Glycogen synthase kinase-3 (GSK-3) a magic enzyme: it's role in diabetes mellitus and glucose homeostasis, interactions with fluroquionlones. A mini-review / Glicogênio sintase quinase-3 (GSK-3), uma enzima mágica: seu papel no diabetes mellitus e na homeostase da glicose: interações com fluoroquinolonas. Uma mini-revisão

Abstract Diabetes mellitus (DM) is a non-communicable disease throughout the world in which there is persistently high blood glucose level from the normal range. The diabetes and insulin resistance are mainly responsible for the morbidities and mortalities of humans in the world. This disease is mainly regulated by various enzymes and hormones among which Glycogen synthase kinase-3 (GSK-3) is a principle enzyme and insulin is the key hormone regulating it. The GSK-3, that is the key enzyme is normally showing its actions by various mechanisms that include its phosphorylation, formation of protein complexes, and other cellular distribution and thus it control and directly affects cellular morphology, its growth, mobility and apoptosis of the cell. Disturbances in the action of GSK-3 enzyme may leads to various disease conditions that include insulin resistance leading to diabetes, neurological disease like Alzheimer's disease and cancer. Fluoroquinolones are the most common class of drugs that shows dysglycemic effects via interacting with GSK-3 enzyme. Therefore, it is the need of the day to properly understand functions and mechanisms of GSK-3, especially its role in glucose homeostasis via effects on glycogen synthase.

Resumo O diabetes mellitus (DM) é uma doença não transmissível em todo o mundo, na qual existe nível glicêmico persistentemente alto em relação à normalidade. O diabetes e a resistência à insulina são os principais responsáveis ​​pelas morbidades e mortalidades de humanos no mundo. Essa doença é regulada principalmente por várias enzimas e hormônios, entre os quais a glicogênio sintase quinase-3 (GSK-3) é uma enzima principal e a insulina é o principal hormônio que a regula. A GSK-3, que é a enzima-chave, normalmente mostra suas ações por vários mecanismos que incluem sua fosforilação, formação de complexos de proteínas e outras distribuições celulares e, portanto, controla e afeta diretamente a morfologia celular, seu crescimento, mobilidade e apoptose do célula. Perturbações na ação da enzima GSK-3 podem levar a várias condições de doença que incluem resistência à insulina que leva ao diabetes, doenças neurológicas como a doença de Alzheimer e câncer. As fluoroquinolonas são a classe mais comum de drogas que apresentam efeitos disglicêmicos por meio da interação com a enzima GSK-3. Portanto, é necessário hoje em dia compreender adequadamente as funções e mecanismos da GSK-3, principalmente seu papel na homeostase da glicose via efeitos na glicogênio sintase.

Glycogen synthase kinase-3 (GSK-3) a magic enzyme: it’s role in diabetes mellitus and glucose homeostasis, interactions with fluroquionlones. A mini-review / Glicogênio sintase quinase-3 (GSK-3), uma enzima mágica: seu papel no diabetes mellitus e na homeostase da glicose: interações com fluoroquinolonas. Uma mini-revisão

Diabetes mellitus (DM) is a non-communicable disease throughout the world in which there is persistently high blood glucose level from the normal range. The diabetes and insulin resistance are mainly responsible for the morbidities and mortalities of humans in the world. This disease is mainly regulated by various enzymes and hormones among which Glycogen synthase kinase-3 (GSK-3) is a principle enzyme and insulin is the key hormone regulating it. The GSK-3, that is the key enzyme is normally showing its actions by various mechanisms that include its phosphorylation, formation of protein complexes, and other cellular distribution and thus it control and directly affects cellular morphology, its growth, mobility and apoptosis of the cell. Disturbances in the action of GSK-3 enzyme may leads to various disease conditions that include insulin resistance leading to diabetes, neurological disease like Alzheimer’s disease and cancer. Fluoroquinolones are the most common class of drugs that shows dysglycemic effects via interacting with GSK-3 enzyme. Therefore, it is the need of the day to properly understand functions and mechanisms of GSK-3, especially its role in glucose homeostasis via effects on glycogen synthase.

O diabetes mellitus (DM) é uma doença não transmissível em todo o mundo, na qual existe nível glicêmico persistentemente alto em relação à normalidade. O diabetes e a resistência à insulina são os principais responsáveis pelas morbidades e mortalidades de humanos no mundo. Essa doença é regulada principalmente por várias enzimas e hormônios, entre os quais a glicogênio sintase quinase-3 (GSK-3) é uma enzima principal e a insulina é o principal hormônio que a regula. A GSK-3, que é a enzima-chave, normalmente mostra suas ações por vários mecanismos que incluem sua fosforilação, formação de complexos de proteínas e outras distribuições celulares e, portanto, controla e afeta diretamente a morfologia celular, seu crescimento, mobilidade e apoptose do célula. Perturbações na ação da enzima GSK-3 podem levar a várias condições de doença que incluem resistência à insulina que leva ao diabetes, doenças neurológicas como a doença de Alzheimer e câncer. As fluoroquinolonas são a classe mais comum de drogas que apresentam efeitos disglicêmicos por meio da interação com a enzima GSK-3. Portanto, é necessário hoje em dia compreender adequadamente as funções e mecanismos da GSK-3, principalmente seu papel na homeostase da glicose via efeitos na glicogênio sintase.

