RESUMO
Aims: To determine the impact of breastfeeding on the risk of postpartum glucose intolerance in women with gestational diabetes. Methods: Sub-analysis of two multi-centric prospective cohort studies (BEDIP-N and MELINDA) in 1008 women with gestational diabetes. Data were collected during pregnancy and at a mean of 12 weeks postpartum. Multivariate logistic regression was used to estimate the effect of breastfeeding on glucose intolerance, with adjustment for ethnicity, education, income, professional activity and BMI. Results: Of all participants, 56.3% (567) breastfed exclusively, 10.1% (102) gave mixed milk feeding and 33.6% (339) did not breastfeed. Mean breastfeeding duration was 3.8 ± 2.4 and 3.7 ± 2.1 months in the breastfeeding and mixed milk feeding groups (p=0.496). The rate of glucose intolerance was lower in both the breastfeeding [22.3% (126)] and mixed milk feeding [25.5% (26)] groups compared to the no breastfeeding group [29.5% (100)], with an adjusted OR of 0.7 (95% CI 0.5-1.0) for glucose intolerance in the breastfeeding group compared to no breastfeeding group and an adjusted OR of 0.7 (95% CI 0.4-1.2) for the mixed milk feeding group compared to the no breastfeeding group. Postpartum, breastfeeding women had a lower BMI, less often postpartum weight retention, lower fasting triglycerides, less insulin resistance and a higher insulin secretion-sensitivity index-2 than the mixed milk feeding and no breastfeeding group. The mixed milk feeding group was more often from an non-White background, had a lower blood pressure and lower fasting triglycerides compared to the no breastfeeding group. Conclusions: Breastfeeding (exclusive and mixed milk feeding) is associated with less glucose intolerance and a better metabolic profile in early postpartum in women with gestational diabetes.
Assuntos
Aleitamento Materno , Diabetes Gestacional , Intolerância à Glucose , Período Pós-Parto , Humanos , Feminino , Gravidez , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/etiologia , Adulto , Estudos Prospectivos , Fatores de Risco , Glicemia/metabolismoRESUMO
INTRODUCTION: High-fat diet (HFD) consumption and being exposed to daily psychological stress, common environmental factors in modern lifestyle, play an important role on metabolic disorders such as glucose homeostasis impairment. The aim of this study was to investigate the effects of high-fat diet (HFD) and psychological stress combination on metabolic response to chronic psychological stress in male rats. METHOD: Male Wistar rats were divided into HFD, and normal diet (ND) groups and then into stress and nonstress subgroups. The diets were applied for 5 weeks, and psychological stress was induced for 7 consecutive days. Then, blood samples were taken to measure glucose, insulin, free fatty acids (FFA), and leptin and corticosterone concentrations. Subsequently, glucose-stimulated insulin release from pancreatic isolated islets was assessed. RESULTS: HFD did not significantly change fasting plasma glucose, insulin and corticosterone levels, whereas increased plasma leptin (7.05 ± 0.33) and FFA (p < 0.01) levels and impaired glucose tolerance. Additionally, HFD and stress combination induced more profound glucose intolerance associated with increased plasma corticosterone (p < 0.01) and leptin (8.63 ± 0.38) levels. However, insulin secretion from isolated islets did not change in the presence of high-fat diet and/or stress. CONCLUSION: HFD should be considered as an intensified factor of metabolic impairments caused by chronic psychological stress.
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Glicemia , Corticosterona , Dieta Hiperlipídica , Insulina , Leptina , Ratos Wistar , Estresse Psicológico , Animais , Masculino , Estresse Psicológico/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ratos , Corticosterona/sangue , Insulina/sangue , Leptina/sangue , Glicemia/metabolismo , Ácidos Graxos não Esterificados/sangue , Ilhotas Pancreáticas/metabolismo , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismoRESUMO
Fatty liver is characterized by the expansion of lipid droplets (LDs) and is associated with the development of many metabolic diseases. We assessed the morphology of hepatic LDs and performed quantitative proteomics in lean, glucose-tolerant mice compared with high-fat diet (HFD) fed mice that displayed hepatic steatosis and glucose intolerance as well as high-starch diet (HStD) fed mice who exhibited similar levels of hepatic steatosis but remained glucose tolerant. Both HFD- and HStD-fed mice had more and larger LDs than Chow-fed animals. We observed striking differences in liver LD proteomes of HFD- and HStD-fed mice compared with Chow-fed mice, with fewer differences between HFD and HStD. Taking advantage of our diet strategy, we identified a fatty liver LD proteome consisting of proteins common in HFD- and HStD-fed mice, as well as a proteome associated with glucose tolerance that included proteins shared in Chow and HStD but not HFD-fed mice. Notably, glucose intolerance was associated with changes in the ratio of adipose triglyceride lipase to perilipin 5 in the LD proteome, suggesting dysregulation of neutral lipid homeostasis in glucose-intolerant fatty liver. We conclude that our novel dietary approach uncouples ectopic lipid burden from insulin resistance-associated changes in the hepatic lipid droplet proteome.NEW & NOTEWORTHY This study identified a fatty liver lipid droplet proteome and one associated with glucose tolerance. Notably, glucose intolerance was linked with changes in the ratio of adipose triglyceride lipase to perilipin 5 that is indicative of dysregulation of neutral lipid homeostasis.
