealed that metformin reduced the relative abundance of Bifidobacterium, which produces bile salt hydrolase (BSH). The reduction in BSH was probably crucial for the accumulation of TUDCA. Metformin also increased the proportion of Akkermanisia muciniphlia in gut microbiota of ob/ob mice via TUDCA. These beneficial effects of metformin in remodeling gut microbiota, reducing oxidative stress and improving insulin sensitivity were partly due to the accumulation of TUDCA, suggesting that TUDCA may be a potential therapy for metabolic syndrome.

Metformin improves neurobehavioral impairments of streptozotocin-treated and western diet-fed mice: Beyond glucose-lowering effects.

Brain insulin resistance has been pointed to as a possible link between diabetes and neuropsychiatric disorders; therefore, therapeutic approaches using anti-diabetic drugs to improve insulin levels or signaling could prevent type 1 (T1D) and type 2 diabetes mellitus (T2D)-induced brain dysfunction. The present study aimed to determine whether metformin exerts beneficial effects on metabolic and neurobehavioral outcomes in the streptozotocin (STZ)-induced T1D model and western diet (WD)-induced obesity model in male Swiss mice. T1D was induced by intraperitoneal injection of STZ (50 mg/kg, for five consecutive days). The animals were then treated daily with saline or metformin (200 mg/kg/day, oral gavage), and a battery of tests recapitulating different neurobehavioral anomalies related to anxiogenic/depressive-like phenotype was conducted after 18 days. WD-induced obesity was modeled in mice by high-fat and high-fructose diet (HFFD) feeding for 15 days. In the sequence, control and diet-induced obesity mice were treated daily with saline or metformin (200 mg/kg/day), and a battery of behavioral tests was performed after 17 days. STZ injection and WD feeding induced metabolic and neurobehavioral impairments in mice. Remarkably, metformin improved the metabolic and neurobehavioral parameters in WD-induced obesity mice. Moreover, metformin ameliorated STZ-induced neurobehavioral deficits while it failed to improve the associated metabolic impairments. The beneficial effects of metformin in STZ-induced neurobehavioral impairments were not mediated by improving peripheral insulin signaling. Our results suggest that conventional diabetes treatment could be repurposed to simultaneously improve neurobehavioral symptoms and diabetes.

Metformina farmaco anti-aging? Tra promesse ed evidenze

Biological aging results from molecular and cellular damage over time. This process determines a progressive decrease in physical and functional capacity, an increased risk of disease and death. Therefore, the identification of the molecular mechanisms of aging has led to research for senotherapeutic strategies. Metformin is an oral hypo¬glycaemic drug. It is the first choice for the treatment of type 2 dia-betes mellitus (T2DM). However, clinical and preclinical evidence has shown the beneficial effects of metformin also in cardiovascular dis-eases, neurodegenerative diseases, and aging. This editorial explores the recent evidence on metformin as an anti-aging drug.