It's About Timing: Contrasting the Metabolic Effects of Early vs. Late Time-Restricted Eating in Humans.

PURPOSE OF REVIEW: Time-restricted eating (TRE), a form of intermittent fasting, restricts feeding time across the day, imposing a daily 'eating window'. The time of day when the eating window occurs could result in differential metabolic effects. Here, we describe recent intervention studies in humans assessing the metabolic consequences of an early- (i.e., eating window starting in the early morning) vs. late (i.e., eating window starting after midday)-TRE protocol. RECENT FINDINGS: Well-controlled studies indicate that both TRE protocols effectively reduce body weight and improve altered glucose metabolism, lipid profile, inflammation, or blood pressure levels. An early-TRE (e-TRE) might have a further positive impact on improving blood glucose, insulin levels, and insulin resistance. However, the studies directly assessing the metabolic consequences of an early- vs. late-TRE have shown dissimilar findings, and more well-controlled clinical trials are needed on the metabolic benefits of these two types of TRE. Evidence suggests that an e-TRE might have enhanced metabolic results, particularly regarding glucose homeostasis. More long-term studies, including larger sample sizes, are needed to assess the metabolic, circadian, and adherence benefits, together with socio-cultural acceptance of both TRE approaches.

Adaptive responses of the ileum of NOD mice to low-dose fluoride: A proteomic exploratory study.

Fluoride (F) has been employed worldwide to control dental caries. More recently, it has been suggested that the consumption of low doses of F in the drinking water may reduce blood glucose levels, introducing a new perspective for the use of F for the management of blood glucose. However, the exact mechanism by which F affects blood glucose levels remains largely unexplored. Given that the small gut plays a pivotal role in glucose homeostasis, the aim of this study was to investigate the proteomic changes induced by low doses of F in the ileum of female nonobese-diabetic (NOD) mice. Forty-two female NOD mice were divided into two groups based on the F concentration in their drinking water for 14 weeks: 0 (control) or 10 mgF/L. At the end of the experimental period, the ileum was collected for proteomic and Western blot analyses. Proteomic analysis indicated an increase in isoforms of actin, gastrotropin, several H2B histones, and enzymes involved in antioxidant processes, as well as a decrease in enzymes essential for energy metabolism. In summary, our data indicates an adaptive response of organism to preserve protein synthesis in the ileum, despite significant alterations in energy metabolism typically induced by F, therefore highlighting the safety of controlled fluoridation in water supplies.

Interesterified palm oil promotes insulin resistance and altered insulin secretion and signaling in Swiss mice.

Interesterified fats have been used to replace trans-fat in ultra-processed foods. However, their metabolic effects are not completely understood. Hence, this study aimed to investigate the effects related to glucose homeostasis in response to interesterified palm oil or refined palm oil intake. Four-week-old male Swiss mice were randomly divided into four experimental groups and fed the following diets for 8 weeks: a normocaloric and normolipidic diet containing refined palm oil (PO group) or interesterified palm oil (IPO group); a hypercaloric and high-fat diet containing refined PO (POHF group) or interesterified PO (IPOHF group). Metabolic parameters related to body mass, adiposity and food consumption showed no significant differences. As for glucose homeostasis parameters, interesterified palm oil diets (IPO and IPOHF) resulted in higher glucose intolerance than unmodified palm oil diets (PO and POHF). Euglycemic-hyperinsulinemic clamp assessment showed a higher endogenous glucose production in the IPO group compared with the PO group. Moreover, the IPO group showed significantly lower p-AKT protein content (in the muscle and liver tissues) when compared with the PO group. Analysis of glucose-stimulated static insulin secretion (11.1 mmol/L glucose) in isolated pancreatic islets showed a higher insulin secretion in animals fed interesterified fat diets (IPO and IPOHF) than in those fed with palm oil (PO and POHF). Interesterified palm oil, including in normolipidic diets, can impair insulin signaling in peripheral tissues and increase insulin secretion by ß-cells, characterizing insulin resistance in mice.

Association between protein undernutrition and diabetes: Molecular implications in the reduction of insulin secretion.

