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BACKGROUND: Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. METHODS: COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. RESULTS: The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. CONCLUSIONS: In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04510194.
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Background: Polycystic ovarian syndrome (PCOS) is one of the significant causes of infertility. Impaired glucose metabolism and insulin resistance add chiefly to the pathogenesis of PCOS. This study aimed to evaluate the efficacy of metformin and pioglitazone (insulin sensitizers) on the quality of the ovum and pregnancy rate in the IVF cycle. Methods: In this randomized clinical trial study, 172 infertile women with PCO were enrolled and randomly assigned to receive either 15 mg pioglitazone (case group) or 1000 mg metformin (control group) twice a day for 6 weeks before IVF, and the pregnancy rate was compared across the groups. The number of ovum and embryos were also accessed and compared between the two groups. Results: In the study, 172 patients participated. The mean age in the control and case groups was 32.09±3.9 years and 32.12±3.9 years, respectively, with no significant age difference. In both groups, the mean number of IVF eggs retrieved was 11.76±3.7 (control) and 11.86±3.7 (case), and the number of embryos formed was 7.43±2.8 (control) and 7.87±3.5 (case), with no significant disparities (P<0.05). Regarding positive pregnancies, 28 out of 86 (32.6%) occurred in the control group, while 42 out of 86 (48.8%) happened in the case group, demonstrating a significant difference (P=0.03). Conclusions: According to the results obtained in this study, it may be concluded that pioglitazone is superior to metformin in IVF cycles in PCOS-associated infertile women leading to a higher pregnancy rate.
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Background: To observe the basic metabolic characteristics of obese patients with polycystic ovarian syndrome (PCOS), and observe and compare the effect of laparoscopic sleeve gastrectomy and metformin treatment after 3 months. Methods: In January to December 2018, the Second Hospital of Hebei Medical University selected 104 women who were classified as obese with a body mass index (BMI) of 28 kg/cm2 or higher and had PCOS. They were divided into obese PCOS group (53 cases) and obese non-PCOS group (51 cases). Results: 1. There was no significant difference in waist circumference and WHR between patients who are obese with PCOS and patients who are obese without PCOS (P > 0.05). Obese PCOS patients were significantly higher in anti-Müllerian hormone (AMH), LH/FSH, T, FAI, homa-ir, triglyceride (TG), low density lipoprotein (LDL), Apo-B and uric acid than the group of non-PCOS patients who were obese. (P<0.05). The SHBG levels of obese patients with PCOS were obviously lower when contrasted with the levels in obese patients without PCOS (P < 0.05). 2. Body weight, BMI, INS, homa-ir and TG of obese PCOS patients were significantly decreased 3 months after laparoscopic sleeve gastrectomy compared with that before surgery (P < 0.05). After three months of medical treatment with metformin, the patients' homeostatic model assessment of insulin resistance (HOMA-IR) was obviously reduced when contrasted with the pre-treatment HOMA-IR levels (P < 0.05), and there was no significant difference in the improvement degree of homa-ir between the two groups (P > 0.05). Conclusions: 1. Obese patients with PCOS demonstrated higher expression of AMH, LH/FSH, T, SHBG, and FAI when contrasted with the control group. Additionally, they experienced more severe insulin resistance and lipid metabolism disorders. 2. The weight and BMI of obese PCOS patients were significantly decreased after weight loss, while IR and blood lipid were significantly improved, while IR was improved in metformin group, and no significant discrepancy was observed in the degree of improvement of insulin resistance between both groups.
