Le mélanome représente 8000 nouveaux cas par an et plus d'un millier de décès. Dés l'apparition de métastases, le pronostic devient très mauvais en raison de l'inefficacité de tous les traitements. Enfin, bien que des résultats encourageants aient été obtenus récemment avec des thérapies ciblées, ces réponses restent insuffisantes. L'identification de nouvelles molécules candidates est donc un élément essentiel pour le traitement du mélanome. Pendant la 1ère partie de ma thèse, je me suis intéressé à la metformine. Nous avons observé une diminution de l’invasion des cellules de mélanome dépendante de l'activation de l’axe AMPK/ p53 en réponse à la metformine. Ainsi, nous avons démontré pour la 1ère fois que la metformine peut être utilisée pour inhiber l'invasion des cellules de mélanome. Ensuite, je me suis intéressé à d'autres antidiabétiques, les TZD. Grâce à un criblage structure / activité, nous avons identifié une nouvelle molécule, le HA15, dérivé des TZD et ayant une très forte activité anti-mélanome. Nous avons montré que le HA15 induit un stress du RE (UPR), par l'intermédiaire de la protéine chaperon Bip, conduisant à l'activation de l'apoptose et de l'autophagie, entraînant ainsi la mort des cellules. Cette étude a permis d’identifier une nouvelle molécule efficace contre le mélanome et renforce l'idée que l'UPR pourrait être une cible thérapeutique pour le traitement du mélanome. / Melanoma accounts for 8000 new cases each year and more than a thousand deaths. If diagnosed early enough, wide surgical excision may be sufficient to treat. However, at the onset of metastasis, the prognosis becomes very bad due to the ineffectiveness of all treatments. Finally, although encouraging results were recently obtained with B-Raf inhibitors and immunotherapy, these responses are insufficient. So identification of new candidate molecules is an essential element for melanoma treatment. During the first part of my PhD, I was interested in metformin, the most commonly used molecule for the treatment of type 2 diabetes mellitus. It had been shown in our laboratory that metformin reduces melanoma cells viability in vitro and in vivo. Melanoma is a highly metastatic cancer, so I focused on the potential effect of metformin on melanoma cells invasion. We observed a decrease of melanoma cells invasion dependent on the activation of AMPK / p53 axis in vitro and in vivo. So we have shown for the first time that metformin can be used to inhibit melanoma cells invasion.During the second part of my PhD, I have been interested in other antidiabetic drugs, thiazolidinediones (TZD). Through a structure / activity screening we identified a molecule, HA15, derived from TZD and having a very strong anti-melanoma activity in vitro and in vivo. We showed that HA15 induced unfolded protein response (UPR), via the chaperone protein Bip, leading to autophagy and apoptosis activation, and resulting in cell death. This study identified a new molecule potentially effective against melanoma and reinforces the idea that UPR could be a therapeutic target for melanoma treatment.

There is substantial evidence of the elevated risk of cancer among individuals with type 2 diabetes. Very little is known, however, about the role that antidiabetic therapies play in this relationship. The objective of this program of research was to examine whether there is a therapeutic risk associated with antidiabetic therapies that increase circulating insulin levels, such as sulfonylureas and exogenous insulin, or a therapeutic benefit associated with antidiabetic therapies that reduce insulin resistance, such as metformin and the glitazones. This objective was achieved through four related population-based cohort studies using the administrative databases from Saskatchewan Health. The first study looked at the effect of the older antidiabetic therapies metformin and sulfonylureas on cancer mortality. The focus of the second study was to explore more closely the effect of metformin and sulfonylurea by using a time-varying Cox regression to define drug exposures. The third study looked more closely at the effect of exogenous insulin therapy and cancer mortality, and the last study focused on the more recently available antidiabetic therapy the glitazones and cancer mortality. We found that individuals with type 2 diabetes exposed to sulfonylurea monotherapy had a significantly increased risk of cancer-related mortality, compared to patients exposed to metformin. We also observed a dose-response gradient with exogenous insulin therapy and cancer mortality, whereby individuals exposed to higher levels of insulin had a higher risk of cancer mortality. In the last study, we found that the newer class of antidiabetic therapies, the glitazones, were associated with a decreased risk of cancer mortality. These finding add further support that antidiabetic therapies may play a moderating role in the relationship between type 2 diabetes and cancer outcomes. However, it is unclear whether the increased risk of cancer mortality we observed was related to a toxic effect of sulfonylureas and exogenous insulin or a protective effect of metformin and glitazones, or due to some unmeasured effect related to both choice of drug therapy and cancer risk. Future research should incorporate a non-diabetes control cohort for comparison and examine the more proximal outcome measure cancer incidence. / Epidemiology

No description available.

