Metformin is the first-line oral antidiabetic drug for patients with type 2 diabetes mellitus. As the rate of new diagnosed cases of diabetes increases year-on-year, the number of patients who are prescribed metformin rises as well. In the Czech Republic only, 858,010 patients were treated for diabetes in 2015. 786,586 of them were treated for the type 2 diabetes mellitus. Metformin intoxication, called also MALA (metformin- associated lactic acidosis) after its main symptom, is a rare complication (≤ 10 cases per 100,000 patients per year) in the metformin treatment, but the mortality is high (up to 50%). Metformin-induced lactic acidosis develops when the contraindications of metformin therapy are not respected or in the event of an acute disease linked with dehydration and hypoxia. Patients with MALA are hospitalized at the int ernal medicine intensive care unit or the department of anesthesiology and critical care with multiple organ failure. This thesis aims at determining whether procedural nursing care standards, implemented in the form of a nursing process, are actively used in practice on intensive care beds. Methodology: The empirical part is compiled in the form of a qualitative research, as a case study of a female patient suffering from metformin intoxication, caused by a suicide...

CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / O diabetes mellitus tipo 2 (DM2) à uma sÃndrome que pode ser definida como uma condiÃÃo de distÃrbios metabÃlicos heterogÃneos caracterizados por hiperglicemia resultante de defeitos na secreÃÃo e aÃÃo da insulina, ou ambos. A metformina à o fÃrmaco de primeira escolha para tratamento de DM2, sendo o anti-hiperglicemiante oral mais amplamente prescrito, devido ao seu perfil de toxicidade reduzida e eficÃcia clÃnica. Os estudos de biodisponibilidade apresentam diversas funÃÃes, entres elas podem-se listar: avaliaÃÃo da bioequivalÃncia de medicamentos, avaliaÃÃo de medicamentos com princÃpios ativos novos e avaliaÃÃo de novas formulaÃÃes. Este estudo teve o objetivo de avaliar a biodisponibilidade entre uma formulaÃÃo de cloridrato de metformina 850 mg em comprimidos revestidos, chamada formulaÃÃo teste, versus uma formulaÃÃo de referÃncia no mercado nacional com a mesma dose do fÃrmaco e mesma forma farmacÃutica, em voluntÃrios sadios de ambos os sexos. Trata-se de um ensaio clÃnico do tipo aberto, randomizado, cruzado, com dois perÃodos, duas sequÃncias, nos quais os voluntÃrios receberam em cada perÃodo distinto, 01 comprimido revestido da formulaÃÃo teste ou 01 da formulaÃÃo de referÃncia. As formulaÃÃes foram administradas em dose Ãnica, via oral, seguida de coletas de sangue, de pelo menos quatro meias-vidas do fÃrmaco em estudo. Os perÃodos de tratamento obedeceram a um intervalo de sete meias-vidas, entre eles (washout). As concentraÃÃes plasmÃticas de metformina foram dosadas por mÃtodo analÃtico especÃfico e validado, baseado em cromatografia lÃquida de alta eficiÃncia acoplada à espectrometria de massa (CLAE/EM). Os dados deste estudo revelaram que a formulaÃÃo teste e a formulaÃÃo referÃncia apresentaram resultados equivalentes, dentro dos limites de variaÃÃo previstos nas normativas reguladoras (80-125%) para os parÃmetros ASCinf (Ãrea sob a curva) e Cmax (concentraÃÃo sÃrica mÃxima do fÃrmaco). Desse modo, serà possÃvel garantir uma intercambialidade entre as formulaÃÃes, que poderà gerar competiÃÃo no mercado e consequentemente preÃos mais competitivos e facilidade de acesso ao medicamento. / Type 2 diabetes mellitus (DM2 is a syndrome which may be defined as a condition of heterogeneous metabolic disorder characterized by hyperglycemia resulting from defects in insulin secretion and action, or both. Metformin is the drug of choice for the treatment of type 2 diabetes, and it is the oral antihyperglyciemic most widely prescribed, due to their favorable toxicity profile and efficacy. Bioavailability studies have several functions including assessment of drugs bioequivalence, evaluation of drugs with new active principles and evaluating new formulations. This study aimed to assess the bioavailability of a formulation of metformin hydrochloride 850 mg film coated tablets, called test formulation, versus a reference formulation in the national market with the same dose of the drug in healthy volunteers of both genders. This is a clinical trial open-type, randomized, crossed, two-period, two-sequence, in which the volunteers received in each distinct period of 01 film coated tablet formulation of 01 test or reference formulation. The formulations were administered in a single oral dose, followed by blood sampling, at least four half-lives of study drug. The treatment periods obeyed an interval of seven half-lives, between them (washout). The metformin plasma concentrations were measured by a specific and validated analytical method based on high efficiency liquid chromatography coupled to mass spectrometry (HELC / MS). The data from this study reveal that the test formulation and the reference formulation showed similar results within the variation limits provided in the regulator norms (80-125%) for AUCinf (area under the curve) and Cmax (maximum serum concentration of drug). Thus, it will be possible ensure interchangeability between the formulations, which could lead to market competition and therefore more competitive prices and easy access to the drug.

