Combinação de metformina e licopeno e impactos sobre parâmetros fisiometabólicos e biomarcadores do estresse glico-oxidativo em sistema-modelo in vivo de obesidade e resistência à insulina
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Data
2021-12-17
Autores
Motta, Bruno Pereira [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
A manutenção da hiperglicemia por longos períodos é considerada um dos principais fatores responsáveis pelo estabelecimento do estresse glico-oxidativo no diabetes mellitus (DM), e este tem participação no desenvolvimento e progressão das complicações da doença, especialmente via aumento na geração dos produtos finais de glicação avançada (AGEs). Portanto, a exposição à hiperglicemia pode gerar alterações em longo prazo nas células, desencadeando uma série de eventos conhecidos como “memória metabólica”, caracterizada pela persistência das complicações do DM mesmo após a conquista do controle glicêmico. A metformina tem sido o agente antidiabético oral de primeira linha para o tratamento do DM tipo 2. Apesar de seu uso permitir aos indivíduos com DM tipo 2 um efetivo controle glicêmico, variações nas respostas individuais à terapia antihiperglicêmica são frequentes. Logo, estratégias terapêuticas baseadas na combinação de fármacos antidiabéticos com compostos bioativos naturais são interessantes na prevenção e/ou atenuação dos efeitos relacionados à memória metabólica e ao estresse glico-oxidativo. Dentre os compostos bioativos com potencial para associação com a metformina, destacase o licopeno. Diversos benefícios do licopeno no combate às disfunções metabólicas têm sido descritos; em sistemas-modelos in vivo de obesidade e DM, o tratamento ou a suplementação com licopeno ou com alimentos ricos em licopeno é capaz de promover aumento da tolerância a glicose, diminuição da resistência à insulina, inibição do desenvolvimento de esteatose hepática, diminuição nos níveis de LDL-oxidada e do risco cardiovascular, atenuação da nefropatia diabética via atenuação do estresse oxidativo, entre outros benefícios. O objetivo deste estudo foi avaliar as alterações em parâmetros fisiometabólicos e biomarcadores do estresse glico-oxidativo de camundongos sob sistemamodelo in vivo de obesidade/resistência à insulina e tratados com metformina ou licopeno, sozinhos ou co-administrados. Foram utilizados camundongos C57BL/6J machos alimentados com dietas normolipídica (P) ou hiperlipídica (HL). Após 9 semanas de oferta das dietas, os tratamentos com água, sistema lipídico nanoestruturado (SLN; veículo) e SLN contendo metformina e/ou licopeno foram iniciados e duraram 8 semanas. Peso corporal foi monitorado duas vezes por semana. Ao término dos tratamentos, os animais foram eutanasiados e diversos tecidos foram retirados e pesados. O plasma foi utilizado para as análises de biomarcadores relacionados ao metabolismo de carboidratos e lipídeos, integridade hepática, função renal e estresse glico-oxidativo [biomarcadores de glicação avançada (AGEs fluorescentes), biomarcadores de peroxidação lipídica (substâncias reativas ao ácido tiobarbitúrico, TBARS)] e atividade da enzima antioxidante paraoxonase 1 (PON 1). Os níveis de AGEs e TBARS também foram determinados em fígado e rins. Após 17 semanas, houve maior ganho de peso corporal e aumento nas massas dos tecidos adiposos brancos (epididimal, retroperitoneal) nos animais alimentados com dieta HL, quando comparados aos animais alimentados com dieta P, confirmando assim a instalação da obesidade devido à maior ingestão energética. As massas dos tecidos adiposos e os valores de peso corporal final foram diminuídos em animais em dieta HL e tratados com metformina e/ou licopeno. Intolerância à glicose e resistência à insulina foram observadas em animais alimentados com dieta HL. Os tratamentos com metformina e/ou licopeno melhoraram a tolerância à glicose e a sensibilidade à insulina em animais alimentados com dieta HL. Além disso, os tratamentos com metformina e/ou licopeno foram capazes de diminuir os níveis plasmáticos de colesterol total, colesterol-HDL, ALT, ALP e a glicemia de jejum. Foram observados aumentos nos níveis de AGEs fluorescentes e de TBARS em plasma, fígado e rins de animais HL. Os tratamentos de animais em dieta HL com metformina e/ou licopeno promoveram diminuição nos níveis desses biomarcadores do estresse glico-oxidativo em plasma, fígado e rins. A atividade de PON 1 em plasma de animais HL apresentou-se diminuída, em relação ao grupo P. O tratamento de animais em dieta HL com metformina foi capaz de impedir a diminuição na atividade da PON 1, mantendo-a em níveis semelhantes àqueles observados em animais P. Já os tratamentos com licopeno ou licopeno+metformina promoveram significativos aumentos nas atividades de PON 1, as quais alcançaram valores superiores àqueles de animais P. Pode-se concluir que os tratamentos com metformina e/ou licopeno são eficazes na promoção de melhorias das complicações observadas na obesidade, com ênfase na diminuição do peso corporal, aumento da tolerância à glicose e da sensibilidade à insulina, diminuição nos níveis plasmáticos de colesterol total e colesterol-HDL, diminuição nos níveis plasmáticos, hepáticos e renais de AGEs fluorescentes e TBARS e aumento na atividade de PON 1.
