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1.
Adv Exp Med Biol ; 1207: 463-466, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671768

RESUMO

Polycystic Ovary Syndrome (PCOS) is a common obesity-related reproductive disease in women of child-bearing age,which is usually accompanied with endocrine and metabolic abnormalities such as hyperandrogenemia and hyperinsulinemia. The abnormal reproductive function of PCOS is mainly characterized by the morphological and functional changes of ovary. Autophagy is involved in the maintenance of human ovarian physiological function as well as in the process of luteal degeneration, and affects the survival of granulosa cells. This chapter introduces the latest research progress of the relationship between autophagy and PCOS. How autophagy is involved in the occurrence and development of PCOS remains to be further studied.


Assuntos
Autofagia , Síndrome do Ovário Policístico , Feminino , Células da Granulosa , Humanos , Hiperandrogenismo/complicações , Hiperinsulinismo/complicações , Obesidade/complicações , Ovário/patologia , Ovário/fisiologia , Ovário/fisiopatologia , Síndrome do Ovário Policístico/complicações
2.
Nat Commun ; 11(1): 3746, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32719315

RESUMO

Recently, the clinical proof of concept for the first ultra-long oral insulin was reported, showing efficacy and safety similar to subcutaneously administered insulin glargine. Here, we report the molecular engineering as well as biological and pharmacological properties of these insulin analogues. Molecules were designed to have ultra-long pharmacokinetic profile to minimize variability in plasma exposure. Elimination plasma half-life of ~20 h in dogs and ~70 h in man is achieved by a strong albumin binding, and by lowering the insulin receptor affinity 500-fold to slow down receptor mediated clearance. These insulin analogues still stimulate efficient glucose disposal in rats, pigs and dogs during constant intravenous infusion and euglycemic clamp conditions. The albumin binding facilitates initial high plasma exposure with a concomitant delay in distribution to peripheral tissues. This slow appearance in the periphery mediates an early transient hepato-centric insulin action and blunts hypoglycaemia in dogs in response to overdosing.


Assuntos
Insulina/administração & dosagem , Engenharia de Proteínas , Administração Oral , Sequência de Aminoácidos , Animais , Glicemia/metabolismo , Simulação por Computador , Cães , Relação Dose-Resposta a Droga , Overdose de Drogas/sangue , Técnica Clamp de Glucose , Meia-Vida , Humanos , Hiperinsulinismo/tratamento farmacológico , Hipoglicemia/diagnóstico , Insulina/análogos & derivados , Insulina/química , Insulina/farmacocinética , Masculino , Estabilidade Proteica , Proteólise , Ratos Sprague-Dawley , Suínos , Resultado do Tratamento
3.
Eur J Endocrinol ; 183(1): 51-61, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32503004

RESUMO

Objective: We investigated the effects of a 12-week exercise intervention on insulin sensitivity (SI) and hyperinsulinemia and associated changes in regional and ectopic fat. Research design and methods: Healthy, black South African women with obesity (mean age 23 ± 3.5 years) and of isiXhosa ancestry were randomised into a 12-week aerobic and resistance exercise training group (n = 23) and a no exercise group (control, n = 22). Pre and post-intervention testing included assessment of SI, insulin response to glucose (AIRg), insulin secretion rate (ISR), hepatic insulin extraction (FEL) and disposition index (DI) (AIRg × SI) (frequently sampled i.v. glucose tolerance test); fat mass and regional adiposity (dual-energy X-ray absorptiometry); hepatic, pancreatic and skeletal muscle fat content and abdominal s.c. and visceral adipose tissue volumes (MRI). Results: Exercise training increased VO2peak (mean ± s.d.: 24.9 ± 2.42 to 27.6 ± 3.39 mL/kg/min, P < 0.001), SI (2.0 (1.2-2.8) to 2.2 (1.5-3.7) (mU/l)-1 min-1, P = 0.005) and DI (median (interquartile range): 6.1 (3.6-7.1) to 6.5 (5.6-9.2) × 103 arbitrary units, P = 0.028), and decreased gynoid fat mass (18.5 ± 1.7 to 18.2 ± 1.6%, P < 0.001) and body weight (84.1 ± 8.7 to 83.3 ± .9.7 kg, P = 0.038). None of these changes were observed in the control group, but body weight increased (P = 0.030). AIRg, ISR and FEL, VAT, SAT and ectopic fat were unaltered after exercise training. The increase in SI and DI were not associated with changes in regional or ectopic fat. Conclusion: Exercise training increased SI independent from changes in hyperinsulinemia and ectopic fat, suggesting that ectopic fat might not be a principal determinant of insulin resistance in this cohort.