Orientador: Edson Antunes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-21T14:09:45Z (GMT). No. of bitstreams: 1 Calixto_MarinaCiarallo_D.pdf: 2454146 bytes, checksum: 3f9d2c9797c668d719c59ae5fd3f277f (MD5) Previous issue date: 2012 / Resumo: A obesidade e a asma são doenças prevalentes e crescentes, e ambas têm impacto significativo na saúde pública mundial. O aumento simultâneo da prevalência da asma e da obesidade tem levado investigadores a sugerir que a obesidade possa ser um fator importante no desenvolvimento da asma, ou até piorar um quadro de asma pré-existente. Numerosos estudos populacionais conduzidos em todo o mundo indicam que a prevalência de asma é maior em indivíduos obesos versus magros. Além disso, diversos estudos prospectivos, tanto em adultos quanto em crianças, indicam que o risco relativo da incidência de asma aumenta com o índice de massa corporal (IMC). A obesidade também piora o controle medicamentoso da asma e a gravidade desta doença. Recentemente, diversos dados emergiram indicando que a inflamação associada à obesidade pode aumentar a propensão para o desenvolvimento de asma. Acredita-se que a resistência à insulina associada à obesidade desempenha importante papel no desenvolvimento da asma, explicando, ao menos em parte, a associação da asma com obesidade. Relatos recentes indicam uma alta prevalência de resistência à insulina em pacientes obesos e asmáticos versus obesos não asmáticos, sugerindo que a resistência à insulina possa contribuir com este fenótipo. Baseado nestas informações, o objetivo deste trabalho foi verificar se doenças metabólicas associadas à obesidade, tal como a resistência à insulina, podem estar envolvidas na exacerbação da asma associada à obesidade. No presente estudo observamos que o tratamento de camundongos obesos com metformina corrige a resistência à ação sistêmica da insulina. Além disso, metformina normaliza o trânsito dos eosinófilos da medula óssea até o lúmen em animais obesos e desafiados com OVA. Essa normalização parece ser mediada pela ativação da AMPK no pulmão e diminuição das concentrações de TNF-? e NOx no LBA e inibição da expressão de iNOS induzida pelo fator de transcrição NF-?B no pulmão. Além disso, ao normalizar o tráfego de eosinófilos da região peribronquiolar para a luz das vias aéreas, o tratamento com metformina induz concomitante diminuição do acúmulo de eosinófilos na medula óssea devido à regulação positiva da expressão de moléculas de adesão VLA-4 e Mac-1 na superfície das células e posterior aumento da resposta adesiva à ICAM-1 e VCAM-1. Os resultados descritos neste estudo parecem confirmar a hipótese que a resistência à insulina, resultante da obesidade, medeia a exacerbação da resposta inflamatória pulmonar observada em animais obesos. Dessa forma, ao corrigir a resistência à insulina sistêmica através da ativação da AMPK, camundongos sensibilizados obesos aceleram o início do processo de resolução da inflamação pulmonar alérgica / Abstract: Obesity and asthma are prevalent and increasing diseases, and both have significant impact on global public health. The increase in prevalence of asthma and obesity has led researchers to suggest that obesity may be an important factor in the development of asthma, or even worse the pre-existing asthma. Numerous populational studies conducted around the world indicate that the prevalence of asthma is higher in obese versus lean person. In addition, several prospective studies, both in adults and in children, indicate that the relative risk of incident asthma increases with body mass index (BMI). Obesity also worsens the drug therapy of asthma and the severity of this disease. Recently, several data emerged showing that the inflammation associated with obesity increase the propensity for development of asthma. It is believed that insulin resistance associated with obesity plays an important role in the development of asthma, explaining, at least in part, asthma associated with obesity. Recent reports indicate a high prevalence of insulin resistance in obese asthmatics versus obese non-asthmatics patients, suggesting that insulin resistance may contribute to this phenotype. Based on this information, the purpose of this study was to determine whether metabolic diseases associated with obesity such as insulin resistance, are involved in asthma exacerbation associated with obesity. In the present study we observed that obese