Diabetes mellitus (DM) represents a series of metabolic conditions associated with hyperglycemia and caused by defects in insulin secretion, and/ insulin action. Exposure to chronic hyperglycemia may result in microvascular complications in the retina, kidney or peripheral nerves. According to the World Health Organization (WHO) global burden of disease, more than 176 million people are diabetic with about two thirds of these living in developing countries. With a long course and serious complications that often result in high incidences of mobility and mortality rate, the treatment of diabetes is often costly. The management of this disease is not without side effects and this is a challenge to the medical system. This has led the researches to seek new antidiabetic agents from plants. Acetone extract of 8 plants namely Terminalia sericea Burch. Ex DC, Euclea natalensis A.DC, Warbugia salutaris Bertol.f.) Chiov., Artemisia afra Jacq.ex Willd., Aloe ferox Mill, Sclerocarya birrea (A.Richi.) Hochst. subsp. caffra , Spirostachys Africana Sond and Psidium guajava L were evaluated for antidiabetic and antioxidant properties. In addition extracts were tested for cytotoxicity. Different parts of all these plants are traditionally used in South Africa for diabetes treatment. Plants were selected based on ethnobotanical information and phytochemical constituents. For determining inhibitory activity against each enzyme (α-glucosidase and α- amylase), all extracts were tested at concentration that ranged from 2x10-5 to 0.2mg/ml for α-glucosidase and 0.025 to 1.25mg/ml for α-amylase and fifty percent inhibition or higher was taken as significant (p<0.05). The extracts of A. ferox and S. africana showed no inhibition against α-glucosidase at the highest concentration tested (0.2mg/ml) whereas A. afra showed weak inhibition (47.15%). T. sericea showed to be a potent inhibitor of α-glucosidase exhibiting 97.44 % inhibition of the enzyme (p<0.05). W. salutaris, S birrea and E. natalensis also showed good activity on α-glucosidase as they demonstrated 71.84; 97.44 and 92.60 % inhibition respectively (p<0.05). Other plant extracts such as A. ferox and S. africana did not exhibit any activity on α-glucosidase. T. sericea and S. birrea showed the best inhibitory activity on α-amylase enzyme, exhibiting 91.91 and 94.94 % inhibition respectively at 1.25mg/ml. A. afra, E. natalensis, P. guajava and W. salutaris also showed good inhibitory activity on -amylase enzyme at 1.25mg/ml which was the highest concentration tested (p<0.05). Low levels of plasma antioxidants is a risk factor associated with diabetes therefore, it has been suggested that plant-based medicines that contain antioxidant properties add an advantage in curbing complications that arise during DM aetiology. The antioxidant activity of plant extracts was carried out using 2, 2-Diphenyl-1-Picrylhydrazyl (DPPH) assay. Six plant extracts which showed good α-glucosidase and α-amylase inhibitory activity were evaluated for antioxidant activity. The radical scavenging activity was measured in terms of the amount of antioxidants necessary to decrease the initial DPPH absorbance (EC50). The EC50 is the amount of antioxidants necessary to decrease initial DPPH absorbance by 50%. All 6 tested plant extracts showed good activity. W. salutaris and T. sericea demonstrated the highest activity exhibiting EC50 values of 5.08 and 5.56βg/ml respectively as compared to ascorbic acid/Vitamin C (EC50=2.52μg/ml), a well- known potent antioxidant. This was followed by P. guajava (EC50=6.97μg/ml); E. natalensis (EC50=8.46μg/ml) and S. birrea (EC50=9.41μg/ml). A. ferox showed EC50 value of 48.53μg/ml. It has been suggested that plant extracts and compounds must undergo toxicity test for safety before drug discovery is taken into consideration. Due to the large number of plants screened in this study and limited resources in our laboratory, only the acetone extract of T. sericea (which demonstrated good α-glucosidase and -amylase