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Background: Despite its widespread use and favored profile, there are extensive variations in the treatment outcome of metformin therapy. Furthermore, studies reported that the inter-individual variability in the occurrence of metformin treatment associated side effects were related to the differences in individual genetic profiles. Thus, this study aimed to evaluate whether the reduced function methionine deletion at codon 420 (Met420del) variant of SLC22A1 (rs72552763) is associated with metformin induced gastrointestinal intolerance in Ethiopian patients with type 2 diabetes mellitus (T2DM). Patients and Methods: A retrospective observational study was conducted on 47 T2DM patients on metformin treatment for <3 years to assess the association of SLC22A1 (rs72552763) polymorphism with metformin induced gastrointestinal intolerance. Accordingly, 24 metformin tolerant and 23 metformin intolerant individuals with T2DM were recruited. Genotyping of rs72552763 was performed using TaqMan® Drug Metabolism Enzyme Genotyping Assay and its association to metformin induced gastrointestinal intolerance was assessed based on switching to a new class of glucose lowering agents or failure to up titrate dose due to metformin induced gastrointestinal intolerance. Chi-square, logistic regression and Mann-Whitney statistical tests were used as appropriate. Statistical significance was set at p < 0.05. Results: In our study, no significant association was observed between rs72552763 and metformin induced gastrointestinal intolerance. We found that the female gender and physical inactivity were risk factors for metformin gastrointestinal intolerance. Conclusion: Our study found that the Met420del variant of SLC22A1 (rs72552763) was not associated with metformin induced gastrointestinal intolerance in Ethiopian patients with T2DM. This is the study first to investigate the association of rs72552763 with metformin intolerance in the Ethiopian population with T2DM. However, the findings need to be cautiously interpreted given the relatively small sample size. In addition, a more complete investigation of SLC22A1 variants would be required to fully assess the effect of the gene on metformin induced gastrointestinal intolerance as several variants with a more severe loss of function have been described.
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Metformin toxicity is a life-threatening condition with high morbidity and mortality. Toxicity predominantly occurs in the setting of acute renal dysfunction, as the drug is solely eliminated by the kidneys. While this risk is widely known to clinicians, diagnosing metformin toxicity is challenging because commercially available serum metformin levels require days to weeks to result. Therefore, the intensivist must rely on medical history, clinical presentation, and routine laboratory findings to make the preliminary diagnosis. Treatment of metformin toxicity includes supportive fluid hydration, vasopressors, and emergent hemodialysis (HD). We report three critically ill patients who had near-fatal severe metformin-induced lactic acidosis. Their metformin levels were markedly higher than the toxicity threshold reported by the Federal Drug Agency. These patients made a prompt and complete recovery after the initiation of HD. We also review the pathophysiology, clinical presentation, diagnosis, and treatment of metformin toxicity.
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OBJECTIVE: To investigate the impact of combining metformin with insulin aspart on blood glucose control, renal injury, and pregnancy outcome in gestational diabetes mellitus (GDM) patients. METHODS: In this retrospective analysis, the clinical data of 140 GDM patients treated at Baoji Maternal and Child Health Hospital between March 2020 and March 2022 were studied. The patients were divided into a control group (insulin aspart alone, n=64) and an observation group (combination of insulin aspart and metformin, n=76) according to their treatment regimen. The blood glucose metabolism, renal injury markers, and pregnancy outcomes between the two groups were assessed and compared. RESULTS: The observation group demonstrated significantly lower levels of blood glucose metabolism markers (fasting plasma glucose [FPG], fasting insulin [FINS], mean amplitude of glycemic excursions [MAGE], and mean of daily differences [MODD]), renal injury indicators (microalbuminuria [mAlb], serum cystatin C [CysC], free fatty acids [FFA], and neutrophil gelatinase-associated lipocalin [NGAL]), and inflammatory markers (interleukin-6 [IL-6], transforming growth factor-ß1 [TGF-ß1], and lipoprotein-associated phospholipase A2 [Lp-PLA2]) compared to the control group (all P<0.05). Additionally, the incidence of adverse pregnancy outcomes in both newborns and mothers was lower in the observation group (P<0.05). Logistic regression analysis identified the treatment regimen, patient age, and pre-pregnancy BMI as independent risk factors for adverse pregnancy outcome. CONCLUSION: The combination of metformin and insulin aspart in treating GDM can effectively reduce blood glucose levels, mitigate renal injury, and improve pregnancy outcome. This treatment approach presents a viable option for optimizing maternal and fetal health in GDM cases.
