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1.
Medicine (Baltimore) ; 100(5): e24061, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33592858

RESUMO

ABSTRACT: Irisin, a novel myokine, is believed to be the crucial factor in converting white adipose tissue to beige adipose tissue. For this paper, we studied the relationship among irisin and components of metabolic syndrome (MetS), and insulin secretion and resistance in schoolchildren of Taiwan.Subjects receiving routine annual health examination at elementary school were enrolled. Demographic data, anthropometry, MetS components, irisin, and insulin secretion and resistance were collected. Subjects were divided into normal, overweight, and obese groups for evaluation of irisin in obesity. Finally, the relationship between irisin and MetS was analyzed.There were 376 children (179 boys and 197 girls), aged 10.3 ±â€Š1.5 years, were enrolled. In boys, irisin levels were not associated with body mass index percentile, body fat, blood pressure, lipid profiles, insulin secretion or resistance. After adjusting for age, the irisin level in boys was negatively related to fasting plasma glucose (FPG) (r = -0.21, P = .006). In girls, after adjusting for age, the irisin levels were positively related only to FPG (r = 1.49, P = .038). In both genders, irisin levels were similar among normal, overweight, and obese groups, and between subjects with and without MetS.The irisin levels were not associated with MetS in either boys or girls. In girls, circulating irisin levels have a nonsignificant declining trend in overweight and obese girls. However, irisin levels were negatively related to FPG in boys and positively related to FPG in girls. The contrary relationship between irisin and FPG in boys and girls needs further exploration.


Assuntos
Tecido Adiposo/metabolismo , Fibronectinas , Secreção de Insulina/fisiologia , Insulina , Síndrome Metabólica , Sobrepeso , Antropometria/métodos , Determinação da Pressão Arterial/métodos , Índice de Massa Corporal , Criança , Estudos Transversais , Feminino , Fibronectinas/sangue , Fibronectinas/metabolismo , Humanos , Insulina/sangue , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/epidemiologia , Obesidade/diagnóstico , Obesidade/epidemiologia , Obesidade/metabolismo , Sobrepeso/diagnóstico , Sobrepeso/epidemiologia , Sobrepeso/metabolismo , Serviços de Saúde Escolar/estatística & dados numéricos , Taiwan/epidemiologia
2.
J Diabetes Res ; 2021: 8822702, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33490287

RESUMO

Aims: The current study aims to explore if a family history of diabetes can influence the efficiency of lifestyle intervention on insulin secretion and study the insulin resistance in Chinese men and women with metabolic syndrome in a cohort with a 2-year follow-up. Methods: 151 individuals (90 individuals did not have a family history of diabetes (DMFH (-)) and 61 with a family history of diabetes (DMFH (+)) with metabolic syndrome participated in the lifestyle intervention program at baseline and finished with 1-year follow-up. 124 individuals have two-year follow-up data. A family history of diabetes was ascertained by self-report. Lifestyle interventions were individual sessions on lifestyle changes. Results: During the 1-year follow-up, Ln Insulinogenic index (Δbaseline-1year = 0.29 ± 0.65, P = 0.001) and 30-min glucose (Δbaseline-1year = -0.41 ± 1.71, P = 0.024) changed significantly in the DMFH(-) group; in the DMFH(+) group, Ln ISIm (Δbaseline-1year = -0.22 ± 0.60, P = 0.022) and 30-min glucose (Δbaseline-1year = 0.53 ± 1.89, P = 0.032) changed significantly, and there was no significant change of other parameters. The change of 30 min glucose during a 1-year intervention has shown a significant difference between the two groups (P = 0.002). During the 2 years intervention, Ln Insulinogenic index changed significantly in the DMFH(-) group (Δbaseline-1year = 0.33 ± 0.66, P < 0.001 and Δbaseline-2year = 0.43 ± 1.17, P = 0.034). Fasting insulin (Δbaseline-2year = 2.95 ± 8.69, P = 0.034), 2 h insulin (Δbaseline-2year = 23.75 ± 44.89, P = 0.002), Ln HOMA-B (Δbaseline-2year = 0.43 ± 1.02, P = 0.009), Ln HOMA-IR (Δbaseline-2year = 0.53 ± 1.04, P = 0.002), Ln ISIm (Δbaseline-2year = 0.52 ± 0.95, P = 0.004), and Ln Insulinogenic index (Δbaseline-2year = 0.66 ± 1.18, P = 0.047) changed significantly after 2 years of intervention, compared to the baseline in the DMFH(+) group. The change of Ln ISIm (P = 0.023), fasting (P = 0.030), and 2 h insulin (P = 0.007) during the 2-year intervention has shown a significant difference between the two groups. Family history of diabetes was related with a 0.500 unit increase in 2-year ISIm (P = 0.020) modified by lifestyle intervention adjusted for age, baseline BMI, sex, and baseline waist circumference and a 0.476 unit increase in 2-year ISIm (P = 0.027) with extra adjustment for weight change. Conclusions: Patients with a family history of diabetes benefit more from lifestyle intervention in regard to insulin resistance than those without a family history of diabetes adjusting for age, baseline BMI, sex, baseline waist circumference, and weight change.