inhibitory activities) was tested for cytotoxicity. Acetone extract of T. sericea demonstrated moderate toxicity against primary vervet monkey kidney cells (VK) cells exhibiting IC50 values of 20.94 μg/ml when tested at 400μg/ml. Consequently, the acetone extract of T. sericea was selected for the isolation and identification of bioactive compounds. A bio-assay guided fractionation of the acetone extract of T. sericea led to the isolation of 4 pure compounds namely β-sitosterol, β-sitosterol-3-acetate, lupeol and 3-onestigmasterol and two sets of mixtures of isomers (epicatechin-catechin; MI1 and epigallocatechingallocatechin; MI2). Antidiabetic, antioxidant and cytotoxicity activities of isolated compounds were evaluated. μ–Sitosterol and lupeol showed best inhibitory activity on α-glucosidase exhibiting 50% inhibitory concentration (IC50) value of 54.50 μM and 66.48 μM respectively (p<0.05). This was followed by the MI2; epigallocatechin-gallocatechin (IC50=119.34 μM); β-sitosterol-3-acetate (IC50=129.34 μM); 3-one-stigmasterol (IC50=164.87 μM) and the MI1; epicatechin-catechin (IC50=255.76 μM). During the evaluation of purified compound’s inhibitory activity on α-amylase, compounds of interest were lupeol and β-sitosterol which exhibited IC50 values of 140.72 μM and 216.02 μM respectively as compared to the positive drug-control acarbose (IC50=65.25 μM). Epicatechincatechin and epigallocatechin-gallocatechin also demonstrated α-amylase inhibitory properties and the IC50 values were found to be lower than 100μg/ml. Epigallocatechin-gallocatechin, epicatechin-catechin and lupeol showed good free radical scavenging activity as they inhibited DPPH by 98.19; 96.98 and 70.90 % at 100ìg/ml respectively (p<0.05). The DPPH scavenging activity was very low in case of 3-one-stigmasterol (21.5% inhibition), whilst β-sitosterol and its derivative β-sitosterol-3-acetate did not show any activity. During cytotoxicity evaluation of pure compounds against monkey kidney cells, all the compounds except β-sitosterol did not inhibit the growth of these cells lines at the highest concentration tested (200μg/ml). β-Sitosterol showed moderate toxicity exhibiting IC50 values of 197.72 μM. β- Sitosterol-3-acetate, epicatechin-catechin, lupeol and epigallocatechin-gallocatechin were found to be non-toxic to Vero cells as 100% cell viability was observed when Vero cells were exposed to these samples at 200μg/ml. The compounds isolated and the extract of T. sericea demonstrated significant antidiabetic and antioxidant properties as compared to well known drugs acarbose (a known -glucosidase and α- amylase inhibitor) and Vitamin C (a well known antioxidant). This study is the first to report α- glucosidase, α-amylase and antioxidant properties of epicatechin-catechin, epigallocatechingallocatechin, β-sitosterol-3-acetate and stigma-4-ene-3-one isolated from T. sericea. In addition, epicatechin-catechin, epigallocatechin-gallocatechin, β-sitosterol-3-acetate and stigma-4-ene-3-one are isolated from T. sericea for the first time. Overall all results scientifically validated the traditional use of the bark of T. sericea for diabetes in South Africa. / Dissertation (MSc)--University of Pretoria, 2011. / Plant Science / unrestricted

Background: Type 2 Diabetes is a chronic metabolic condition which occurs as a result of insufficient insulin production and insulin resistance. This results in less glucose uptake by muscle and fat cells, allowing blood glucose levels to rise in the body. Higher blood glucose levels place patients at an increased risk of diabetes-related complications. The treatment is characterised by the initiation, switching and intensification of antidiabetic medications. The goal for patients with diabetes is to maintain glycaemic control, with blood glucose levels (HbA1c) between 6.5-7.0%(48-53mmol/mol). International guidelines recommend prescribing of metformin at initiation but there is no consensus on optimal agents in a combination regimen. The aim of