Metformin Inhibits ROS/TNF-alpha Axis-Mediated Chronic Kidney Disease Induced by TAA Independent of Leukocyte Infiltration in Association with the Inhibition of Kidney Injury Biomarkers / La Metformina Inhibe la Enfermedad Renal Crónica Mediada por el Eje ROS/TNF-alfa Inducida por TAA Independientemente de la Infiltración de Leucocitos en Asociación con la Inhibición de Biomarcadores de Lesión Renal

SUMMARY: The toxic effects of thioacetamide (TAA) and carbon tetrachloride on the human body are well recognized. In this study, we examined whether TAA intoxication can induce kidney leukocyte infiltration (measured as leukocyte common antigen CD45) associated with the augmentation of the reactive oxygen species (ROS)/tumor necrosis factor-alpha (TNF-α) axis, as well as biomarkers of kidney injury with and without metformin treatment. Rats were either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being sacrificed after 10 weeks (experimental group) or were pre-treated with metformin (200 mg/kg) daily for two weeks prior to TAA injections and continued receiving both agents until the end of the experiment, at week 10 (protective group). Using basic histology staining, immunohistochemistry methods, and blood chemistry analysis, we observed profound kidney tissue injury such as glomerular and tubular damage in the experimental group, which were substantially ameliorated by metformin. Metformin also significantly (p0.05) increase in kidney expression of CD45 positive immunostaining cells. In conclusion, we found that TAA induces kidney injury in association with the augmentation of ROS/TNF-α axis, independent of leukocyte infiltration, which is protected by metformin.

Son bien conocidosos los efectos tóxicos de la tioacetamida (TAA) y el tetracloruro de carbono en el cuerpo humano. En este estudio, examinamos si la intoxicación por TAA puede inducir la infiltración de leucocitos renales (medida como antígeno leucocitario común CD45) asociada con el aumento de las especies reactivas de oxígeno (ROS)/factor de necrosis tumoral-alfa (TNF-α), así como biomarcadores de daño renal con y sin tratamiento con metformina. A las ratas se les inyectó TAA (200 mg/kg; dos veces por semana durante 8 semanas) antes de sacrificarlas a las 10 semanas (grupo experimental) o se les pretrató con metformina (200 mg/kg) diariamente durante dos semanas antes de las inyecciones de TAA y continuaron recibiendo ambos agentes hasta el final del experimento, en la semana 10 (grupo protector). Usando tinción histológica básica, métodos de inmunohistoquímica y análisis químico de la sangre, observamos una lesión profunda del tejido renal, como daño glomerular y tubular en el grupo experimental, que mejoraron sustancialmente con la metformina. La metformina también inhibió significativamente (p0,05) en la expresión renal de células de inmunotinción positivas para CD45. En conclusión, encontramos que el TAA induce la lesión renal en asociación con el aumento del eje ROS/TNF-α, independientemente de la infiltración de leucocitos, que está protegida por metformina.

Análise de sobrevida de pacientes com câncer de cabeça e pescoço, com diagnóstico de diabetes mellitus tipo II e o efeito da metformina / Survival analysis of patients with head and neck cancer diagnosed with type II diabetes mellitus and the effect of metformin

Os dados sobre a associação entre o diabetes mellitus II e câncer de cabeça e pescoço ainda são escassos, melhorar nossa compreensão na sobrevida dos pacientes com câncer de cabeça e pescoço pode colaborar nas tomadas de decisão dos processos que envolvem o tratamento e acompanhamento. Objetivo: Avaliar o efeito da DM II, da metformina e do Indice de massa corpórea (IMC) na sobrevida de pacientes com CCP atendidos em 5 centros de referência para o câncer no Estado de São Paulo. Metodologia: Foi realizado um estudo de coorte prospectivo utilizando dados coletados no projeto GENCAP II pacientes com câncer de cabeça e pescoço acompanhados de 2011 a 2017 em cinco hospitais de referência no tratamento de câncer no Estado de SP. Foram incluídos 810 pacientes com câncer de cabeça e pescoço (CID0): cavidade oral, orofaringe, hipofaringe, laringe e cabeça e pescoço não especificados, onde 565 apresentavam o diagnóstico de diabetes mellitus II. A sobrevida global foi definida como o tempo de sobrevida dos pacientes com CCP com ou sem DM II, controlando as covariáveis sexo, idade, tabagismo, uso de álcool, localização do tumor, estadiamento (TNM) e IMC. As funções de risco (H(t)), foram estimadas a partir do modelo de regressão de Cox ajustado por sexo e idade. Taxas de risco e 95% de IC foram fornecidos. Resultados: Considerando os riscos ao longo dos 3 anos, o grupo com DM II apresentou aumento de sobrevida com (HR=0,71; IC 95%: 0,55-0,92) e p valor de <0,01. No estadiamento clínico avançado (T3, T4a, T4b) aumento de sobrevida com (HR=0,65; IC 95%: 0,47-0,88) e p valor 0,06, DM II. O grupo com IMC (>25m2kg) apresentou aumento de sobrevida com (HR=0,39; IC 95%: 0,29-0,54) com p valor de <0,001. Em relação a localização anatômica a orofaringe apresentou aumento de sobrevida com (HR=0,32; IC 95%: 0,15-0,69) p valor 0,003, no grupo com IMC (>25 m2kg) apresentou aumento de sobrevida se estendendo também em todos os estadiamentos clínicos (T1-T4b) respectivamente. Conclusão: Neste estudo os pacientes com IMC >25 m2kg apresentaram uma maior sobrevida global num período de 3 anos, quando comparados aos pacientes com CCP eutróficos ou baixo peso, sendo observado também nos estadiamentos clínicos mais avançados. (T3-T4b e N2-N3), bem como observou-se aumento de sobrevida global na presença da DM II dos pacientes com CCP, porém o efeito da metformina não pode ser avaliado pela amostra apresentar um N reduzido de pacientes usuários de metformina.