Assuntos
Diabetes Mellitus Tipo 2/prevenção & controle , Insulina/metabolismo , Anamnese , Síndrome Metabólica/terapia , Comportamento de Redução do Risco , Adulto , Idoso , China/epidemiologia , Feminino , Seguimentos , Humanos , Resistência à Insulina/fisiologia , Secreção de Insulina/fisiologia , Estilo de Vida , Masculino , Anamnese/estatística & dados numéricos , Síndrome Metabólica/etnologia , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Resultado do Tratamento
3.
Nat Commun ; 12(1): 674, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514698

RESUMO

Transcriptionally mature and immature ß-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in ß-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH ß-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH ß-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the ß-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in ß-cell maturity, might be important for the maintenance of islet function.


Assuntos
Secreção de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Técnicas de Introdução de Genes , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Fatores de Transcrição Maf Maior/genética , Fatores de Transcrição Maf Maior/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Cultura Primária de Células , Transativadores/genética , Transativadores/metabolismo
4.
Metabolism ; 114: 154414, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33129839

RESUMO

AIMS/HYPOTHESIS: Type 2 diabetes (T2D) is characterized by a progressive loss of beta-cell function, and the "disappearance" of beta-cells in T2D may also be caused by the process of beta -cell dedifferentiation. Since noradrenergic innervation inhibits insulin secretion and density of noradrenergic fibers is increased in type 2 diabetes mouse models, we aimed to study the relation between islet innervation, dedifferentiation and beta-cell function in humans. METHODS: Using immunohistochemistry and electron microscopy, we analyzed pancreata from organ donors and from patients undergoing pancreatic surgery. In the latter, a pre-surgical detailed metabolic characterization by oral glucose tolerance test (OGTT) and hyperglycemic clamp was performed before surgery, thus obtaining in vivo functional parameters of beta-cell function and insulin secretion. RESULTS: The islets of diabetic subjects were 3 times more innervated than controls (0.91 ±â€¯0.21 vs 0.32 ±â€¯0.10, n.fibers/islet; p = 0.01), and directly correlated with the dedifferentiation score (r = 0.39; p = 0.03). In vivo functional parameters of insulin secretion, assessed by hyperglycemic clamp, negatively correlated with the increase in fibers [beta-cell Glucose Sensitivity (r = -0.84; p = 0.01), incremental second-phase insulin secretion (r = -0.84, p = 0.03) and arginine-stimulated insulin secretion (r = -0.76, p = 0.04)]. Moreover, we observed a progressive increase in fibers, paralleling worsening glucose tolerance (from NGT through IGT to T2D). CONCLUSIONS/INTERPRETATION: Noradrenergic fibers are significantly increased in the islets of diabetic subjects and this positively correlates with beta-cell dedifferentiation score. The correlation between in vivo insulin secretion parameters and the density of pancreatic noradrenergic fibers suggests a significant involvement of these fibers in the pathogenesis of the disease, and indirectly, in the islet dedifferentiation process.


Assuntos
Neurônios Adrenérgicos/fisiologia , Desdiferenciação Celular/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Glibureto/metabolismo , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Fibras Nervosas/fisiologia , Idoso , Glicemia/metabolismo , Feminino , Intolerância à Glucose/metabolismo , Humanos , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Pessoa de Meia-Idade
5.
Medicine (Baltimore) ; 99(43): e22215, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120730

RESUMO

The Increasing prevalence of type 2 diabetes mellitus (T2DM) has been observed in younger adults. Insulin resistance [IR], decreased first-, second-phase insulin secretion, and glucose effectiveness (GE) (IR, first phase insulin secretion [FPIS], second phase insulin secretion [SPIS], and GE), denoted as diabetes factors (DF), are core for developing T2DM. A body of evidence has shown that inflammation contributes to the development of diabetes. In the present study, our goals were first, evaluate the relationships between white blood cell (WBC) count and, second, examine the relative tightness between the 4 DFs to WBC count. Thus, the pathophysiology of T2DM in Chinese young men could be more understood.21112 non-obese males between 18 to 27 years old were recruited (mean age: 24.3 ±â€Š0.017), including 1745 subjects with metabolic syndrome. DFs were calculated by the published equations by our groups as follows:The association between DFs and WBC count was analyzed using a simple correlation. The r-values of the simple correlation are regarded as the tightness of the relationships.Higher WBC, FPIS, SPIS, IR, age, BMI, blood pressure, FPG, TG, Cholesterol, low-density lipoprotein cholesterol and lower HDL-C and GE were observed in subjects with metabolic syndrome. A similar trend was seen across the quartiles of WBC levels. Among the 4 DFs, GE has the highest r-value (r = -0.093, P < .001), followed by IR (r = 0.067, P < .001), SPIS (r = 0.029, P < .001) and FPIS (r = 0.027, P < .001).Elevated WBC count is significantly associated with all the 4 DFs and the relative order of the tightness, from the highest to the lowest, are GE, IR, SPIS, and FPIS in Chinese young men.