this thesis was to assess the drug utilisation patterns of first-line therapies and the impact of this pathway on second-line regimens. This entailed: (i.) observing the prescribing of the first-line therapy, (ii.) characterising the medication-taking process of the first-line therapy and effectiveness of the regimens, and (iii.) determining the most effective second-line regimen in delaying the onset of microvascular complications. Methods: Patients with type 2 diabetes, prescribed a first-line antidiabetic regimen, were identified from the Clinical Practice Research Datalink (a large UK anonymised primary care database) between 01/01/05 and 31/12/09, were followed-up until 31/12/12. A multinomial logistic regression model was used to assess the relationship between patient characteristics and the choice of first-line agent. Adherence to first-line therapy was estimated using the Medication Possession Ratio calculation, expressing the percentage of days covered by a drug supply. To assess the factors influencing achievement of glycaemic goals from the first-line therapy, a logistic regression analysis was performed. To investigate second-line regimens, a Marginal Structural Cox model was implemented to explore the causal relationships between the time to development of microvascular complications and the second-line regimens. Results: Of the 72,429 individuals diagnosed with type 2 diabetes, 44,838 started therapy with an antidiabetic medication regimen. Metformin and sulphonylureas were the most frequently prescribed agents at initiation (82.9% and 9.8%,respectively). Deviations from metformin were associated with patients presenting with higher HbA1c levels, lower BMI values and had concurrent prescriptions (immunosuppressants and oral corticosteroids). Achieving glycaemic control, to the target of 6.5% (48mmol/mol), was only met in 22.7% of patients. Characteristics of the patient, choice of first-line agent and medical support influenced the effectiveness of the treatments. Patients at the greatest risk of failing to achieve the target glycaemic goal from therapy had HbA1c levels>8.0% (64mmol/mol) and a BMI≥25kg/m2. Adherence was significantly associated with greater lowering of HbA1c levels but these reductions did not guarantee reaching the ideal glycaemic target. Intensification of the monotherapy to a dual therapy regimen was observed in 30.2% of patients in a mean time of 2 years. The most frequently prescribed second-line regimens consisted of metformin/sulphonylurea (SU) (74.5%), metformin/thiazolidinediones(TZD) (11.3%) and metformin/DPP-4 inhibitors (14.2%). Metformin/SU was the most effective dual therapy regimen for delaying the onset of microvascular diagnoses. The rate of development of these events was significantly higher for the DPP-4 combination in comparison to the SU combination with a hazard ratio of 1.85 (95% CI: 1.53,2.24). A TZD combination resulted in a non-significant increase of 19% in the rate of development compared to the SU combination (HR 1.19; 95% CI: 0.98,1.47). Metformin/SU resulted in the greatest lowering in HbA1c levels (-3.3%; 12mmol/mol) in comparison to the DPP-4 and TZD regimens. Conclusions: It is unlikely that patients starting first-line therapy with high HbA1c levels will be able to reduce blood glucose levels sufficiently on a monotherapy regimen. It is important for practitioners to consider a faster uptake of a dual therapy regimen (metformin/SU) to prevent sustained suboptimal glycaemic control and reduce the risk of future complications. Other important considerations in the optimal treatment pathway would be to provide more frequent support from health professionals; this may help to highlight inadequate drug regimens, offer management of risk factors and provide education. These aspects may help patients to achieve better control of their condition, with the aim of reducing the risk of diabetes-related complications; which, severely impact patient quality of life and NHS costs and resources.