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Fanconi anemia (FA) is a disease caused by defective deoxyribonucleic acid (DNA) repair that manifests as bone marrow failure, cancer predisposition, and developmental defects. We previously reported that monotherapy with either metformin (MET) or oxymetholone (OXM) improved peripheral blood (PB) counts and the number and functionality of bone marrow hematopoietic stem progenitor cells (HSPCs) number in Fancd2-/- mice. To evaluate whether the combination treatment of these drugs has a synergistic effect to prevent bone marrow failure in FA, we treated cohorts of Fancd2-/- mice and wildtype controls with either MET alone, OXM alone, MET+OXM, or placebo diet from age 3 weeks to 18 months. The OXM treated animals showed modest improvements in blood parameters including platelet count (p = .01) and hemoglobin levels (p < .05). In addition, the percentage of quiescent hematopoietic stem cell (HSC) (LSK [Lin-Sca+c-Kit+]) was significantly increased (p = .001) by long-term treatment with MET alone. The combination of metformin and oxymetholone did not result in a significant synergistic effect in any hematopoietic parameter. Gene expression analysis of liver tissue from these animals showed that some of the expression changes caused by Fancd2 deletion were partially normalized by metformin treatment. Importantly, no adverse effects of the individual or combination therapies were observed, despite the long-term administration. We conclude that androgen therapy is not a contraindication to concurrent metformin administration in clinical trials. HIGHLIGHTS: Long-term coadministration of metformin in combination with oxymetholone is well tolerated by Fancd2-/- mice. Hematopoietic stem cell quiescence in mutant mice was enhanced by treatment with metformin alone. Metformin treatment caused a partial normalization of gene expression in the livers of mutant mice.
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BACKGROUND: Similar to metformin, dipeptidyl peptidase-4 inhibitors (DPP-4 Is), glucagon-like peptidase 1 receptor agonists (GLP-1 RAs), and sodium glucose co-transporter-2 inhibitors (SGLT-2 Is) may improve control of asthma owing to their multiple potential mechanisms, including differential improvements in glycemic control, direct anti-inflammatory effects, and systemic changes in metabolism. OBJECTIVE: To investigate whether these novel antihyperglycemic drugs were associated with fewer asthma exacerbations compared with metformin in patients with asthma comorbid with type 2 diabetes. METHODS: Using a Japanese national administrative database, we constructed three active comparators-new user cohorts of 137,173 patients with a history of asthma starting the novel antihyperglycemic drugs and metformin between 2014 and 2022. Patient characteristics were balanced using overlap propensity score weighting. The primary outcome was the first exacerbation requiring systemic corticosteroids, and the secondary outcomes included the number of exacerbations requiring systemic corticosteroids. RESULTS: DPP-4 Is and GLP-1 RAs were associated with a higher incidence of exacerbations requiring systemic corticosteroids compared with metformin (DPP-4 Is: 18.2 vs. 17.4 per 100 person-years; hazard ratio 1.09, 1.05 to 1.14; GLP-1 RAs: 24.9 vs. 19.0 per 100 person-years; 1.14, 1.01 to 1.28). In contrast, the incidence of exacerbations requiring systemic corticosteroids was similar between the SGLT-2 Is and metformin groups (17.3 vs. 18.1 per 100 person-years; hazard ratio 1.00, 0.97 to 1.03). While DPP-4 Is and GLP-1 RAs were associated with more exacerbations requiring systemic corticosteroids, SGLT-2 Is were associated with slightly fewer exacerbations requiring systemic corticosteroids (53.7 vs. 56.6 per 100 person-years; rate ratio 0.95, 0.91 to 0.99). CONCLUSIONS: While DPP-4 Is and GLP-1 RAs were associated with poorer control of asthma compared with metformin, SGLT-2 Is offered asthma control comparable to that of metformin.