Undernutrition is still a recurring nutritional problem in low and middle-income countries. It is directly associated with the social and economic sphere, but it can also negatively impact the health of the population. In this sense, it is believed that undernourished individuals may be more susceptible to the development of non-communicable diseases, such as diabetes mellitus, throughout life. This hypothesis was postulated and confirmed until today by several studies that demonstrate that experimental models submitted to protein undernutrition present alterations in glycemic homeostasis linked, in part, to the reduction of insulin secretion. Therefore, understanding the changes that lead to a reduction in the secretion of this hormone is essential to prevent the development of diabetes in undernourished individuals. This narrative review aims to describe the main molecular changes already characterized in pancreatic ß cells that will contribute to the reduction of insulin secretion in protein undernutrition. So, it will provide new perspectives and targets for postulation and action of therapeutic strategies to improve glycemic homeostasis during this nutritional deficiency.

Chloroquine attenuates diet-induced obesity and glucose intolerance through a mechanism that might involve FGF-21, but not UCP-1-mediated thermogenesis and inhibition of adipocyte autophagy.

Chloroquine diphosphate (CQ), a weak base used to inhibit autophagic flux and treat malaria and rheumatoid diseases, has been shown, through unknown mechanisms, to improve glucose and lipid homeostasis in patients and rodents. We investigate herein the molecular mechanisms underlying these CQ beneficial metabolic actions in diet-induced obese mice. For this, C57BL6/J mice fed with either a chow or a high-fat diet (HFD) and uncoupling protein 1 (UCP-1) KO and adipocyte Atg7-deficient mice fed with a HFD were treated or not with CQ (60 mg/kg of body weight/day) during 8 weeks and evaluated for body weight, adiposity, glucose homeostasis and brown and white adipose tissues (BAT and WAT) UCP-1 content. CQ reduced body weight gain and adipose tissue and liver masses in mice fed with a HFD, without altering food intake, oxygen consumption, respiratory exchange ratio, spontaneous motor activity and feces caloric content. CQ attenuated the insulin intolerance, hyperglycemia, hyperinsulinemia, hypertriglyceridemia and hypercholesterolemia induced by HFD intake, such effects that were associated with increases in serum and liver fibroblast growth factor 21 (FGF-21) and BAT and WAT UCP-1 content. Interestingly, CQ beneficial metabolic actions of reducing body weight and adiposity and improving glucose homeostasis were preserved in HFD-fed UCP-1 KO and adipocyte Atg7 deficient mice. CQ reduces body weight gain and adiposity and improves glucose homeostasis in diet-induced obese mice through mechanisms that might involve FGF-21, but not UCP1-mediated nonshivering thermogenesis or inhibition of adipocyte autophagy.

Time-restricted feeding combined with resistance exercise prevents obesity and improves lipid metabolism in the liver of mice fed a high-fat diet.

Nonalcoholic fatty liver disease (NAFLD), a condition characterized by the accumulation of fat in the liver, is estimated to be the most common liver disease worldwide. Obesity is a major risk factor and contributor, and, accordingly, weight loss can improve NAFLD. Previous studies in preclinical models of diet-induced obesity and fatty liver disease have shown the independent benefits of resistance exercise training (RT) and time-restricted feeding (TRF) in preventing weight gain and hepatic build-up of fat. Here, we tested the combined effect of TRF and RT on obesity and NAFLD in mice fed a high-fat diet. Our results showed that both TRF-8-h food access in the active phase-and RT-consisting of three weekly sessions of ladder climbing-attenuated body weight gain, improved glycemic homeostasis, and decreased the accumulation of lipids in the liver. TRF combined with RT improved the respiratory exchange rate, energy expenditure, and mitochondrial respiration in the liver. Furthermore, gene expression analysis in the liver revealed lower mRNA expression of lipogenesis and inflammation genes along with increased mRNA of fatty acid oxidation genes in the TRF + RT group. Importantly, combined TRF + RT was shown to be more efficient in preventing obesity and metabolic disorders. In conclusion, TRF and RT exert complementary actions compared with isolated interventions, with significant effects on metabolic disorders and NAFLD in mice.NEW & NOTEWORTHY Whether time-restricted feeding (TRF) combined with resistance exercise training (RT) may be more efficient compared with these interventions alone is still unclear. We show that when combined with RT, TRF provided additional benefits, being more effective in increasing energy expenditure, preventing weight gain, and regulating glycemic homeostasis than each intervention alone. Thus, our results demonstrate that TRF and RT have complementary actions on some synergistic pathways that prevented obesity and hepatic liver accumulation.