mice treated with metformin, impairs the resistantance to the systemic action of insulin. Furthermore, in obese mice challend with OVA, metformin normalizes the transit of eosinophils from bone marrow to the lung lumen. This normalization is mediated by AMPK activation in the lung, as well as decreased concentrations of TNF-? and nitrite and nitrate in BAL fluid accompanied by the inhibition of NF-?B induced iNOS expression in the lung. Furthermore, by normalizing the eosinophils trafficking from peribronchiolar region to airway lumen, metformin treatment induces concomitant reduction in the accumulation of eosinophils in bone marrow through the upregulation of adhesion molecules VLA-4 and Mac-1 on cell surface and subsequent increase in the adhesive response to plates coated with ICAM-1 and VCAM-1. Our data seem to confirm the hypothesis that insulin resistance resulting from obesity mediates the exacerbation of airway inflammation in high fat-diet mice. Thus, by normalizing the systemic insulin resistance through the atictivation of AMPK, obese sensitized mice progress to resolution of allergic airway inflammation / Doutorado / Farmacologia / Doutora em Farmacologia

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Metformin är ett biguanidderivat som främst används vid diabetes mellitus typ 2. Det verkar genom ett flertal mekanismer och ökar bland annat insulinkänsligheten. Forskning har visat att det finns ett samband mellan metformin och överlevnad i cancer. Studier pågår för att undersöka metformins antineoplastiska effekt. Övervikt och diabetes ökar risken för endometriecancer och epidemiologiska studier har visat att metformin ger bättre total överlevnad vid endometriecancer. Genom artikelsökning via PubMed erhölls fem studier där metformins effekt på endometriecancervävnad undersöktes. Resultaten i dem varierar men majoriteten pekar på en antiproliferativ effekt av metformin, med avseende på Ki-67. Med vilken verkningsmekanism den effekten erhålls är tvetydligt, då vissa resultat tyder på inhiberad mTOR-signalering medan andra inte visar effekt på de variablerna. En minskning i cirkulerande tillväxtfaktorer insulin och IGF-1 ses, vilket kan ha en inhiberande effekt. Större studier krävs för att kunna avgöra vilken effekt metformin har på endometriecancer.

[ES] El cáncer de mama es el cáncer más común en mujeres en todo el mundo y la principal causa de muerte por cáncer en mujeres junto al cáncer de pulmón. Este cáncer tiene muy buen pronóstico en general, con una supervivencia del 80%. Sin embargo, el pronóstico del cáncer de mama triple negativo es mucho peor, al no conocerse ninguna diana farmacológica y tratarse de forma inespecífica. La metformina, fármaco prescrito para la diabetes, ha mostrado algunos buenos resultados preliminares como potencial terapia. Por otro lado, el principal tratamiento dirigido de las pacientes HER2+ es el trastuzumab, que neutraliza al receptor HER2 amplificado; sin embargo, un elevado número de pacientes desarrollan resistencias al tratamiento. Los microRNAs son pequeños RNAs no codificantes capaces de regular la expresión génica epigenéticamente, y pueden ser secretados de la célula en vesículas llamadas exosomas. El objetivo de este trabajo es abordar estas dos problemáticas en cáncer de mama. Son necesarios estudios de los mecanismos de acción o resistencia de estos fármacos a través de la regulación epigenética por microRNAs. Queremos determinar la relación del miR-26a y sus dianas con el efecto de la metformina en cáncer de mama triple negativo y estudiar las diferencias de expresión de microRNAs que generan resistencias a trastuzumab en cáncer de mama HER2+, así como estudiar su modo de transmisión entre células. Se realizaron ensayos celulares tratando con metformina las líneas MDA-MB-231, MDA-MB-468 y MCF-7 así como sobreexpresando o inhibiendo miR-26a y se midieron sus dianas teóricas por qPCR. Para las líneas HER2+ se realizó un Affymetrix Genechip miRNA 4.0 microarray comparando líneas SKBR-3wt y BT-474wt con sus respectivas líneas con resistencia generada a trastuzumab y HCC-1954 como resistente innata. Se estudiaron los microRNAs más relevantes del array en las líneas celulares y en pacientes y se comprobó su presencia en exosomas, así como el efecto de los exosomas en la transmisión de la resistencia. La sobreexpresión de miR-26a resultó en una reducción en la viabilidad celular que se recuperó parcialmente