Assuntos
Tecido Adiposo/metabolismo , Terapia por Exercício/métodos , Hiperinsulinismo/metabolismo , Hiperinsulinismo/terapia , Resistência à Insulina , Obesidade/metabolismo , Obesidade/terapia , Adiposidade , Adulto , Glicemia , Feminino , Humanos , Hiperinsulinismo/complicações , Obesidade/complicações , África do Sul , Resultado do Tratamento , Adulto Jovem
4.
Ann Endocrinol (Paris) ; 81(2-3): 110-117, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32409005

RESUMO

Hypoglycemia is defined by a low blood glucose level associated to clinical symptoms. Hypoglycemia may be related to treatment of diabetes, but also to drugs, alcohol, critical illness, cortisol insufficiency including hypopituitarism, insulinoma, bariatric or gastric surgery, pancreas transplantation or glucagon deficiency, or may be surreptitious. Some hypoglycemic episodes remain unexplained, and genetic, paraneoplastic and immune causes should be considered. Genetic causes may be related to endogenous hyperinsulinism and to inborn errors of metabolism (IEM). Endogenous hyperinsulinism is related to monogenic congenital hyperinsulinism, and especially to mutations of the glucokinase-activating gene or of insulin receptors, both characterised by postprandial hypoglycemia with major hyperinsulinism. In adulthood, IEM-related hypoglycemia can persist in a previously diagnosed childhood disease or may be a presenting sign. It is suggested by systemic involvement (rhabdomyolysis after fasting or exercising, heart disease, hepatomegaly), sometimes associated to a family history of hypoglycemia. The timing of hypoglycemic episodes with respect to the last meal also helps to orientate diagnosis. Fasting hypoglycemia may be related to type 0, I or III glycogen synthesis disorder, fatty acid oxidation or gluconeogenesis disorder. Postprandial hypoglycemia may be related to inherited fructose intolerance. Exercise-induced hyperinsulinism is mainly related to activating mutation of the SLC16A1 gene. Besides exceptional ectopic insulin secretion, paraneoplastic causes involve NICTH (Non-Islet-Cell Tumour Hypoglycemia), caused by Big-IGF2 secretion by a large tumour, with low blood levels of insulin, C-peptide and IGF1. Autoimmune causes involve antibodies against insulin (HIRATA syndrome), especially in case of Graves' disease, or against the insulin receptor. Medical history, timing, and insulin level orientate the diagnosis.


Assuntos
Hipoglicemia/epidemiologia , Hipoglicemia/etiologia , Adulto , Idade de Início , Antígenos CD/genética , Criança , Complicações do Diabetes/sangue , Complicações do Diabetes/epidemiologia , Jejum/sangue , Humanos , Hiperinsulinismo/sangue , Hiperinsulinismo/complicações , Hiperinsulinismo/epidemiologia , Insulinoma/sangue , Insulinoma/complicações , Insulinoma/epidemiologia , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/genética , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/epidemiologia , Receptor de Insulina/genética , Fatores de Risco
5.
Metabolism ; 109: 154263, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32445642

RESUMO

OBJECTIVE: The hyperinsulinemic euglycemic clamp (HEC) is the "gold standard" for measuring insulin sensitivity (Si-clamp). Here, we determined the reproducibility of serial HEC data in healthy subjects. RESEARCH DESIGN AND METHODS: The Pathobiology of Prediabetes in A Biracial Cohort study assessed incident prediabetes in healthy African Americans (AA) and European Americans (EA) with parental type 2 diabetes mellitus during 5.5 years of follow-up. Assessments included anthropometry, OGTT, and HEC. Ninety subjects (44 AA, 46 EA) who underwent Year-1HEC consented to Year-3 HEC. We calculated coefficients of variation (CVs), 95% limits of agreement, and repeatability coefficients for Year-1 and Year-3 data, and assessed the association of change in Si-clamp with incident prediabetes. RESULTS: The mean (SD) baseline age was 47.5 ±â€¯8.13y, body mass index was 30.4 ±â€¯9.16 kg/m2, fasting plasma glucose was 93.7 ±â€¯7.82 mg/dL and 2-hrPG was 126 ±â€¯26.8 mg/dL. Si-clamp (umol/kg/min·pmol/L-1) was 0.071 ±â€¯0.04 in Year 1 and 0.067 ±â€¯0.04 in Year 3 (P = 0.22). Year 1 and Year 3 values were strongly correlated (r = 0.81, P < 0.0001); the CV was 13.6% and repeatability coefficient was ±0.025. Intrasubject differences in serial Si-clamp were less than the repeatability coefficients and within the 95% limits of agreement. After 5.5 years of follow-up, 40 subjects progressed to prediabetes and 50 were nonprogressors. The change in Si-clamp was greater in progressors than nonprogressors (-10% vs. -2.5%, P = 0.02). CONCLUSIONS: The HEC is reproducible over ~2 years in free-living individuals, with a temporal decline in Si-clamp that predicts prediabetes risk.