Glycogen synthase kinase-3 (GSK-3) a magic enzyme: its role in diabetes mellitus and glucose homeostasis, interactions with fluroquionlones. A mini-review

Abstract Diabetes mellitus (DM) is a non-communicable disease throughout the world in which there is persistently high blood glucose level from the normal range. The diabetes and insulin resistance are mainly responsible for the morbidities and mortalities of humans in the world. This disease is mainly regulated by various enzymes and hormones among which Glycogen synthase kinase-3 (GSK-3) is a principle enzyme and insulin is the key hormone regulating it. The GSK-3, that is the key enzyme is normally showing its actions by various mechanisms that include its phosphorylation, formation of protein complexes, and other cellular distribution and thus it control and directly affects cellular morphology, its growth, mobility and apoptosis of the cell. Disturbances in the action of GSK-3 enzyme may leads to various disease conditions that include insulin resistance leading to diabetes, neurological disease like Alzheimers disease and cancer. Fluoroquinolones are the most common class of drugs that shows dysglycemic effects via interacting with GSK-3 enzyme. Therefore, it is the need of the day to properly understand functions and mechanisms of GSK-3, especially its role in glucose homeostasis via effects on glycogen synthase.

Resumo O diabetes mellitus (DM) é uma doença não transmissível em todo o mundo, na qual existe nível glicêmico persistentemente alto em relação à normalidade. O diabetes e a resistência à insulina são os principais responsáveis pelas morbidades e mortalidades de humanos no mundo. Essa doença é regulada principalmente por várias enzimas e hormônios, entre os quais a glicogênio sintase quinase-3 (GSK-3) é uma enzima principal e a insulina é o principal hormônio que a regula. A GSK-3, que é a enzima-chave, normalmente mostra suas ações por vários mecanismos que incluem sua fosforilação, formação de complexos de proteínas e outras distribuições celulares e, portanto, controla e afeta diretamente a morfologia celular, seu crescimento, mobilidade e apoptose do célula. Perturbações na ação da enzima GSK-3 podem levar a várias condições de doença que incluem resistência à insulina que leva ao diabetes, doenças neurológicas como a doença de Alzheimer e câncer. As fluoroquinolonas são a classe mais comum de drogas que apresentam efeitos disglicêmicos por meio da interação com a enzima GSK-3. Portanto, é necessário hoje em dia compreender adequadamente as funções e mecanismos da GSK-3, principalmente seu papel na homeostase da glicose via efeitos na glicogênio sintase.

Research progress on the effects of arsenic and high-fat diet exposure on diabetes in mice / 中华地方病学杂志

Inorganic arsenic is an environmental carcinogen. Arsenic exposure is closely related to diabetes. Obesity is an important risk factor for diabetes, and excess energy is the main cause of obesity. High-fat diet feeding is a common method of modeling obese animals. This paper reviews the research progress of diabetes induced by arsenic and the combined exposure of arsenic and high-fat diet in mice. It is found that the diabetes induced by arsenic in mice is mainly manifested in glucose intolerance, and arsenic can aggravate the glucose intolerance caused by high-fat diet, but the diabetes induced by arsenic and its mechanism are different from the typical type 2 diabetes caused by high-fat diet.

Correlations among vitamin K intake, body fat, lipid profile and glucose homeostasis in adults and the elderly

ABSTRACT Objective Recent research has investigated the possible inverse relationship between vitamin K intake and body fat. In addition, an increasing number of studies are supporting a key role for this vitamin in improving lipid profile and insulin sensitivity and reducing the risk of type 2 diabetes mellitus, but little is known about what mechanisms would be involved. Thus, the objective of this study was to investigate the relationship between vitamin K intake (in the form of phylloquinone - PK), body fat, lipid profile and markers of glucose homeostasis in adults and the elderly. Subjects and methods A cross-sectional study with 298 participants (46% men) in the São Paulo Health Survey 2014-2015. Spearman correlations were performed to evaluate the associations between vitamin K intake and the biochemical and body composition measures. Results Among normal-weight male adults (n = 15), PK intake presented a positive correlation with the quantitative insulin sensitivity check index (QUICKI) (r = 0.525; p = 0.045). Among men with high fat mass index (FMI) (n = 101), PK intake had a negative correlation with homeostasis model assessment estimate for β-cell function (HOMA-β) (r = −0.227; p = 0.022). In women with high FMI (n = 122), PK intake had a negative correlation with HOMA-β (r = −0.199, p = 0.032) and insulin (r = −0.207, p = 0.026). No correlations were found between PK intake and lipid profile. Conclusions Our findings support a potential relationship among PK intake, body fat and markers of glucose homeostasis in adults and the elderly.