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Dieta Hiperlipídica , Fígado Gorduroso , Intolerância à Glucose , Gotículas Lipídicas , Fígado , Camundongos Endogâmicos C57BL , Proteoma , Animais , Masculino , Camundongos , Intolerância à Glucose/metabolismo , Intolerância à Glucose/etiologia , Proteoma/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fígado/metabolismo , Gotículas Lipídicas/metabolismo , Fígado Gorduroso/metabolismo , Metabolismo dos Lipídeos , Proteômica/métodos , Resistência à InsulinaRESUMO
AIM: Type 1 diabetes results from autoimmune events influenced by environmental variables, including changes in diet. This study investigated how feeding refined versus unrefined (aka 'chow') diets affects the onset and progression of hyperglycaemia in non-obese diabetic (NOD) mice. METHODS: Female NOD mice were fed either unrefined diets or matched refined low- and high-fat diets. The onset of hyperglycaemia, glucose tolerance, food intake, energy expenditure, circulating insulin, liver gene expression and microbiome changes were measured for each dietary group. RESULTS: NOD mice consuming unrefined (chow) diets developed hyperglycaemia at similar frequencies. By contrast, mice consuming the defined high-fat diet had an accelerated onset of hyperglycaemia compared to the matched low-fat diet. There was no change in food intake, energy expenditure, or physical activity within each respective dietary group. Microbiome changes were driven by diet type, with chow diets clustering similarly, while refined low- and high-fat bacterial diversity also grouped closely. In the defined dietary cohort, liver gene expression changes in high-fat-fed mice were consistent with a greater frequency of hyperglycaemia and impaired glucose tolerance. CONCLUSION: Glucose intolerance is associated with an enhanced frequency of hyperglycaemia in female NOD mice fed a defined high-fat diet. Using an appropriate matched control diet is an essential experimental variable when studying changes in microbiome composition and diet as a modifier of disease risk.
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Diabetes Mellitus Tipo 1 , Dieta Hiperlipídica , Hiperglicemia , Camundongos Endogâmicos NOD , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/microbiologia , Camundongos , Hiperglicemia/etiologia , Intolerância à Glucose/etiologia , Metabolismo Energético , Fígado/metabolismo , Dieta com Restrição de Gorduras , Insulina/metabolismo , Insulina/sangue , Glicemia/metabolismoRESUMO
Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) (TP) is a non-narcotic antitussive used in Japan. Recently, the potential application of TP in the treatment of neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder, has been suggested; however, its functions in energy metabolism are unknown. Here, we demonstrate that TP exhibits a metabolism-improving action. The administration of TP reduced high-fat diet-induced body weight gain in mice and lipid accumulation in the liver and increased the weight of epididymal white adipose tissue (eWAT) in diet-induced obese (DIO) mice. Furthermore, TP inhibited obesity-induced fibrosis in the eWAT. We also found that TP induced AMP-activated protein kinase (AMPK) activation in the eWAT of DIO mice and 3T3-L1 cells. TP-induced AMPK activation was abrogated by the transfection of liver kinase B1 siRNA in 3T3-L1 cells. The metabolic effects of TP were almost equivalent to those of metformin, an AMPK activator that is used as a first-line antidiabetic drug. In summary, TP is a potent AMPK activator, suggesting its novel role as an antidiabetic drug owing to its antifibrotic effect on adipose tissues.