The maintenance of hyperglycemia for long periods is considered one important factor in the establishment of the glycoxidative stress in diabetes mellitus (DM), which participates in the onset and progression of various complications, mainly via increased generation of advanced glycation end products (AGEs). Therefore, the exposure to hyperglycemia can generate long-term changes in cells, triggering a series of events known as “metabolic memory”, characterized by the persistence of the diabetic complications even after achieving the glycemic control. Metformin has been the first-line oral antidiabetic agent for the treatment of type 2 DM. Although the use of metformin allows individuals with type 2 DM an effective glycemic control, variations in individual responses to this antihyperglycemic therapy are frequent. Therefore, therapeutic strategies based on the combination of antidiabetic drugs with natural bioactive compounds are interesting in preventing and/or mitigating the effects related to the metabolic memory and glycoxidative stress. Among the bioactive compounds with potential for association with metformin, it can be cited the lycopene. Several benefits of lycopene in contrst the metabolic disorders have been described; in in vivo model systems of obesity and DM, treatment or supplementation with lycopene or with foods rich in lycopene is able to increase the glucose tolerance, decrease the insulin resistance, inhibit the development of fatty liver disease, decrease the levels of oxidized-LDL and the cardiovascular risk, attenuate the diabetic nephropathy by decreasing oxidative stress, among other benefits. The aim of this study was to evaluate the changes in physiometabolic parameters and biomarkers of glycoxidative stress in mice under an in vivo model system of obesity/insulin resistance and treated with metformin or lycopene, alone or in combination. Male C57BL/6J mice fed with control diet (C) or highfat diet (HFD) were used. After 9 weeks of diet offering, treatments with water, nanostructured lipid system (NLS; vehicle) and NLS containing metformin and/or lycopene were started and performed during 8 weeks. Body weight was monitored twice a week. At the end of the treatments, the animals were euthanized and several tissues were removed and weighed. Plasma samples were used for the analysis of biomarkers related to carbohydrate and lipid metabolism, liver integrity, renal function, in adittion to biomarkers of glycoxidative stress [biomarkers of advanced glycation (fluorescent AGEs) and lipid peroxidation (thiobarbituric acid reactive substances, TBARS)], and the activity of the antioxidant enzyme paraoxonase 1 (PON 1). The levels of AGEs and TBARS were also determined in the liver and kidneys. After 17 weeks, increases in the body weight gain and in the weights of white adipose tissues (epididymal, retroperitoneal) were observed in animals fed a HFD, when compared to animals fed a C diet, thus confirming the onset of the obesity. The weights of adipose tissues anf the terminal values of body weight were decreased by the treatments of mice fed a HFD with metformin and/or lycopene. Glucose intolerance and insulin resistance were observed in animals fed a HFD. Treatments with metformin and/or lycopene improved the glucose tolerance and increased the insulin sensitivity in animals fed a HFD. In addition, treatments with metformin and/or lycopene were able to decrease the plasma levels of total cholesterol, HDL-cholesterol, ALT, ALP and fasting blood glucose levels. Increases in the levels of fluorescent AGEs and TBARS were observed in plasma, liver and kidneys of untreated HFD mice. Treatments of mice fed a HFD with metformin and/or lycopene promoted a decrease in the levels of these biomarkers of glycoxidative stress in plasma, liver and kidneys. The activity of PON 1 in plasma from animals fed a HFD was decreased in comparison to the corresponding values in C mice. The treatment of mice fed a HFD with metformin was able to prevent the decrease in the PON 1 activity, maintaining PON 1 activity at values similar from those observed in C mice. In addition, the treatments with lycopene or lycopene+metformin promoted significant increases in the activity of PON 1, which reached values higher than those of C mice. It can be concluded that the treatments with metformin and/or lycopene are effective in promoting improvements of various complications observed in obesity, with emphasis on decreasing the body weight gain, increasing the glucose tolerance and insulin sensitivity, decreasing the plasma levels of cholesterol and HDL-cholesterol, decreasing the levels of fluorescent AGEs and TBARS (plasma, liver, kidneys) and increasing the PON 1 activity.
