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1.
Arterioscler Thromb Vasc Biol ; 41(11): 2740-2755, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34615372

RESUMO

Objective: MR (mineralocorticoid receptor) activation associates with increased risk of cardiovascular ischemia while MR inhibition reduces cardiovascular-related mortality and plaque inflammation in mouse atherosclerosis. MR in myeloid cells (My-MR) promotes inflammatory cell infiltration into injured tissues and atherosclerotic plaque inflammation by unclear mechanisms. Here, we examined the role of My-MR in leukocyte trafficking and the impact of sex. Approach and Results: We confirm in vivo that My-MR deletion (My-MR-KO) in ApoE-KO mice decreased plaque size. Flow cytometry revealed fewer plaque macrophages with My-MR-KO. By intravital microscopy, My-MR-KO significantly attenuated monocyte slow-rolling and adhesion to mesenteric vessels and decreased peritoneal infiltration of myeloid cells in response to inflammatory stimuli in male but not female mice. My-MR-KO mice had significantly less PSGL1 (P-selectin glycoprotein ligand 1) mRNA in peritoneal macrophages and surface PSGL1 protein on circulating monocytes in males. In vitro, MR activation with aldosterone significantly increased PSGL1 mRNA only in monocytes from MR-intact males. Similarly, aldosterone induced, and MR antagonist spironolactone inhibited, PSGL1 expression in human U937 monocytes. Mechanistically, aldosterone stimulated MR binding to a predicted MR response element in intron-1 of the PSGL1 gene by ChIP-qPCR. Reporter assays demonstrated that this PSGL1 MR response element is necessary and sufficient for aldosterone-activated, MR-dependent transcriptional activity. Conclusions: These data identify PSGL1 as a My-MR target gene that drives leukocyte trafficking to enhance atherosclerotic plaque inflammation. These novel and sexually dimorphic findings provide insight into increased ischemia risk with MR activation, cardiovascular protection in women, and the role of MR in atherosclerosis and tissue inflammation.


Assuntos
Aorta Torácica/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Adesão Celular , Migração e Rolagem de Leucócitos , Macrófagos Peritoneais/metabolismo , Glicoproteínas de Membrana/metabolismo , Monócitos/metabolismo , Receptores de Mineralocorticoides/metabolismo , Adulto , Animais , Aorta Torácica/patologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Doenças da Aorta/prevenção & controle , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Adesão Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Hipoglicemia/tratamento farmacológico , Hipoglicemia/genética , Hipoglicemia/metabolismo , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Macrófagos Peritoneais/patologia , Masculino , Glicoproteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Monócitos/efeitos dos fármacos , Monócitos/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Mineralocorticoides/efeitos dos fármacos , Receptores de Mineralocorticoides/genética , Fatores Sexuais , Transdução de Sinais , Espironolactona/uso terapêutico , Transcrição Genética , Migração Transendotelial e Transepitelial , Resultado do Tratamento , Células U937 , Adulto Jovem
2.
Nat Commun ; 12(1): 4818, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376687

RESUMO

The enteroendocrine cell (EEC)-derived incretins play a pivotal role in regulating the secretion of glucagon and insulins in mammals. Although glucagon-like and insulin-like hormones have been found across animal phyla, incretin-like EEC-derived hormones have not yet been characterised in invertebrates. Here, we show that the midgut-derived hormone, neuropeptide F (NPF), acts as the sugar-responsive, incretin-like hormone in the fruit fly, Drosophila melanogaster. Secreted NPF is received by NPF receptor in the corpora cardiaca and in insulin-producing cells. NPF-NPFR signalling resulted in the suppression of the glucagon-like hormone production and the enhancement of the insulin-like peptide secretion, eventually promoting lipid anabolism. Similar to the loss of incretin function in mammals, loss of midgut NPF led to significant metabolic dysfunction, accompanied by lipodystrophy, hyperphagia, and hypoglycaemia. These results suggest that enteroendocrine hormones regulate sugar-dependent metabolism through glucagon-like and insulin-like hormones not only in mammals but also in insects.