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Dieta Hiperlipídica , Intolerância à Glucose , Piperidinas , Animais , Camundongos , Dieta Hiperlipídica/efeitos adversos , Proteínas Quinases Ativadas por AMP , Camundongos Obesos , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/etiologia , Tecido Adiposo , Hipoglicemiantes , FibroseRESUMO
Maternal glucose intolerance in late pregnancy can easily impair pregnancy outcomes and placental development. The impairment of placental angiogenesis is closely related to the occurrence of glucose intolerance during pregnancy, but the mechanism remains largely unknown. In this study, the pregnant mouse model of maternal high-fat diet and endothelial injury model of porcine vascular endothelial cells (PVECs) was used to investigate the effect of glucose intolerance on pregnancy outcomes and placental development. Feeding pregnant mice, a high-fat diet was shown to induce glucose intolerance in late pregnancy, and significantly increase the incidence of resorbed fetuses. Moreover, a decrease was observed in the proportion of blood sinusoids area and the expression level of CD31 in placenta, indicating that placental vascular development was impaired by high-fat diet. Considering that hyperglycemia is an important symptom of glucose intolerance, we exposed PVECs to high glucose (50 mM), which verified the negative effects of high glucose on endothelial function. Bioinformatics analysis further emphasized that high glucose exposure could significantly affect the angiogenesis-related functions of PVECs and predicted that Krüppel-like factor 4 (KLF4) may be a key mediator of these functional changes. The subsequent regulation of KLF4 expression confirmed that the inhibition of KLF4 expression was an important reason why high glucose impaired the endothelial function and angiogenesis of PVECs. These results indicate that high-fat diet can aggravate maternal glucose intolerance and damage pregnancy outcome and placental angiogenesis, and that regulating the expression of KLF4 may be a potential therapeutic strategy for maintaining normal placental angiogenesis.
Assuntos
Intolerância à Glucose , Placenta , Animais , Feminino , Camundongos , Gravidez , Angiogênese , Dieta Hiperlipídica/efeitos adversos , Regulação para Baixo , Células Endoteliais/metabolismo , Glucose/metabolismo , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Fator 4 Semelhante a Kruppel , Placenta/metabolismo , Placentação , SuínosRESUMO
OBJECTIVES: We evaluate the effect of myosteatosis on new-onset diabetes mellitus after kidney transplantation. METHODS: Consecutive patients who had renal transplant between 2006 and 2021 were reviewed, and 219 patients were finally included. Psoas muscle index was used to evaluate sarcopenia and average total psoas density (calculated by computed tomography before surgery) for myosteatosis. We used Cox proportional regression analyses in investigation of whether skeletal muscle depletion before surgery inclusive of sarcopenia and myosteatosis is a new additional predictor of new-onset diabetes mellitus. RESULTS: Median recipient age and body mass index were 45 years and 21.1 kg/m2 , respectively, and 123 patients (56%) were male. Preoperative impaired glucose tolerance was present in 58 patients (27%) and new-onset diabetes mellitus in 30 patients (14%), with median psoas muscle index of 6 cm2 /m2 and average total psoas density of 41 Hounsfield Unit. In multivariate analysis, significant risk factors were body mass index ≥25 kg/m2 (p < 0.01), impaired glucose tolerance (p < 0.01), and average total psoas density < 41.9 Hounsfield Unit (p = 0.03). New-onset diabetes mellitus had incidence rates of 3.7% without risk factors, 10% with a single risk factor, 33% with two, and 60% with three. Patients with new-onset diabetes mellitus were effectively stratified by the number of risk factors (p < 0.01). CONCLUSIONS: Myosteatosis could be a new risk factor used to predict new-onset diabetes mellitus.
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Diabetes Mellitus , Intolerância à Glucose , Transplante de Rim , Sarcopenia , Humanos , Masculino , Feminino , Sarcopenia/diagnóstico por imagem , Sarcopenia/epidemiologia , Sarcopenia/etiologia , Intolerância à Glucose/etiologia , Intolerância à Glucose/complicações , Transplante de Rim/efeitos adversos , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Músculo Esquelético , Músculos Psoas/diagnóstico por imagem , Músculos Psoas/patologia , Estudos RetrospectivosRESUMO
CONTEXT: Glucose tolerance worsens after distal pancreatectomy (DP); however, the long-term incidence and factors affecting interindividual variation in this worsening are unclear. OBJECTIVE: To investigate the changes in diabetes-related traits before and after DP and to clarify the incidence of diabetes and its predictors. METHODS: Among 493 registered patients, 117 underwent DP. Among these, 56 patients without diabetes before surgery were included in the study. Glucose and endocrine function were prospectively assessed using a 75-g oral glucose tolerance test preoperatively, 1 month after DP, and every 6 months thereafter for up to 36 months. Pancreatic volumetry was performed using multidetector row computed tomography before and after surgery. RESULTS: Insulin secretion decreased and blood glucose levels worsened after DP. Residual pancreatic volume was significantly associated with the reserve capacity of insulin secretion but not with blood glucose levels or the development of diabetes. Among 56 patients, 33 developed diabetes mellitus. The cumulative incidence of diabetes at 36 months after DP was 74.1%. Multivariate Cox regression analysis showed that impaired glucose tolerance as a preoperative factor as well as a decreased insulinogenic index and impaired glucose tolerance at 1 month postoperatively were identified as risk factors for diabetes following DP. CONCLUSION: Impaired glucose tolerance and reduced early-phase insulin response to glucose are involved in the development of new-onset diabetes after DP; the latter is an additional factor in the development of diabetes and becomes apparent when pancreatic beta cell mass is reduced after DP.