Assuntos
Técnica Clamp de Glucose/métodos , Hiperinsulinismo , Resistência à Insulina , Estado Pré-Diabético/diagnóstico , Valor Preditivo dos Testes , Adulto , Afro-Americanos , Antropometria , Diabetes Mellitus Tipo 2 , Grupo com Ancestrais do Continente Europeu , Seguimentos , Teste de Tolerância a Glucose , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/etnologia , Reprodutibilidade dos Testes , Fatores de Tempo
6.
Wiad Lek ; 73(2): 384-389, 2020.
Artigo em Polonês | MEDLINE | ID: mdl-32248180

RESUMO

Reactive hypoglycemia is characterized by low blood glucose level in non-diabetic patients. It manifests as a syndrome of adrenergic and neuroglycopenic symptoms in the postprandial period, and their resolution occurs after consuming carbohydrates. The etiology of reactive hypoglycemia is not fully understood. It may occur in patients after gastrointestinal surgery due to too fast gastric emptying. Decreases in postprandial glucose are also observed in people with a pre-diabetes condition in which insulin secretion is disturbed. Hypoglycaemia can also be seen in patients with insulin resistance and hyperinsulinism. The aim of this study was to summarize existing knowledge about reactive hypoglycemia - etiology, diagnostic model and treatment.


Assuntos
Hiperinsulinismo , Hipoglicemia , Resistência à Insulina , Glicemia , Humanos , Insulina , Período Pós-Prandial
7.
Am J Chin Med ; 48(3): 615-629, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32329641

RESUMO

Mitochondrial metabolism plays a crucial role in insulin resistance and insulin secretion in type 2 diabetes mellitus (T2D). Some studies have focused on how Cassia tora extracts affect insulin resistance and hyperglycemia. However, the effects of Cassia tora extracts on mitochondrial dysfunction associated with insulin secretion have not been well explained. In this study, well-known effective compounds extracted from Cassia tora using 70% ethanol were administered to a high-fat diet (HFD) fed mouse to examine the effects of Cassia tora ethanolic extracts (CSEE) on mitochondrial dysfunction in the pancreas. Furthermore, we examined how CSEE regulates the basal mechanism of insulin secretion through mitochondrial functions. Our experimental data suggest that pancreatic mitochondrial metabolism in HFD mice is enhanced to compensate for constrained glucose consumption. HFD-fed mice treated with CSEE showed improved pancreatic mitochondrial functions resulting in alleviation of insulin resistance at target tissue as well as basal hyperinsulinemia.


Assuntos
Cassia/química , Glucose/metabolismo , Mitocôndrias/metabolismo , Pâncreas , Extratos Vegetais/farmacologia , Animais , Dieta Hiperlipídica , Hiperglicemia/tratamento farmacológico , Hiperinsulinismo/tratamento farmacológico , Resistência à Insulina , Secreção de Insulina/efeitos dos fármacos , Camundongos , Fitoterapia , Extratos Vegetais/uso terapêutico
8.
Adv Exp Med Biol ; 1228: 123-136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32342454

RESUMO

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy affecting both the metabolism and reproductive system of women of reproductive age. Prevalence ranges from 6.1-19.9% depending on the criteria used to give a diagnosis. PCOS accounts for approximately 80% of women with anovulatory infer-tility, and causes disruption at various stages of the reproductive axis. Evidence suggests lifestyle modification should be the first line of therapy for women with PCOS. Several studies have examined the impact of exercise interventions on reproductive function, with results indicating improvements in menstrual and/or ovulation frequency following exercise. Enhanced insulin sensitivity underpins the mechanisms of how exercise restores reproductive function. Women with PCOS typically have a cluster of metabolic abnormalities that are risk factors for CVD. There is irrefutable evidence that exercise mitigates CVD risk factors in women with PCOS. The mechanism by which exercise improves many CVD risk factors is again associated with improved insulin sensitivity and decreased hyperinsulinemia. In addition to cardiometabolic and reproductive complications, PCOS has been associated with an increased prevalence of mental health disorders. Exercise improves psychological well-being in women with PCOS, dependent on certain physiological factors. An optimal dose-response relationship to exercise in PCOS may not be feasible because of the highly individualised characteristics of the disorder. Guidelines for PCOS suggest at least 150 min of physical activity per week. Evidence confirms that this should form the basis of any clinician or healthcare professional prescription.


Assuntos
Exercício Físico , Síndrome do Ovário Policístico , Doenças Cardiovasculares , Feminino , Humanos , Hiperinsulinismo , Resistência à Insulina , Estilo de Vida , Ovulação , Síndrome do Ovário Policístico/terapia
10.
Proc Natl Acad Sci U S A ; 117(14): 8166-8176, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32188779