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Diabetes mellitus is a global health issue characterized by hyperglycemia which leads over time to severe damage to numerous tissues. The present study aimed to estimate the effect of Egyptian Sidr honey against streptozotocin-induced diabetes in rats. Diabetic rats were treated with Sidr honey daily for 4 consecutive weeks. The biochemical profile of blood samples was measured. Furthermore, the activity of antioxidant enzymes, nitric oxide (NO), and malonaldehyde (MDA) were examined in liver and pancreas tissues. Moreover, the expression of Bax, Caspase-3, and Bcl2 proteins were measured. Results revealed that the capability of Sidr honey to decline the elevated blood glucose and fructosamine levels compared to diabetic rats. Also, the honey decreased the levels of NO and MDA. Furthermore, it regulated the antioxidant enzymes activity. Moreover, it reduced the expression levels of Caspase-3 and Bax while increased the Bcl2 level. In conclusion, Sidr honey can regulate hyperglycemia, oxidative stress, apoptosis, and antioxidant enzymes in STZ-induced diabetic rats.
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Heart failure and cardiac remodeling are both characterized by mitochondrial dysfunction. Healthy mitochondria are required for adequate contractile activity and appropriate regulation of cell survival. In the mammalian heart, enhancement of the mitochondrial unfolded protein response (UPRmt) is cardioprotective under pressure overload conditions. We explored the UPRmt and the underlying regulatory mechanism in terms of hypertension-induced cardiac remodeling and the cardioprotective effect of metformin. Male spontaneously hypertensive rats and angiotensin II-treated neonatal rat cardiomyocytes were used to induce cardiac hypertrophy. The results showed that hypertension induced the formation of aberrant mitochondria, characterized by a reduced mtDNA/nDNA ratio and swelling, as well as lower levels of mitochondrial complexes I to V and inhibition of the expression of one protein subunit of each of complexes I to IV. Such changes eventually enlarged cardiomyocytes and increased cardiac fibrosis. Metformin treatment increased the mtDNA/nDNA ratio and regulated the UPRmt, as indicated by increased expression of activating transcription factor 5, Lon protease 1, and heat shock protein 60, and decreased expression of C/EBP homologous protein. Thus, metformin improved mitochondrial ultrastructure and function in spontaneously hypertensive rats. In vitro analyses revealed that metformin reduced the high levels of angiotensin II-induced mitochondrial reactive oxygen species in such animals and stimulated nuclear translocation of heat shock factor 1 (HSF1). Moreover, HSF1 small-interfering RNA reduced the metformin-mediated improvements in mitochondrial morphology and the UPRmt by suppressing hypertrophic signals and cardiomyocyte apoptosis. These results suggest that HSF1/UPRmt signaling contributes to the beneficial effects of metformin. Metformin-mediated targeting of mitochondrial protein homeostasis and modulation of HSF1 levels have potential therapeutic implications in terms of cardiac remodeling.
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Fatores de Transcrição de Choque Térmico, Metformina, Miócitos Cardíacos, Ratos Endogâmicos SHR, Resposta a Proteínas não Dobradas, Animais, Metformina/farmacologia, Resposta a Proteínas não Dobradas/efeitos dos fármacos, Masculino, Ratos, Fatores de Transcrição de Choque Térmico/metabolismo, Fatores de Transcrição de Choque Térmico/genética, Miócitos Cardíacos/metabolismo, Miócitos Cardíacos/efeitos dos fármacos, Hipertensão/metabolismo, Hipertensão/tratamento farmacológico, Remodelação Ventricular/efeitos dos fármacos, Mitocôndrias Cardíacas/metabolismo, Mitocôndrias Cardíacas/efeitos dos fármacos, Angiotensina II/farmacologia, Cardiomegalia/metabolismo, Cardiomegalia/tratamento farmacológico, Cardiomegalia/patologia, Fatores de Transcrição/metabolismo, Fatores de Transcrição/genética, Proteínas de Ligação a DNA/metabolismo, Proteínas de Ligação a DNA/genética, Ratos Endogâmicos WKYRESUMO
Hepatitis C virus is an important global cause of hepatitis and subsequently cirrhosis and hepatocellular carcinoma. These infections may also cause extrahepatic manifestations, including insulin resistance and type 2 diabetes mellitus. These two complications can potentially reduce sustained virologic responses (SVR) in some drug regimens for this infection. Metformin has important biochemical effects that can limit viral replication in cellular cultures and can improve the response to antiviral drug therapy based on ribavirin and interferon. Clinical studies comparing treatment regimens with interferon, ribavirin, metformin with these regimens without metformin have demonstrated that metformin increases viral clearance, establishes higher rates of SVRs, and increases insulin sensitivity. Metformin also reduces the frequency of hepatocellular carcinoma in patients who have had SVRs. Larger treatment trials are needed to determine metformin's short-term and long-term treatment effects in patients with diabetes using newer antiviral drugs. In particular, if metformin reduces the frequency of cirrhosis and hepatocellular carcinoma, this would significantly reduce the morbidity and mortality associated with this infection.