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Diabetes Mellitus , Intolerância à Glucose , Neoplasias Pancreáticas , Humanos , Pancreatectomia/efeitos adversos , Pancreatectomia/métodos , Seguimentos , Incidência , Intolerância à Glucose/etiologia , Intolerância à Glucose/complicações , Glicemia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/complicaçõesRESUMO
AIM: To investigate the prevalence and possible risk factors for the development of impaired glucose metabolism in children and adolescents with obesity. METHODS: This was a cross-sectional retrospective cohort study, including 634 patients with obesity and 98 normal weight controls aged 4-18 years from the Beta-cell function in Juvenile Diabetes and Obesity (Beta-JUDO) cohort, a dual-centre study at Uppsala University Hospital (Sweden) and Paracelsus Medical University Hospital (Salzburg, Austria) conducted between 2012 and 2021. A longitudinal subgroup analysis, including 188 of these subjects was performed. Impaired glucose metabolism was diagnosed by oral glucose tolerance tests according to American Diabetes Association criteria. RESULTS: The prevalence of impaired glucose metabolism was 72% in Uppsala patients, 24% in Salzburg patients, 30% in Uppsala controls and 13% in Salzburg controls. The prevalence was lower at the follow-up visits compared with baseline both in Uppsala and Salzburg patients. A family history of type 2 diabetes showed the strongest association with impaired glucose metabolism at the follow-up visits besides belonging to the Uppsala cohort. CONCLUSION: The prevalence of impaired glucose metabolism was extraordinarily high in Swedish children and adolescents with obesity, but decreased during the follow-up period.
Assuntos
Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Obesidade Infantil , Criança , Adolescente , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Suécia/epidemiologia , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Obesidade Infantil/epidemiologia , Obesidade Infantil/complicações , Prevalência , Estudos Retrospectivos , Estudos Transversais , Glicemia/metabolismo , Fatores de RiscoRESUMO
INTRODUCTION: The supramammillary nucleus (SuMN) exerts influences on a wide range of brain functions including feeding and feeding-independent fuel metabolism. However, which specific neuronal type(s) within the SuMN manifest this influence has not been delineated. This study investigated the effect of SuMN tyrosine hydroxylase (TH) (rate-limiting enzyme in dopamine synthesis) knockdown (THx) on peripheral fuel metabolism. METHODS: SuMN-THx was accomplished using a virus-mediated shRNA to locally knockdown TH gene expression at the SuMN. The impact of SuMN-THx was examined over 35-72 days in rats least prone to developing metabolic syndrome (MS) - female Sprague-Dawley rats resistant to the obesogenic effect of high fat diet (HFDr) and fed regular chow (RC) - upon body weight/fat, feeding, glucose tolerance, and insulin sensitivity. The influence of HFD, gender, and long-term response of SuMN-THx was subsequently investigated in female HFDr rats fed HFD, male HFDr rats fed RC, and female HFD-sensitive rats fed RC over 1 year, respectively. RESULTS: SuMN-THx induced obesity and glucose intolerance, elevated plasma leptin and triglycerides, increased hepatic mRNA levels of gluconeogenic, lipogenic, and pro-inflammatory genes, reduced white adipose fatty acid oxidation rate, and altered plasma corticosterone level and hepatic circadian gene expression. Moreover, SuMN-THx increased feeding during the natural resting/fasting period and altered ghrelin feeding response suggesting ghrelin resistance. This MS-inducing effect was enhanced by HFD feeding, similarly observed in male rats and persisted over 1 year. DISCUSSION/CONCLUSION: SuMN-THx induced long-term, gender-nonspecific, multiple pathophysiological changes leading to MS suggesting SuMN dopaminergic circuits communicating with other brain metabolism and behavior control centers modulate peripheral fuel metabolism.