Photobiomodulation in diabetic rats: Effects on morphological, pancreatic parameters, and glucose homeostasis.

Photobiomodulation (PBM) has therapeutic effects on wound healing, diabetic microangiopathy, and retinopathy. However, little is known about the use of PBM for the treatment of diabetes mellitus (DM). In this context, we aimed to evaluate the effects of PBM on pancreas morphology and insulin and glucose tolerance in an experimental model of DM. Thus, DM was induced by streptozotocin (STZ) (60 mg/kg). Subsequently, the rats were treated with PBM (808 nm and 30 J/cm2 ). After euthanasia, morphometric parameters and immunoreactivity for insulin and 8-OHdG were evaluated in the pancreas. The results showed that treated animals had higher values of body mass and higher values in the number of beta cells in the pancreas. In conclusion, PBM resulted in decreased weight loss in STZ-induced diabetic rats and presented a stimulatory effect on the pancreas of the treated animals, highlighting the promising effects of this therapy in the clinical condition of DM.

Mexican Plants Involved in Glucose Homeostasis and Body Weight Control: Systematic Review.

BACKGROUND: Obesity is defined as abnormal or excessive fat accumulation, provoking many different diseases, such as obesity and type 2 diabetes. Type 2 diabetes is a chronic-degenerative disease characterized by increased blood glucose levels. Obesity and type 2 diabetes are currently considered public health problems, and their prevalence has increased over the last few years. Because of the high cost involved in the treatment of both diseases, different alternatives have been sought. However, the general population uses medicinal plants, in the form of tea or infusions, to treat different diseases. Therefore, traditional medicine using medicinal plants has been investigated as a possible treatment for type 2 diabetes and body weight control. AIM OF THE STUDY: The purpose of this review is to find medicinal plants used in Mexico that could exert their beneficial effect by regulating insulin secretion and body weight control. MATERIAL AND METHOD: For the development of this review, Mexican plants used in traditional medicine to treat type 2 diabetes and body weight control were searched in PubMed, Google Scholar, and Scopus. The inclusion criteria include plants that presented a significant reduction in blood glucose levels and/or an increase in insulin secretion. RESULTS: We found 306 Mexican plants with hypoglycemic effects. However, plants that did not show evidence of an increase in insulin secretion were eliminated. Finally, only five plants were included in this review: Momordica charantia L. (melón amargo), Cucurbita ficifolia bouché (chilacayote), Coriandrum sativum L. (cilantro), Persea americana Mill. (aguacate) Bidens pilosa (amor seco), including 39 articles in total. Here, we summarized the plant extracts (aqueous and organic) that have previously been reported to present hypoglycemic effects, body weight control, increased secretion and sensitivity of insulin, improvement of pancreatic ß cells, and glucose tolerance. Additionally, these effects may be due to different bioactive compounds present in the plants' extracts. CONCLUSION: Both in vivo and in vitro studies are required to understand the mechanism of action of these plant extracts regarding insulin secretion to be used as a possible treatment for type 2 diabetes and body weight control in the future.

Short-chain fatty acids are associated with adiposity, energy and glucose homeostasis among different metabolic phenotypes in the Nutritionists' Health Study.

BACKGROUND AND AIMS: The gut microbiome is associated with obesity, mainly mediated by bacteria-produced short-chain fatty acids (SCFAs). It is unknown how SCFA concentrations are associated with the phenotypes metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy obese/overweight (MHO), and metabolically unhealthy obese/overweight (MUO). We compared plasma and fecal SCFA concentrations among adult women categorized according to the metabolic phenotypes mentioned above and examined associations between SCFA and adiposity and components of energy and glucose homeostasis. METHODS: This was a cross-sectional study involving 111 participants. Body composition was assessed by DEXA. Energy and glycemic homeostasis were assessed by the standard mixed-meal tolerance test coupled with indirect calorimetry. SCFAs were quantified by gas chromatography and mass spectrometry. RESULTS: Only plasma propionate was increased in the MHNW phenotype compared to the MHO and MUO phenotypes [p < 0.05]. Fecal propionate and butyrate concentrations and plasma propionate concentrations were inversely associated with total and visceral adiposity [p < 0.05]. Fecal and plasma SCFA concentrations were associated with reduced glucose, insulin and HbA1c levels, increased fasting and postprandial GLP-1 levels; and more preserved beta-cell function [p < 0.05]. Fecal and plasma SCFA concentrations were positively correlated with resting energy expenditure and lipid oxidation rate and inversely correlated with the oxidation rate of carbohydrates [p < 0.05]. CONCLUSION: These findings reinforce the concept that fecal and plasma SCFA concentrations are linked to specific components of energy and glucose homeostasis; and body adiposity. However, it was not possible to discriminate the different metabolic phenotypes of adiposity based on the determination of fecal SCFA concentrations.