Assuntos
Glicemia/análise , Resistência à Insulina/fisiologia , Secreção de Insulina/fisiologia , Contagem de Leucócitos , Síndrome Metabólica/sangue , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático , Pressão Sanguínea , Índice de Massa Corporal , Colesterol/sangue , HDL-Colesterol , LDL-Colesterol , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Jejum , Humanos , Masculino , Síndrome Metabólica/fisiopatologia , Taiwan , Adulto Jovem
6.
Med Sci (Paris) ; 36(10): 879-885, 2020 Oct.
Artigo em Francês | MEDLINE | ID: mdl-33026330

RESUMO

Pancreatic islet transplantation is a valid cure for selected type-1 diabetic patients. It offers a minimally invasive ß-cell replacement approach and has proven its capacity to significantly enhance patients quality of life. However, these insulin-secreting mini-organs suffer from the loss of intrinsic vascularization and extra-cellular matrix occurring during isolation, resulting in hypoxic stress and necrosis. In addition, they have to face inflammatory and immune destruction once transplanted in the liver. Organoid generation represents a strategy to overcome these obstacles by allowing size and shape control as well as composition. It does offer the possibility to add supporting cells such as endothelial cells, in order to facilitate revascularization or cells releasing anti-inflammatory and/or immunomodulatory factors. This review describes the limitations of pancreatic islet transplantation and details the benefits offered by organoids as a cornerstone toward the generation of a bioartificial pancreas.


Assuntos
Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Organoides/metabolismo , Pâncreas Artificial , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/terapia , Humanos , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/citologia , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Transplante das Ilhotas Pancreáticas/métodos , Organoides/citologia , Pâncreas Artificial/provisão & distribução , Técnicas de Cultura de Tecidos/métodos
7.
Am J Physiol Regul Integr Comp Physiol ; 319(4): R485-R496, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877242

RESUMO

Maternal low-protein diet (LP) throughout gestation affects pancreatic ß-cell fraction of the offspring at birth, thus increasing their susceptibility to metabolic dysfunction and type 2 diabetes in adulthood. The present study sought to strictly examine the effects of LP during the last week of gestation (LP12.5) alone as a developmental window for ß-cell programming and metabolic dysfunction in adulthood. Islet morphology analysis revealed normal ß-cell fraction in LP12.5 newborns. Normal glucose tolerance was observed in 6- to 8-wk-old male and female LP12.5 offspring. However, male LP12.5 offspring displayed glucose intolerance and reduced insulin sensitivity associated with ß-cell dysfunction with aging. High-fat diet exposure of metabolically normal 12-wk-old male LP12.5 induced glucose intolerance due to increased body weight, insulin resistance, and insufficient ß-cell mass adaptation despite higher insulin secretion. Assessment of epigenetic mechanisms through microRNAs (miRs) by a real-time PCR-based microarray in islets revealed elevation in miRs that regulate insulin secretion (miRs 342, 143), insulin resistance (miR143), and obesity (miR219). In the islets, overexpression of miR143 reduced insulin secretion in response to glucose. In contrast to the model of LP exposure throughout pregnancy, islet protein levels of mTOR and pancreatic and duodenal homeobox 1 were normal in LP12.5 islets. Collectively, these data suggest that LP diet during the last week of pregnancy is critical and sufficient to induce specific and distinct developmental programming effects of tissues that control glucose homeostasis, thus causing permanent changes in specific set of microRNAs that may contribute to the overall vulnerability of the offspring to obesity, insulin resistance, and type 2 diabetes.


Assuntos
Dieta Hiperlipídica , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Dieta com Restrição de Proteínas , Feminino , Teste de Tolerância a Glucose , Secreção de Insulina/fisiologia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Gravidez
8.
Life Sci ; 259: 118268, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32800830

RESUMO

AIM: Cadmium is a persistent ubiquitous environmental toxicant that elicits several biological defects on delicate body organs. Growing evidence suggests that cadmium (Cd) may perturb signaling pathways to induce oxidative pancreatitis. Thus, we explored whether hesperidin, a flavonone, could mitigate Cd-induced oxidative stress-mediated inflammation and pancreatitis in Wistar rats. MAIN METHODS: Forty (40) rats randomly assigned to 5 groups (n = 8) were administered normal saline or hesperidin (Hsp) followed by Cd intoxication for 28 days. KEY FINDINGS: Cadmium accumulated in the pancreas of rats, and markedly decreased insulin, pancreatic superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities and glutathione (GSH) level. Cadmium considerably increased malondialdehyde (MDA), serum lipase and amylase activities. Cadmium induced pancreatic pro-inflammation via over-expression of inducible nitric oxide synthase (iNOS), nuclear factor-ĸB (NF-κB), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), along with histopathological alterations. Hesperidin prominently decreased serum amylase and lipase activities, and markedly increased insulin level, pancreatic antioxidant defense mechanism, whereas iNOS, NF-κB, IL-6 and TNF-α levels significantly decreased. Changes in histology confirmed our biochemical findings. SIGNIFICANCE: Our findings suggest that Cd induced pancreatitis via pro-inflammation and oxidative stress; Hsp, thus, protects against Cd-induced pancreatitis via attenuation of oxidative stress and proinflammatory responses in pancreas.