Assuntos
Dieta Hiperlipídica , Intolerância à Glucose , Obesidade , Ratos Sprague-Dawley , Tirosina 3-Mono-Oxigenase , Animais , Feminino , Obesidade/metabolismo , Obesidade/genética , Masculino , Tirosina 3-Mono-Oxigenase/metabolismo , Intolerância à Glucose/metabolismo , Intolerância à Glucose/etiologia , Dieta Hiperlipídica/efeitos adversos , Ratos , Hipotálamo Posterior/metabolismo , Técnicas de Silenciamento de GenesRESUMO
Apolipoprotein A-IV (apoA-IV), synthesized by enterocytes, is potentially involved in regulating lipid absorption and metabolism, food intake, and glucose metabolism. In this study, we backcrossed apoA-IV knockout (apoA-IV-/-) mice onto the 129/SvJ background for eight generations. Compared to the wild-type (WT) mice, the 129/SvJ apoA-IV-/- mice gained more weight and exhibited delayed glucose clearance even on the chow diet. During a 16-week high-fat diet (20% by weight of fat) study, apoA-IV-/- mice were more obese than the WT mice, which was associated with their increased food intake as well as reduced energy expenditure and physical activity. In addition, apoA-IV-/- mice developed significant insulin resistance (indicated by HOMA-IR) with severe glucose intolerance even though their insulin levels were drastically higher than the WT mice. In conclusion, we have established a model of apoA-IV-/- mice onto the 129/SvJ background. Unlike in the C57BL/6J strain, apoA-IV-/- 129/SvJ mice become significantly more obese and insulin-resistant than WT mice. Our current investigations of apoA-IV in the 129/SvJ strain and our previous studies in the C57BL/6J strain underline the impact of genetic background on apoA-IV metabolic effects.
Assuntos
Intolerância à Glucose , Camundongos , Animais , Intolerância à Glucose/etiologia , Camundongos Endogâmicos C57BL , Apolipoproteínas A/genética , Obesidade/genética , Dieta Hiperlipídica/efeitos adversos , Insulina/metabolismo , Camundongos KnockoutRESUMO
Obesity is a state of metabolic dysfunction that can lead to dyslipidemia and impaired glucose homeostasis. Apple polyphenols have been shown to ameliorate dyslipidemia/metabolic dysfunction in humans. The influence of apple (poly)phenols on energy metabolism in high-fat (HF) diet-induced obese mice remains controversial. This study examined the effect of dietary supplementation of (poly)phenol-rich 'Daux Belan' apple (DB; 6.2 mg gallic acid equivalence (GAE)/mouse/day; 0.15% (poly)phenol) in the form of freeze-dried powder on glucose and lipid metabolism in male HF-fed C57BL/6NCrl mice, in comparison to low-(poly)phenol-containing 'Zestar' apple (Z; 0.4 mg GAE/mouse/day). Obesity, glucose intolerance, hypertriglyceridemia, and hepatic lipid vacuolation were induced by HF feeding while circulating cholesterol levels remained unchanged. DB apple supplementation did not protect against HF-induced body weight gain, hyperglycemia, hepatic triglyceride level elevation, and hepatic lipid vacuolation at the tested dosage. Future studies should be conducted with increased DB dosage and employ apple (poly)phenols supplemented in the form of extracts or sugar-free powder.