Assuntos
Drosophila melanogaster/metabolismo , Células Enteroendócrinas/metabolismo , Glucagon/metabolismo , Hormônios/metabolismo , Insulina/metabolismo , Neuropeptídeos/metabolismo , Animais , Animais Geneticamente Modificados , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemia/genética , Hipoglicemia/metabolismo , Incretinas/metabolismo , Secreção de Insulina , Metabolismo dos Lipídeos/genética , Mutação , Neuropeptídeos/genética , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo , Açúcares/metabolismo
3.
Sci Rep ; 11(1): 17057, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34426634

RESUMO

Heat shock proteins contribute to diabetes-induced complications and are affected by glycemic control. Our hypothesis was that hypoglycemia-induced heat shock and related protein changes would be amplified in type 2 diabetes (T2D). This prospective, case-control study enrolled 23 T2D patients and 23 control subjects who underwent hyperinsulinemic-induced hypoglycemia (≤ 2.0 mmol/L (36 mg/dl)) with blood sampling at baseline, at hypoglycemia and after a 24-h post-hypoglycemia follow-up period. Proteomic analysis of heat shock-related and pro-inflammatory proteins was performed. At baseline, MAPKAPK5 (p = 0.02) and UBE2G2 (p = 0.003) were elevated and STUB1 decreased (p = 0.007) in T2D. At hypoglycemia: PPP3CA (p < 0.03) was increased and EPHA2 (p = 0.01) reduced in T2D; by contrast, three proteins were reduced in controls [HSPA1A (p = 0.007), HSPB1 (p < 0.02), SMAD3 (p = 0.005)] while only MAPKAPK5 was elevated (p = 0.02). In the post-hypoglycemia follow-up period, most proteins normalized to baseline by 24-h; however, STIP1 (p = 0.003), UBE2N (p = 0.004) and UBE2L3 (p < 0.04) were decreased in controls at 24-h. No protein differed from baseline at 24-h in T2D. Pro-inflammatory interleukin-6 increased at 4-h post-hypoglycemia in controls and T2D (p < 0.05 and p < 0.003, respectively) and correlated with HSPA1A; anti-inflammatory IL-10 decreased 2-h post-hypoglycemia in T2D only. Other pro-inflammatory proteins, IL-1α, IFN-γ and TNF-α, were unchanged. Heat shock and related proteins differed at baseline between T2D and controls, with an exaggerated response of heat shock and related proteins to hypoglycemia that returned to baseline, though with changes at 24-h in controls alone. An increase in pro-inflammatory IL-6, with a decrease in anti-inflammatory IL-10, suggests that the HSP system is overactivated due to underlying inflammation in T2D.Trial registration: ClinicalTrials.gov NCT03102801.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Resposta ao Choque Térmico , Hipoglicemia/metabolismo , Proteoma/metabolismo , Adulto , Idoso , Feminino , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteoma/genética , Receptor EphA2/genética , Receptor EphA2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
4.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445217

RESUMO

Selenoprotein T (SELENOT, SelT), a thioredoxin-like enzyme, exerts an essential oxidoreductase activity in the endoplasmic reticulum. However, its precise function remains unknown. To gain more understanding of SELENOT function, a conventional global Selenot knockout (KO) mouse model was constructed for the first time using the CRISPR/Cas9 technique. Deletion of SELENOT caused male sterility, reduced size/body weight, lower fed and/or fasting blood glucose levels and lower fasting serum insulin levels, and improved blood lipid profile. Tandem mass tag (TMT) proteomics analysis was conducted to explore the differentially expressed proteins (DEPs) in the liver of male mice, revealing 60 up-regulated and 94 down-regulated DEPs in KO mice. The proteomic results were validated by western blot of three selected DEPs. The elevated expression of Glycogen [starch] synthase, liver (Gys2) is consistent with the hypoglycemic phenotype in KO mice. Furthermore, the bioinformatics analysis showed that Selenot-KO-induced DEPs were mainly related to lipid metabolism, cancer, peroxisome proliferator-activated receptor (PPAR) signaling pathway, complement and coagulation cascades, and protein digestion and absorption. Overall, these findings provide a holistic perspective into SELENOT function and novel insights into the role of SELENOT in glucose and lipid metabolism, and thus, enhance our understanding of SELENOT function.


Assuntos
Regulação da Expressão Gênica , Glucose/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Proteômica , Selenoproteínas , Animais , Glucose/genética , Hipoglicemia/genética , Hipoglicemia/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Selenoproteínas/deficiência , Selenoproteínas/metabolismo , Transdução de Sinais/genética
5.
Front Endocrinol (Lausanne) ; 12: 658304, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248840