al inhibirla. E2F3, MCL-1, EZH2, MTDH y PTEN fueron regulados negativamente por miR-26a y la proteína PTEN también se redujo tras la sobreexpresión de miR-26a. El tratamiento con metformina redujo la viabilidad de las células de cáncer de mama, aumentó la expresión de miR-26a y condujo a una reducción en la expresión de BCL-2, EZH2 y PTEN. La inhibición de miR-26a previene parte del efecto en viabilidad de la metformina y la reducción de la expresión de PTEN y EZH2. En las líneas HER2+, miR-23b-3p y miR-146a-5p fueron los principales candidatos extraídos del array. miR-23b-3p inhibió PTEN significativamente en la línea BT-474. miR-146a-5p aumentó la resistencia de las células SKBR-3 al trastuzumab y su inhibición redujo la resistencia de las SKBR-3r. El aumento de miR-146a-5p en SKBR-3wt tuvo un efecto en ciclo celular aumentando la fase S y la G2/M, inhibiendo la expresión de CDKN1A y aumentando la de CCNB1. Los exosomas de las SKBR-3 contenían miR-146a-5p, con mayores niveles en los de las resistentes (exoR). Los exoR aumentaron la resistencia a trastuzumab, la transición epitelio-mesenquimal y la migración al co-cultivarse con SKBR-3wt, y la angiogénesis en las HUVEC. Nuestros resultados sugieren que el efecto de la metformina está mediado por una mayor expresión de miR-26a y reducción de sus dianas, PTEN y EHZ2. Por tanto, el uso de metformina en el tratamiento del cáncer de mama constituye una prometedora potencial terapia. En HER2+, miR-23b parece provocar resistencia a trastuzumab vía PTEN y miR-146a a través del ciclo celular. Además, miR-146a se transmite en exosomas, que son capaces de reducir la sensibilidad al trastuzumab de las células sensibles y aumentar la TEM, migración y angiogénesis. / [EN] Breast cancer is the most common cancer in women worldwide and the leading cause of cancer death in women along with lung cancer. This cancer has a very good general prognosis, with a survival of 80%. However, the prognosis for triple negative breast cancer is much worse, as it has no pharmacological target and treats it nonspecifically. Metformin, a prescribed diabetes drug, has shown some good preliminary results as potential therapy. On the other hand, the main targeted treatment for HER2 + patients is trastuzumab, which neutralizes the amplified HER2 receptor, but a large number of patients experienced resistance to treatment. MicroRNAs are small non-coding RNAs that are part of epigenetics and are capable of regulating gene expression, and which can be secreted from the cell into vesicles called exosomes. The objective of this work is to address these two problems in breast cancer, which need to study the mechanism of action or resistance of these drugs, through the epigenetics of microRNAs. We want to determine the relationship of miR-26a and its targets with the effect of metformin in triple negative breast cancer and to study the differences in the expression of microRNAs that process resistance to trastuzumab in HER2 + breast cancer, as well as to study its mode of transmission between cells. Cellular assays were performed treating the MDA-MB-231, MDA-MB-468 and MCF-7 lines with metformin as well as overexpressing or inhibiting miR-26a, and their theoretical targets were measured by qPCR. For the HER2+ cell lines, an Affymetrix Genechip miRNA 4.0 microarray was performed comparing SKBR-3wt and BT-474wt lines with their respective cell lines with generated resistance to trastuzumab and HCC-1954 as innate resistance. The most relevant microRNAs of the array in cell lines and in patients were studied and their presence in exosomes was verified, as well as the effect of exosomes in the transmission of resistance. The overexpression of miR-26a resulted in a reduction in cell viability that was partially recovered by inhibiting it. E2F3, MCL-1, EZH2, MTDH, and PTEN were down-regulated by miR-26a, and the PTEN protein was also reduced after overexpression of miR-26a. Metformin treatment reduced the viability of breast cancer cells, increased miR-26a expression, and led to a reduction in BCL-2, EZH2, and PTEN expression. Inhibition of miR-26a partly prevents the effect of metformin in viability and the reduction of the expression of PTEN and EZH2. In the HER2+ lines, miR-23b-3p and miR-146a-5p were the main candidates extracted from the array. miR-23b-3p was shown to significantly inhibit PTEN in the BT-474 cell line. miR-146a-5p increased resistance