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AIMS: This study aims to investigate the trends in treatment coverage through dispensing diabetes medications in Vietnam from 2015 to 2021. The findings will serve to inform health policies to mitigate the health burden of Type 2 diabetes mellitus (T2DM). METHODS: We collected information on major antidiabetic medicines from General Department of Vietnam Customs and payments for antidiabetics via the National Health Insurance Program. We applied ordinary least squares models, accounting for economic and health outcome characteristics, to estimate the association between the annual mass of medications and related factors. RESULTS: Nationally, the total mass/doses of all antidiabetic drugs increased rapidly from 2015 to 2021, based on both databases. Metformin was the most frequently prescribed medicine, with the total mass increasing nearly threefold over the study period. Gliclazide, a Sulfonylureas drug, ranked second. In the multivariate regression analysis, a one-unit increase in adults with diabetes (in 1,000 s) was associated with 0.11 % (95 %CI = 0.0005; 0.0076) and 0.13 % (95%CI = 0.0007; 0.0242) higher mass of Metformin and Glimepiride, respectively. CONCLUSION: Our data suggested that policies changes were related to significant increase in antidiabetic medication dispenses in Vietnam. The high treatment coverage indicates impressive progress in achieving universal health coverage in Vietnam, meeting the UN Sustainable Development Goal (SDG).
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INTRODUCTION: There has been increasing evidence that the gut microbiota is closely related to type 2 diabetes (T2D). Metformin (Met) is often used in combination with saxagliptin (Sax) and repaglinide (Rep) for the treatment of T2D. However, little is known about the effects of these combination agents on gut microbiota in T2D. RESEARCH DESIGN AND METHODS: A T2D mouse model induced by a high-fat diet (HFD) and streptozotocin (STZ) was employed. The T2D mice were randomly divided into six groups, including sham, Met, Sax, Rep, Met+Sax and Met+Rep, for 4 weeks. Fasting blood glucose level, serum biochemical index, H&E staining of liver, Oil red O staining of liver and microbiota analysis by 16s sequencing were used to access the microbiota in the fecal samples. RESULTS: These antidiabetics effectively prevented the development of HFD/STZ-induced high blood glucose, and the combination treatment had a better effect in inhibiting lipid accumulation. All these dosing regimens restored the decreasing ratio of the phylum Bacteroidetes: Firmicutes, and increasing abundance of phylum Desulfobacterota, expect for Met. At the genus level, the antidiabetics restored the decreasing abundance of Muribaculaceae in T2D mice, but when Met was combined with Rep or Sax, the abundance of Muribaculaceae was decreased. The combined treatment could restore the reduced abundance of Prevotellaceae_UCG-001, while Met monotherapy had no such effect. In addition, the reduced Lachnospiraceae_NK4A136_group was well restored in the combination treatment groups, and the effect was much greater than that in the corresponding monotherapy group. Therefore, these dosing regimens exerted different effects on the composition of gut microbiota, which might be associated with the effect on T2D. CONCLUSIONS: Supplementation with specific probiotics may further improve the hypoglycemic effects of antidiabetics and be helpful for the development of new therapeutic drugs for T2D.