Role and mechanism of glucagon-like peptide-1 in drug addiction / 中国药理学通报

Glucagon-like peptide-1 (GLP-1) is an incretin which plays a role in regulating glucose hornêbstasis and appetite, involved in the occurrence and development of type 2 diabetes and obesity. GLP-1 plays the role through regulating insulin secretion and activating the GLP-1 receptor (GLP-1R). Recent studies have found the association between GLP-1 and addictive behaviors caused by cocaine, nicotine, alcohol and amphetamine. This article reviews the role and mechanism of GLP-1 in drug addiction.

On the regulation of bone metabolism: A research review of neuropeptide Y / 中华内分泌代谢杂志

Skeleton metabolic diseases such as osteoporosis and fracture have posed an detrimental impact on the elderly, which is a primary cause of paralysis and even death in patients. Osteoblast and osteoclast are the two major parts in the regulation of bone homeostasis and imbalance of these two cells, which may result in dysfunction of bone metabolism. Recent researches indicated that bone homeostasis was primarily regulated by endocrine, paracrine, and local mechanical processes. However, increasing evidences have indicated that the significant role of nerve system may involve in bone metabolism via both central and peripheral pathways. Neuropeptide Y(NPY), a neurotransmitter that belongs to a family of peptides,serves as a critical hinge connecting nerve system and skeleton system. Several studies have suggested that NPY generated by both central and peripheral nerve system could regulate bone homeostasis and that NPY-energic nerve fibers distributed on bone surface and in intramedullary cavity and NPY receptors located at osteoblast, chondrocyte, and osteocytes also provide a basis for nerve-skeleton metabolic pathways. NPY can directly regulate osteoprogenitor, involving in the production and differentiation of osteoblast and osteoclast. In addition, as a pivotal molecular of energy homeostasis, NPY may affect glucose and fat homeostasis. Studies of animal models also have further indicated energy metabolism may directly or indirectly participate in the regulation of bone mass. Therefore, further researches on the relationship between NPY and bone homeostasis may facilitate to unveil the central and peripheral regulatory effect of NPY on bone homeostasis and provide a new sight for the treatment of skeleton metabolism-related diseases in the future.

Inhibidores del cotransportador de sodio y glucosa tipo 2 (SGLT2), el riñón como objetivo en el control glucémico de la diabetes mellitus tipo 2 / Sodium-glucose co-transporter 2 (SGLT2) inhibitors, kidney as objective in the glycemic control of diabetes mellitus type 2

Resumen La diabetes mellitus tipo 2 es una de las enfermedades crónicas más graves y prevalentes a la fecha, y constituye una causa muy importante de morbilidad y mortalidad en el mundo. A pesar del gran número de fármacos que existen para el control de la diabetes muchas personas con esta afección no logran un buen control de las cifras de glucosa. La hiperglucemia es el blanco terapéutico primordial en el tratamiento de la diabetes mellitus tipo 2, y se han desarrollado múltiples familias de fármacos para lograr el control glucémico que evite complicaciones a corto y largo plazos. Los inhibidores del cotransportador de sodio y glucosa tipo 2 (SGLT2) son una nueva familia de fármacos que reducen la reabsorción renal de glucosa e incrementan su eliminación urinaria, disminuyendo las concentraciones de glucosa.

Abstract Type 2 diabetes is the most important and prevalent chronic disease today, being an important morbidity and mortality cause worldwide. Despite the great number of medications for diabetes control, many people with this condition do not achieve good glycemic control. Hyperglycemia is the key therapeutic focus in diabetes mellitus management, with many drug families developed to the date for get the target glucose level for prevent the acute and long term complications of this disease. Sodium glucose co-transporter type 2 inhibitors (SGLT2) are a new drug family that reduce renal glucose reabsorption and increase the urinary glucose elimination, thus lowering the blood glucose levels.