Data on the association between diabetes mellitus II and head and neck cancer are still scarce, improving our understanding of the survival of patients with head and neck cancer can collaborate in decision-making processes involving treatment and follow-up. Objective: To evaluate the effect of DM II, metformin and body mass index (BMI) on the survival of patients with HNC treated at 5 reference centers for cancer in the State of São Paulo. Methodology: A prospective cohort study was carried out using data collected in the GENCAP II project from patients with head and neck cancer followed from 2011 to 2018 in five reference hospitals in the treatment of cancer in the State of São Paulo. We included 810 patients with head and neck cancer (ICD0): oral cavity, oropharynx, hypopharynx, larynx and unspecified head and neck, where 565 had the diagnosis of diabetes mellitus II. Overall survival was defined as the survival time of patients with HNC with or without DM II, controlling for the covariates sex, age, smoking, alcohol use, tumor location, staging (TNM) and BMI. The risk functions (H(t)) were estimated from the Cox regression model adjusted for sex and age. Hazard ratios and 95% CI were provided. Results: Considering the risks over the 3 years, the group with DM II showed an increase in survival with (HR=0.71; 95% CI: 0.55-0.92) and p value of <0.01. In advanced clinical staging (T3, T4a, T4b) increased survival with (HR=0.65; 95% CI: 0.47-0.88) and p value 0.06, DM II. The BMI group (>25m2kg) showed increased survival with (HR=0.39; 95% CI: 0.29-0.54) with p value <0.001. Regarding the anatomical location, the oropharynx showed an increase in survival with (HR=0.32; CI 95%: 0.15-0.69) p value 0.003, in the group with BMI (>25 m2kg) it showed an increase in survival extending also in all clinical stages (T1-T4b) respectively. Conclusion: In this study, patients with BMI >25 m2kg had a longer overall survival over a period of 3 years, when compared to patients with eutrophic HNC or low weight, also being observed in more advanced clinical stages. (T3-T4b and N2-N3). as well as an increase in overall survival in the presence of DM II of patients with HNC, however the effect of metformin could not be evaluated due to the sample presenting a reduced N of patients using metformin.

Chinese expert consensus on metformin in clinical practice: 2023 update / 中华内科杂志

Metformin has robust glucose-lowering effects and multiple benefits beyond hypoglycemic effects. It can also be used in combination with various hypoglycemic drugs and is cost effective. In the absence of the strong indications of glucagon like peptide-1 receptor agonist (GLP-1RA) or sodium glucose cotransporter 2 inhibitor (SGLT2i) for cardiorenal protection, metformin should be used as the first-line pharmacological treatment for newly diagnosed type 2 diabetes and the basic drug for the combined treatment of hypoglycemic drugs. Metformin does not increase the risk of liver and kidney function damage, but patients with renal dysfunction should adjust the dosage of metformin based on estimated glomerular filtration rate (eGFR) levels. Moreover, the correct use of metformin does not increase the risk of lactic acidosis. Because long-term use of metformin is associated with a decrease in vitamin B12 levels, patients with insufficient intake or absorption of vitamin B12 should be regularly monitored and appropriately supplemented with vitamin B12. In view of the new progress made in the basic and clinical research related to metformin, the consensus updating expert group updated the consensus on the basis of the Expert Consensus on the Clinical Application of Metformin (2018 Edition).

Metformin use and risk of ischemic stroke in patients with type 2 diabetes: A cohort study / 北京大学学报(医学版)

OBJECTIVE@#To explore the association between the use of metformin and the risk of ischemic stroke in patients with type 2 diabetes.@*METHODS@#A prospective cohort study was designed from the Fangshan family cohort in Beijing. According to metformin use at baseline, 2 625 patients with type 2 diabetes in Fangshan, Beijing were divided into metformin group or non-metformin group and the incidence of ischemic stroke between the different groups during follow-up was estimated and compared by Cox proportional hazard regression model. The participants with metformin were first compared with all the parti-cipants who did not use metformin, and then were further compared with those who did not use hypoglycemic agents and those who used other hypoglycemic agents.@*RESULTS@#The patients with type 2 diabetes were with an average age of (59.5±8.7) years, and 41.9% of them were male. The median follow-up time was 4.5 years. A total of 84 patients developed ischemic stroke during follow-up, with a crude incidence of 6.4 (95%CI: 5.0-7.7) per 1 000 person-years. Among all the participants, 1 149 (43.8%) took metformin, 1 476 (56.2%) were metformin non-users, including 593 (22.6%) used other hypoglycemic agents, and 883 (33.6%) did not use any hypoglycemic agents. Compared with metformin non-users, the Hazard ratio (HR) for ischemic stroke in metformin users was 0.58 (95%CI: 0.36-0.93; P = 0.024). Compared with other hypoglycemic agents, HR was 0.48 (95%CI: 0.28-0.84; P < 0.01); Compared with the group without hypoglycemic agents, HR was 0.65 (95%CI: 0.37-1.13; P=0.13). The association between metformin and ischemic stroke was statistically significant in the patients ≥ 60 years old compared with all the metformin non-users and those who used other hypoglycemic agents (HR: 0.48, 95%CI: 0.25-0.92; P < 0.05). Metformin use was associated with a lower incidence of ischemic stroke in the patients with good glycemic control (0.32, 95%CI: 0.13-0.77; P < 0.05). In the patients with poor glycemic control, and the association was not statistically significant (HR: 0.97, 95%CI: 0.53-1.79; P>0.05). There was an interaction between glycemic control and metformin use on incidence of ischemic stroke (Pinteraction < 0.05). The results of the sensitivity analysis were consistent with the results in the main analysis.@*CONCLUSION@#Among patients with type 2 diabetic in rural areas of northern China, metformin use was associated with lower incidence of ischemic stroke, especially in patients older than 60 years. There was an interaction between glycemic control and metformin use in the incidence of ischemic stroke.

Research progresses on interventions of obesity in children and adolescents / 中华预防医学杂志

Childhood and adolescent obesity has become a global epidemic. The interventions mainly include lifestyle intervention, medication treatment and bariatric surgery. Among them, lifestyle intervention, especially intensive lifestyle intervention with participation of family members, is the first-line treatment for obesity in children and adolescents. Both medication and bariatric surgery are adjuvant treatments for severely obese children and adolescents. Currently, metformin is the most widely used drug for the treatment of obesity in children and adolescents in both China and other countries; orlistat and liraglutide are also the drugs that are safe and often used in other countries; other drugs are not recommended. As a tertiary prevention and treatment strategy for obesity, bariatric surgery should be carried out on the basis of good compliance from both the children and their family members, with the cooperation of multiple disciplines. Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) are the most common types of procedure performed. Meanwhile, as a new treatment method, intra-gastric balloon procedure needs to be paid more attention to its efficacy and safety.