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Adamantano, Glicemia, Carbamatos, Diabetes Mellitus Experimental, Diabetes Mellitus Tipo 2, Dieta Hiperlipídica, Dipeptídeos, Microbioma Gastrointestinal, Hipoglicemiantes, Metformina, Piperidinas, Animais, Microbioma Gastrointestinal/efeitos dos fármacos, Metformina/farmacologia, Metformina/uso terapêutico, Camundongos, Dieta Hiperlipídica/efeitos adversos, Diabetes Mellitus Tipo 2/tratamento farmacológico, Diabetes Mellitus Tipo 2/microbiologia, Hipoglicemiantes/farmacologia, Hipoglicemiantes/uso terapêutico, Diabetes Mellitus Experimental/tratamento farmacológico, Carbamatos/farmacologia, Dipeptídeos/farmacologia, Masculino, Adamantano/análogos & derivados, Adamantano/farmacologia, Adamantano/uso terapêutico, Piperidinas/farmacologia, Piperidinas/uso terapêutico, Glicemia/análise, Glicemia/efeitos dos fármacos, Camundongos Endogâmicos C57BL, Quimioterapia Combinada, EstreptozocinaRESUMO
This mini-narrative review explores the relationship between diabetes and dementia, focusing on the potential mitigating role of metformin in reducing cognitive decline among individuals with type 2 diabetes. The interplay of factors such as glycemic control, diabetic complications, and lifestyle influences characterises diabetes-related dementia. This review emphasises the significance of comprehensive diabetes management in addressing the heightened risk of dementia in this population. Methodologically, the review synthesises evidence from 23 studies retrieved through searches on PubMed, Embase, Google Scholar, and Scopus. Current evidence suggests a predominantly positive association between metformin use and a reduced risk of dementia in individuals with diabetes. However, the review shows the complex nature of these outcomes, revealing variations in results in some studies. These discrepancies show the importance of exploring dose-response relationships, long-term effects, and demographic diversity to unravel the complexities of metformin's impact on cognitive health. Limitations in the existing body of research, including methodological disparities and confounding variables, necessitate refined approaches in future studies. Large-scale prospective longitudinal studies and randomised controlled trials focusing specifically on cognitive effects are recommended. Propensity score matching and exploration of molecular mechanisms can enhance the validity of findings in clinical practice. From a clinical perspective, metformin can serve as a potential adjunctive therapy for individuals with diabetes at risk of cognitive decline.
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BACKGROUND: Radiation proctitis (RP) is a significant complication of pelvic radiation. Effective treatments for chronic RP are currently lacking. We report a case where chronic RP was successfully managed by metformin and butyrate (M-B) enema and suppository therapy. CASE PRESENTATION: A 70-year-old Asian male was diagnosed with prostate cancer of bilateral lobes, underwent definitive radiotherapy to the prostate of 76 Gy in 38 fractions and six months of androgen deprivation therapy. Despite a stable PSA nadir of 0.2 ng/mL for 10 months post-radiotherapy, he developed intermittent rectal bleeding, and was diagnosed as chronic RP. Symptoms persisted despite two months of oral mesalamine, mesalamine enema and hydrocortisone enema treatment. Transition to daily 2% metformin and butyrate (M-B) enema for one week led to significant improvement, followed by maintenance therapy with daily 2.0% M-B suppository for three weeks, resulting in continued reduction of rectal bleeding. Endoscopic examination and biopsy demonstrated a good therapeutic effect. CONCLUSIONS: M-B enema and suppository may be an effective treatment for chronic RP.