The maintenance of hyperglycemia for long periods is considered one important factor in the establishment of the glycoxidative stress in diabetes mellitus (DM), which participates in the onset and progression of various complications, mainly via increased generation of advanced glycation end products (AGEs). Therefore, the exposure to hyperglycemia can generate long-term changes in cells, triggering a series of events known as “metabolic memory”, characterized by the persistence of the diabetic complications even after achieving the glycemic control. Metformin has been the first-line oral antidiabetic agent for the treatment of type 2 DM. Although the use of metformin allows individuals with type 2 DM an effective glycemic control, variations in individual responses to this antihyperglycemic therapy are frequent. Therefore, therapeutic strategies based on the combination of antidiabetic drugs with natural bioactive compounds are interesting in preventing and/or mitigating the effects related to the metabolic memory and glycoxidative stress. Among the bioactive compounds with potential for association with metformin, it can be cited the lycopene. Several benefits of lycopene in contrst the metabolic disorders have been described; in in vivo model systems of obesity and DM, treatment or supplementation with lycopene or with foods rich in lycopene is able to increase the glucose tolerance, decrease the insulin resistance, inhibit the development of fatty liver disease, decrease the levels of oxidized-LDL and the cardiovascular risk, attenuate the diabetic nephropathy by decreasing oxidative stress, among other benefits. The aim of this study was to evaluate the changes in physiometabolic parameters and biomarkers of glycoxidative stress in mice under an in vivo model system of obesity/insulin resistance and treated with metformin or lycopene, alone or in combination. Male C57BL/6J mice fed with control diet (C) or highfat diet (HFD) were used. After 9 weeks of diet offering, treatments with water, nanostructured lipid system (NLS; vehicle) and NLS containing metformin and/or lycopene were started and performed during 8 weeks. Body weight was monitored twice a week. At the end of the treatments, the animals were euthanized and several tissues were removed and weighed. Plasma samples were used for the analysis of biomarkers related to carbohydrate and lipid metabolism, liver integrity, renal function, in adittion to biomarkers of glycoxidative stress [biomarkers of advanced glycation (fluorescent AGEs) and lipid peroxidation (thiobarbituric acid reactive substances, TBARS)], and the activity of the antioxidant enzyme paraoxonase 1 (PON 1). The levels of AGEs and TBARS were also determined in the liver and kidneys. After 17 weeks, increases in the body weight gain and in the weights of white adipose tissues (epididymal, retroperitoneal) were observed in animals fed a HFD, when compared to animals fed a C diet, thus confirming the onset of the obesity. The weights of adipose tissues anf the terminal values of body weight were decreased by the treatments of mice fed a HFD with metformin and/or lycopene. Glucose intolerance and insulin resistance were observed in animals fed a HFD. Treatments with metformin and/or lycopene improved the glucose tolerance and increased the insulin sensitivity in animals fed a HFD. In addition, treatments with metformin and/or lycopene were able to decrease the plasma levels of total cholesterol, HDL-cholesterol, ALT, ALP and fasting blood glucose levels. Increases in the levels of fluorescent AGEs and TBARS were observed in plasma, liver and kidneys of untreated HFD mice. Treatments of mice fed a HFD with metformin and/or lycopene promoted a decrease in the levels of these biomarkers of glycoxidative stress in plasma, liver and kidneys. The activity of PON 1 in plasma from animals fed a HFD was decreased in comparison to the corresponding values in C mice. The treatment of mice fed a HFD with metformin was able to prevent the decrease in the PON 1 activity, maintaining PON 1 activity at values similar from those observed in C mice. In addition, the treatments with lycopene or lycopene+metformin promoted significant increases in the activity of PON 1, which reached values higher than those of C mice. It can be concluded that the treatments with metformin and/or lycopene are effective in promoting improvements of various complications observed in obesity, with emphasis on decreasing the body weight gain, increasing the glucose tolerance and insulin sensitivity, decreasing the plasma levels of cholesterol and HDL-cholesterol, decreasing the levels of fluorescent AGEs and TBARS (plasma, liver, kidneys) and increasing the PON 1 activity.
Descrição
Palavras-chave
obesidade, resistência à insulina, diabetes mellitus, estresse glico-oxidativo, metformina, licopeno, obesity, insulin resistance, diabetes mellitus, glycoxidative stress, metformin, lycopene