Hypoglycemic effect of electroacupuncture at "Tianshu" (ST 25) combined with metformin on rats with type 2 diabetes mellitus based on AMPK / 中国针灸

OBJECTIVE@#To observe the hypoglycemic effect of electroacupuncture (EA) at "Tianshu" (ST 25) combined with metformin on rats with type 2 diabetes mellitus (T2DM) as well as its effect on expression of adenosine monophosphate activated protein kinase (AMPK) in liver and pancreas.@*METHODS@#Thirty-six male SD rats were randomly divided into a blank group (6 rats) and a model establishing group (30 rats). The rats in the model establishing group were fed with high-fat diet and treated with intraperitoneal injection of low-dose streptozotocin (STZ) to establish T2DM model. The rats with successful model establishment were randomly divided into a model group, a control group, a metformin group, an EA group and a combination group, 6 rats in each group. The rats in the EA group were treated with EA at "Tianshu" (ST 25), dense-disperse wave, 2 Hz/15 Hz in frequency and 2 mA in current intensity, 20 min each time. The rats in the metformin group were treated with intragastric administration of metformin (190 mg/kg) dissolved in 0.9% sodium chloride solution (2 mL/kg). The rats in the combination group were treated with EA at "Tianshu" (ST 25) and intragastric administration of metformin. The rats in the control group were treated with intragastric administration of 0.9% sodium chloride solution with the same dose. All the treatments were given once a day for 5 weeks. After the intervention, the body mass and random blood glucose were detected; the serum insulin level was detected by ELISA; the expression of AMPK and phosphorylated adenosine monophosphate activated protein kinase (p-AMPK) in liver and pancreas was detected by Western blot method; the expression of protein gene product 9.5 (PGP9.5) was detected by immunofluorescence.@*RESULTS@#①Compared with the blank group, the body mass in the model group was decreased (P<0.05); compared with the model group, the body mass in the EA group and the combination group was decreased (P<0.05); the body mass in the EA group and the combination group was lower than the metformin group (P<0.05). Compared with the blank group, the random blood glucose in the model group was increased (P<0.01); compared with the model group, the random blood glucose in the metformin group, the EA group and the combination group was decreased (P<0.01). The random blood glucose in the combination group was lower than the metformin group and the EA group (P<0.05). ②Compared with the blank group, the insulin level in the model group was decreased (P<0.05); compared with the model group, the insulin level in the metformin group, the EA group and the combination group was all increased (P<0.05). The insulin level in the combination group was higher than the metformin group and the EA group (P<0.05). ③Compared with the blank group, the protein expression of AMPK and p-AMPK in liver tissue was decreased (P<0.05), and the protein expression of AMPK and p-AMPK in pancreatic tissue was increased (P<0.05) in the model group. Compared with the model group, the protein expression of AMPK and p-AMPK in liver tissue in the metformin group, the EA group and the combination group was increased (P<0.05, P<0.01); the protein expression of AMPK in pancreatic tissue in the metformin group was increased (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was decreased (P<0.05); the protein expression of p-AMPK in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05). The protein expression of AMPK and p-AMPK in liver tissue in the combination group was higher than that in the metformin group and the EA group (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was less than that in the metformin group (P<0.05), and the expression of p-AMPK protein in pancreatic tissue in the combination group was less than that in the metformin group and the EA group (P<0.05). ④Compared with the blank group, the expression of PGP9.5 in pancreatic tissue in the model group was increased (P<0.01); compared with the model group, the expression of PGP9.5 in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05, P<0.01). The expression of PGP9.5 in pancreatic tissue in the EA group was lower than the metformin group and the combination group (P<0.05).@*CONCLUSION@#Electroacupuncture at "Tianshu" (ST 25) could promote the effect of metformin on activating AMPK in liver tissue of T2DM rats, improve the negative effect of metformin on AMPK in pancreatic tissue, and enhance the hypoglycemic effect of metformin. The mechanism may be related to the inhibition of pancreatic intrinsic nervous system.

The development and benefits of metformin in various diseases / 医学前沿

Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.

Effects of plateau hypoxia on population pharmacokinetics and pharmacodynamics of metformin in patients with Type 2 diabetes / 中南大学学报(医学版)

OBJECTIVES@#Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM).@*METHODS@#A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups.@*RESULTS@#The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T1/2), area under the curve (AUC), time to reach maximum concentration (Tmax). Compared with the control group, AUC was increased by 23.5%, Tmax and T1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population.@*CONCLUSIONS@#Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.

Antiproliferative effects of 13α/ß-steroids on triple-negative MDA-MB-231 breast cancer cells: unraveling intracellular signaling without ERα

Abstract This study aimed to investigate the activities of novel 20(R)-3,20-dihydroxy-19-norpregn-1,3,5(10)-trienes (kuz7 and kuz8b) of natural 13ß- and epimeric 13α-series against triple-negative MDA-MB-231 breast cancer cells. High antiproliferative activity of synthesized compounds kuz8b and kuz7 against MDA-MB-231 triple-negative cancer cells was revealed. The steroid kuz7 of natural 13ß-configuration was more active against MDA-MB-231 cells than the 13α-steroid kuz8b. Cell cycle analysis revealed common patterns for the action of both tested compounds. The number of cells in the subG1 phase increased in a dose-dependent manner, indicating induction of apoptosis, which was also verified by PARP cleavage. In contrast, the number of cells in the G0/G1 phase decreases with increasing compound concentration. Steroid kuz7 at micromolar concentrations reduced the expression of GLUT1, a glucose transporter. High efficacy of the combination of kuz7 with biguanide metformin was shown, and synergistic effects on MDA-MB-231 cell growth and expression of the anti-apoptotic protein Bcl-2 were revealed. According to the obtained results, including the high activity of kuz7 against triple-negative cancer cells, the detected induction of apoptosis, and the decrease in GLUT1 expression, 13ß-steroid kuz7 is of interest for further preclinical studies both alone and in combination with the metabolic drug metformin

Development of metformin HCl granules using brown flaxseed mucilage as a retardant polymer: effects of polymer and drug ratio

Abstract Flaxseed (Linum usitatissimum L.) is the seed of a multipurpose plant of pharmaceutical interest, as its mucilage can be used as a natural matrix to develop extended-release dosage forms and potentially replace synthetic polymers. In this study, a 3² factorial design with two replicates of the central point was applied to optimize the development of extended-release granules of metformin HCl. The total fiber content of the mucilage as well as the friability and dissolution of the formulations were evaluated. The lyophilized mucilage presented a high total fiber content (42.63%), which suggests a high efficiency extraction process. Higher concentrations of the mucilage and metformin HCl yielded less friable granules. In addition, lower concentrations of metformin HCl and higher concentrations of the mucilage resulted in slower drug release during the dissolution assays. The release kinetics for most formulations were better represented by the Hixson-Crowell model, while formulations containing a higher concentration of the mucilage were represented by the Korsmeyer-Peppas model. Nonetheless, five formulations showed a longer release than the reference HPMC formulation. More desirable results were obtained with a higher concentration of the mucilage (13-18%) and a lower concentration of metformin (40%).

