Se evaluó el efecto hipoglicemiante del extracto acuoso de las hojas de Smallanthus sonchifolius (yacón) en pacientes con Diabetes Mellitus Tipo 2 determinándose periódicamente las concentraciones de glucosa, hemoglobina glicosilada (HbA1c), fructosamina y perfil lipídico, como factores de riesgo. El estudio se realizó en un grupo de 206 pacientes Diabéticos Tipo 2 que acuden al Servicio Académico Asistencial de Análisis Clínicos (SAAAC), Gabinete de Atención Farmacéutica (GAF) de la Facultad de Farmacia y Bioquímica, Club de diabéticos tipo 2 del hospital Cayetano Heredia, el Centro de Salud (CERIT) Raúl Patrucco Puig, además de un grupo control de personas aparentemente sanas. El ensayo se realizó durante 90 días en 206 sujetos de 30 a 70 años de edad, hombres y mujeres, quienes firmaron un consentimiento informado según las normas de Helsinki: 105 con diagnóstico de Diabetes Mellitus Tipo 2 y tratamiento farmacológico, de los cuales: 46 estaban controlados metabólicamente y 59 no controlados (a pesar del tratamiento farmacológico). A este último grupo se les dió para determinar la eficacia bolsas filtrantes de hojas de yacón de 1 g. cada uno, para infusión, tres veces al día por 90 días más glibenclamida; y 101 sujetos aparentemente sanos que sirvieron de control, subdivididos en dos grupos: un grupo ingirió la infusión de hojas de yacón y el otro no. La administración de la infusión de hojas de yacón disminuyó los valores de glucosa en un 42.7%, hemoglobina glicosilada de 11.12 a 8.87 % y fructosamina de 33.78% al final del tratamiento disminuyendo considerablemente respecto a los basales, a los 30, 60 y 90 días, observándose una diferencia estadísticamente significativa por grupos de edad. De lo que se puede concluir que la infusión conteniendo hojas de Smallanthus sonchifolius (Yacón) administrada a pacientes con Diabetes Mellitus Tipo 2 tiene un efecto protector beneficioso sobre el control glucémico. La eficacia de la combinación estudiada, logra reducir las cifras de HbA1c entre un 0.5 y un 3.71%. Palabras clave: Smallanthus sonchifolius, Yacón, Diabetes Mellitus tipo 2, Hemoglobina glicosilada, Fructosamina, Glucosa. / It was evaluated the hypoglycemic effect of aqueous extract of leaves of Smallanthus sonchifolius (yacon) in patients with Type 2 Diabetes Mellitus periodically determined concentrations of glucose, glycated hemoglobin (HbA1c), fructosamine and lipid profile, as risk factors . The study was conducted in a group of 206 type 2 diabetic patients attending the Academic- Assistance Service of Clinical Analyses (SAAAC) and the Office of Pharmaceutical Care (GAF) of The Faculty of Pharmacy and Biochemistry, type 2 diabetes Club of Cayetano Heredia Hospital, Patrucco Puig Raul Health Center (CERIT), Apart from a control group of apparently healthy people. The trial lasted 90 days in 206 subjects from 30 to 70 years old, men and women who signed the informed consent according to the rules of Helsinki: 105 diagnosed with Type 2 Diabetes Mellitus and pharmacologic treatment from which 46 were controlled and 59 metabolically controlled (despite the drug treatment). The latter group were given to determine the effectiveness filter bags yacon leaves 1 g. each infusion, three times a day for 90 days plus glybenclamide; and 101 apparently healthy subjects served as controls, subdivided into two groups: one group intook the yacon leaf tea and the other not. The administration of yacon leaf tea lowered glucose in a 42.7 %, glycated hemoglobin from 11.12 to 8.87% and fructosamine from 33.78% at end of treatment, decreasing considerably compared to baseline, at 30, 60 and 90 days, observing a statistically significant difference by age group. It can be concluded that the infusion of the aqueous extract of leaves of Smallanthus sonchifolius (yacon) administered to patients with type 2 diabetes mellitus has a beneficial protective effect on glycemic control. The effectiveness of the combination studied, succeeded in reducing HbA1c values between 0.5 and 3.71%. Keywords: Smallanthus sonchifolius, Yacon, type 2 diabetes mellitus, glycated hemoglobin, fructosamine, glucose.