Assuntos
Hesperidina/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Cádmio/toxicidade , Catalase/metabolismo , Glutationa/metabolismo , Hesperidina/metabolismo , Inflamação/metabolismo , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Secreção de Insulina/fisiologia , Masculino , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pancreatite/metabolismo , Substâncias Protetoras , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
9.
Metabolism ; 111: 154335, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32795559

RESUMO

OBJECTIVE: Systemic levels of up-regulated IL-1ß and IL-1 receptors promote the pathogenesis of inflammation-associated diabetes. IL-1 receptor antagonist (IL-Ra) has shown slightly elevated beta cell function in patients with type 2 diabetes without significant improvement of hyperglycaemia. We investigated whether miR-153, an IL-1ß responsive miRNA, could mimic IL-1ß effects and whether its interruption would improve blood glucose control then offer an assistant curative approach to inflammation-associated diabetes. MATERIALS/METHODS: Antago-miR-153 and Ago-miR-153 were injected into the abdominal aorta of leptin receptor-mutant db/db mice and C57BL/6 J mice, respectively. Blood glucose levels, glucose tolerance tests, insulin tolerance tests and insulin levels were regularly checked. Proteomic profiling combined with unbiased bioinformatics analysis, as well as experimental techniques, were utilized to identify target genes of miR-153. Anti-miR-153 and plasmid-based recovery assays were also performed using primary mouse islets and beta cell lines. RESULTS: The miR-153 expression level was increased in IL-1ß-treated beta cells and primary islets from the diabetic rodents. Pancreas overexpression of miR-153 caused glucose intolerance in C57BL/6 J mice but no alterations in body weight or insulin sensitivity. The inhibition of miR-153 temporarily reduced hyperglycaemia of db/db mice due to enhanced insulin secretion. Antago-miR-153 treatment ameliorated glucose intolerance in db/db mice during our observation period but did not improve insulin sensitivity. Mechanistically, miR-153 targeted three members of SNAREs to disturb insulin granule docking, thereby decreasing basal insulin secretion. Overexpression of anti-miR-153 or SNARE rescued the IL-1ß-induced basal insulin secretion defect. Furthermore, miR-153 targeted beta cell-specific transcriptional factors and survival molecules to inhibit insulin biosynthesis and cell viability. CONCLUSIONS: The IL-1ß-responsive miR-153 targets SNAREs, beta cell specific TFs and other key factors to eventually causes beta cell failure. Inhibiting miR-153 with Antago-miR-153 prevents hyperglycaemia in db/db mice, indicating that miR-153 may be a promising therapeutic target for the treatment of inflammation-associated diabetes.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Inflamação/metabolismo , Células Secretoras de Insulina/metabolismo , Interleucina-1beta/metabolismo , MicroRNAs/metabolismo , Animais , Glicemia/metabolismo , Linhagem Celular , Glucose/metabolismo , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose/métodos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Secreção de Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos Wistar , Receptores para Leptina/metabolismo
10.
Am J Physiol Endocrinol Metab ; 319(2): E410-E426, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32663101

RESUMO

Diabetes is a chronic, progressive disease that calls for longitudinal data and analysis. We introduce a longitudinal mathematical model that is capable of representing the metabolic state of an individual at any point in time during their progression from normal glucose tolerance to type 2 diabetes (T2D) over a period of years. As an application of the model, we account for the diversity of pathways typically followed, focusing on two extreme alternatives, one that goes through impaired fasting glucose (IFG) first and one that goes through impaired glucose tolerance (IGT) first. These two pathways are widely recognized to stem from distinct metabolic abnormalities in hepatic glucose production and peripheral glucose uptake, respectively. We confirm this but go beyond to show that IFG and IGT lie on a continuum ranging from high hepatic insulin resistance and low peripheral insulin resistance to low hepatic resistance and high peripheral resistance. We show that IFG generally incurs IGT and IGT generally incurs IFG on the way to T2D, highlighting the difference between innate and acquired defects and the need to assess patients early to determine their underlying primary impairment and appropriately target therapy. We also consider other mechanisms, showing that IFG can result from impaired insulin secretion, that non-insulin-dependent glucose uptake can also mediate or interact with these pathways, and that impaired incretin signaling can accelerate T2D progression. We consider whether hyperinsulinemia can cause insulin resistance in addition to being a response to it and suggest that this is a minor effect.


Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etiologia , Progressão da Doença , Jejum , Glucose/biossíntese , Intolerância à Glucose , Teste de Tolerância a Glucose , Humanos , Hiperinsulinismo/fisiopatologia , Incretinas/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/fisiologia , Fígado/metabolismo , Modelos Teóricos , Transdução de Sinais/fisiologia
11.
Am J Physiol Endocrinol Metab ; 319(2): E338-E344, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32574111

RESUMO

Obesity is associated with dyslipidemia and subclinical inflammation that promotes metabolic disturbances including insulin resistance and pancreatic ß-cell dysfunction. The nuclear protein, transcriptional regulator 1 (NUPR1) responds to cellular stresses and features tissue protective properties. To characterize the role of NUPR1 in endocrine pancreatic islets during inflammatory stress, we generated transgenic mice with ß-cell-specific Nupr1 overexpression (ßNUPR1). Under normal conditions, ßNUPR1 mice did not differ from wild type (WT) littermates and display normal glucose homeostasis and ß-cell mass. For induction of inflammatory conditions, mice were treated with multiple low-dose streptozotocin (mld-STZ) and/or fed a high-fat diet (HFD). All treatments significantly worsened glycaemia in WT mice, while ßNUPR1 mice substantially preserved insulin secretion and glucose tolerance. HFD increased ß-cell mass in all animals, with ßNUPR1 mice tending to show higher values. The improved outcome of ßNUPR1 mice was accompanied by decreased NF-κB activation and lymphocyte infiltration in response to mld-STZ. In vitro, isolated ßNUPR1 islets preserved insulin secretion and content with insignificantly low apoptosis during culture stress and IL-1ß exposure. These findings suggest that NUPR1 plays a vital role in the protection of ß-cells from apoptosis, related degradation of insulin storages and subsequent secretion during inflammatory and obesity-related tissue stress.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Dieta Hiperlipídica/efeitos adversos , Inflamação/fisiopatologia , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/fisiologia , Proteínas de Neoplasias/fisiologia , Estreptozocina/administração & dosagem , Animais , Apoptose/fisiologia , Glicemia/análise , Células Cultivadas , Proteínas de Ligação a DNA/genética , Feminino , Expressão Gênica , Homeostase , Inflamação/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Fatores Sexuais
12.
Life Sci ; 255: 117810, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32473248

RESUMO

AIMS: The aim of the present study was to clarify if in utero exposure to DEX would affect the development of different types of pancreatic endocrine cells during postnatal life. MAIN METHODS: We investigated morphological and transcriptional features of both pancreatic ß- and α-cell populations within the pancreatic islets during the early postnatal life of rats born to mothers treated with DEX (0.1 mg/kg) from day 14 to 19 of pregnancy. Untreated pregnant Wistar rats of the same age (12-week-old) were used as control (CTL). Pups were euthanized on the 1st, 3rd and 21st (PND1, PND3 and PND21, respectively) days of life, regardless of sex. Serum insulin and glucagon levels were also evaluated. KEY FINDINGS: Rats born to DEX-treated mothers exhibited increased pancreatic α-cell mass, circulating glucagon levels and Gcg, Pax6, MafB and Nkx2.2 expression. Rats born to DEX-treated mothers also presented a rise in serum insulin levels on the PND3 that was paralleled by reduced ß-cell mass. Such increase in serum insulin levels, instead, was associated with increased expression of genes associated to insulin secretion such as Gck and Slc2a2. SIGNIFICANCE: Altogether, the present data reveals yet unknown changes in endocrine pancreas during early postnatal life of rats exposed to DEX in utero. Such data may contribute to the understanding of the metabolic features of rats born to DEX-treated mothers.


Assuntos
Dexametasona/toxicidade , Células Secretoras de Glucagon/efeitos dos fármacos , Glucocorticoides/toxicidade , Células Secretoras de Insulina/efeitos dos fármacos , Animais , Dexametasona/administração & dosagem , Feminino , Regulação da Expressão Gênica , Glucagon/sangue , Células Secretoras de Glucagon/citologia , Glucocorticoides/administração & dosagem , Insulina/sangue , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/citologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar
13.
Curr Opin Endocrinol Diabetes Obes ; 27(3): 140-145, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32250974

RESUMO

PURPOSE OF REVIEW: Impairment of glucose metabolism is commonly encountered in Cushing's syndrome. It is the source of significant morbidity and mortality even after successful treatment of Cushing's. This review is to understand the recent advances in understanding the pathophysiology of diabetes mellitus from excess cortisol. RECENT FINDINGS: In-vitro studies have led to significant advancement in understanding the molecular effects of cortisol on glucose metabolism. Some of these findings have been translated with human data. There is marked reduction in insulin action and glucose disposal with a concomitant, insufficient increase in insulin secretion. Cortisol has a varied effect on adipose tissue, with increased lipolysis in subcutaneous adipose tissue in the extremities, and increased lipogenesis in visceral and subcutaneous truncal adipose tissue. SUMMARY: Cushing's syndrome results in marked impairment in insulin action and glucose disposal resulting in hyperglycemia. Further studies are required to understand the effect on incretin secretion and action, gastric emptying, and its varied effect on adipose tissue.