Impact on Glycemic Variation Caused by a Change in the Dietary Intake Sequence.

This work presents an analysis of the effect on glycemic variation caused by modifying the macronutrient intake sequence in a person without a diagnosis of diabetes. In this work, three types of nutritional studies were developed: (1) glucose variation under conditions of daily intake (food mixture); (2) glucose variation under conditions of daily intake modifying the macronutrient intake sequence; (3) glucose variation after a modification in the diet and macronutrient intake sequence. The focus of this research is to obtain preliminary results on the effectiveness of a nutritional intervention based on the modification of the sequence of macronutrient intake in a healthy person during 14-day periods. The results obtained corroborate the positive effect on the glucose of consuming vegetables, fiber, or proteins before carbohydrates, decreasing the peaks in the postprandial glucose curves (vegetables: 113-117 mg/dL; proteins: 107-112 mg/dL; carbohydrates: 115-125 mg/dL) and reducing the average levels of blood glucose concentrations (vegetables: 87-95 mg/dL; proteins: 82-99 mg/dL; carbohydrates: 90-98 mg/dL). The present work demonstrates the preliminary potential of the sequence in the macronutrient intake for the generation of alternatives of prevention and solution of chronic degenerative diseases, improving the management of glucose in the organism and permeating in the reduction of weight and the state of health of the individuals.

Cinnamaldehyde supplementation acts as an insulin mimetic compound improving glucose metabolism during adolescence, but not during adulthood, in healthy male rats.

PURPOSE: Adolescence is a critical period of increased vulnerability to nutritional modifications, and adolescents may respond differently from adults to dietary intake and nutraceuticals. Cinnamaldehyde, a major bioactive compound of cinnamon, improves energy metabolism, as has been shown in studies conducted primarily in adult animals. We hypothesized that cinnamaldehyde treatment may have a higher impact on the glycemic homeostasis of healthy adolescent rats than on healthy adult rats. METHODS: Male adolescent (30 days) or adult (90 days) Wistar rats received cinnamaldehyde (40 mg/kg) for 28 days by gavage. The oral glucose tolerance test (OGTT), liver glycogen content, serum insulin concentration, serum lipid profile, and hepatic insulin signaling marker expression were evaluated. RESULTS: Cinnamaldehyde-treated adolescent rats showed less weight gain (P = 0.041), improved OGTT (P = 0.004), increased expression of phosphorylated IRS-1 (P = 0.015), and a trend to increase phosphorylated IRS-1 (P = 0.063) in the liver of adolescent rats in the basal state. None of these parameters was modified after treatment with cinnamaldehyde in the adult group. Cumulative food intake, visceral adiposity, liver weight, serum insulin, serum lipid profile, hepatic glycogen content, and liver protein expression of IRß, phosphorylated IRß, AKT, phosphorylated AKT, and PTP-1B in the basal state were similar between both age groups. CONCLUSION: In a healthy metabolic condition, cinnamaldehyde supplementation affects glycemic metabolism in adolescent rats while promoting no changes in adult rats.

Exercise training restores weight gain and attenuates hepatic inflammation in a rat model of non-celiac gluten sensitivity.