The effects of metformin, acetylsalicylic acid and ibuprofen on telomerase enzyme activity: inhibitory effect of ibuprofen

Abstract Telomerase enzyme is necessary for the elongation of telomeres while telomerase being critical for aging and cancer. Metformin, ibuprofen, and acetylsalicylic acid used in this research are drugs that millions of people already use and that many are likely to use in future. In this study, the effects of these drugs on telomerase activity of Mus musculus swiss albino mice in liver tissue were investigated and the telomerase activity was measured with a PCR-ELISA based kit. In the study a possible connection between telomerase enzyme activity and activities of antioxidant enzymes was also investigated by determining the activity of superoxide dismutase (SOD) and catalase enzymes. The data obtained show that metformin slightly decreased telomerase enzyme activity in low dose application; however, this change was not statistically significant. In ibuprofen application, there was a significant inhibitory effect when high doses were used; whereas, there was a slight inhibitory effect at low doses. In acetylsalicylic acid application, a slight activator effect was detected; it was not statistically significant, though. Metformin was observed to increase catalase and SOD activities in general while low and high doses of acetyl salicylic acid showed different effects. In addition, ibuprofen caused a statistically significant increase in liver SOD values. It is important to note that this study demonstrated a significant inhibitory effect of ibuprofen on telomerase enzyme activity in animal models..

Polineuropatia diabética assintomática induzida pelo uso crônico de metformina e correlação com vitamina B12 / Asymptomatic diabetic polyneuropathy induced by chronic metformin use and correlation with vitamin B12

Introdução: Diabetes Mellitus é doença metabólica, caracterizada pela deficiência absoluta ou relativa de insulina, que acomete cerca de 382 milhões de pessoas em todo mundo, tendo uma das complicações mais comuns a polineuropatia. A Metformina, medicamento amplamente utilizado como tratamento do Diabetes, foi descrita como responsável, em algumas literaturas, por causar ou agravar deficiência de vitamina B12, que está similarmente relacionada ao desenvolvimento de polineuropatia.Métodos: Nesse sentido, foi conduzido um estudo no município de Soledade ­ RS, com objetivo de verificar se essa relação é condizente com a realidade da localidade. Foram escolhidos 58 pacientes, dos quais 30 responderam questionários adaptados baseados na literatura e na Classificação de Neuropatia de Michigan (MNSS-Brasil), então colhidos 5 ml de sangue venoso da fossa antecubital, preparado soro do qual uma alíquota foi separada para determinação bioquímica da vitamina B12.Resultados: Analisando os resultados, a maioria dos pacientes analisados apresentou sintomas de polineuropatia, e 10% deste, deficiência vitamínica.Conclusão: nenhuma variável explicou a correlação do uso crônico da Metformina, dose e gênero com a deficiência da vitamina B12, o que indica que não há evidências fortes o suficiente que sustentem esse fato, de acordo com as particularidades da localidade analisada.

Introduction: Diabetes Mellitus is a metabolic disease, characterized by absolute or relative insulin deficiency, which affects about 382 million people, with polyneuropathy being one of the most common complications. Metformin, a drug widely used as a treatment for diabetes, has been described as responsible, in some literature, for causing or aggravating vitamin B12 deficiency, which is similarly related to the development of polyneuropathy.Methods: In this sense, a study was conducted in Soledade ­ RS, in order to verify whether this relationship is consistent with the reality of the locality. Fifty-eight patients were selected, of which 30 answered adapted questionnaires based on the literature and on the Michigan Neuropathy Classification (MNSS-Brazil), then 5 ml of venous blood was collected from the antecubital fossa, serum prepared from which an aliquot was separated for biochemical determination of the vitamin B12.Results: Analyzing the results, most of these patients presented symptoms of polyneuropathy and, 10% of them, vitamin deficiency.Conclusion: no variable explained the correlation of chronic use of Metformin, dose and gender with vitamin B12 deficiency, which indicates that there is not enough evidence to support this fact, according to the particularities of the analyzed locality.

Efeitos da nanopartícula de ácido poli lático-co-glicólico (PLGA) associada ao cloridrato de metformina na doença periodontal em ratos diabéticos / Effects of polylactic-co-glycolic acid (PLGA) nanoparticle associated with metformin hydrochloride on periodontal disease in diabetic rats

Existe uma associação entre diabetes e a periodontite, e a Metformina (MET) além de controlar os níveis glicêmicos, tem apresentado efeitos antiinflamatórios e na diminuição da perda óssea periodontal. Ao se veicular a MET a um sistema de nanopartículas pode-se apresentar a vantagem de aumento da eficácia terapêutica. Objetivos: esse estudo consistiu na avaliação dos efeitos antiinflamatórios, perda óssea e disponibilidade in vitro/in vivo de uma nanopartícula de ácido poli lático-co-glicólico (PLGA) associada à MET em um modelo de periodontite induzida por ligadura. Materiais e métodos: o PLGA carreado com diferentes doses da MET foi caracterizado pelo seu diâmetro médio, tamanho da partícula, índice de polidispensão e eficiência de aprisionamento. Foram utilizados ratos machos da linhagem Wistar, divididos aleatoriamente, em grupos controles e experimentais com diferentes doses de MET associadas ou não ao PLGA, os quais receberam diferentes tratamentos. Amostras de maxilas e tecidos gengivais foram utilizadas para avaliação de perda óssea e inflamação, por meio da microtomografia computadorizada, histopatológico, imunohistoquímica, análise de citocinas inflamatórias e expressão gênica de proteínas por RT-PCR quantitativo. Para o ensaio de liberação in vitro, utilizou-se o dispositivo de células de difusão vertical de Franz estáticas. Para a disponibilidade in vivo, as amostras de sangue foram coletadas em diferentes intervalos de tempo e analisadas por cromatografia líquida de alta eficiência acoplado a espectrometria de massas (HPLC-MS/MS). Resultados: o diâmetro médio das nanopartículas de PLGA carreadas com MET estava em um intervalo de 457,1 ± 48,9 nm (p <0,05) com um índice de polidispersidade de 0,285 (p <0,05), potencial Z de 8,16 ± 1,1 mV (p <0,01) e eficiência de aprisionamento (EE) de 66,7 ± 3,73. O tratamento com a MET 10 mg / kg + PLGA mostrou uma baixa concentração de células inflamatórias, fraca imunomarcação para RANKL, Catepsina K, OPG e osteocalcina. Diminuição dos níveis de IL-1ß e TNF-α (p <0,05), aumento da expressão gênica do AMPK (p <0,05) e diminuição do NF-κB p65, HMGB1 e TAK-1 (p <0,05). O 10 mg/kg MET + PLGA foi liberado no ensaio in vitro sugerindo um modelo cinético de difusão parabólica com um perfil de liberação que atinge 50% de seu conteúdo em 2h e permanece em liberação constante em torno de 60% até o final de 6h. O ensaio in vivo mostrou o volume aparente de distribuição Vz/F (10 mg/kg MET + PLGA, 46,31 mL/kg vs. 100 mg/kg MET + PLGA, 28,8 mL/kg) e o tempo médio de residência MRTinf (PLGA + MET 10 mg /kg, 37,66h vs. MET 100 mg/kg, 3,34h). Conclusão: o PLGA carreado com MET diminuiu a inflamação e a perda óssea na periodontite em ratos diabéticos. O 10 mg/kg MET + PLGA teve uma taxa de eliminação mais lenta em comparação com o MET 100 mg/kg. A formulação modifica os parâmetros farmacocinéticos, como volume de distribuição aparente e tempo médio de residência (AU).