Sapium ellipticum (Hochst) Pax ethanol leaf extract modulates glucokinase and glucose-6-phosphatase activities in streptozotocin induced diabetic rats

Objective To examine the effects of Sapium ellipticum (SE) leaf extract on the hepatic activities of glucokinase and glucose-6-phosphatase in streptozotocin-induced diabetic Wistar rats. Methods STZ-induced diabetic Wistar rats (four groups, n = 8) were used in this study. SE was assessed at two different doses, 400 and 800 mg/kg BW, in comparison with metformin (METF) (12 mg/kg BW) as a reference antidiabetic drug. All treatments were done orally (p.o), twice daily at 8 h interval for a period of 21 days. Glucokinase and glucose-6-phosphatase activities were respectively determined using standard protocols. Hepatic and muscle glycogen contents were estimated as well. Results STZ caused significant decrease in glucose-6-phosphatase activity and concomitant increase in glucokinase activity. SE extract especially at 400 mg dosage significantly reversed the alterations by increasing glucokinase activity by 40.31% and inhibiting glucose-6-phosphatase activity by 37.29% compared to diabetic control animals. However, the effects were significantly lower than that of METF which enhanced glucokinase activity by 94.76% and simultaneously inhibited glucose-6-phosphatase activity by 49.15%. The extract also improved hepatic glycogen level by 32.37 and 27.06% at 400 and 800 mg dosage respectively. HPLC-MS analysis of some SE fractions in dynamic MRM mode (using the optimized compound-specific parameters) revealed among other active compounds, the presence of amentoflavone, which has been associated with antidiabetic function. Conclusions The ability of SE extract to concurrently inhibit glucose-6-phosphatase and activate glucokinase in this study suggests that it may be a treatment option for type 2 diabetes patients, and the presence of amentoflavone in the plant extract may account for its anti-diabetic potential.

Nonfunctional overreaching and hepatic adaptations of APPL1 and APPL2

Abstract AIMS Previously, we verified that overtrained mice upregulated the TRB3 levels, its association with Akt, and the hepatic concentrations of glycogen. It is known that APPL1 can limit the interaction between TRB3 and Akt, playing an important role in the glucose homeostasis. Thus, we verified the effects of three overtraining protocols on the hepatic levels of APPL1 and APPL2. METHODS Rodents were divided into control (CT), overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up) and overtrained by running without inclination (OTR). The hepatic contents of APPL1 and APPl2 were measured by the immunoblotting technique. RESULTS Significant elevation of APPL1 observed in the OTR/down and OTR/up groups, as well as the tendency of increase (p=0.071) observed in the OTR group. CONCLUSION These results indicate that this particular protein is likely to participate in the glucose homeostasis previously observed in response to these OT protocols.(AU)

Improvement effect of duodenal-jejunal bypass on inflammatory status of biliopancreatic limb of ZDF rats and its mechanism / 吉林大学学报(医学版)

Objective:To investigate the improvement effects of duodenal-jejunal bypass (DJB)on the blood glucose homeostasis,insulin resistance and inflammation of the obese type 2 diabetic (T2DM)ZDF rats,and to discuss its possible mechanism.Methods:A total of 20 ZDF rats were randomly divided into DJB operation group and sham operation group (n = 10).There were 8 rats survived in each group after operation.The level of blood glucose (FBG)was detected by Roche glucose meter at 1 week before operation,2 weeks,4 weeks and 6 weeks after operation;the fasting serum insulin level of the rats was measured by ELISA kit;the insulin sensitivity index (HOMA-ISI)and insulin resistance index (HOMA-IR)were calculated.The rats were executed 6 weeks after operation.HE staining was used to observe the morphology of the inflammatory cells in BP limb of the rats;the expression levels of AMPK and pAMPK in BP lamb of the rats were observed by immunohistochemical staining;the expression levels of interleukin 1β(IL-1β),interleukin 6 (IL-6),tumor necrosis factorα(TNF-α),nuclear factorκB (NF-κB),and interleukin 10 (IL-10)mRNA of the rats were detected by QRT-PCR method.Results:From the 2nd week after operation,compared with before operation,the FBG levels of the rats in DJB operation group were decreased (t=3.798,P <0.05);compared with sham operation group,the FBG level of the rats in DJB operation group was decreased (t=3.205,P <0.05).Six weeks after operation,compared with sham operation group,the HOMA-IR of the rats in DJB operation group was significantly decreased (t=4.441,P <0.05)and the HOMA-ISI was significantly increased (t=-8.65,P < 0.05).The HE staining results showed that compared with sham operation group,the morphology of the inflammatory cells in BP limb of the rats in DJB operation group was significantly improved.The QRT-PCR results showed that the expression levels of IL-1β,IL-6,TNF-αand NF-κB of the rats in DJB operation group was significantly decreased compared with sham operation group (P < 0.05), while the expression level of IL-10 was significantly increased (P < 0.05).The immunohistochemical test results showed that the expression levels of AMPK and pAMPK in BP lamb of the rats in DJB operation group were increased compared with sham operation group.Conclusion:DJB can significantly improve the blood glucose homeostasis and insulin resistance in the T2DM rats,and its mechanism may be related to the decreased expressions of inflammatory factors and the activation of AMPK molecules in BP lamb of the T2DM rats.