Gluten intolerance is associated with several disorders in the body. Although research has grown in recent years, the understanding of its impact on different tissues and the effects of physical exercise in mitigating health problems in the condition of gluten intolerance are still limited. Therefore, our objective was to test whether gliadin would affect metabolism and inflammation in liver tissue and whether aerobic physical exercise would mitigate the negative impacts of gliadin administration in rodents. Wistar rats were divided into exercised gliadin, gliadin, and control groups. Gliadin was administered by gavage from birth to 60 days of age. The rats in the exercised gliadin group performed an aerobic running exercise training protocol for 15 days. At the end of the experiments, physiological, histological, and molecular analyzes were performed in the study. Compared to the control group, the gliadin group had impaired weight gain and increased gluconeogenesis, lipogenesis, and inflammatory biomarkers in the liver. On the other hand, compared to the gliadin group, animals in the exercise-gliadin group had a recovery in body weight, improved insulin sensitivity, and a reduction in some gluconeogenesis, lipogenesis, and inflammatory biomarkers in the liver. In conclusion, our results revealed that the administration of gliadin from birth impaired weight gain and induced an increase in hepatic inflammatory cytokines, which was associated with an impairment of glycemic homeostasis in the liver, all of which were attenuated by adding aerobic exercise training in the gliadin group.

Maternal adaptations of the pancreas and glucose homeostasis in lactation and after lactation.

During lactation, the maternal physiology adapts to bear the nutritional requirements of the offspring. The exocrine and endocrine pancreas are central to nutrient handling, promoting digestion and metabolism. In concert with prolactin, insulin is a determinant factor for milk synthesis. The investigation of the pancreas during lactation has been scattered over several periods. The investigations that laid the foundation of lactating pancreatic physiology and glucose homeostasis were conducted in the decades of 1970-1980. With the development of molecular biology, newer studies have revealed the molecular mechanisms involved in the endocrine pancreas during breastfeeding. There has been a surge of information recently about unexpected changes in the pancreas at the end of the lactation period and after weaning. In this review, we aim to gather information on the changes in the pancreas and glucose homeostasis during and after lactation and discuss the outcomes derived from the current discoveries.

Glycogen synthase kinase-3 (GSK-3) a magic enzyme: its 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 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.(AU)

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.(AU)

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.

Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats.

BACKGROUND: Insulin resistance (IR) is a condition in which the response of organs to insulin is impaired. IR is an early marker of metabolic dysfunction. However, IR also appears in physiological contexts during critical developmental windows. The molecular mechanisms of physiological IR are largely unknown in both sexes. Sexual dimorphism in insulin sensitivity is observed since early stages of development. We propose that during periods of accelerated growth, such as around weaning, at postnatal day 20 (p20) in rats, the kinase S6K1 is overactivated and induces impairment of insulin signaling in its target organs. This work aimed to characterize IR at p20, determine its underlying mechanisms, and identify whether sexual dimorphism in physiological IR occurs during this stage. METHODS: We determined systemic insulin sensitivity through insulin tolerance tests, glucose tolerance tests, and blood glucose and insulin levels under fasting and fed conditions at p20 and adult male and female Wistar rats. Furthermore, we quantified levels of S6K1 phosphorylated at threonine 389 (T389) (active form) and its target IRS1 phosphorylated at serine 1101 (S1101) (inhibited form). In addition, we assessed insulin signal transduction by measuring levels of Akt phosphorylated at serine 473 (S473) (active form) in white adipose tissue and skeletal muscle through western blot. Finally, we determined the presence and function of GLUT4 in the plasma membrane by measuring the glucose uptake of adipocytes. Results were compared using two-way ANOVA (With age and sex as factors) and one-way ANOVA with post hoc Tukey's tests or t-student test in each corresponding case. Statistical significance was considered for P values < 0.05. RESULTS: We found that both male and female p20 rats have elevated levels of glucose and insulin, low systemic insulin sensitivity, and glucose intolerance. We identified sex- and tissue-related differences in the activation of insulin signaling proteins in p20 rats compared to adult rats. CONCLUSIONS: Male and female p20 rats present physiological insulin resistance with differences in the protein activation of insulin signaling. This suggests that S6K1 overactivation and the resulting IRS1 inhibition by phosphorylation at S1101 may modulate to insulin sensitivity in a sex- and tissue-specific manner. Video Abstract.