RESUMO

Multiple insulin-regulated enzymes participate in hepatic glycogen synthesis, and the rate-controlling step responsible for insulin stimulation of glycogen synthesis is unknown. We demonstrate that glucokinase (GCK)-mediated glucose phosphorylation is the rate-controlling step in insulin-stimulated hepatic glycogen synthesis in vivo, by use of the somatostatin pancreatic clamp technique using [13C6]glucose with metabolic control analysis (MCA) in three rat models: 1) regular chow (RC)-fed male rats (control), 2) high fat diet (HFD)-fed rats, and 3) RC-fed rats with portal vein glucose delivery at a glucose infusion rate matched to the control. During hyperinsulinemia, hyperglycemia dose-dependently increased hepatic glycogen synthesis. At similar levels of hyperinsulinemia and hyperglycemia, HFD-fed rats exhibited a decrease and portal delivery rats exhibited an increase in hepatic glycogen synthesis via the direct pathway compared with controls. However, the strong correlation between liver glucose-6-phosphate concentration and net hepatic glycogen synthetic rate was nearly identical in these three groups, suggesting that the main difference between models is the activation of GCK. MCA yielded a high control coefficient for GCK in all three groups. We confirmed these findings in studies of hepatic GCK knockdown using an antisense oligonucleotide. Reduced liver glycogen synthesis in lipid-induced hepatic insulin resistance and increased glycogen synthesis during portal glucose infusion were explained by concordant changes in translocation of GCK. Taken together, these data indicate that the rate of insulin-stimulated hepatic glycogen synthesis is controlled chiefly through GCK translocation.


Assuntos
Fígado Gorduroso/patologia , Glucoquinase/metabolismo , Glucose/metabolismo , Glicogênio Hepático/biossíntese , Fígado/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Técnicas de Silenciamento de Genes , Glucoquinase/genética , Glucose/administração & dosagem , Glucose-6-Fosfato/análise , Glucose-6-Fosfato/metabolismo , Humanos , Hiperglicemia/etiologia , Hiperglicemia/patologia , Hiperinsulinismo/etiologia , Hiperinsulinismo/patologia , Insulina/metabolismo , Resistência à Insulina , Fígado/patologia , Masculino , Metabolômica , Fosforilação , Ratos
11.
PLoS Biol ; 18(2): e3000603, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32092075

RESUMO

Type 2 diabetes (T2D) is characterized by insulin resistance along with pancreatic ß cell failure. ß cell factors are traditionally thought to control glucose homeostasis by modulating insulin levels, not insulin sensitivity. Exosomes are emerging as new regulators of intercellular communication. However, the role of ß-cell-derived exosomes in metabolic homeostasis is poorly understood. Here, we report that microRNA-26a (miR-26a) in ß cells not only modulates insulin secretion and ß cell replication in an autocrine manner but also regulates peripheral insulin sensitivity in a paracrine manner through circulating exosomes. MiR-26a is reduced in serum exosomes of overweight humans and is inversely correlated with clinical features of T2D. Moreover, miR-26a is down-regulated in serum exosomes and islets of obese mice. Using miR-26a knockin and knockout mouse models, we showed that miR-26a in ß cells alleviates obesity-induced insulin resistance and hyperinsulinemia. Mechanistically, miR-26a in ß cells enhances peripheral insulin sensitivity via exosomes. Meanwhile, miR-26a prevents hyperinsulinemia through targeting several critical regulators of insulin secretion and ß cell proliferation. These findings provide a new paradigm for the far-reaching systemic functions of ß cells and offer opportunities for the treatment of T2D.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , MicroRNAs/metabolismo , Animais , Proliferação de Células , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Exossomos/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Hiperinsulinismo/prevenção & controle , Hiperplasia/prevenção & controle , Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Obesos , Camundongos Transgênicos , MicroRNAs/sangue , MicroRNAs/genética , Comunicação Parácrina , Transdução de Sinais
12.
J Nutr ; 150(4): 704-711, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32060554

RESUMO

BACKGROUND: The association between high selenium (Se) intake and metabolic disorders such as type 2 diabetes has raised great concern, but the underlying mechanism remains unclear. OBJECTIVE: Through targeted metabolomics analysis, we examined the liver sugar and acylcarnitine metabolism responses to supranutritional selenomethionine (SeMet) supplementation in pigs. METHODS: Thirty-six castrated male pigs (Duroc-Landrace-Yorkshire, 62.0 ± 3.3 kg) were fed SeMet adequate (Se-A, 0.25 mg Se/kg) or SeMet supranutritional (Se-S, 2.5 mg Se/kg) diets for 60 d. The Se concentration, biochemical, gene expression, enzyme activity, and energy-targeted metabolite profiles were analyzed. RESULTS: The Se-S group had greater fasting serum concentrations of glucose (1.9-fold), insulin (1.4-fold), and free fatty acids (FFAs,1.3-fold) relative to the Se-A group (P < 0.05). The liver total Se concentration was 4.2-fold that of the Se-A group in the Se-S group (P < 0.05), but expression of most selenoprotein genes and selenoenzyme activity did not differ between the 2 groups. Seven of 27 targeted sugar metabolites and 4 of 21 acylcarnitine metabolites significantly changed in response to high SeMet (P < 0.05). High SeMet supplementation significantly upregulated phosphoenolpyruvate carboxy kinase (PEPCK) activity by 64.4% and decreased hexokinase and succinate dehydrogenase (SDH) activity by 46.5-56.7% (P < 0.05). The relative contents of glucose, dihydroxyacetone phosphate, α-ketoglutarate, fumarate, malate, erythrose-4-phosphate, and sedoheptulose-7-phosphate in the Se-S group were 21.1-360% greater than those in the Se-A group (P < 0.05). The expression of fatty acid synthase (FASN) and the relative contents of carnitine, hexanoyl-carnitine, decanoyl-carnitine, and tetradecanoyl-carnitine in the Se-S group were 35-97% higher than those in the Se-A group (P < 0.05). CONCLUSIONS: Dietary high SeMet-induced hyperglycemia and hyperinsulinemia were associated with suppression of sugar metabolism and elevation of lipid synthesis in pig livers. Our research provides novel insights into high SeMet intake-induced type 2 diabetes.