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Enema, Metformina, Proctite, Neoplasias da Próstata, Lesões por Radiação, Humanos, Masculino, Proctite/tratamento farmacológico, Proctite/etiologia, Idoso, Metformina/uso terapêutico, Metformina/administração & dosagem, Neoplasias da Próstata/radioterapia, Neoplasias da Próstata/tratamento farmacológico, Lesões por Radiação/tratamento farmacológico, Doença Crônica, Resultado do Tratamento, Butiratos/uso terapêutico, Hemorragia Gastrointestinal/tratamento farmacológico, Hemorragia Gastrointestinal/terapia, Hemorragia Gastrointestinal/etiologia, SupositóriosRESUMO
Introduction: Insulin resistance is being increasingly reported in type-1 Diabetes (T1D) and is known to accelerate microvascular complications. The Asian Indian population has a higher risk of double diabetes development compared to Caucasians. Hence, we studied the effect of adding Metformin to standard insulin therapy on glycemic control, insulin sensitivity (IS), cardiometabolic parameters and body composition in Indian adolescents with T1D. Methods: A Randomized controlled trial was conducted spanning 9 months (Registration number:CTRI/2019/11/022126). Inclusion: Age 10-19 years, T1D duration>1year, HbA1c>8% Exclusion: Uncontrolled vascular complications/comorbidities, Metformin intolerance, concomitant drugs affecting insulin sensitivity. Participants were randomized to Metformin/Placebo (n=41 each) groups and age, sex, duration-matched. Assessments were performed at baseline, 3 and 9 months. Results: 82 participants aged 14.7 ± 3years (40 females) were enrolled, with a mean diabetes duration of 5.2 ± 2.3 years. Over 9 months, HbA1c decreased significantly by 0.8 (95% confidence interval: -1.2 to -0.3) from 9.8 ± 1.8% to 9.1 ± 1.7% on Metformin but remained largely unchanged (difference of 0.2, 95% confidence interval: -0.7 to 0.2) i.e. 9.9 ± 1.6% and 9.7 ± 2.2% on placebo. HbA1c improvement correlated negatively with baseline IS (EGDR:r= -0.3;SEARCH:r = -0.24, p<0.05) implying better HbA1c-lowering in those with decreased initial IS. CGM-based glycemic variability (standard deviation) reduced by 6.3 mg/dL (95% confidence interval: -12.9 to 0.2) from 100.2 ± 19.1 mg/dL to 93.7 ± 19.9 mg/dL in those on Metformin (p=0.05) but not placebo (94.0 ± 20.5; 90.0 ± 22.6 mg/dL). Insulin sensitivity: CACTIexa & SEARCH scores demonstrated no change with Metformin but significant worsening on placebo. Significant increase in LDL-C(42%), total cholesterol(133.6 to 151.1 mg/dL), triglyceride (60.0 to 88.0 mg/dL) and carotid intima-media thickness was noted on placebo but not Metformin. Weight, BMI, fat Z-scores increased significantly on placebo but not Metformin. Adverse events (AE) were minor; AE, compliance and safety parameters were similar between the two groups. Conclusion: Metformin as an adjunct to insulin in Asian Indian adolescents with T1D demonstrated beneficial effect on glycemic control, glycemic variability, IS, lipid profile, vascular function, weight and body fat, with a good safety profile when administered for 9 months.
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Diabetes is a risk factor for thyroid cancer development. Serum thyroglobulin (Tg) levels are useful as sensitive and specific tumor markers for monitoring radioiodine (RAI)-refractory thyroid cancer; however, the impact of glycemic control on serum Tg levels is poorly understood. Here, we present a case of a female patient with lung metastases of RAI-refractory thyroid cancer in whom glycemic control may have influenced the serum Tg levels. Despite receiving thyroid-stimulating hormone suppression therapy, her serum Tg levels remained elevated. Subsequently, she developed type 2 diabetes and was administered antidiabetic medications for 6 years. Throughout the course of diabetes management, her serum Tg levels fluctuated according to the level of glycemic control, showing a strong correlation with her hemoglobin A1c levels (r = 0.92, P < .01). Similar to the serum levels of other tumor markers, such as the carcinoembryonic antigen and carbohydrate antigen 19-9, the serum levels of Tg can be influenced by glycemic control. Therefore, serum Tg levels in patients with RAI-refractory thyroid cancer and diabetes should be monitored with attention to glycemic control.