Assuntos
Síndrome de Cushing/metabolismo , Glucose/metabolismo , Tecido Adiposo/metabolismo , Síndrome de Cushing/fisiopatologia , Diabetes Mellitus/metabolismo , Humanos , Hidrocortisona/metabolismo , Insulina/metabolismo , Secreção de Insulina/fisiologia , Gordura Subcutânea/metabolismo
14.
Sci Rep ; 10(1): 5198, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32251344

RESUMO

Sialidase cleaves sialic acid residues from a sialoglycoconjugate: oligosaccharides, glycolipids and glycoproteins that contain sialic acid. Histochemical imaging of the mouse pancreas using a benzothiazolylphenol-based sialic acid derivative (BTP3-Neu5Ac), a highly sensitive histochemical imaging probe used to assess sialidase activity, showed that pancreatic islets have intense sialidase activity. The sialidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA) remarkably enhances glutamate release from hippocampal neurons. Since there are many similar processes between synaptic vesicle exocytosis and secretory granule exocytosis, we investigated the effect of DANA on insulin release from ß-cells. Insulin release was induced in INS-1D cells by treatment with 8.3 mM glucose, and the release was enhanced by treatment with DANA. In a mouse intraperitoneal glucose tolerance test, the increase in serum insulin levels was enhanced by intravenous injection with DANA. However, under fasting conditions, insulin release was not enhanced by treatment with DANA. Calcium oscillations induced by 8.3 mM glucose treatment of INS-1D cells were not affected by DANA. Blood insulin levels in sialidase isozyme Neu3-deficient mice were significantly higher than those in WT mice under ad libitum feeding conditions, but the levels were not different under fasting conditions. These results indicate that DANA is a glucose-dependent potentiator of insulin secretion. The sialidase inhibitor may be useful for anti-diabetic treatment with a low risk of hypoglycemia.


Assuntos
Glucose/fisiologia , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Ácido N-Acetilneuramínico/análogos & derivados , Neuraminidase/antagonistas & inibidores , Animais , Sinalização do Cálcio/efeitos dos fármacos , Corantes/análise , Avaliação Pré-Clínica de Medicamentos , Jejum/sangue , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacologia , Injeções Intravenosas , Insulina/sangue , Secreção de Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácido N-Acetilneuramínico/farmacologia , Neuraminidase/fisiologia
15.
Rev. cuba. endocrinol ; 31(1): e205, ene.-abr. 2020. tab
Artigo em Espanhol | LILACS, CUMED | ID: biblio-1126452

RESUMO

RESUMEN Introducción: La prueba de tolerancia de comida mixta es considerada la prueba de oro para la medición de la producción de insulina endógena en pacientes con diabetes tipo 1. Objetivo: Determinar la utilidad de la prueba de tolerancia de comida mixta con Nutrial I para evaluar la función de las células ß en diabéticos tipo 1 de diagnóstico reciente y la relación de esa función con algunas características clínicas y bioquímicas. Métodos: Se estudiaron variables bioquímicas como la glucemia, hemoglobina glucosilada (HbA1c), péptido C y fracciones lipídicas. La prueba de tolerancia de comida mixta con Nutrial I se aplicó a 18 sujetos con diabetes tipo 1 de diagnóstico reciente y a 8 voluntarios con edades comprendidas entre 19 y 35 años. El consumo del suplemento Nutrial I se calculó según el peso del paciente. Se obtuvieron muestras para glucemia y péptido C a los -10, 0, 30, 60, 90 y 120 minutos. Resultados: Se observaron concentraciones elevadas de glucemia y disminuidas de péptido C durante la prueba de tolerancia de comida mixta en los diabéticos tipo 1 de diagnóstico reciente, en comparación con los voluntarios, así como, diferencias en las áreas bajo la curva de péptido C (AUC-pc) (p= 0,001). En los diabéticos tipo 1 de diagnóstico reciente se evidenció una correlación negativa entre el AUC-pc con los niveles de glucemia en ayunas (r= -0,747; p ( 0,0001) y la HbA1c (r= -0,535; p= 0,022). Por el contrario, se encontró una correlación positiva entre el AUC-pc y el péptido C en ayunas (r= 0,722; p= 0,001). El AUC-pc después de la prueba de tolerancia de comida mixta es mayor en los sujetos con glucemia en ayunas si GA < 7 mmol/L con respecto a los sujetos con glucemia en ayunas ( 7 mmol/L (p= 0,012). Conclusiones: El empleo del Nutrial I en la prueba de tolerancia de comida mixta fue útil en la evaluación de la función de las células β en diabéticos tipo 1 de diagnóstico reciente. Los valores bajos de glucemia en ayunas durante esta prueba son marcadores indirectos de una función residual de células ( más conservada en los diabéticos tipo 1 de diagnóstico reciente(AU)