Establishment of a mouse model of intermittent fasting and characterization of its effect on glucose homeostasis / 中国比较医学杂志

Objective To establish a stable and reliable mouse model as an alternative to the traditional model of impaired glucose tolerance induced by calorie restriction and its effect on glucose homeostasis.Methods Forty 16-week-old SPF C57BL/6J mice (half male and half female) were randomly divided into four groups by sex and the way of feeding.The mice in the ad libitum (AL) group had free access to basic diet, while the mice in the intermittent fasting (IF) group had normal diet and fasting on alternate days, with free access to water on the fasting days.The changes of body weight and blood glucose concentration in each group were monitored, and intraperitoneal glucose tolerance test and insulin tolerance test in mice were performed before and after the 12-week IF treatment.Results At 12 weeks after IF treatment, the body weight and blood glucose concentration of mice did not show significant difference.After i.p.injection of glucose, the blood glucose concentration of IF mice was less increased than the AL group, and after the insulin injection, the blood glucose concentration was more decreased.Compared to the AL group, the areas under the curve of tolerance test in the IF group were significantly decreased (P < 0.05).Conclusions After IF treatment, the mice show an enhanced sensitivity to insulin and improved glucose tolerance.This establishment method of mouse model of intermittent fasting is easy and simple, therefore, can be used as an effective alternative to traditional calorie restriction model of impaired glucose tolerance.

Sapium ellipticum (Hochst) Pax ethanol leaf extract modulates glucokinase and glucose-6-phosphatase activities in streptozotocin induced diabetic rats

Objective: To examine the effects of Sapium ellipticum (SE) leaf extract on the hepatic activities of glucokinase and glucose-6-phosphatase in streptozotocin-induced diabetic Wistar rats. Methods: STZ-induced diabetic Wistar rats (four groups, n=8) were used in this study. SE was assessed at two different doses, 400 and 800 mg/kg BW, in comparison with metformin (METF) (12 mg/kg BW) as a reference antidiabetic drug. All treatments were done orally (p.o), twice daily at 8 h interval for a period of 21 days. Glucokinase and glucose-6-phosphatase activities were respectively determined using standard protocols. Hepatic and muscle glycogen contents were estimated as well. Results: STZ caused significant decrease in glucose-6-phosphatase activity and concomi-tant increase in glucokinase activity. SE extract especially at 400 mg dosage significantly reversed the alterations by increasing glucokinase activity by 40.31%and inhibiting glucose-6-phosphatase activity by 37.29%compared to diabetic control animals. However, the ef-fects were significantly lower than that of METF which enhanced glucokinase activity by 94.76%and simultaneously inhibited glucose-6-phosphatase activity by 49.15%. The extract also improved hepatic glycogen level by 32.37 and 27.06% at 400 and 800 mg dosage respectively. HPLC-MS analysis of some SE fractions in dynamic MRM mode (using the optimized compound-specific parameters) revealed among other active compounds, the presence of amentoflavone, which has been associated with antidiabetic function. Conclusions: The ability of SE extract to concurrently inhibit glucose-6-phosphatase and activate glucokinase in this study suggests that it may be a treatment option for type 2 diabetes patients, and the presence of amentoflavone in the plant extract may account for its anti-diabetic potential.

Intermuscular Adipose Tissue Content and Intramyocellular Lipid Fatty Acid Saturation Are Associated with Glucose Homeostasis in Middle-Aged and Older Adults

BACKGROUND: Insulin resistance is associated with the higher content of intermuscular adipose tissue (IMAT) and the saturation of intramyocellular lipid (IMCL), but a paucity of data exist in humans. This study examined associations among IMAT content, IMCL saturation, and fasting glucose concentration in middle-aged and older adults with overweight or obesity. METHODS: Seventy-five subjects (26 males, 49 females) were recruited and thigh muscle and IMAT were assessed using magnetic resonance imaging. Vastus lateralis tissue was acquired from a subset of nine subjects and IMCL content and saturation were assessed using nonlinear dual complex microscopy. RESULTS: The characteristics of the 75 subjects were as follows: age 59±11 years, body mass index 30±5 kg/m², fasting glucose concentration 5.2±0.5 mmol/L, fasting insulin concentration 12.2±7.3 µU/mL, fasting homeostatic model assessment of insulin resistance (HOMA-IR) 2.9±2.0 (mean±SD). IMAT to muscle tissue (MT) volume ratio was positively associated with the saturated fatty acid to unsaturated fatty acid ratio in IMCL. IMAT:MT was positively associated with fasting glucose concentration and HOMA-IR. IMCL saturation was positively associated with fasting glucose concentration while muscle cell area, IMCL area, and % IMCL in muscle cell were not associated with fasting glucose concentration. CONCLUSION: These results indicate that higher intermuscular fat content and IMCL saturation may impact fasting glucose concentration in middle-aged and older adults with overweight or obesity. The centralization of adipose tissue in the appendicular region of the body may promote insulin resistance.