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Introduction: Focal segmental glomerulosclerosis (FSGS), the most common primary glomerular disease leading to end-stage kidney disease (ESKD), is characterized by podocyte injury and depletion, whereas minimal change disease (MCD) has better outcomes despite podocyte injury. Identifying mechanisms capable of preventing podocytopenia during injury could transform FSGS to an "MCD-like" state. Preclinical data have reported conversion of an MCD-like injury to one with podocytopenia and FSGS by inhibition of AMP-kinase (AMPK) in podocytes. Conversely, in FSGS, AMPK-activation using metformin (MF) mitigated podocytopenia and azotemia. Observational studies also support beneficial effects of MF on proteinuria and chronic kidney disease (CKD) outcomes in diabetes. A randomized controlled trial (RCT) to test MF in podocyte injury with FSGS has not yet been conducted. Methods: We report the rationale and design of phase 2, double-blind, placebo-controlled RCT evaluating the efficacy and safety of MF as adjunctive therapy in FSGS. By randomizing 30 patients with biopsy-confirmed FSGS to MF or placebo (along with standard immunosuppression), we will study mechanistic biomarkers that correlate with podocyte injury or depletion and evaluate outcomes after 6 months. We specifically integrate novel urine, blood, and tissue markers as surrogates for FSGS progression along with unbiased profiling strategies. Results and Conclusion: Our phase 2 trial will provide insight into the potential efficacy and safety of MF as adjunctive therapy in FSGS-a crucial step to developing a larger phase 3 study. The mechanistic assays here will guide the design of other FSGS trials and contribute to understanding AMPK activation as a potential therapeutic target in FSGS. By repurposing an inexpensive agent, our results will have implications for FSGS treatment in resource-poor settings.
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INTRODUCTION: Despite the well-recognized health benefits, the mechanisms and site of action of metformin remains elusive. Metformin-induced global lipidomic changes in plasma of animal models and human subjects have been reported. However, there is a lack of systemic evaluation of metformin-induced lipidomic changes in different tissues. Metformin uptake requires active transporters such as organic cation transporters (OCTs), and hence, it is anticipated that metformin actions are tissue-dependent. In this study, we aim to characterize metformin effects in non-diabetic male mice with a special focus on lipidomics analysis. The findings from this study will help us to better understand the cell-autonomous (direct actions in target cells) or non-cell-autonomous (indirect actions in target cells) mechanisms of metformin and provide insights into the development of more potent yet safe drugs targeting a particular organ instead of systemic metabolism for metabolic regulations without major side effects. OBJECTIVES: To characterize metformin-induced lipidomic alterations in different tissues of non-diabetic male mice and further identify lipids affected by metformin through cell-autonomous or systemic mechanisms based on the correlation between lipid alterations in tissues and the corresponding in-tissue metformin concentrations. METHODS: A dual extraction method involving 80% methanol followed by MTBE (methyl tert-butyl ether) extraction enables the analysis of free fatty acids, polar metabolites, and lipids. Extracts from tissues and plasma of male mice treated with or without metformin in drinking water for 12 days were analyzed using HILIC chromatography coupled to Q Exactive Plus mass spectrometer or reversed-phase liquid chromatography coupled to MS/MS scan workflow (hybrid mode) on LC-Orbitrap Exploris 480 mass spectrometer using biologically relevant lipids-containing inclusion list for data-independent acquisition (DIA), named as BRI-DIA workflow followed by data-dependent acquisition (DDA), to maximum the coverage of lipids and minimize the negative effect of stochasticity of precursor selection on experimental consistency and reproducibility. RESULTS: Lipidomics analysis of 6 mouse tissues and plasma allowed a systemic evaluation of lipidomic changes induced by metformin in different tissues. We observed that (1) the degrees of lipidomic changes induced by metformin treatment overly correlated with tissue concentrations of metformin; (2) the impact on lysophosphatidylcholine (lysoPC) and cardiolipins was positively correlated with tissue concentrations of metformin, while neutral lipids such as triglycerides did not correlate with the corresponding tissue metformin concentrations; (3) increase of intestinal tricarboxylic acid (TCA) cycle intermediates after metformin treatment. CONCLUSION: The data collected in this study from non-diabetic mice with 12-day metformin treatment suggest that the overall metabolic effect of metformin is positively correlated with tissue concentrations and the effect on individual lipid subclass is via both cell-autonomous mechanisms (cardiolipins and lysoPC) and non-cell-autonomous mechanisms (triglycerides).