Smallanthus sonchifolius (Poepp. & Endl.) H. Robinson (Asteraceae), conhecida popularmente como yacón, é um erva utilizada na medicina popular para o tratamento do diabetes. A ação hipoglicemiante do extrato aquoso das folhas do yacón foi comprovada em estudos recentes realizados por outros autores em animais diabéticos. Análises fitoquímicas preliminares revelaram que a espécie é rica em lactonas sesquiterpênicas (LST) e em derivados dos ácidos clorogênicos (ACG). Ambas as classes de substâncias possuem inúmeras atividades biológicas, como ação antioxidante, anti-inflamatória, e inibidora de enzimas que podem contribuir no quadro de melhora do estado diabético. Contudo, ainda não está comprovado se as atividades biológicas da espécie são resultantes da ação dos ACG ou das LST. Adicionalmente, análises toxicológicas do consumo das folhas do yacón ainda não foram realizadas. Assim, o objetivo deste trabalho foi avaliar três extratos preparados com folhas do yacón, com o intuito de analisar o papel das diferentes classes químicas no desenvolvimento das atividades biológicas descritas para a espécie, bem como de seus potenciais efeitos tóxicos. Os extratos obtidos foram: o extrato aquoso (EA), no qual foram detectados tanto ACG (2,0 e 1,3 µg/mL dos picos mais intensos), quanto LST (99,7 e 319,0 µg/mL dos picos mais intensos); extrato de lavagem foliar (ELF), rico em LST (1257,4 e 1997,7 µg/mL das majoritárias) e o extrato polar (EP), rico em ACG (9,9 e 9,6 µg/mL dos picos mais intensos), mas sem LST. Os estudos toxicológicos demonstraram que o EP não causou efeitos tóxicos significativos em ratos, enquanto alterações em parâmetros bioquímicos específicos no sangue (creatinina 7,0 mg/dL, glicose 212,0 mg/dL, albumina 2,8 g/dL) de ratos tratados com o EA (10, 50 e 100 mg/kg) e ELF (10 e 100 mg/kg) apontaram para dano renal, confirmado por análises histológicas dos rins. Todos os extratos apresentaram atividade anti-edematogênica in vivo, em especial no modelo de edema induzido por óleo de cróton (EA: 25,9% inibição do edema a 0,5 mg/orelha; EP: 42,7% de inibição a 0,25 mg/orelha, ELF: 44,1% de inibição a 0,25 mg/orelha). O ELF demonstrou os melhores resultados na inibição da migração de neutrófilos, na indução da IL-10, na inibição do NO, TNF- e PGE2, quando comparado aos demais extratos. Todos os extratos inibiram de forma estatisticamente similar a atividade da -amilase, enquanto o EA e o EP foram mais eficazes na redução dos níveis glicêmicos após a administração oral de glicose (controle glicêmico: 201,8±5,2, EA: 169,0±4,9, EP: 176,7,3±7,3, ELF: 219,1±7,6 mg/dL). Com os dados obtidos neste trabalho pode-se concluir que o consumo do chá das folhas do yacón por períodos prolongados pode ser tóxico e seu uso não deve ser recomendado na medicina popular. As LST parecem ser as substâncias responsáveis por essa toxicidade. Tanto as LST, quanto os ACG contribuem para atividade anti-inflamatória, embora as LST parecem ter efeitos mais pronunciados. Contudo, a atividade anti-diabética da espécie parece estar relacionada principalmente à presença ao ACG e não à LST, sendo necessários estudos mais detalhados com ACG puros para verificar seu uso potencial no tratamento do diabetes. / Smallanthus sonchifolius (Poepp. & Endl.) H. Robinson (Asteraceae), known as yacón is a herb used in folk medicine to treat diabetes. The hypoglycaemic effect of the aqueous extract from yacón leaves was demonstrated in recent studies in diabetic animal models. Phytochemical analyzes have demonstrated that this species is rich in chorogenic acids (CGAs) and sesquiterpene lactones (STLs). Both classes of compounds have many biological activities such as antioxidant, anti-inflammatory and inhibit enzymes that can contribute in the improvement of the diabetic state. However, it is not yet established whether the biological activities of this species are due to the action of the CGAs or STLs. In addition, toxicological analysis of the consumption of yacón leaves has not yet been performed. Thus, the purpose of this study was to evaluate three extracts prepared from leaves of yacón, with the aim to analyze the role of different chemical classes in the development of the biological activities described for