Efeito dos compostos fenólicos do camu-camu e do cupuaçu no desenvolvimento da obesidade e diabetes mellitus tipo 2 / Effects of camu camu and cupuassu phenolic compounds on obesity and type 2 diabetes mellitus development

A incidência da obesidade e do diabetes do tipo 2 tomou proporções epidêmicas nos últimos anos, atingindo bilhões de indivíduos em todo o mundo. A descoberta de formas inovadoras capazes de reduzir as alterações metabólicas associadas a estas doenças é fundamental para minimizar o seu impacto na qualidade de vida da população e na economia dos países. Muitos estudos têm demonstrado que os compostos bioativos de alimentos possuem efeitos benéficos à saúde. O camu-camu e o cupuaçu são frutas nativas da região amazônica com potencial agroeconômico ainda inexplorado, que contêm um grande número de compostos fitoquímicos que podem atuar sobre o metabolismo corporal. Desta forma, o objetivo deste estudo foi verificar os efeitos dos compostos fenólicos de extratos do camu-camu e do cupuaçu no desenvolvimento da obesidade e do diabetes tipo 2 em ensaios in vivo e in vitro, e identificar os possíveis metabólitos envolvidos nestes efeitos. Os extratos ricos em compostos fenólicos da polpa comercial destes frutos foram extraídos em fase sólida, caracterizados por cromatografia líquida de alta eficiência (CLAE/DAD) e avaliados quanto à inibição da atividade de enzimas digestivas in vitro. Os extratos obtidos foram então testados em duas diferentes concentrações (2,25 e 4,5 mg de equivalentes de catequina/Kg de peso corporal para o cupuaçu; 7 e 14 mg de equivalentes de ácido gálico/Kg de peso corporal para o camu camu) em um modelo animal de obesidade e resistência insulínica induzida por dieta com alto teor de lipídios e sacarose em camundongos C57BL/6J. Foram investigados os efeitos destes compostos sobre as homeostases glicídica e lipídica através de análises séricas, testes de tolerância à insulina e à glicose e conteúdo de lipídios hepáticos e fecais. O extrato do camu camu apresentou flavonóis, ácido elágico e elagitaninos em sua composição. A suplementação com o extrato de compostos fenólicos do camu camu reduziu o ganho de peso corporal e diminuiu a intolerância à glicose e à insulina, independente da dose administrada. No entanto, a administração destes extratos não apresentou efeitos sobre o metabolismo lipídico. Estes resultados foram associados a um possível efeito de saciedade, com consequente redução da ingestão da dieta e da glicolipotoxicidade, e com um efeito anti-inflamatório devido à diminuição dos níveis de proteína C reativa. Já o extrato de cupuaçu apresentou flavanóis, flavonas e proantocianidinas em sua composição. A suplementação com o extrato de cupuaçu na maior dose testada melhorou a homeostase da glicose e principalmente dos lipídios, protegendo o tecido hepático dos danos causados pela dieta com alto teor de lipídios e sacarose. Estes efeitos foram associados à inibição de enzimas digestivas, com consequente menor absorção de lipídios provenientes da dieta, reduzindo assim a resistência à insulina no fígado, a hiperglicemia e a dislipidemia. Ainda, foi avaliada a distribuição de metabólitos no trato gastrointestinal de camundongos após a administração aguda do extrato de cupuaçu. Foi possível identificar a complexa mistura de polifenóis presentes no extrato de cupuaçu ao longo do trato gastrointestinal, que posteriormente foi metabolizada pela microbiota. Entre os metabólitos encontrados estão as agliconas hipolaetina e isoscutelareína, e os metabolitos microbianos da epicatequina como o 3,4-diHPP-2-ol e a 5-(3,4-dihidroxiphenil)-γ-valerolactona. De acordo com estes resultados, as diferenças na composição de compostos fenólicos encontradas entre os extratos das duas frutas foram responsáveis pelos diferentes resultados nos protocolos in vivo e a identificação dos metabólitos microbianos possibilita o conhecimento dos compostos possivelmente implicados nos efeitos benéficos. Novos estudos podem contribuir para um melhor entendimento dos mecanismos, bem como quais metabólitos estão associados aos efeitos benéficos que os compostos presentes nestas duas frutas apresentaram neste estudo