ABSTRACT Introduction: The tolerance test of mixed food is considered the gold standard for the measurement of endogenous insulin production in patients with diabetes type 1. Objective: To determine the usefulness of the tolerance test of mixed food with Nutrial I to assess the ß-cells function in patients with diabetes type 1 of recent diagnosis and the relation of this function with some clinical and biochemical characteristics. Methods: There were studied biochemical variables as the blood glucose, glycosylated haemoglobin (HbA1c), C-peptide and lipid fractions. The tolerance test of mixed food with Nutrial I was applied to 18 individuals with diabetes type 1 of recent diagnosis and in 8 volunteers aged between 19 and 35 years old. The consumption of Nutrial I supplement was calculated according to the weight of the patient. Samples were obtained for blood glucose and C-peptide at -10, 0, 30, 60, 90 and 120 minutes. Results: There were observed high concentrations of glycemia and decreased amounts of C-peptide during the tolerance test of mixed food in recently diagnosed type 1 diabetics in comparison with the volunteers, as well as differences in areas under the curve of C-peptide (AUC-pc) (p= 0.001). In the recently diagnosed type 1 diabetics was evident a negative correlation between the AUC-pc with fasting plasma glucose levels (r= -0,747; p(0.0001) and HbA1c (r= -0,535; p= 0.022). On the contrary, it was found a positive correlation between the AUC-pc and fasting C-peptide (r = 0.722; p = 0.001). The AUC-pc after the tolerance test of mixed food was greater in subjects with fasting blood glucose < 7 mmol/L with respect to the subjects with fasting blood glucose ( 7 mmol/L (p= 0.012). Conclusions: The use of Nutrial I in the tolerance test of mixed food was useful in the assessment of the role of the β-cells in patients with recently diagnosed diabetes type 1. Low values of fasting blood glucose during this test are indirect markers of a residual function of (cells more preserved in type 1 diabetics of recent diagnosis(AU)


Assuntos
Humanos , Glicemia/fisiologia , Diabetes Mellitus Tipo 1/diagnóstico , Secreção de Insulina/fisiologia , Epidemiologia Descritiva , Estudos Transversais
16.
Diabetes ; 69(4): 499-507, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32198193

RESUMO

In type 2 diabetes, ß-cells endure various forms of cellular stress, including oxidative stress and endoplasmic reticulum stress, secondary to increased demand for insulin production and extracellular perturbations, including hyperglycemia. Chronic exposure to stress causes impaired insulin secretion, apoptosis, and loss of cell identity, and a combination of these processes leads to ß-cell failure and severe hyperglycemia. Therefore, a better understanding of the molecular mechanisms underlying stress responses in ß-cells promises to reveal new therapeutic opportunities for type 2 diabetes. In this perspective, we discuss posttranscriptional control of gene expression as a critical, but underappreciated, layer of regulation with broad importance during stress responses. Specifically, regulation of mRNA translation occurs pervasively during stress to activate gene expression programs; however, the convenience of RNA sequencing has caused translational regulation to be overlooked compared with transcriptional controls. We highlight the role of RNA binding proteins in shaping selective translational regulation during stress and the mechanisms underlying this level of regulation. A growing body of evidence indicates that RNA binding proteins control an array of processes in ß-cells, including the synthesis and secretion of insulin. Therefore, systematic evaluations of translational regulation and the upstream factors shaping this level of regulation are critical areas of investigation to expand our understanding of ß-cell failure in type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Células Secretoras de Insulina/metabolismo , Estresse Oxidativo/fisiologia , Processamento Pós-Transcricional do RNA/fisiologia , Proteínas de Ligação a RNA/metabolismo , Animais , Apoptose/fisiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Regulação da Expressão Gênica , Humanos , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/patologia , Processamento de Proteína Pós-Traducional/fisiologia , Proteínas de Ligação a RNA/genética
17.
Sci Rep ; 10(1): 5629, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221326

RESUMO

Gpr27 is a highly conserved, orphan G protein coupled receptor (GPCR) previously implicated in pancreatic beta cell insulin transcription and glucose-stimulated insulin secretion in vitro. Here, we characterize a whole-body mouse knockout of Gpr27. Gpr27 knockout mice were born at expected Mendelian ratios and exhibited no gross abnormalities. Insulin and Pdx1 mRNA in Gpr27 knockout islets were reduced by 30%, but this did not translate to a reduction in islet insulin content or beta cell mass. Gpr27 knockout mice exhibited slightly worsened glucose tolerance with lower plasma insulin levels while maintaining similar insulin tolerance. Unexpectedly, Gpr27 deletion reduced expression of Eif4e3, a neighboring gene, likely by deleting transcription start sites on the anti-sense strand of the Gpr27 coding exon. Our data confirm that loss of Gpr27 reduces insulin mRNA in vivo but has only minor effects on glucose tolerance.


Assuntos
Diabetes Mellitus/metabolismo , Insulina/metabolismo , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Glucose/metabolismo , Secreção de Insulina/fisiologia , Células Secretoras de Insulina , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Knockout
18.
Medicine (Baltimore) ; 99(12): e19562, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32195965