this species, as well as their potential toxic effects. The following extracts were obtained: aqueous extract (AE), were detected CGAs (2.0 and 1.3 mg / mL of the more intense peaks), and STLs (99.7 and 319 mg / mL of most intense peaks); leaf rinse extract (LRE), rich in STLs (1257.4 and 1997.7 mg / mL of major peaks), and the polar extract (PE) rich in CGAs (9.9 and 9.6 mg / mL of the more intense peaks), but without STLs. The toxicological studies in animals showed that the PE did not cause significant toxic effects, while changes in specific biochemical parameters in blood (creatinine 7.0 mg / dL, glucose 212.0 mg / dL, albumin 2.8 g / dL) of rats treated with AE (10, 50 and 100 mg / kg) and LRE (10 and 100 mg / kg) indicated kidney damage, which was confirmed by histological analysis of kidneys. All extracts showed anti-oedematogenics activity in vivo, particularly in the model of oedema induced by croton oil (AE: 25.9% of oedema inhibition at 0.5 mg / ear, PE: 42.7% of inhibition at 0.25 mg / ear, LRE: 44.1% inhibition at 0.25 mg / ear). The LRE showed the best results in the inhibition of neutrophil migration, induction of IL-10, as well as NO, TNF- and PGE2 inhibition, when compared to other extracts. All extracts inhibited in a statistically similar way the activity of -amylase, while the AE and the PE were more effective in reducing blood glucose levels after oral glucose adminstration (glycaemic control: 201.8 ± 5.2; AE: 169, 0 ± 4.9; PE: 7.3 ± 176,7,3; LRE: 219.1 ± 7.6 mg / dL). The data obtained in this work suggested that the consumption of tea from yacón leaves for prolonged periods can be toxic and their use should not be recommended in folk medicine. The STLs seem to be the substances responsible for this toxicity. Both STLs and CGAs contribute to the anti-inflammatory activity, although the STLs seem to have more pronounced effects. However, the anti-diabetic activity of the yacón leaves seems to be related to the presence of the CGAs and not to LST. More detailed studies with pure CGAs are required in order to determine their potential use in treatment of diabetes.

Smallanthus sonchifolius (Poepp. & Endl.) H. Robinson (Asteraceae), conhecida popularmente como yacón, é um erva utilizada na medicina popular para o tratamento do diabetes. A ação hipoglicemiante do extrato aquoso das folhas do yacón foi comprovada em estudos recentes realizados por outros autores em animais diabéticos. Análises fitoquímicas preliminares revelaram que a espécie é rica em lactonas sesquiterpênicas (LST) e em derivados dos ácidos clorogênicos (ACG). Ambas as classes de substâncias possuem inúmeras atividades biológicas, como ação antioxidante, anti-inflamatória, e inibidora de enzimas que podem contribuir no quadro de melhora do estado diabético. Contudo, ainda não está comprovado se as atividades biológicas da espécie são resultantes da ação dos ACG ou das LST. Adicionalmente, análises toxicológicas do consumo das folhas do yacón ainda não foram realizadas. Assim, o objetivo deste trabalho foi avaliar três extratos preparados com folhas do yacón, com o intuito de analisar o papel das diferentes classes químicas no desenvolvimento das atividades biológicas descritas para a espécie, bem como de seus potenciais efeitos tóxicos. Os extratos obtidos foram: o extrato aquoso (EA), no qual foram detectados tanto ACG (2,0 e 1,3 µg/mL dos picos mais intensos), quanto LST (99,7 e 319,0 µg/mL dos picos mais intensos); extrato de lavagem foliar (ELF), rico em LST (1257,4 e 1997,7 µg/mL das majoritárias) e o extrato polar (EP), rico em ACG (9,9 e 9,6 µg/mL dos picos mais intensos), mas sem LST. Os estudos toxicológicos demonstraram que o EP não causou efeitos tóxicos significativos em ratos, enquanto alterações em parâmetros bioquímicos específicos no sangue (creatinina 7,0 mg/dL, glicose 212,0 mg/dL, albumina 2,8 g/dL) de ratos tratados com o EA (10, 50 e 100 mg/kg) e ELF (10 e 100 mg/kg) apontaram para dano renal, confirmado por análises histológicas dos rins. Todos os extratos apresentaram atividade anti-edematogênica in vivo, em especial no modelo de edema induzido por óleo de cróton (EA: 25,9% inibição do edema a 0,5 mg/orelha; EP: 42,7% de inibição a 0,25 mg/orelha, ELF: 44,1% de