The incidence of obesity and type 2 diabetes reached epidemic proportions in recent years, arriving to billions of people around the world. The discovery of innovative ways that can reduce the metabolic abnormalities associated with these diseases is essential to minimize its impact on the population's quality of life and the economy of the countries. Many studies have demonstrated that food bioactive compounds have beneficial health effects. Camu-camu and cupuassu are native fruits of the Amazon region with unexplored agroeconomic potential, which contain a large number of phytochemical compounds that can act on body metabolism. Thus, the objective of this study was verify the effects of phenolic compounds of camu-camu and cupuassu extracts on the development of obesity and type 2 diabetes in vivo and in vitro, and identfy the possible metabolites involved in these effects. The phenolic compound-rich extracts were obtained from commercial frozen fruit pulps by solid phase extraction, characterized by high-performance liquid chromatography (HPLC/DAD) and evaluated for inhibition of digestive enzymes activities in vitro. Then, the extracts were tested at two different doses (2.25 and 4.5 mg catechin equivalents/kg body weight for cupuassu; 7 and 14 mg of gallic acid equivalents/kg body weight for camu camu) in an animal model (C57BL/6J mice) of obesity and insulin resistance induced by high fat high sucrose diet. The effects of extract supplementation on glucose and lipid homeostasis were assessed by serum analysis, insulin and glucose tolerance tests in mice, and contents of fat in liver and fecal samples. Camu camu extract presented flavonols, ellagic acid and ellagitannins in its composition. Supplementation with camu camu phenolic extract reduced weight gain and decreased glucose and insulin intolerance independent of the dose administered. However, no effects on lipid metabolism were found. These findings were associated with a possible effect of satiety with a consequent reduction in energy intake and glicolipotoxicity, and anti-inflammatory properties. Cupuassu extract presented flavanols, flavones and proanthocyanidins in its composition. Supplementation with cupuacu extract at the highest dose improved glucose homeostasis and plasmatic lipid levels, protecting the liver tissue from damage caused by diet rich in lipids and sucrose. These effects were associated with inhibition of digestive enzymes, with consequent lower absorption of lipids from the diet, thereby reducing the insulin resistance in the liver, the hyperglycemia and dyslipidemia. Furthermore, the distribution of metabolites in the gastrointestinal tract of mice was evaluated after acute administration of cupussu extract by HPLC-ESI-QTOF. We identified the complex mixture of polyphenols present in cupuassu extract along the gastrointestinal tract, which was subsequently metabolized by the intestinal microbiota. Among detected metabolites are hypolaetin and isoscutellarein aglycones and microbial metabolites of epicatechin as 3,4-diHPP-2-ol and 5-(3,4-dihydroxyphenyl)-γvalerolactone. According to these results, the differences in the composition of phenolic compounds found between the two fruit extracts were responsible for the different effects in vivo and identification of microbial metabolites enables the knowledge of the compounds potentially implicated in the beneficial effects. New studies can contribute to a better understanding of the metabolism and mechanisms of action

An unusual case of trifluoperazine induced hypoglycemia.

Hypoglycemia is a serious condition which if not diagnosed and treated urgently may cause irreversible damage to the brain and may be life threatening. There are various causes attributed to hypoglycemia, but drugs are one of the most important one of them. Various drugs are documented to cause hypoglycemia but we present a rare case report of a 52-year-old male patient with schizoaffective disorder on trifluoperazine who presented in emergency department with documented hypoglycemia and this hypoglycemic episode improved when the drug was withdrawn. When WHO causality assessment scale was applied, trifluoperazine was found as the probable cause of the episodes of hypoglycemia. Therefore, this possibility of hypoglycemia should always be kept in mind while prescribing trifluoperazine.

Intracellular, serum and 24-hour urinary Magnesium in patients with Type 2 Diabetes Mellitus.

Low magnesium status has been shown to have a negative impact on glucose homeostasis and insulin sensitivity, as well as on the evolution of diabetic complications. In the present study, 45- to 65- year old type 2 diabetic patients and normal age-matched subjects (n = 40 each) were recruited and their intracellular total magnesium level, serum total magnesium level, and 24-hour urinary total magnesium excretion were assessed. The magnesium levels were measured by spectrophotometric method using calmagite. In type 2 diabetic patients, intracellular magnesium concentration was significantly lower (4.26 ± 0.61 vs. 5.76 ± 0.59 mg/dL, P < 0.001) and 24-hour urinary magnesium concentration significantly higher (125.60 ± 33.32 vs. 72.04 ± 14.55 mg/24 hr, P < 0.001) compared with those of healthy subjects. Serum magnesium levels of diabetic patients and healthy subjects showed no significant difference (1.69 ± 0.30 vs. 1.76 ± 0.31 mg/dL, P > 0.05). There was a significant negative correlation between intracellular and 24-hour urinary magnesium excretion (r = -0.548, n = 80, P < 0.01). There was no correlation between serum and intracellular magnesium (r = -0.021, n = 80, P > 0.05) and, serum and 24 hour urinary magnesium excretion (r = -0.128, n = 80, P > 0.05).