Assuntos
Carnitina/análogos & derivados , Dieta , Fígado/metabolismo , Selenometionina/administração & dosagem , Açúcares/metabolismo , Animais , Carnitina/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Homeostase/efeitos dos fármacos , Hiperglicemia/induzido quimicamente , Hiperinsulinismo/induzido quimicamente , Lipídeos/biossíntese , Fígado/química , Fígado/enzimologia , Masculino , Metabolômica/métodos , Modelos Animais , Oxirredução , RNA Mensageiro/análise , Selênio/administração & dosagem , Selênio/efeitos adversos , Selênio/análise , Selenometionina/efeitos adversos , Selenoproteínas/genética , Sus scrofa
13.
Mymensingh Med J ; 29(1): 222-227, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31915362

RESUMO

Insulinoma is a rare variety of endocrine neoplasm and is usually benign, solitary, and small in size. The hallmark of this disorder is high endogenous insulin secretion resulting in development of symptoms of hypoglycemia. Insulinomas account for 60% of islet cell tumors (ICT) of the pancreas. Ninety percent (90%) of the insulinomas measure less than 2cm. Early localization of the disease is essential to prevent lethal hypoglycemia. Here we report a case of insulinoma in a 28 year old female who subsequently underwent distal pancreatectomy with splenectomy on February 2017 in Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.


Assuntos
Hipoglicemia , Insulinoma/cirurgia , Neoplasias Pancreáticas/cirurgia , Adulto , Bangladesh , Diabetes Mellitus Tipo 2/etiologia , Feminino , Humanos , Hiperinsulinismo/etiologia , Hipoglicemia/etiologia , Insulinoma/patologia , Pancreatectomia , Neoplasias Pancreáticas/patologia , Resultado do Tratamento
14.
Pesqui. vet. bras ; 40(1): 39-45, Jan. 2020. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1091655

RESUMO

Insulin deregulation (ID) is a central player in the pathophysiology of equine metabolic syndrome (EMS), which is associated with generalized and/or regional obesity. The objective of this experiment was to characterize the alterations in the hormonal profile in horses exposed to a hypercaloric diet. A total of nine Mangalarga Marchador adult horses with initial body condition score (BCS) of 2.9±1/9 (mean±SD) were submitted to a high calorie grain-rich diet for 5 months. The data was collected before the start of the experiment and every 15 days until the end of the experiment and glucose and insulin concentrations were measured in the plasma. Proxies G:I, RISQI, HOMA-IR and MIRG were calculated. The low-dose oral glucose tolerance test (OGTT) was performed and the total area under the glucose (GTA) and insulin (ITA) curves at three different timepoints (before inducing obesity, after 90 days and after 150 days) was used. Analysis of variance of the results was performed considering the time effects and the means were compared with repeated measures by the Tukey's test (P≤0.05). The ID was observed during the first 90 days of the experiment and was characterized as a decompensated ID, showing an increase of basal glucose and insulin plasma levels, changes in all proxies and a significant increase in GTA (P<0.001) and ITA (P<0.05). However, a clear compensation of the ID was evident after 150 days of experiment, which was supported by data from the insulin secretory response of ß cells of the pancreas that showed an increase in insulin plasma levels, after fasting or exposure to gastric glucose, with a concomitant decrease in fasting glucose and fructosamine levels, and a decrease of GTA and marked increase of ITA (P<0.0001) in the dynamic test. These findings confirm the occurrence of hyperinsulinemia associated with insulin deregulation in Mangalarga Marchador horses exposed to hypercaloric diets.(AU)