inibição a 0,25 mg/orelha). O ELF demonstrou os melhores resultados na inibição da migração de neutrófilos, na indução da IL-10, na inibição do NO, TNF- e PGE2, quando comparado aos demais extratos. Todos os extratos inibiram de forma estatisticamente similar a atividade da -amilase, enquanto o EA e o EP foram mais eficazes na redução dos níveis glicêmicos após a administração oral de glicose (controle glicêmico: 201,8±5,2, EA: 169,0±4,9, EP: 176,7,3±7,3, ELF: 219,1±7,6 mg/dL). Com os dados obtidos neste trabalho pode-se concluir que o consumo do chá das folhas do yacón por períodos prolongados pode ser tóxico e seu uso não deve ser recomendado na medicina popular. As LST parecem ser as substâncias responsáveis por essa toxicidade. Tanto as LST, quanto os ACG contribuem para atividade anti-inflamatória, embora as LST parecem ter efeitos mais pronunciados. Contudo, a atividade anti-diabética da espécie parece estar relacionada principalmente à presença ao ACG e não à LST, sendo necessários estudos mais detalhados com ACG puros para verificar seu uso potencial no tratamento do diabetes. / Smallanthus sonchifolius (Poepp. & Endl.) H. Robinson (Asteraceae), known as yacón is a herb used in folk medicine to treat diabetes. The hypoglycaemic effect of the aqueous extract from yacón leaves was demonstrated in recent studies in diabetic animal models. Phytochemical analyzes have demonstrated that this species is rich in chorogenic acids (CGAs) and sesquiterpene lactones (STLs). Both classes of compounds have many biological activities such as antioxidant, anti-inflammatory and inhibit enzymes that can contribute in the improvement of the diabetic state. However, it is not yet established whether the biological activities of this species are due to the action of the CGAs or STLs. In addition, toxicological analysis of the consumption of yacón leaves has not yet been performed. Thus, the purpose of this study was to evaluate three extracts prepared from leaves of yacón, with the aim to analyze the role of different chemical classes in the development of the biological activities described for this species, as well as their potential toxic effects. The following extracts were obtained: aqueous extract (AE), were detected CGAs (2.0 and 1.3 mg / mL of the more intense peaks), and STLs (99.7 and 319 mg / mL of most intense peaks); leaf rinse extract (LRE), rich in STLs (1257.4 and 1997.7 mg / mL of major peaks), and the polar extract (PE) rich in CGAs (9.9 and 9.6 mg / mL of the more intense peaks), but without STLs. The toxicological studies in animals showed that the PE did not cause significant toxic effects, while changes in specific biochemical parameters in blood (creatinine 7.0 mg / dL, glucose 212.0 mg / dL, albumin 2.8 g / dL) of rats treated with AE (10, 50 and 100 mg / kg) and LRE (10 and 100 mg / kg) indicated kidney damage, which was confirmed by histological analysis of kidneys. All extracts showed anti-oedematogenics activity in vivo, particularly in the model of oedema induced by croton oil (AE: 25.9% of oedema inhibition at 0.5 mg / ear, PE: 42.7% of inhibition at 0.25 mg / ear, LRE: 44.1% inhibition at 0.25 mg / ear). The LRE showed the best results in the inhibition of neutrophil migration, induction of IL-10, as well as NO, TNF- and PGE2 inhibition, when compared to other extracts. All extracts inhibited in a statistically similar way the activity of -amylase, while the AE and the PE were more effective in reducing blood glucose levels after oral glucose adminstration (glycaemic control: 201.8 ± 5.2; AE: 169, 0 ± 4.9; PE: 7.3 ± 176,7,3; LRE: 219.1 ± 7.6 mg / dL). The data obtained in this work suggested that the consumption of tea from yacón leaves for prolonged periods can be toxic and their use should not be recommended in folk medicine. The STLs seem to be the substances responsible for this toxicity. Both STLs and CGAs contribute to the anti-inflammatory activity, although the STLs seem to have more pronounced effects. However, the anti-diabetic activity of the yacón leaves seems to be related to the presence of the CGAs and not to LST. More detailed studies with pure CGAs are required in order to determine their potential use in treatment of diabetes.