Epidemiology studies have found that type 2 diabetics treated with metformin are at a lower risk for developing cancer. It was speculated that the lowered risk might be attributed metformin's indirect physiological effect of lowering blood insulin levels, which is the opposite of many other antidiabetic drugs. However, further study of metformin's mechanism of action at the cellular level helped develop an understanding of its effect on the individual cell. This helped show why, mechanistically, it makes sense to use metformin for the treatment of cancer. As an activator of AMP-activated protein kinase (AMPK) via inhibition of complex 1 of the mitochondrial electron transport chain, metformin causes suppression of tumor growth and cell cycle arrest by acting on the mTOR pathway and cyclin/CDKs, respectively. Metformin has been most extensively studied in breast cancer, showing great efficacy in numerous breast cancer cell lines that include ER positive, HER2 positive, and triple negative breast cancer cell lines. This compilation of data and results of metformin's efficacy in various cancer subtypes will help push metformin forward as a new chemotherapeutic for breast cancer, and eventually for other cancer types as well.

Dietary proteins from Atlantic salmon and cod have previously been shown to have antidiabetic effects. Since dietary proteins are digested into small peptides before being absorbed through the intestinal mucosa, it is reasonable to deduce that the antidiabetic effect is due to enzymatically-digested peptides rather than the proteins themselves. The aim of this study was to develop a protocol to recover peptides with antidiabetic effects from salmon and cod protein digests and then scale up and optimize the salmon protein hydrolysate production process for industrial-scale production. The peptide mixtures were screened using cell culture assays for insulin-modulating activities and were further fractionated and purified for the final identification. Total yields of salmon and cod protein hydrolysates (<1 kDa) as measured by Kjeldahl nitrogen were 16.9% and 40.1%, respectively. The production process used for the salmon protein hydrolysate (<1 kDa) showed good reproducibility and potential for the industrial-scale production.

Dietary proteins from Atlantic salmon and cod have previously been shown to have antidiabetic effects. Since dietary proteins are digested into small peptides before being absorbed through the intestinal mucosa, it is reasonable to deduce that the antidiabetic effect is due to enzymatically-digested peptides rather than the proteins themselves. The aim of this study was to develop a protocol to recover peptides with antidiabetic effects from salmon and cod protein digests and then scale up and optimize the salmon protein hydrolysate production process for industrial-scale production. The peptide mixtures were screened using cell culture assays for insulin-modulating activities and were further fractionated and purified for the final identification. Total yields of salmon and cod protein hydrolysates (<1 kDa) as measured by Kjeldahl nitrogen were 16.9% and 40.1%, respectively. The production process used for the salmon protein hydrolysate (<1 kDa) showed good reproducibility and potential for the industrial-scale production.

Background: T2DM patients can be treated with both Insulin or/and non-insulin antidiabetic drugs. Biguanide-derivate is the first-line antidiabetic that is cost-effective and safe. DPP-4Is are antidiabetic drugs that can be used to treat old patients and those with kidney failure. While SGLT2-inhibitors and GLP-1analogues can be used by T2DM patients with cardiovascular problems and those with overweight. The initiation of antidiabetic drug is influenced by several factors such as patient characteristic, physician’s knowledge and guidelines. Aim: The aim of this study was to study the type of antidiabetic medication initiated to naïve T2DM patients, how age and sex affect the choice of medication and difference in prescribing between Primary healthcare centers in Region Uppsala. Methods: The study was a cross-sectional based on health record data from Region Uppsala. The study included 2473 T2DM patients that were initiated antidiabetic medication between January 2019 and December 2020. Results: Non-insulins accounted for 88 % and insulins for 21.1% of the prescriptions. The proportion of men that received both insulin and non-insulins were higher than women. The proportion of patients that received insulins was higher for the age group 80 years and older. The proportion of men that received SGLT2- inhibitors was higher than for women, while women received more GLP-1- analogues. There was a variation between PHCs, but non-insulins were mostly prescribed at all PHCs. Conclusions: Initiation of antidiabetic drugs to naïve T2DM patients in region Uppsala fallowed the guidelines. There are some differences in prescription pattern between the two sexes and the age groups.