of SKBR-3wt cells to trastuzumab and its inhibition reduced resistance of SKBR-3r. The increase of miR-146a-5p in SKBR-3wt had effect on the cell cycle by increasing the S phase and the G2/M, inhibiting the expression of CDKN1A and increasing CCNB1 levels. Exosomes isolated from SKBR-3 cell lines contained miR-146a-5p, with higher levels in exosomes from the resistant cell line (exoR). The exoR were shown to increase trastuzumab resistance, EMT, and migration when co-cultivated with SKBR-3wt, and angiogenesis when in culture with HUVEC. Our results indicate that metformin effectively reduces breast cancer cell viability and suggests that the effects of the drug are mediated by an increase in miR-26a expression and a reduction of its targets, PTEN and EHZ2. Thus, the use of metformin constitutes a promising potential triple negative breast cancer therapy. In HER2+ breast cancer, miR-23b appears to elicit resistance to trastuzumab via PTEN and miR-146a throughout the cell cycle. Furthermore, miR-146a is transmitted in exosomes, which have been shown to reduce the sensitivity to trastuzumab of sensitive cells and increase EMT, migration, and angiogenesis. / [CA] El càncer de mama és el càncer més comú en dones arreu del món i la principal causa de mort per càncer en dones junt amb el càncer de pulmó. Aquest càncer té molt bon pronòstic en general, amb una supervivència del 80%. No obstant això, el pronòstic del càncer de mama triple negatiu és molt pitjor, al no conèixer-se'n cap diana farmacològica i tractar-se de forma inespecífica. La metformina, fàrmac prescrit per a la diabetis, ha mostrat alguns bons resultats preliminars com a potencial teràpia. D'altra banda, el principal tractament dirigit de les pacients HER2+ és el trastuzumab, que neutralitza el receptor HER2 amplificat; tanmateix, un elevat nombre de pacients desenvolupen resistències al tractament. Els microRNAs són xicotets RNAs no codificants capaços de regular l'expressió gènica epigenèticament, i poden ser secretats de la cèl·lula en vesícules anomenades exosomes. L'objectiu d'aquest treball és abordar aquestes dues problemàtiques en càncer de mama. Són necessaris estudis dels mecanismes d'acció o resistència d'aquests fàrmacs a través de la regulació epigenètica per microRNAs. Volem determinar la relació del miR-26a i les seues dianes amb l'efecte de la metformina en càncer de mama triple negatiu i estudiar les diferències d'expressió dels microRNAs que generen resistències al trastuzumab en càncer de mama HER2+, així com estudiar la seua manera de transmissió entre cèl·lules. Es van realitzar assajos cel·lulars tractant amb metformina les línies MDA-MB-231, MDA-MB-468 i MCF-7 així com sobreexpressant o inhibint miR-26a i es van mesurar les seues dianes teòriques per qPCR. Per a les línies HER2+ es va realitzar un Affymetrix Genechip miRNA 4.0 microarray comparant línies SKBR-3wt i BT-474wt amb les seues respectives línies amb resistència generada a trastuzumab i HCC-1954 com resistent innata. Es van estudiar els microRNAs més rellevants de l'array en les línies cel·lulars i en pacients i es va comprovar la seua presència a exosomes, així com l'efecte dels exosomes en la transmissió de la resistència. La sobreexpressió de miR-26a resultà en una reducció de la viabilitat cel·lular que es recuperà parcialment en inhibir-la. E2F3, MCL-1, EZH2, MTDH i PTEN foren regulats negativament per miR-26a i la proteïna PTEN també es va reduir en sobreexpressar miR-26a. El tractament amb metformina va reduir la viabilitat de les cèl·lules de càncer de mama, va augmentar l'expressió de miR-26a i va conduir a una reducció en l'expressió de BCL-2, EZH2 i PTEN. La inhibició de miR-26a prevé part de l'efecte en la viabilitat de la metformina i la reducció de l'expressió de PTEN i EZH2. En les línies HER2+, miR-23b-3p i miR-146a-5p foren els principals candidats extrets de l'array. miR-23b-3p va inhibir PTEN significativament en la línia BT-474. miR-146a-5p va augmentar la resistència de les cèl·lules SKBR-3 al trastuzumab i la seua inhibició va reduir la resistència de les SKBR-3r. L'augment de miR-146a-5p en SKBR-3wt va tindre un efecte en cicle cel·lular augmentant la fase S i la G2/M, inhibint l'expressió de CDKN1A i augmentant la de CCNB1. Els exosomes de les SKBR-3 contenien miR-146a-5p, amb majors nivells en els de les resistents (exoR). Els exoR van augmentar la resistència a trastuzumab, la transició