El Smallantus sonchifolius (yacón) es una planta natural de la región andina, utilizada popularmente para el control de la diabetes mellitus. Los objetivos del presente estudio fueron; demostrar que el extracto hidroalcohólico al 10% p/v de las hojas del Smallantus sonchifolius (yacón) presenta actividad hipoglucemiante en ratas con diabetes mellitus tipo 2, determinar su probable mecanismo de acción y dosis efectiva; demostrar que no presenta actividad hipoglucemiante en ratas con diabetes mellitus tipo 1; determinar sus posibles efectos adversos sobre variables bioquímicas y hematológicas en ratas con diabetes mellitus tipo 2. Para el estudio de diabetes mellitus tipo 1 se usaron 45 ratas machos, se determinaron los niveles de glucosa e insulina en sangre. Para el estudio de diabetes mellitus tipo 2 se usaron 24 ratas machos, se determinaron los niveles de glucosa en sangre, los efectos adversos a nivel bioquímico y hematológico. Los resultados, en la diabetes mellitus tipo 1 no hubo variación significativa de los niveles de glucosa en sangre (p maypr a 0.05), los niveles de insulina aumentaron significativamente (p menor a 0.05). En la diabetes mellitus tipo 2 los grupos de yacón y glibenclamida disminuyeron significativamente los niveles de glucosa (p menor a 0.001); los estudios de efectos adversos a nivel bioquímico no existe diferencia significativa (p mayor a 0.05) y, a nivel hematológico los niveles de hematíes, hemoglobina y hematocrito disminuyeron significativamente en el grupo del yacón (p menor a 0.05). Conclusiones; el extracto hidroalcohólico al 10% p/v de las hojas del Smallantus sonchifolius (yacón) presenta actividad hipoglucemiante en ratas con diabetes mellitus tipo 2, su probable mecanismo de acción es por que mejoran las concentraciones de insulina en sangre, la dosis efectiva es entre 500 y 1000 mg/Kg de peso corporal, no presenta actividad hipoglucemiante en ratas con diabetes mellitus tipo 1, no presenta efectos adversos significativos. / The Smallanthus sonchifolius (yacón) is a natural plant of the Andean region, popularly it is used for the control of diabetes mellitus. The aims of this present study were the following: to prave that the hydroalcoholic extract 10% (p/v) of the Smallanthus sonchifolius’ leaves presents hypoglycemic activity in rats with diabetes mellitus type 2, moreover to determine its probable mechanism of action and its effective dose, furthermore to prove that the hydroalcoholic extract 10% (p/v) doesn’t present any hypoglycemic activity in rats with diabetes mellitus type 1, finally, another aim of this study was to determine its potentially adverse effects on biochemical and hematological variables in rats with diabetes mellitus type 2. For the study of diabetes mellitus type 1 were used 45 male rats, as a result it was determined the levels of glucose and insulin in the blood. Then for the study of diabetes mellitus type 2 were used 24 male rats, as a consequence it was determined the levels of blood glucose and the adverse effects at the biochemical and hematological. The results were the following in diabetes mellitus type 1 there was no significant variation in levels of blood glucose (p is more than 0.05), but the level of insulin had a significant increasing (p less than 0.05). And in type 2 diabetes mellitus group yacón and glibenclamide decreased significantly the level of glucose (p more than 0.001), studies of adverse effects on biochemical level there is no significant difference (p more than 0.05) and at blood levels of red blood cells, hemoglobin and hematocrit levels decreased significantly in the group’s yacón (p less than 0.05). In conclusión, the hydroalcoholic extract 10% of the Smallanthus sonchifolius presents hypoglycemic activity in rats with diabetes mellitus type 2, and its probable mechanism of action is by enhancing insulin concentrations in blood; moreover its effective dose is between 500 and 1000 mg/Kg body weight, however the hydroalcoholic extract doesn’t present hypoglycemic activity in rat with diabetes mellitus type 1, and it doesn’t present significant adverse effects.