A desregulação insulínica (DI) é o ponto central dos mecanismos fisiopatológicos da síndrome metabólica equina (SME), que é associada à obesidade generalizada e/ou regional. O objetivo deste experimento foi caracterizar as alterações no perfil hormonal em equinos submetidos à dieta hipercalórica. Foram utilizados nove equinos Mangalarga Marchador adultos com escore corporal (EC) médio (±DP) inicial de 2,9±1 (escala de 1-9) submetidos à dieta hipercalórica atingindo um EC de 8,3±1 após cinco meses. Os dados foram coletados antes do início do experimento e com o intervalo de 15 dias até o final do experimento, os valores plasmáticos foram obtidos para mensuração das concentrações de glicose e insulina. Foram calculados os proxies G:I, RISQI, HOMA-IR e o MIRG. Foi realizado o teste de baixa dose de glicose oral (TBDGO) utilizando a área total sob a curva de glicose (ATG) e insulina (ATI) em três momentos, antes da indução a obesidade, após 90 e 150 dias. Os resultados foram submetidos à análise de variância considerando-se os efeitos de tempo e as médias comparadas com medidas repetidas pelo teste de Tukey, com o valor P≤0,05. A DI foi observada nos primeiros 90 dias de experimento, se caracterizando como um quadro de DI descompensada, apresentando um aumento dos níveis plasmáticos basais de glicose e insulina, pelas alterações em todos os proxies e com um aumento significativo da ATG (P<0,001) e ATI (P<0,05). Contudo, ficou evidente uma compensação do quadro de DI após 150 dias de experimento, sendo demonstrado pelos dados da resposta secretória insulínica das células ß do pâncreas, que se manifestaram pelo aumento dos níveis plasmáticos de insulina pós-jejum ou exposição à glicose gástrica com concomitante redução nos níveis de glicose e frutosamina pós-jejum e pela redução da ATG e pela marcada elevação de ATI (P<0,0001) no teste dinâmico. Tais achados comprovam a ocorrência de hiperinsulinemia associada à desregulação insulínica em equinos Mangalarga Marchador expostos a dietas à dieta hipercalórica.(AU)


Assuntos
Animais , Resistência à Insulina , Síndrome Metabólica/etiologia , Síndrome Metabólica/veterinária , Dieta/veterinária , Cavalos/metabolismo , Hiperinsulinismo/etiologia , Hiperinsulinismo/veterinária , Obesidade/etiologia , Ganho de Peso , Obesidade/veterinária
15.
Circ Res ; 126(4): 456-470, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31896304

RESUMO

RATIONALE: Lipid overload-induced heart dysfunction is characterized by cardiomyocyte death, myocardial remodeling, and compromised contractility, but the impact of excessive lipid supply on cardiac function remains poorly understood. OBJECTIVE: To investigate the regulation and function of the mitochondrial fission protein Drp1 (dynamin-related protein 1) in lipid overload-induced cardiomyocyte death and heart dysfunction. METHODS AND RESULTS: Mice fed a high-fat diet (HFD) developed signs of obesity and type II diabetes mellitus, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and hypertension. HFD for 18 weeks also induced heart hypertrophy, fibrosis, myocardial insulin resistance, and cardiomyocyte death. HFD stimulated mitochondrial fission in mouse hearts. Furthermore, HFD increased the protein level, phosphorylation (at the activating serine 616 sites), oligomerization, mitochondrial translocation, and GTPase activity of Drp1 in mouse hearts, indicating that Drp1 was activated. Monkeys fed a diet high in fat and cholesterol for 2.5 years also exhibited myocardial damage and Drp1 activation in the heart. Interestingly, HFD decreased nicotinamide adenine dinucleotide (oxidized) levels and increased Drp1 acetylation in the heart. In adult cardiomyocytes, palmitate increased Drp1 acetylation, phosphorylation, and protein levels, and these increases were abolished by restoration of the decreased nicotinamide adenine dinucleotide (oxidized) level. Proteomics analysis and in vitro screening revealed that Drp1 acetylation at lysine 642 (K642) was increased by HFD in mouse hearts and by palmitate incubation in cardiomyocytes. The nonacetylated Drp1 mutation (K642R) attenuated palmitate-induced Drp1 activation, its interaction with voltage-dependent anion channel 1, mitochondrial fission, contractile dysfunction, and cardiomyocyte death. CONCLUSIONS: These findings uncover a novel mechanism that contributes to lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which, in turn, increased its activity and mitochondrial translocation, resulting in cardiomyocyte dysfunction and death. Thus, Drp1 may be a critical mediator of lipid overload-induced heart dysfunction as well as a potential target for therapy.


Assuntos
Dinaminas/metabolismo , Lipídeos/análise , Miócitos Cardíacos/metabolismo , Acetilação , Animais , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Morte Celular/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Dinaminas/genética , Feminino , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Hipertensão/etiologia , Hipertensão/metabolismo , Macaca mulatta , Masculino , Camundongos Endogâmicos C57BL , Mutação , Miócitos Cardíacos/patologia , Obesidade/etiologia , Obesidade/metabolismo , Ratos Sprague-Dawley
16.
FASEB J ; 34(1): 945-959, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914664

RESUMO

The dynamics of cytoplasmic free Ca2+ concentration ([Ca2+]i) in pancreatic ß cells is central to our understanding of ß-cell physiology and pathology. In this context, there are numerous in vitro studies available but existing in vivo data are scarce. We now critically evaluate the anterior chamber of the eye as an in vivo, non-invasive, imaging site for measuring [Ca2+]i dynamics longitudinally in three dimensions and at single-cell resolution. By applying a fluorescently labeled glucose analogue 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose in vivo, we followed how glucose almost simultaneously distributes to all cells within the islet volume, resulting in [Ca2+]i changes. We found that almost all ß cells in healthy mice responded to a glucose challenge, while in hyperinsulinemic, hyperglycemic mice about 80% of the ß cells could not be further stimulated from fasting basal conditions. This finding indicates that our imaging modality can resolve functional heterogeneity within the ß-cell population in terms of glucose responsiveness. Importantly, we demonstrate that glucose homeostasis is markedly affected using isoflurane compared to hypnorm/midazolam anesthetics, which has major implications for [Ca2+]i measurements. In summary, this setup offers a powerful tool to further investigate in vivo pancreatic ß-cell [Ca2+]i response patterns at single-cell resolution in health and disease.