epiteli-mesenquimal i la migració en co-cultivar-los amb SKBR-3wt, i l'angiogènesi de les HUVEC. Els nostres resultats suggereixen que l'efecte de la metformina està intervingut per una major expressió de miR-26a i reducció de les seues dianes, PTEN i EHZ2. Per tant, l'ús de metformina al tractament de el càncer de mama constitueix una prometedora potencial teràpia. En HER2+, miR-23b sembla provocar resistència a trastuzumab mitjançant PTEN i miR-146a a través del cicle cel·lular. A més, miR-146a es transmet en exosomes, que són capaços de reduir la sensibilitat al trastuzumab de les cèl·lules sensibles i augmentar la TEM, migració i angiogènesi. / Cabello Navarro, P. (2020). Epigenetic regulation of resistance to treatments in triple negative and HER2+ breast cancer: miRNAs involved [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/153807 / TESIS

Metformin has been used clinically since 1957 for its efficacy and safety as therapy for type 2 diabetes. Besides ameliorating hyperglycemia without risk of hypoglycemia, metformin also lowers plasma triglyceride levels. Furthermore, a wealth of data shows that metformin facilitates weight loss in mice as well as humans. Due to its numerous metabolic benefits, researchers and clinicians are interested in the possibility of using metformin as treatment to combat obesity and other metabolic disorders such as non-alcoholic fatty liver disease (NAFLD). Despite being the most commonly prescribed anti-diabetic, metformin’s complete mechanism(s) for weight loss or for lowering glucose and lipids remains an enigma. Our studies show that metformin-treated mice exhibited decreased caloric intake, providing a viable mechanism for metformin to bring about weight loss. Intriguingly, we found that metformin induces PRDM16 to promote browning of iWAT and increase expression of thermogenic genes such as UCP1 and DIO2. However, metformin did not appear to increase energy expenditure. It’s possible that metformin’s effect on energy expenditure was masked since energy expenditure measurements were taken when metformin-treated mice were still losing weight and were in a state of negative energy balance. Recently, there has been much attention given to AMPK activators as exercise mimetics. Metformin is known to activate AMPK and similarly brings about many beneficial effects as exercise such as alleviation of obesity-induced NAFLD. SIRT1 stimulation by resveratrol and delivery of exogenous FGF21 mimics metformin’s ability to combat obesity and improve NAFLD. Collectively, these results implicate metformin, resveratrol, and exogenous administration of FGF21 as beneficial therapies for weight loss and amelioration of NAFLD.

Gestational diabetes mellitus (GDM ) is a disease that appears during pregnancy due to an insulin resistance. GDM is associated with increased risks for complications both to the mother and the child during pregnancy. These risks include conditions such as neonatal macrosomi and hypoglycemia for the child. This leads to increased risk for cesarean section and birth injuries. GDM can be treated with a changed diet supported with exercise. If the blood glucose levels still remain high, insulin or metformin medication can be introduced to treat the patient. Metformin is a safe and effective anti-diabetic drug and it is used as a treatment for GDM. Since the treatment during GDM varies, the effect of insulin versus metformin was examined. The aim of this litterature study was to compare the treatment with metformin versus insulin and to investigate the differences between the two drugs in the treatment of GDM. The medical databases PubMed and Google Scholar were used to search for clinical studies that compare the effects of the two treatments. Four studies were selected for this litterature study. The results in this study indicated that both insulin and metformin are effective as  glucose lowering drugs in the treatment of GDM. All patients do not respond to metformin and therefore insulin may be preferable in the treatment of some patient. Both insulin and metformin lead to better glycemic control in GDM patients. Both drugs are safe and effective but metformin has several advantages. The cost is low, it is easier to use and leads to fewer cases of hypoglycemia compared to insulin, even though all patients do not respond to metformin, it is considered a good alternative.

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