El Smallantus sonchifolius (yacón) es una planta natural de la región andina, utilizada popularmente para el control de la diabetes mellitus. Los objetivos del presente estudio fueron; demostrar que el extracto hidroalcohólico al 10% p/v de las hojas del Smallantus sonchifolius (yacón) presenta actividad hipoglucemiante en ratas con diabetes mellitus tipo 2, determinar su probable mecanismo de acción y dosis efectiva; demostrar que no presenta actividad hipoglucemiante en ratas con diabetes mellitus tipo 1; determinar sus posibles efectos adversos sobre variables bioquímicas y hematológicas en ratas con diabetes mellitus tipo 2. Para el estudio de diabetes mellitus tipo 1 se usaron 45 ratas machos, se determinaron los niveles de glucosa e insulina en sangre. Para el estudio de diabetes mellitus tipo 2 se usaron 24 ratas machos, se determinaron los niveles de glucosa en sangre, los efectos adversos a nivel bioquímico y hematológico. Los resultados, en la diabetes mellitus tipo 1 no hubo variación significativa de los niveles de glucosa en sangre (p maypr a 0.05), los niveles de insulina aumentaron significativamente (p menor a 0.05). En la diabetes mellitus tipo 2 los grupos de yacón y glibenclamida disminuyeron significativamente los niveles de glucosa (p menor a 0.001); los estudios de efectos adversos a nivel bioquímico no existe diferencia significativa (p mayor a 0.05) y, a nivel hematológico los niveles de hematíes, hemoglobina y hematocrito disminuyeron significativamente en el grupo del yacón (p menor a 0.05). Conclusiones; el extracto hidroalcohólico al 10% p/v de las hojas del Smallantus sonchifolius (yacón) presenta actividad hipoglucemiante en ratas con diabetes mellitus tipo 2, su probable mecanismo de acción es por que mejoran las concentraciones de insulina en sangre, la dosis efectiva es entre 500 y 1000 mg/Kg de peso corporal, no presenta actividad hipoglucemiante en ratas con diabetes mellitus tipo 1, no presenta efectos adversos significativos. / The Smallanthus sonchifolius (yacón) is a natural plant of the Andean region, popularly it is used for the control of diabetes mellitus. The aims of this present study were the following: to prave that the hydroalcoholic extract 10% (p/v) of the Smallanthus sonchifolius’ leaves presents hypoglycemic activity in rats with diabetes mellitus type 2, moreover to determine its probable mechanism of action and its effective dose, furthermore to prove that the hydroalcoholic extract 10% (p/v) doesn’t present any hypoglycemic activity in rats with diabetes mellitus type 1, finally, another aim of this study was to determine its potentially adverse effects on biochemical and hematological variables in rats with diabetes mellitus type 2. For the study of diabetes mellitus type 1 were used 45 male rats, as a result it was determined the levels of glucose and insulin in the blood. Then for the study of diabetes mellitus type 2 were used 24 male rats, as a consequence it was determined the levels of blood glucose and the adverse effects at the biochemical and hematological. The results were the following in diabetes mellitus type 1 there was no significant variation in levels of blood glucose (p is more than 0.05), but the level of insulin had a significant increasing (p less than 0.05). And in type 2 diabetes mellitus group yacón and glibenclamide decreased significantly the level of glucose (p more than 0.001), studies of adverse effects on biochemical level there is no significant difference (p more than 0.05) and at blood levels of red blood cells, hemoglobin and hematocrit levels decreased significantly in the group’s yacón (p less than 0.05). In conclusión, the hydroalcoholic extract 10% of the Smallanthus sonchifolius presents hypoglycemic activity in rats with diabetes mellitus type 2, and its probable mechanism of action is by enhancing insulin concentrations in blood; moreover its effective dose is between 500 and 1000 mg/Kg body weight, however the hydroalcoholic extract doesn’t present hypoglycemic activity in rat with diabetes mellitus type 1, and it doesn’t present significant adverse effects. / Tesis