RESUMO

It has been established that prediabetes can causes significant comorbidities, particularly in the elderly. The deterioration of glucose metabolism are generally considered to be results of the impairment of the 4 factors: first, second insulin secretion (FPIS, SPIS, respectively), glucose effectiveness (GE), and insulin resistance. In this study, we enrolled older women to investigate their relationships with prediabetes.Five thousand four hundred eighty-two nonobese, nondiabetic women were included. They were divided into normal glucose tolerance and prediabetes groups. Receiver operating characteristic curve was performed to investigate the effects on whether to have prediabetes for each factors. Two models were built: Model 1: FPIS + SPIS, and Model 2: model 1 + GE. The area under the receiver operating characteristic (aROC) curve was used to determine the predictive power of these models.The aROC curve of GE was significantly higher than the diagonal line followed by SPIS and FPIS accordingly. The aROC curve of Model 1 (0.611) was not different from GE. However, Model 2 improved significantly up to 0.663. Based on this model, an equation was built (-0.003 × GE - 212.6 × SPIS - 17.9 × insulin resistance + 4.8). If the calculated value is equal or higher than 0 (≥0), then the subject has higher chance to have prediabetes (sensitivity = 0.607, specificity = 0.635).Among the 4 factors, GE is the most important contributor for prediabetes in older women. By building a model composed of FPIS, SPIS, and GE, the aROC curve increased significantly. The equation built from this model could predict prediabetes precisely.


Assuntos
Grupo com Ancestrais do Continente Asiático/etnologia , Glucose/metabolismo , Resistência à Insulina/fisiologia , Secreção de Insulina/fisiologia , Estado Pré-Diabético/epidemiologia , Idoso , Índice de Massa Corporal , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Teste de Tolerância a Glucose/métodos , Humanos , Pessoa de Meia-Idade , Estado Pré-Diabético/fisiopatologia , Prevalência , Sensibilidade e Especificidade , Taiwan/epidemiologia
19.
Diabetes ; 69(4): 634-646, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32005704

RESUMO

The host environment is a crucial factor for considering the transplant of stem cell-derived immature pancreatic cells in patients with type 1 diabetes. Here, we investigated the effect of insulin (INS)-deficient diabetes on the fate of immature pancreatic endocrine cell grafts and the underlying mechanisms. Human induced pluripotent stem cell-derived pancreatic endocrine progenitor cells (EPCs), which contained a high proportion of chromogranin A+ NK6 homeobox 1+ cells and very few INS+ cells, were used. When the EPCs were implanted under the kidney capsule in immunodeficient mice, INS-deficient diabetes accelerated increase in plasma human C-peptide, a marker of graft-derived INS secretion. The acceleration was suppressed by INS infusion but not affected by partial attenuation of hyperglycemia by dapagliflozin, an INS-independent glucose-lowering agent. Immunohistochemical analyses indicated that the grafts from diabetic mice contained more endocrine cells including proliferative INS-producing cells compared with that from nondiabetic mice, despite no difference in whole graft mass between the two groups. These data suggest that INS-deficient diabetes upregulates the INS-secreting capacity of EPC grafts by increasing the number of endocrine cells including INS-producing cells without changing the graft mass. These findings provide useful insights into postoperative diabetic care for cell therapy using stem cell-derived pancreatic cells.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Pâncreas/metabolismo , Animais , Imuno-Histoquímica , Camundongos
20.
Endocrinology ; 161(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32065829

RESUMO

ß-Cell dysfunction in type 2 diabetes (T2D) is associated with loss of cellular identity and mis-expression of alternative islet hormones, including glucagon. The molecular basis for these cellular changes has been attributed to dysregulation of core ß-cell transcription factors, which regulate ß-cell identity through activating and repressive mechanisms. The TLE1 gene lies near a T2D susceptibility locus and, recently, the glucagon repressive actions of this transcriptional coregulator have been demonstrated in vitro. We investigated whether TLE1 expression is disrupted in human T2D, and whether this is associated with increased islet glucagon-expressing cells. Automated image analysis following immunofluorescence in donors with (n = 7) and without (n = 7) T2D revealed that T2D was associated with higher islet α/ß cell ratio (Control: 0.7 ± 0.1 vs T2D: 1.6 ± 0.4; P < .05) and an increased frequency of bihormonal (insulin+/glucagon+) cells (Control: 0.8 ± 0.2% vs T2D: 2.0 ± 0.4%, P < .05). In nondiabetic donors, the majority of TLE1-positive cells were mono-hormonal ß-cells (insulin+/glucagon-: 98.2 ± 0.5%; insulin+/glucagon+: 0.7 ± 0.2%; insulin-/glucagon+: 1.1 ± 0.4%; P < .001). TLE1 expression was reduced in T2D (Control: 36 ± 2.9% vs T2D: 24 ± 2.6%; P < .05). Reduced islet TLE1 expression was inversely correlated with α/ß cell ratio (r = -0.55; P < .05). TLE1 knockdown in EndoC-ßH1 cells was associated with a 2.5-fold increase in glucagon gene mRNA and mis-expression of glucagon in insulin-positive cells. These data support TLE1 as a putative regulator of human ß-cell identity, with dysregulated expression in T2D associated with increased glucagon expression potentially reflecting ß- to α-cell conversion.


Assuntos
Proteínas Correpressoras/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Glucagon/metabolismo , Glucagon/metabolismo , Adulto , Idoso , Diabetes Mellitus Tipo 2/patologia , Feminino , Células Secretoras de Glucagon/patologia , Humanos , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Pessoa de Meia-Idade
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