Insulin regulates the synthesis of carbohydrates, lipids and proteins differently between males, and females. One of its primary functions is maintaining adequate blood glucose levels favoring glucose entry in muscle and adipose tissue after food consumption. Insulin resistance (IR) is a condition in which the response of organs to insulin is impaired. IR is frequently associated with metabolic dysfunction such as inflammation, obesity, or type 2 diabetes. However, physiological IR develops in healthy individuals during periods of rapid growth, pregnancy, or aging by mechanisms not fully understood. We studied the postnatal development, specifically around weaning at postnatal day 20 (p20) of Wistar rats. In previous works, we identified insulin resistance during this period in male rats. This work aimed to characterize IR at p20, determine its underlying mechanisms, and identify whether sexual dimorphism in physiological IR occurs during this stage. We found that p20 rats of both sexes have elevated blood glucose and insulin levels, low systemic insulin sensitivity, and glucose intolerance. We identified differences in insulin-regulated protein activation (S6K1, IRS1, Akt, and GLUT4) between sexes in different tissues and adipose tissue depots. Studying these mechanisms and their differences between males and females is essential to understanding insulin actions and their relationship with the possible development of metabolic diseases in both sexes.

Socs3 ablation in kisspeptin cells partially prevents lipopolysaccharide-induced body weight loss.

Many cytokines have been proposed to regulate reproduction due to their actions on hypothalamic kisspeptin cells, the main modulators of gonadotropin-releasing hormone (GnRH) neurons. Hormones such as leptin, prolactin and growth hormone are good examples of cytokines that lead to Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation, consequently exerting effects in kisspeptin neurons. Different studies have investigated how specific components of the JAK/STAT signaling pathway affect the functions of kisspeptin cells, but the role of the suppressor of cytokine signaling 3 (SOCS3) in mediating cytokine actions in kisspeptin cells remains unknown. Cre-Loxp technology was used in the present study to ablate Socs3 expression in kisspeptin cells (Kiss1/Socs3-KO). Then, male and female control and Kiss1/Socs3-KO mice were evaluated for sexual maturation, energy homeostasis features, and fertility. It was found that hypothalamic Kiss1 mRNA expression is significantly downregulated in Kiss1/Socs3-KO mice. Despite reduced hypothalamic Kiss1 mRNA content, these mice did not present any sexual maturation or fertility impairments. Additionally, body weight gain, leptin sensitivity and glucose homeostasis were similar to control mice. Interestingly, Kiss1/Socs3-KO mice were partially protected against lipopolysaccharide (LPS)-induced body weight loss. Our results suggest that Socs3 ablation in kisspeptin cells partially prevents the sickness behavior induced by LPS, suggesting that kisspeptin cells can modulate energy metabolism in mice in certain situations.

Perinatal exposure to isocaloric diet with moderate-fat promotes pancreatic islets insulin hypersecretion and susceptibility to islets exhaustion in response to fructose intake in adult male rat offspring.

AIMS: Perinatal maternal hypercaloric diets increase the susceptibility to metabolic disorders in the offspring. We hypothesized that maternal intake of an isocaloric moderate-fat diet (mMFD) would disturb the glucose homeostasis and favor the ß-cell failure in response to fructose overload in adult male offspring. METHODS: Female Wistar rats received an isocaloric diet (3.9 kcal/g) containing 29 % (mMFD) or 9 % as fat (mSTD) prior mating and throughout gestation and lactation. After weaning, male offspring received standard chow and fructose-drinking water (15 %) between 120 and 150 days old. KEY FINDINGS: mMFD offspring had higher body weight, visceral adiposity and, fasting glycemia, with normal insulinemia. Fructose increased glycemia at 15 min from oral glucose administration, but only mMFD had returned to basal glucose levels at 120 min. Fructose increased HOMA-IR index regardless diet, but only mMFD exhibited hyperinsulinemia and a higher HOMA-ß index. mMFD pancreatic islets showed increased area and insulin immunostaining density, suggesting ß-cell hypertrophy. Fructose induced the expected compensatory hypertrophy in mSTD islets, while the opposite occurred in mMFD islets, associated with reduced insulin immunostaining, suggesting lower insulin storage. Pancreatic islets isolated from mMFD offspring exhibited higher glucose-stimulated insulin release at physiological concentrations. However, at higher glucose concentrations, the islets from fructose-treated mMFD reduced dramatically their insulin release, suggesting exhaustion. SIGNIFICANCE: Isocaloric mMFD induced adaptive mechanism in the offspring allowing insulin hypersecretion, but under metabolic challenge with fructose, ß-cell compensation shifts to exhaustion, favoring dysfunction. Therefore, a maternal MFD may contribute to developing diabetes under fructose overload in the adult offspring.