Assuntos
Cálcio/química , Células Secretoras de Insulina/metabolismo , Anestésicos/farmacologia , Animais , Câmara Anterior/cirurgia , Cálcio/metabolismo , Cruzamentos Genéticos , Feminino , Glucose/farmacologia , Teste de Tolerância a Glucose , Heterozigoto , Homeostase , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Ilhotas Pancreáticas/citologia , Transplante das Ilhotas Pancreáticas , Isoflurano/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Midazolam/farmacologia , Fenótipo
17.
Arch Physiol Biochem ; 126(2): 183-186, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30450993

RESUMO

Polycystic Ovary Syndrome is a multifactorial reproductive problem and a leading cause of female infertility worldwide. Evidences have shown that Oxidative Stress and decreased antioxidant status are often linked with PCOS. Insulin Resistance in PCOS patients ranges from 50% to 70% and may encourage OS by production of reactive oxygen species.Objective: Our study determines serum MDA levels along with plasma glucose, serum insulin, and insulin resistance in obese and nonobese PCOS subjects.Materials and methods: A case control study was conducted on diagnosed 100 PCOS patients and 100 controls. Fasting plasma glucose was measured by enzymatic method. Insulin was estimated by chemiluminescent microparticle immunoassay using Abott Architect i 2000 SR analyser. Insulin resistance was calculated by HOMA-IR. Malonaldehyde is determined as Thiobarbituric acid reactive substances.Results: CRP and serum MDA levels were increased in women with PCOS irrespective of obesity compared to their respective controls with a p value of < .001. However, though fasting glucose, serum insulin, and IR were increased in both obese and nonobese women with PCOS compared to their BMI adjusted controls with p value of < .001, the values were within reference range in nonobese women.Conclusion: Our study suggests that women with PCOS have oxidative stress and elevated CRP irrespective of obesity. However, hyperinsulinemia and Insulin resistance are seen only in obese women with PCOS, indicating that these women are at high risk for developing low grade inflammation and cardiovascular diseases.


Assuntos
Proteína C-Reativa/metabolismo , Hiperinsulinismo/sangue , Resistência à Insulina , Malondialdeído/sangue , Obesidade/sangue , Síndrome do Ovário Policístico/sangue , Adolescente , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Jejum/sangue , Feminino , Humanos , Hiperinsulinismo/diagnóstico , Hiperinsulinismo/patologia , Insulina/sangue , Obesidade/diagnóstico , Obesidade/patologia , Ovário/metabolismo , Ovário/patologia , Estresse Oxidativo , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/patologia , Fatores de Risco
18.
PLoS One ; 14(12): e0225843, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31805097

RESUMO

Equine laminitis is a disease of the digital epidermal lamellae typified by epidermal cell proliferation and structural collapse. Most commonly the disease is caused by hyperinsulinemia, although the pathogenesis is incompletely understood. Insulin can activate the epidermal growth factor (EGF) system in other species and the present study tested the hypothesis that upregulation of EGF receptor (EGFR) signalling is a key factor in laminitis pathophysiology. First, we examined lamellar tissue from healthy Standardbred horses and those with induced hyperinsulinemia and laminitis for EGFR distribution and quantity using immunostaining and gene expression, respectively. Phosphorylation of EGFR was also quantified. Next, plasma EGF concentrations were compared in healthy and insulin-infused horses, and in healthy and insulin-dysregulated ponies before and after feeding. The EGFR were localised to the secondary epidermal lamellae, with stronger staining in parabasal, rather than basal, cells. No change in EGFR gene expression occurred with laminitis, although the receptor showed some phosphorylation. No difference was seen in EGF concentrations in horses, but in insulin-dysregulated ponies mean, post-prandial EGF concentrations were almost three times higher than in healthy ponies (274 ± 90 vs. 97.4 ± 20.9 pg/mL, P = 0.05). Although the EGFR does not appear to play a major pathogenic role in hyperinsulinemic laminitis, the significance of increased EGF in insulin-dysregulated ponies deserves further investigation.