Antagonism of astragalus polysaccharide on activity and nuclear translocation of glycogen synthase kinase 3βinvolved in regulation of glucose homeostasis / 中国生化药物杂志

Objective To observe the effect of astragalus polysaccharides ( APS) on glucose homeostasis regulation and focus on glycogen synthase kinase 3 beta (GSK3 beta) activity and subcellular localization (nuclear translocation).Methods HepG2 human hepatoma cells were cultured in vitro and treated with high glucose of different concentrations (30, 40 mM) to induce hepatocyte endoplasmic reticulum stress model, then acquire optimum operating concentration.The HepG2 cells were treated with APS of different concentrations (50, 100, 200, 400 μg/mL) to select the most effective concentration.The HepG2 cells were divided into seven groups with different treatment: negative control group (C), positive control group (Tm), 30 mM high glucose-induced group (G30), 45 mM high glucose-induced group (G45), negative control+APS group (CA), positive control+APS group ( TA) and high glucose-induced+APS group ( GA).Effect of APS at different concentrations on proliferation activity of HepG2 cells were detected by MTT assay, transcription and shear levels of XBPlmRNA in HepG2 cells by quantitative real-time PCR, and phosphorylation levels of GSK3βin cytoplasm and nucleus by immunoblotting techniques.Results The optimum operating glucose concentration was 30 mM.The most effective APS concentration was 200μg/mL.The transcription and shear levels of XBPlmRNA in HepG2 cells of GA group were lower than those of G30 group ( P<0.05), respectively, but there were no significant differences between TA and Tm group.The phosphorylation levels of GSK3βin cytoplasm and nucleus of GA group were higher than those of G group(P<0.05), respectively, but there were no significant differences between TA and Tm group. Conclusion APS could improve hepatic steatosis, and its mechanism might be that APS inhibits the activity and nuclear localization of GSK3β, then alleviate endoplasmic reticulum stress.

Chlorogenic Acid Maintains Glucose Homeostasis through Modulating the Expression of SGLT-1, GLUT-2, and PLG in Different Intestinal Segments of Sprague-Dawley Rats Fed a High-Fat Diet / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To reveal the effects and related mechanisms of chlorogenic acid (CGA) on intestinal glucose homeostasis.</p><p><b>METHODS</b>Forty male Sprague-Dawley rats were randomly and equally divided into four groups: normal chow (NC), high-fat diet (HFD), HFD with low-dose CGA (20 mg/kg, HFD-LC), and HFD with high-dose CGA (90 mg/kg, HFD-HC). The oral glucose tolerance test was performed, and fast serum insulin (FSI) was detected using an enzyme-linked immunosorbent assay. The mRNA expression levels of glucose transporters (Sglt-1 and Glut-2) and proglucagon (Plg) in different intestinal segments (the duodenum, jejunum, ileum, and colon) were analyzed using quantitative real-time polymerase chain reaction. SGLT-1 protein and the morphology of epithelial cells in the duodenum and jejunum was localized by using immunofluorescence.</p><p><b>RESULTS</b>At both doses, CGA ameliorated the HFD-induced body weight gain, maintained FSI, and increased postprandial 30-min glucagon-like peptide 1 secretion. High-dose CGA inhibited the HFD-induced elevation in Sglt-1 expression. Both CGA doses normalized the HFD-induced downregulation of Glut-2 and elevated the expression of Plg in all four intestinal segments.</p><p><b>CONCLUSION</b>An HFD can cause a glucose metabolism disorder in the rat intestine and affect body glucose homeostasis. CGA can modify intestinal glucose metabolism by regulating the expression of intestinal glucose transporters and Plg, thereby controlling the levels of blood glucose and insulin to maintain glucose homeostasis.</p>

Periodontitis and Insulin Resistance: Casual or Causal Relationship?

Insulin resistance (IR) is now considered as a chronic and low level inflammatory condition. It is closely related to altered glucose tolerance, hypertriglyceridemia, abdominal obesity, and coronary heart disease. IR is accompanied by the increase in the levels of inflammatory cytokines like interleukin-1 and 6, tumor necrosis factor-alpha. These inflammatory cytokines also play a crucial part in pathogenesis and progression of insulin resistance. Periodontitis is the commonest of oral diseases, affecting tooth investing tissues. Pro-inflammatory cytokines are released in the disease process of periodontitis. Periodontitis can be attributed with exacerbation of IR. Data in the literature supports a "two way relationship" between diabetes and periodontitis. Periodontitis is asymptomatic in the initial stages of disease process and it often escapes diagnosis. This review presents the blurred nexus between periodontitis and IR, underlining the pathophysiology of the insidious link. The knowledge of the association between periodontitis and IR can be valuable in planning effectual treatment modalities for subjects with altered glucose homeostasis and diabetics. Presently, the studies supporting this association are miniscule. Further studies are mandatory to substantiate the role of periodontitis in the deterioration of IR.