There is an association between diabetes and periodontitis, and Metformin (MET) in addition to controlling glycemic levels, has shown anti-inflammatory effects and decreased periodontal bone loss. By transferring MET to a nanoparticle system, the advantage of increasing therapeutic efficacy can be presented. Objectives: this study consisted of evaluating the antiinflammatory effects, bone loss and in vitro/in vivo availability of a polylactic-co-glycolic acid (PLGA) nanoparticle associated with MET in a ligature-induced periodontitis model. Materials and methods: PLGA loaded with different doses of MET was characterized by its mean diameter, particle size, polydispension index and entrapment efficiency. Male Wistar rats were used, randomly divided into control and experimental groups with different doses of MET associated or not with PLGA, which received different treatments. Samples of jaws and gingival tissues were used to assess bone loss and inflammation, using computed microtomography, histopathology, immunohistochemistry, analysis of inflammatory cytokines and gene expression of proteins by quantitative RT-PCR. For the in vitro release assay, the static Franz vertical diffusion cell device was used. For in vivo availability, blood samples were collected at different time intervals and analyzed by high performance liquid chromatography coupled with mass spectrometry (HPLC-MS/MS). Results: the mean diameter of MET-loaded PLGA nanoparticles was in the range of 457.1 ± 48.9 nm (p <0.05) with a polydispersity index of 0.285 (p <0.05), Z potential of 8.16 ± 1.1 mV (p <0.01) and trapping efficiency (EE) of 66.7 ± 3.73. Treatment with MET 10 mg/kg + PLGA showed a low concentration of inflammatory cells, weak immunostaining for RANKL, Cathepsin K, OPG and osteocalcin. Decreased IL-1ß and TNF-α levels (p <0.05), increased AMPK gene expression (p <0.05) and decreased NF-κB p65, HMGB1 and TAK-1 (p <0. 05). The 10 mg/kg MET + PLGA was released in the in vitro assay suggesting a kinetic model of parabolic diffusion with a release profile that reaches 50% of its content in 2h and remains in constant release around 60% until the end of 6h . The in vivo assay showed the apparent volume of distribution Vz/F (10 mg/kg MET + PLGA, 46.31 mL/kg vs. 100 mg/kg MET + PLGA, 28.8 mL/kg) and the mean MRTinf residency (PLGA + MET 10 mg/kg, 37.66h vs. MET 100 mg/kg, 3.34h). Conclusion: MET-loaded PLGA decreased inflammation and bone loss in periodontitis in diabetic rats. 10 mg/kg MET + PLGA had a slower rate of elimination compared to 100 mg/kg MET. The formulation modifies pharmacokinetic parameters such as apparent volume of distribution and mean residence time (AU).

Cyperus esculentus L. protects testis and sperm morphology of hyperglycaemic rats / Cyperus esculentus L. protege la morfología de los testículos y los espermatozoides de ratas hiperglicémicas

Cyperus esculentus L. (tiger nut) is a tuberous plant that promotes and protects reproductive functions, which are usually hampered in diabetics. The present study investigated the effect of Cyperus esculentus tuber extract (CETE) on testicular histology and sperm viability of alloxan-induced hyperglycaemic Wistar rats. Twenty-five adult male Wistar rats weighing 150-200g and grouped into five (n=5): Group 1, the control, administered tap water (20mL/kg), while groups 2-5 were administered a single intraperitoneal dose (120mg/kg b.w.) of alloxan, and each further received orally tap water (20mL/kg), CETE (100mg/kg), CETE (500 mg/kg) and metformin (500 mg/kg), respectively for 21 days. The animals were sacrificed, their sperm collected for analysis, while the testes were harvested, and processed for histology. Results showed significantly increased (p<0.05) blood glucose and testosterone, and significantly decreased (p<0.05) sperm pH, motility, count, morphology and density, as well as disruptions and hypertrophy of the spermatogenic and Sertoli cells of the hyperglycaemic group. There were significant (p<0.05) blood glucose decline, while the sperm parameters and testicular weight improved with normal testicular histology in the 100 mg/kg CETE, 500 mg/kg CETE, and metformin-treated groups compared to the control and hyperglycaemic group. Treatment with CETE showed blood glucose amelioration and improved sperm quality, as well as testicular damage attenuation.