Assuntos
Fator de Crescimento Epidérmico/metabolismo , Doenças do Pé/veterinária , Casco e Garras/patologia , Doenças dos Cavalos/metabolismo , Hiperinsulinismo/complicações , Animais , Fator de Crescimento Epidérmico/sangue , Receptores ErbB/genética , Receptores ErbB/metabolismo , Doenças do Pé/sangue , Dosagem de Genes , Regulação da Expressão Gênica , Doenças dos Cavalos/sangue , Cavalos/sangue , Hiperinsulinismo/sangue , Insulina/metabolismo , Fosforilação
19.
PLoS One ; 14(12): e0226303, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31821361

RESUMO

BACKGROUND: Metformin treatment (1000-2000 mg/day) over 6 months in pubertal children and/or adolescents with obesity and hyperinsulinism is associated with a reduction in body mass index (BMI) and the insulin resistance index (HOMA-IR). We aimed to ascertain if long-term treatment (24 months) with lower doses of metformin (850 mg/day) normalizes the endocrine-metabolic abnormalities, improves body composition, and reduces the carotid intima-media thickness (cIMT) in pre-puberal and early pubertal children with obesity. METHODS: A pilot double-blind, placebo-controlled trial was conducted on 18 pre-puberal and early pubertal (Tanner stage I-II) children with obesity and risk markers for metabolic syndrome. Patients were randomly assigned (1:1) to receive metformin (850 mg/day) or placebo for 24 months. Clinical, biochemical (insulin, lipids, leptin, and high-sensitivity C-reactive protein [hsCRP]), and imaging (body composition [dual-energy X-ray absorptiometry and magnetic resonance imaging]) parameters as well as cIMT (ultrasonography) were assessed at baseline and at 6, 12, and 24 months. RESULTS: The 12-month treatment tend to cause a reduction in weight standard deviation scores (SDS), BMI-SDS, leptin, leptin-to-high-molecular-weight (HMW) adiponectin ratio, hsCRP, cIMT, fat mass, and liver fat in metformin-treated children compared with placebo. The effect of metformin on the reduction of BMI-SDS, leptin, leptin-to-HMW adiponectin ratio, hsCRP, and liver fat seemed to be maintained after completing the 24 months of treatment. No changes in insulin sensitivity (HOMA-IR) or adverse effects were detected. CONCLUSION: In this pilot study, metformin treatment in pre-puberal and early pubertal children with obesity seemed to improve body composition and inflammation markers. Our data encourage the development of future fully powered trials using 850 mg/day metformin in young children, highlighting its excellent tolerance and potential long-term benefits.


Assuntos
Hiperinsulinismo/sangue , Síndrome Metabólica/sangue , Metformina/farmacologia , Obesidade/sangue , Adolescente , Índice de Massa Corporal , Peso Corporal , Proteína C-Reativa/análise , Espessura Intima-Media Carotídea , Criança , Método Duplo-Cego , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Hiperinsulinismo/tratamento farmacológico , Insulina/sangue , Leptina/sangue , Masculino , Metformina/uso terapêutico , Obesidade/tratamento farmacológico , Projetos Piloto , Espanha
20.
J Transl Med ; 17(1): 422, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847906

RESUMO

BACKGROUND: The growth differentiation factor 11 (GDF11) was shown to reverse age-related hypertrophy on cardiomyocytes and considered as anti-aging rejuvenation factor. The role of GDF11 in regulating metabolic homeostasis is unclear. In this study, we investigated the functions of GDF11 in regulating metabolic homeostasis and energy balance. METHODS: Using a hydrodynamic injection approach, plasmids carrying a mouse Gdf11 gene were delivered into mice and generated the sustained Gdf11 expression in the liver and its protein level in the blood. High fat diet (HFD)-induced obesity was employed to examine the impacts of Gdf11 gene transfer on HFD-induced adiposity, hyperglycemia, insulin resistance, and hepatic lipid accumulation. The impacts of GDF11 on metabolic homeostasis of obese and diabetic mice were examined using HFD-induced obese and STZ-induced diabetic models. RESULTS: Gdf11 gene transfer alleviates HFD-induced obesity, hyperglycemia, insulin resistance, and fatty liver development. In obese and STZ-induced diabetic mice, Gdf11 gene transfer restores glucose metabolism and improves insulin resistance. Mechanism study reveals that Gdf11 gene transfer increases the energy expenditure of mice, upregulates the expression of genes responsible for thermoregulation in brown adipose tissue, downregulates the expression of inflammatory genes in white adipose tissue and those involved in hepatic lipid and glucose metabolism. Overexpression of GDF11 also activates TGF-ß/Smad2, PI3K/AKT/FoxO1, and AMPK signaling pathways in white adipose tissue. CONCLUSIONS: These results demonstrate that GDF11 plays an important role in regulating metabolic homeostasis and energy balance and could be a target for pharmacological intervention to treat metabolic disease.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Terapia Genética , Fatores de Diferenciação de Crescimento/genética , Fatores de Diferenciação de Crescimento/uso terapêutico , Homeostase , Obesidade/prevenção & controle , Obesidade/terapia , Tecido Adiposo/patologia , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Metabolismo Energético/genética , Fígado Gorduroso/complicações , Comportamento Alimentar , Regulação da Expressão Gênica , Intolerância à Glucose/complicações , Hiperinsulinismo/complicações , Hipertrofia , Inflamação/complicações , Inflamação/genética , Resistência à Insulina , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Masculino , Camundongos Obesos , Obesidade/complicações , Obesidade/genética , Consumo de Oxigênio/genética , Transdução de Sinais , Estreptozocina , Ganho de Peso
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