Assuntos
Dislipidemias , Intolerância à Glucose , Humanos , Masculino , Camundongos , Animais , Intolerância à Glucose/etiologia , Intolerância à Glucose/prevenção & controle , Intolerância à Glucose/metabolismo , Fenol/metabolismo , Camundongos Endogâmicos C57BL , Pós/farmacologia , Obesidade/metabolismo , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glucose/metabolismo , Suplementos Nutricionais , Fenóis/farmacologia , Fenóis/metabolismo , Dislipidemias/etiologia , Dislipidemias/prevenção & controle , Dislipidemias/metabolismo , Lipídeos/farmacologiaRESUMO
Gestational diabetes is a common pregnancy complication that adversely influences the health and survival of mother and child. Pancreatic islet serotonin signaling plays an important role in ß-cell proliferation in pregnancy, and environmental and genetic factors that disrupt serotonin signaling are associated with gestational diabetes in mice. Our previous studies show that pregnant C57BL/6J mice fed a diet that is low in vitamin B6, a critical co-factor in serotonin synthesis, develop hyperglycemia and glucose intolerance, phenotypes that are consistent with gestational diabetes in humans. The current study shows that, unlike in the C57BL/6J mice, low vitamin B6 diet does not alter glucose tolerance and insulin secretion in pregnant DBA/2J mice. The hypothesis to be tested in the current study is that pregnant DBA/2J mice are protected against low vitamin B6-induced gestational diabetes due to their higher expression and enzymatic activities of tissue nonspecific alkaline phosphatase (ALPL) relative to C57BL/6J. ALPL is a rate-limiting enzyme that regulates vitamin B6 bioavailability. Interestingly, treating pregnant DBA/2J mice with 7.5â mg/kg/day of the ALPL inhibitor SBI-425 is associated with glucose intolerance in low vitamin B6-fed mice, implying that inhibition of ALPL activity is sufficient to modulate resilience to low vitamin B6-induced metabolic impairment.
Assuntos
Diabetes Gestacional , Intolerância à Glucose , Humanos , Criança , Feminino , Gravidez , Animais , Camundongos , Camundongos Endogâmicos C57BL , Vitamina B 6/farmacologia , Intolerância à Glucose/etiologia , Camundongos Endogâmicos DBA , Serotonina , Dieta/efeitos adversosRESUMO
Introduction: Gestational diabetes (GDM) is associated with negative outcomes in mothers and their offspring, including greater risks of macrosomia at birth and the development of metabolic disorders. While these outcomes are well-established, the mechanisms by which this increased metabolic vulnerability is conferred on the offspring are comparatively lacking. One proposed mechanism is that maternal glycemic dysregulation alters the development of the hypothalamic regions related to metabolism and energy balance. Methods: To investigate this possibility, in this study, we first examined the effects of STZ-induced maternal glucose intolerance on the offspring on pregnancy day (PD) 19, and, in a second experiment, in early adulthood (postnatal day (PND) 60). Whether effects would be influenced by sex, or exposure of offspring to a high-fat diet was also investigated. The impact of maternal STZ treatment on POMC neuron number in the ARC of offspring at both time points was also examined. Results: As expected, STZ administration on PD 7 decreased maternal glucose tolerance, and increased risk for macrosomia, and loss of pups at birth. Offspring of STZ-treated mothers were also more vulnerable to developing metabolic impairments in adulthood. These were accompanied by sex-specific effects of maternal STZ treatment in the offspring, including fewer POMC neurons in the ARC of female but not male infants in late pregnancy and a higher number of POMC neurons in the ARC of both male and female adult offspring of STZ-treated dams, which was exacerbated in females exposed to a high-fat diet after weaning. Discussion: This work suggests that maternal hyperglycemia induced by STZ treatment, in combination with early-life exposure to an obesogenic diet, leads to adult metabolic alterations that correlate with the increased hypothalamic expression of POMC, showing that maternal glycemic dysregulation can impact the development of hypothalamic circuits regulating energy state with a stronger impact on female offspring.
Assuntos
Diabetes Gestacional , Intolerância à Glucose , Efeitos Tardios da Exposição Pré-Natal , Masculino , Recém-Nascido , Gravidez , Humanos , Feminino , Adulto , Macrossomia Fetal , Intolerância à Glucose/etiologia , Pró-Opiomelanocortina/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Dieta Hiperlipídica/efeitos adversosRESUMO
Sugar substitutes have been recommended to be used for weight and glycemic control. However, numerous studies indicate that consumption of artificial sweeteners exerts adverse effects on glycemic homeostasis. Although sucralose is among the most extensively utilized sweeteners in food products, the effects and detailed mechanisms of sucralose on insulin sensitivity remain ambiguous. In this study, we found that bolus administration of sucralose by oral gavage enhanced insulin secretion to decrease plasma glucose levels in mice. In addition, mice were randomly allocated into three groups, chow diet, high-fat diet (HFD), and HFD supplemented with sucralose (HFSUC), to investigate the effects of long-term consumption of sucralose on glucose homeostasis. In contrast to the effects of sucralose with bolus administration, the supplement of sucralose augmented HFD-induced insulin resistance and glucose intolerance, determined by glucose and insulin tolerance tests. In addition, we found that administration of extracellular signal-regulated kinase (ERK)-1/2 inhibitor reversed the effects of sucralose on glucose intolerance and insulin resistance in mice. Moreover, blockade of taste receptor type 1 member 3 (T1R3) by lactisole or pretreatment of endoplasmic reticulum stress inhibitors diminished sucralose-induced insulin resistance in HepG2 cells. Taken together, sucralose augmented HFD-induced insulin resistance in mice, and interrupted insulin signals through a T1R3-ERK1/2-dependent pathway in the liver.