Cyperus esculentus L. es una planta tuberosa que promueve y protege las funciones reproductivas, que generalmente se ven afectadas en los diabéticos. El presente estudio investigó el efecto del extracto de tubérculo de Cyperus esculentus (CETE) sobre la histología testicular y la viabilidad de los espermatozoides de ratas wistar con hiperglicemia inducida por alloxan. Veinticinco ratas Wistar macho adultas que pesaban 150-200 g y se agruparon en cinco (n = 5): el grupo 1, el control, administró agua del grifo (20ml / kg), mientras que los grupos 2-5 se les administró una dosis intraperitoneal única (120 mg / kg p.v.) de alloxan, y agua del grifo por vía oral (20ml/kg), CETE (100 mg/kg), CETE (500 mg/kg) y metformina (500 mg/kg), respectivamente durante 21 días. Los animales fueron sacrificados, su esperma recolectada para su análisis, mientras que los testículos fueron retirados y procesados para histología. Los resultados mostraron un aumento significativo (p<0,05) de la glucosa en sangre y la testosterona, y una disminución significativa (p<0,05) del pH, la motilidad, el recuento, la morfología y la densidad de los espermatozoides, así como interrupciones e hipertrofia de las células espermatogénicas y sertoli del grupo hiperglucémico. Hubo una disminución significativa (p<0,05) de la glucosa en sangre, mientras que los parámetros espermáticos y el peso testicular mejoraron con la histología testicular normal en los grupos de 100 mg / kg de CETE, 500 mg / kg de CETE y tratados con metformina en comparación con el grupo de control e hiperglucémico. El tratamiento con CETE mostró una mejora de la glucosa en sangre y una mejora de la calidad de los espermatozoides, así como atenuación del daño testicular.

La metformina durante el embarazo en mujeres con síndrome de ovario poliquístico / Metformin during pregnancy in women with polycystic ovary syndrome

Introducción: La resistencia a la insulina tiene gran relevancia en la patogenia del síndrome de ovario poliquístico, por lo que es común que se empleen los sensibilizadores a la insulina. La metformina tiene diversos fines terapéuticos y es la más recomendada. Durante el embarazo desempeña un rol en la reducción del riesgo de aborto, la hipertensión inducida por el embarazo, la macrosomía, la cesárea y la hipoglucemia neonatal. Con resultados menos consistentes también participa en la reducción del riesgo de diabetes gestacional. No obstante, existen preocupaciones sobre su seguridad a largo plazo. Objetivo: Realizar una actualización del estado del arte sobre el empleo de la metformina durante el embarazo en mujeres con síndrome de ovario poliquístico. Métodos: Se realizó una revisión bibliográfica donde se consultaron 57 artículos obtenidos de las bases de datos Google Académico, Medline, Pubmed, SciELO. Conclusiones: El tratamiento con metformina es más fácil, más económico y menos "inquietante" que la insulina. La prescripción y adherencia son más simples, lo que ha contribuido a que en la práctica clínica se emplee la metformina durante el embarazo con una frecuencia cada vez mayor. El posicionamiento actual de la comunidad científica acepta la metformina como una alternativa válida de tratamiento en las mujeres con síndrome de ovario poliquístico durante el embarazo pero recomienda poner cuidado en la observación de su seguridad a largo plazo e incrementar la evidencia(AU)

Introduction: Insulin resistance is highly relevant in the pathogenesis of polycystic ovary syndrome, which is why it is common to use insulin sensitizers. Metformin has various therapeutic purposes and is the most recommended. During pregnancy, it plays a role in reducing the risk of miscarriage, pregnancy-induced hypertension, macrosomia, cesarean section, and neonatal hypoglycemia. With less consistent results, it also participates in reducing the risk of gestational diabetes. However, there are concerns about its long-term safety. Objective: To update the state of the art on the use of metformin during pregnancy in women with polycystic ovary syndrome. Methods: A bibliographic review was carried out where 57 articles obtained from the Google Scholar, Medline, Pubmed, SciELO databases were consulted. Conclusions: Treatment with metformin is easier, cheaper and less "disturbing" than insulin. Prescription and adherence are simpler, which has contributed to the fact that metformin is used in clinical practice during pregnancy with increasing frequency. The current position of the scientific community accepts metformin as a valid treatment alternative in women with polycystic ovary syndrome during pregnancy, but recommends careful observation of its long-term safety and increasing evidence(AU)

Frecuencia de consumo inadecuado de vitamina B12 y sus niveles séricos en personas con diabetes mellitus tipo 2 tratadas con metformina en centros de salud de la Provincia de Buenos Aires / Frequency of inadequate consumption of vitamin B12 and its serum levels in people with diabetes mellitus type 2 under metformin treatment in health centers of the Province of Buenos Aires

Introducción: el uso prolongado de metformina y la carencia de consumo de vitamina B12 (B12) pueden provocar su déficit en pacientes con diabetes mellitus tipo 2 (DM2). Objetivos: analizar la frecuencia de consumo insuficiente de B12 según: características personales, datos antropométricos, de laboratorio y uso de metformina; asociar niveles séricos de cobalamina con dosis y tiempo de metformina; establecer la relación entre la ingesta de B12 y los niveles séricos. Materiales y métodos: diseño transversal. Mediante encuesta de frecuencia de consumo de alimentos fuente de B12 en 200 pacientes tratados con metformina por más de 18 meses. Se analizaron datos clínicos, antropométricos, de laboratorio, tiempo y dosis de metformina, en dos centros de salud de la Provincia de Buenos Aires. Resultados: el porcentual de consumo deficiente fue del 29%. Se registró un 47,5% de desocupación que alcanzó un déficit de ingesta del 32,6%. Se midió B12 sérica en el 65% de la muestra y un 53,8% de los valores fue anormal (0,8% en niveles deficientes o bajos y 23% en niveles normal-bajo), observándose asociación significativa a dosis de metformina ≥1.500 mg. Las deficiencias de consumos de B12 (<2,4 µg/día) fueron casi cuatro veces mayores en el grupo con menor recuento eritrocítico (76,9 % vs 18,5%; p<0,00 ). El volumen corpuscular medio (VCM) y el recuento de plaquetas arrojaron datos estadísticamente significativos. Conclusiones: si bien el 29% de la muestra exhibió consumo vitamínico deficiente, el 90% de los pacientes con déficit sérico registró ingestas adecuadas de B12. Dado que se trató de un diseño transversal, donde no pudo evaluarse causalidad, en pacientes intervenidos farmacológicamente con metformina se sugiere considerar su impacto en situaciones deficitarias.