Objective: To perform pharmacoepidemiological study of the use of oral antidiabetic drugs and insulins in Lithuania on 2006-2009 year and cost-minimization and reference price analysis enabling more rational use of financial resources of national health system. Material ans methods: The search for all literature relating to pharmacokinetic and pharmacodynamic chareacteristics of drugs for diabetes mellitus was done in MEDLINE database. The data on total sales of oral antidiabetic drugs and insulins in Lithuania over a four-year period (2006-2009) were obtained from Softdent, Lithuania data base. Drugs were classified according to the Anatomic Therapeutic Chemical system. Data were calculated by DDD methodology and expressed in DDDs per 1000 inhabitants per day (DDD/TID). Calculations of drug prices and total expenditures for antidiabetic drugs were made by using retail prices from the National Patient Funds Price List on 2006- 2009 years. Pharmacoeconomic calculations were done according to cost minimization and reference price methodologies. Results: The total consumption of hypoglycaemic drugs (incl. insulins) increased by 33.33% from 21.54 DDD/TID in 2006 to 28.72 DDD/TID in 2009. The utilization of insulin increased by 30% reaching the value of 9.43 DDDD/TID, similarly the utilization of oral antidiabetic drugs increased by 35% reaching the value of 19.29 DDD/TID in 2009. In comparison with antidiabetic drug consumption in other countries, this meaning was about... [to full text] / Tikslai: Įvertinti geriamųjų antidiabetinių vaistų ir insulinų suvartojimo tendencijas Lietuvoje 2006–2009 m. ir atlikti farmakoekonominę analizę kaštų mažinimo ir referentinės kainos metodu siekiant racionaliai panaudoti sveikatos apsaugos lėšas cukriniam diabetui gydyti. Medžiaga ir metodai: Duomenys apie antidiabetinių vaistų farmakokinetines ir farmakodinamines savybes buvo surinkti iš MEDLINE elektroninių duomenų šaltinių. Duomenys apie antidiabetinių vaistų pardavimą Lietuvoje 2006–2009 metais gauti iš UAB SoftDent duomenų bazės. Vaistai klasifikuoti pagal anatominę terapinę cheminę (ATC) klasifikaciją. Vaistų suvartojimas buvo vertinamas pagal apibrėžtos dienos dozės (DDD – angl. defined daily dose) metodiką, o duomenys apskaičiuoti pagal DDD skaičių, tenkantį 1000 gyventojų per vieną dieną.Vaistų kainų skaičiavimai atlikti remiantis mažmenine kaina iš „Kompensuojamų vaistinių preparatų kainynų“. Antidiabetinių vaistų farmakoekonominei analizei atlikti taikytas kaštų mažinimo bei referentinės kainos nustatymo metodas. Rezultatai: Bendras antidiabetinių vaistų suvartojimas padidėjo 33,33% nuo 21,54 DDD/TID 2006 metais iki 28,72 DDD/TID 2009 metais. Insulinų suvartojimas padidėjo 30% ir siekė 9,43 DDDD/TID 2009 metais, o geriamųjų antidiabetinių vaistų suvartojimas pakilo 35% iki 19,29 DDD/TID 2009 metais. Palyginus su kitų Europos šalių duomenimis, Lietuvoje antidiabetinių vaistų suvartojimas buvo du-tris kartus mažesnis, nepaisant to, jog sergamumas cukriniu diabetu... [toliau žr. visą tekstą]