Assuntos
Intolerância à Glucose , Resistência à Insulina , Animais , Camundongos , Intolerância à Glucose/etiologia , Proteína Quinase 3 Ativada por Mitógeno , Edulcorantes/farmacologia , Insulina , Glucose , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversosRESUMO
Abnormal glucose tolerance (AGT), which includes type 2 diabetes and pre-diabetes, is highly prevalent in women post gestational diabetes mellitus (post-GDM). Dietary patterns have been associated with the risk of developing AGT in women post-GDM, but evidence in Asian populations is sparse. This study aimed to determine the association between a posteriori dietary patterns and AGT in women post-GDM. This cross-sectional study recruited 157 women post-GDM (mean age 34.8 years) from Seri Kembangan Health Clinic and Universiti Putra Malaysia. AGT was diagnosed according to the Malaysian Clinical Practice Guidelines using a 75 g 2 h oral glucose tolerance test or HbA1c. Food intake was assessed using the 2014 Malaysian Adult Nutrition Survey food frequency questionnaire. Five dietary patterns were derived using principal component analysis: 'Unhealthy', 'Fish-eggs-fruits-vegetables', 'Cereals-confectionaries', 'Legumes-dairy', and 'Meat-sugar-sweetened-beverages'. After adjusting for sociodemographic characteristics and total energy intake, the 'Cereals-confectionaries' dietary pattern was significantly associated with AGT (adjusted odds ratio 1.536, p = 0.049). Targeted lifestyle modification, including dietary intervention, for women post-GDM is warranted to reduce their risk of AGT and its complications.
Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Intolerância à Glucose , Feminino , Humanos , Gravidez , Estudos Transversais , Diabetes Gestacional/epidemiologia , Glucose , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/etiologia , Fatores de Risco , Verduras , Adolescente , Adulto , Pessoa de Meia-IdadeRESUMO
The prevalence of non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), is higher in men than in women of reproductive age, and postmenopausal women are especially susceptible to developing the disease. AIM: we evaluated if female apolipoprotein E (ApoE) KO mice were protected against Western-diet (WD)-induced NASH. METHODS: Female ovariectomized (OVX) ApoE KO mice or sham-operated (SHAM) mice were fed either a WD or a regular chow (RC) for 7 weeks. Additionally, OVX mice fed a WD were treated with either estradiol (OVX + E2) or vehicle (OVX). RESULTS: Whole-body fat, plasma glucose, and plasma insulin were increased and associated with increased glucose intolerance in OVX mice fed a WD (OVX + WD). Plasma and hepatic triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) hepatic enzymes were also increased in the plasma of OVX + WD group, which was associated with hepatic fibrosis and inflammation. Estradiol replacement in OVX mice reduced body weight, body fat, glycemia, and plasma insulin associated with reduced glucose intolerance. Treatment also reduced hepatic triglycerides, ALT, AST, hepatic fibrosis, and inflammation in OVX mice. CONCLUSIONS: These data support the hypothesis that estradiol protects OVX ApoE KO mice from NASH and glucose intolerance.
Assuntos
Intolerância à Glucose , Insulinas , Hepatopatia Gordurosa não Alcoólica , Animais , Feminino , Camundongos , Apolipoproteínas E/genética , Dieta , Estradiol/farmacologia , Glucose , Intolerância à Glucose/etiologia , Intolerância à Glucose/patologia , Inflamação/patologia , Fígado/patologia , Cirrose Hepática/patologia , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , TriglicerídeosRESUMO
Impaired glucose regulation is one of the most important risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which have become a major public health issue worldwide. Dysregulation of carbohydrate metabolism in liver has been shown to play a critical role in the development of glucose intolerance but the molecular mechanism has not yet been fully understood. In this study, we investigated the role of hepatic LCMT1 in the regulation of glucose homeostasis using a liver-specific LCMT1 knockout mouse model. The hepatocyte-specific deletion of LCMT1 significantly upregulated the hepatic glycogen synthesis and glycogen accumulation in liver. We found that the liver-specific knockout of LCMT1 improved high fat diet-induced glucose intolerance and insulin resistance. Consistently, the high fat diet-induced downregulation of glucokinase (GCK) and other important glycogen synthesis genes were reversed in LCMT1 knockout liver. In addition, the expression of GCK was significantly upregulated in MIHA cells treated with siRNA targeting LCMT1 and improved glycogen synthesis. In this study, we provided evidences to support the role of hepatic LCMT1 in the development of glucose intolerance induced by high fat diet and demonstrated that inhibiting LCMT1 could be a novel therapeutic strategy for the treatment of glucose metabolism disorders.