Introduction: the prolonged use of metformin and the lack of consumption of vitamin B12 can cause its deficit, in T2D. Objectives: to analyze the frequency of insufficient consumption of vitamin B12 according to: personal characteristics, anthropometric and laboratory data, and use of metformin; associate serum cobalamin levels with metformin dose and time; establish a relationship between B12 intake and serum levels. Materials and methods: cross-sectional design. Through a survey of the frequency of consumption of food sources of B12 in 200 patients treated with metformin for more than 18 months. Clinical, anthropometric, laboratory data, time and dose of metformin were analyzed in 2 health centers in the Province of Buenos Aires. Results: the percentage of deficient consumption was 29%. 47.5% of unemployment was registered, which reached an intake deficit of 32.6%. Serum B12 was measured in 65% of the sample where 53.8% of values were abnormal (0.8% in deficient levels) and 23% at levels normal lower cut-off point, with a significant association being observed at doses of metformin ≥1,500 mg. Deficiencies in B12 intake (<2.4 µg/day) were almost 4 times higher in the group with the lowest erythrocyte count (76.9% vs 18.5%; p<0.00 ). The MCV and platelet count yielded statistically significant data. Conclusions: although 29% of the sample exhibited poor vitamin intake, 90% of patients with serum deficiency had adequate intakes of vitamin B12. Given that it is a cross-sectional design, where causality cannot be evaluated, it is suggested: in patients undergoing pharmacological intervention with metformin, consider the impact of this in deficient situations.

La asociación del déficit de vitamina B12 y metformina / The association of vitamin B12 deficiency and metformin

La metformina es el agente antidiabético oral más utilizado para el tratamiento de la diabetes mellitus tipo 2 (DM2) y se ha descrito la asociación de su uso con el déficit de vitamina B12. Se realizó una revisión narrativa de estudios para conocer la evidencia de dicha asociación, y las recomendaciones para su pesquisa, prevención y tratamiento. La prevalencia informada del déficit de vitamina B12 en los pacientes tratados con metformina osciló entre el 5,8% y el 52% en las diferentes series. Los pacientes de mayor edad, aquellos que reciben metformina a altas dosis y por más tiempo, y los que no consumen alimentos de origen animal, son quienes presentan mayor riesgo de padecer este déficit. Se recomienda la determinación de vitamina B12 cada año en pacientes con DM2 tratados con metformina y la eventual reposición en caso de déficit. Si bien existe consenso sobre el tratamiento del déficit, aún falta evidencia que permita realizar la recomendación sobre el tratamiento preventivo.

Metformin is the most widely used oral antidiabetic agent for the treatment of type 2 diabetes (T2D) and the association of the use of this drug with vitamin B12 deficiency has been described. A review of studies was carried out to find out the evidence of this association and the recommendations for its detection, prevention and treatment. The reported prevalence of vitamin B12 deficiency in patients treated with metformin ranged from 5.8% to 52% in the different series. Older patients, those who received metformin at high doses and for a longer time, and those who do not consume food of animal origin, are those who are at greater risk of suffering from this deficit. The determination of vitamin B12 every 1 year is recommended in patients with T2D treated with metformin, and the eventual replacement in case of deficiency. Although there is consensus on the treatment of the deficit, there is still a lack of evidence to make recommendations on a preventive treatment

Uso "off label" de plantas medicinais para tratamento do diabete melito / "Off label" use of medicinal plants for the treatment of diabetes mellitus

As plantas medicinais são de fácil aquisição sem receita médica. Algumas delas possuem comprovação científica para o efeito hipoglicemiante, outras não. O objetivo deste estudo foi conhecer a prevalência e o perfil do paciente que usa plantas medicinais como coadjuvantes no tratamento do diabete. Foram entrevistados 140 diabéticos e pré-diabéticos agrupados em quem fazia o uso dessa alternativa e os que não. Em conclusão, a prevalência foi de 15,7%, maior em mulheres. A medicação prescrita foi metformina. A planta mais utilizada foi a pata-de-vaca. O grupo em uso referiu melhora glicêmica com a terapia complementar quando questionados sobre a glicemia uma semana antes e na semana de uso

Medicinal plants are easily available without a prescription. Some of them have scientific proof for the hypoglycemic effect, others do not. The objective of this study was to know the prevalence and profile of patients who use medicinal plants as adjuncts in the treatment of diabetes. A total of 140 diabetics and pre-diabetics were interviewed, grouped into those who used this alternative and those who did not. In conclusion, the prevalence was 15.7%, higher in women. The medication prescribed was metformin. The most used plant was the pata-de-vaca. The group in use reported glycemic improvement with the complementary therapy when asked about the glycemia one week before and in the week of use

Estudio comparativo de la terapia de metformina sola y metformina combinada con terapia de tintura de notholaena nivea en pacientes con diabetes tipo 2 / Comparative study of metformin therapy alone and metformin combined with notholaena nivea tincture therapy in patients with type 2 diabetes

La diabetes tipo 2 es un trastorno metabólico progresivo complejo, que representa una amenaza significativa para la salud humana y representa más del 91% de todos los casos de diabetes. Objetivo: evaluar el efecto de la adición de tintura de Notholaena nivea al tratamiento con metformina en pacientes con tolerancia alterada a la glucosa (IGT) y diabetes de tipo 2 (DMT2). Materiales y Método: Ensayo clínico unicentral, aleatorizado, simple ciego, controlado con placebo. Todos los participantes con diagnóstico de IGT y DMT2 que tomaban metformina fueron asignados aleatoriamente a recibir kits con tintura de Notholaena nivea autentica (40 pacientes) o placebo (58 pacientes), fijando 6 gotas diarias, 30 minutos antes del desayuno y almuerzo durante 26 semanas, se hicieron 3 controles (0, 13 y 26 semanas) midiendo glucosa plasmática en ayunas (FPG), nivel de hemoglobina glucosilada (HbA1C) y perfil lipídico. Resultados: del grupo de tratamiento (tintura de Notholaena nivea más metformina) fueron significativamente eficientes a las 13 semanas de iniciado el ensayo, manteniendo la directriz de reducción de glucosa plasmática (FPG), al iniciar el estudio el grupo control y tratamiento obtuvieron niveles de FPG similares con valores de .57±1.7 y 7.84±1.9 mmol/l respectivamente (p>0.05), a las 13 semanas se redujo a 7.21±1.mmol/l para el grupo control y 6.49±2.33 mmol/l para el grupo tratamiento (p<0.01), mientras que a la semana 26 el grupo control reporto 7.09±1.41 mmol/l en tanto el grupo tratamiento obtuvo 5.98±0.71 mmol/l (p<0.01). Hubo reducción de los niveles de HbA1C dentro de los grupos, pero no se evidenciaron diferencias por efecto del tratamiento. En el perfil lipídico el tratamiento de Metformina sola evidencio una mejor respuesta con la reducción de colesterol total y aumento de lipoproteínas de alta densidad (HDL) pero aumento la concentración de triglicéridos, mientras que el tratamiento con tintura de Notholaena nivea mantuvo los perfiles lipídicos al igual que en un inicio (p>0.05). Conclusiones: el tratamiento combinado de metformina más tintura de Notholaena nivea reduce acelerada y eficazmente las concentraciones de FPG en sangre de pacientes con IGT o DMT2, pero es ineficaz en el tratamiento del perfil lipídico(AU)

Type 2 diabetes is a complex progressive metabolic disorder, which represents a significant threat to human health and accounts for more than 91% of all diabetes cases. Objective: to evaluate the effect of adding Notholaena nivea tincture to metformin treatment in patients with impaired glucose tolerance (IGT) and type 2 diabetes (DMT2). Materials and Method: Unicentral, randomized, single-blind, placebo-controlled clinical trial. All participants diagnosed with IGT and T2DM who were taking metformin were randomly assigned to receive authentic Notholaena nivea tincture kits (40 patients) or placebo (58 patients), setting 6 drops daily, 30 minutes before breakfast and lunch for 26 weeks. , 3 controls were made (0, 13 and 26 weeks) measuring fasting plasma glucose (FPG), glycosylated hemoglobin level (HbA1C) and lipid profile. Results: the treatment group (Notholaena nivea tincture plus metformin) were significantly efficient at 13 weeks from the start of the trial, maintaining the plasma glucose reduction guideline (FPG), at the start of the study the control and treatment groups obtained levels of Similar FPG with values of .57±1.7 and 7.84±1.9 mmol/l respectively (p>0.05), at 13 weeks it was reduced to 7.21±1.mmol/l for the control group and 6.49±2.33 mmol/l for the treatment group (p<0.01), while at week 26 the control group reported 7.09±1.41 mmol/l while the treatment group obtained 5.98±0.71 mmol/l (p<0.01). There was a reduction in HbA1C levels within the groups, but no differences due to treatment effect were observed. In the lipid profile, the treatment with Metformin alone showed a better response with the reduction of total cholesterol and an increase in high-density lipoproteins (HDL) but increased the concentration of triglycerides, while the treatment with Notholaena nivea tincture maintained the lipid profiles at the same as at the beginning (p>0.05). Conclusions: the combined treatment of metformin plus Notholaena nivea tincture rapidly and effectively reduces FPG concentrations in the blood of patients with IGT or DMT2, but it is ineffective in the treatment of the lipid profile.Keywords: Type 2 diabetes, Notholaena nivea, FPG, Metformin, lipid(AU)

Metformin and resveratrol suppress type 2 diabetes mellitus-induced articular cartilage damage in rats associated with the inhibition of inflammation and augmentation of proteoglycans / La metformina y el resveratrol suprimen el daño del cartílago articular inducido por la diabetes mellitus tipo 2 en ratas asociado con la inhibición de la inflamación y el aumento de proteoglicanos

SUMMARY: Induction of osteoarthritis (OA) following diabetes is characterized by a sever inflammation of the joints that can lead to disability. The cartilage content of proteoglycans can substantially be reduced, following the induction of diabetes mellitus associated with inflammation as well as knee joint injury, and the antidiabetic drug metformin combined with the anti-inflammatory agent resveratrol can prevent these deleterious effects. Therefore, insulin-independent diabetes, type 2 diabetes mellitus (T2DM) was induced in Albino rats by streptozotocin (STZ) injection (50 mg/kg) after being fed on a high carbohydrate and fat diets for 2 weeks. The protective group of rats which also received a single injection of STZ was treated daily with metformin (Met; 200 mg/kg) and resveratrol (Res; 30 mg/kg) for 12 weeks. Harvested knee joint tissues were prepared for basic histology stain and for proteoglycans staining using light microscopy. Histology images showed in diabetic rats (T2DM) OA development as demonstrated by profound injury to the knee joint and severe decrease of articular cartilage proteoglycans content, which were substantialy protected by Met+Res. Met+Res also significantly (p< 0.0001) decreased diabetes induced glycemia, dyslipidemia, and the inflammatory biomarkers, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high sensitivity C-reactive protein (hs-CRP). In addition, there was a significant correlation between OA and glycemia, dyslipidemia, and inflammation. Collectively, we demonstrate an association between knee joint damage and biomarkers of glycemia, dyslipidemia, and inflammation in diabetes-induced OA, with metformin plus resveratrol providing protective effects.

RESUMEN: La inducción de osteoartritis (OA) después de la diabetes se caracteriza por una inflamación severa de las articulaciones que puede conducir a la discapacidad. El contenido de cartílago de proteoglicanos se puede reducir sustancialmente, luego de la inducción de diabetes mellitus asociada con inflamación y lesión en la articulación de la rodilla sin embargo, el fármaco antidiabético metformina combinado con el agente antiinflamatorio resveratrol puede prevenir estos efectos nocivos. Por lo tanto, se indujo diabetes insulino dependiente, diabetes mellitus tipo 2 (T2DM) en ratas albinas mediante inyección de estreptozotocina (STZ) (50 mg/kg) después de haber sido alimentadas con dietas ricas en carbohidratos y grasas durante 2 semanas. El grupo protector de ratas que también recibió una inyección única de STZ fue tratado diariamente con metformina (Met; 200 mg/kg) y resveratrol (Res; 30 mg/kg) durante 12 semanas. Tejidos de la articulación de la rodilla fueon retirados y teñidos con histología básica y tinción de proteoglicanos usando microscopía óptica. Las imágenes histológicas en ratas diabéticas mostraban (T2DM) desarrollo de OA visualizadas por una lesión profunda en la articulación de la rodilla y una disminución severa del contenido de proteoglicanos del cartílago articular, los cuales estaban sustancialmente protegidos por Met+Res. Met+Res. También disminuyó significativamente (p< 0,0001) la glucemia inducida por la diabetes, la dislipidemia y los biomarcadores inflamatorios, el factor de necrosis tumoral alfa (TNF-α), la interleucina-6 (IL-6) y la proteína C reactiva de alta sensibilidad (PCR-hs). Además, hubo una correlación significativa entre la OA y la glucemia, la dislipidemia y la inflamación. En conjunto, demostramos una asociación entre el daño de la articulación de la rodilla y los biomarcadores de glucemia, dislipidemia e inflamación en la OA inducida por diabetes, con metformina más resveratrol que brindan efectos protectores.