Assuntos
Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Resistência à Insulina , Proteína O-Metiltransferase , Camundongos , Animais , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Dieta Hiperlipídica/efeitos adversos , Leucina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fígado/metabolismo , Glucose/metabolismo , Glicogênio/metabolismo , Metiltransferases/metabolismo , Proteína O-Metiltransferase/metabolismoRESUMO
Many lines of evidence demonstrate a correlation between liver glycogen content and food intake. We previously demonstrated that mice overexpressing protein targeting to glycogen (PTG) specifically in the liver-which have increased glycogen content in this organ-are protected from high-fat diet (HFD)-induced obesity by reduced food intake. However, the use of PTG to increase liver glycogen implies certain limitations. PTG stimulates glycogen synthesis but also inhibits the enzyme responsible for glycogen degradation. Furthermore, as PTG is a regulatory subunit of protein phosphatase 1 (PP1), which regulates many cellular functions, its overexpression could have side effects beyond the regulation of glycogen metabolism. Therefore, it is necessary to determine whether the direct activation of glycogen synthesis, without affecting its degradation or other cellular functions, has the same effects. To this end, we generated mice overexpressing a non-inactivatable form of glycogen synthase (GS) specifically in the liver (9A-MGSAlb mice). Control and 9a-MGSAlb mice were fed a standard diet (SD) or HFD for 16 weeks. Glucose tolerance and feeding behavior were analyzed. 9A-MGSAlb mice showed an increase in hepatic glycogen in fed and fasting conditions. When fed an HFD, these animals preserved their hepatic energy state, had a reduced food intake, and presented a lower body weight and fat mass than control animals, without changes in energy expenditure. Furthermore, 9A-MGSAlb animals showed improved glucose tolerance when fed an SD or HFD. Moreover, liver triacylglycerol levels that were increased after HFD feeding were lower in these mice. These results confirm that increased liver glycogen stores contribute to decreased appetite and improve glucose tolerance in mice fed an HFD. On the basis of our findings, strategies to preserve hepatic glycogen stores emerge as potential treatments for obesity and hyperglycemia.
Assuntos
Intolerância à Glucose , Glicogênio Hepático , Animais , Camundongos , Peso Corporal , Dieta Hiperlipídica , Ingestão de Alimentos/fisiologia , Glucose/metabolismo , Intolerância à Glucose/etiologia , Intolerância à Glucose/prevenção & controle , Intolerância à Glucose/metabolismo , Glicogênio Sintase/genética , Glicogênio Sintase/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/prevenção & controle , Obesidade/metabolismoRESUMO
OBJECTIVES: Metabolic-associated fatty liver disease (MAFLD) is the most common chronic liver disease that can range from hepatic steatosis to non-alcoholic steatohepatitis (NASH), which can lead to fibrosis and cirrhosis. Recently, ketogenic diet (KD), a low carbohydrate diet, gained popularity as a weight-loss approach, although it has been reported to induce hepatic insulin resistance and steatosis in animal model systems via an undefined mechanism. Herein, we investigated the KD metabolic benefits and its contribution to the pathogenesis of NASH. METHODS: Using metabolic, biochemical and omics approaches, we identified the effects of a KD on NASH and investigated the mechanisms by which KD induces hepatic insulin resistance and steatosis. RESULTS: We demonstrate that KD can induce fibrosis and NASH regardless of body weight loss compared to high-fat diet (HFD) fed mice at thermoneutrality. At ambient temperature (23 °C), KD-fed mice develop a severe hepatic injury, inflammation, and steatosis. In addition, KD increases liver cholesterol, IL-6, and p-JNK and aggravates diet induced-glucose intolerance and hepatic insulin resistance compared to HFD. Pharmacological inhibition of IL-6 and JNK reverses KD-induced glucose intolerance, and hepatic steatosis and restores insulin sensitivity. CONCLUSIONS: Our studies uncover a new mechanism for KD-induced hepatic insulin resistance and NASH potentially via IL-6-JNK signaling and provide a new NASH mouse model.