RESUMO

Objective: Detailed proteomic analysis in a cohort of patients with differing severity of COVID-19 disease identified biomarkers within the complement and coagulation cascades as biomarkers for disease severity has been reported; however, it is unclear if these proteins differ sufficiently from other conditions to be considered as biomarkers. Methods: A prospective, parallel study in T2D (n = 23) and controls (n = 23). A hyperinsulinemic clamp was performed and normoglycemia induced in T2D [4.5 ± 0.07 mmol/L (81 ± 1.2 mg/dl)] for 1-h, following which blood glucose was decreased to ≤2.0 mmol/L (36 mg/dl). Proteomic analysis for the complement and coagulation cascades were measured using Slow Off-rate Modified Aptamer (SOMA)-scan. Results: Thirty-four proteins were measured. At baseline, 4 of 18 were found to differ in T2D versus controls for platelet degranulation [Neutrophil-activating peptide-2 (p = 0.014), Thrombospondin-1 (p = 0.012), Platelet factor-4 (p = 0.007), and Kininogen-1 (p = 0.05)], whilst 3 of 16 proteins differed for complement and coagulation cascades [Coagulation factor IX (p < 0.05), Kininogen-1 (p = 0.05), and Heparin cofactor-2 (p = 0.007)]; STRING analysis demonstrated the close relationship of these proteins to one another. Induced euglycemia in T2D showed no protein changes versus baseline. At hypoglycemia, however, four proteins changed in controls from baseline [Thrombospondin-1 (p < 0.014), platelet factor-4 (p < 0.01), Platelet basic protein (p < 0.008), and Vitamin K-dependent protein-C (p < 0.00003)], and one protein changed in T2D [Vitamin K-dependent protein-C, (p < 0.0002)]. Conclusion: Seven of 34 proteins suggested to be biomarkers of COVID-19 severity within the platelet degranulation and complement and coagulation cascades differed in T2D versus controls, with further changes occurring at hypoglycemia, suggesting that validation of these biomarkers is critical. It is unclear if these protein changes in T2D may predict worse COVID-19 disease for these patients. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT03102801.


Assuntos
Fatores de Coagulação Sanguínea/metabolismo , COVID-19/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemia/metabolismo , Idoso , Biomarcadores/metabolismo , Coagulação Sanguínea , Estudos de Casos e Controles , Ativação do Complemento , Fator IX/metabolismo , Feminino , Técnica Clamp de Glucose , Cofator II da Heparina/metabolismo , Humanos , Cininogênios/metabolismo , Masculino , Pessoa de Meia-Idade , Peptídeos/metabolismo , Ativação Plaquetária , Fator Plaquetário 4/metabolismo , Estudos Prospectivos , Proteína C/metabolismo , Proteômica , SARS-CoV-2 , Índice de Gravidade de Doença , Trombospondina 1/metabolismo , beta-Tromboglobulina/metabolismo
6.
Front Endocrinol (Lausanne) ; 12: 665134, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248841

RESUMO

Introduction: Neuropilin-1(NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with angiotensin-converting enzyme 2(ACE2). The Renin-Angiotensin System (RAS) is activated in type 2 diabetes (T2D); therefore, the aim of this study was to determine if hypoglycaemia-induced stress in T2D would potentiate serum NRP1(sNRP1) levels, reflecting an increased risk for SARS-CoV-2 infection. Methods: A case-control study of aged-matched T2D (n = 23) and control (n = 23) subjects who underwent a hyperinsulinemic clamp over 1-hour to hypoglycemia(<40mg/dl) with subsequent timecourse of 4-hours and 24-hours. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement determined RAS-related proteins: renin (REN), angiotensinogen (AGT), ACE2, soluble NRP1(sNRP1), NRP1 ligands (Vascular endothelial growth factor, VEGF and Class 3 Semaphorins, SEM3A) and NRP1 proteolytic enzyme (A Disintegrin and Metalloproteinase 9, ADAM9). Results: Baseline RAS overactivity was present with REN elevated and AGT decreased in T2D (p<0.05); ACE2 was unchanged. Baseline sNRP1, VEGF and ADAM9 did not differ between T2D and controls and remained unchanged in response to hypoglycaemia. However, 4-hours post-hypoglycemia, sNRP1, VEGF and ADAM9 were elevated in T2D(p<0.05). SEMA3A was not different at baseline; at hypoglycemia, SEMA3A decreased in controls only. Post-hypoglycemia, SEMA3A levels were higher in T2D versus controls. sNRP1 did not correlate with ACE2, REN or AGT. T2D subjects stratified according to ACE inhibitor (ACEi) therapies showed no difference in sNRP1 levels at either glucose normalization or hypoglycaemia. Conclusion: Hypoglycemia potentiated both plasma sNRP1 level elevation and its ligands VEGF and SEMA3A, likely through an ADAM9-mediated mechanism that was not associated with RAS overactivity or ACEi therapy; however, whether this is protective or promotes increased risk for SARS-CoV-2 infection in T2D is unclear. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT03102801.


Assuntos
Proteínas ADAM/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemia/metabolismo , Proteínas de Membrana/metabolismo , Neuropilina-1/metabolismo , Semaforina-3A/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Idoso , Angiotensinas/metabolismo , COVID-19 , Feminino , Técnica Clamp de Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Proteção , Renina/metabolismo , Fatores de Risco , SARS-CoV-2
7.
Am J Trop Med Hyg ; 105(3): 846-851, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34280148

RESUMO

Low blood glucose concentrations < 5 mmol/L in severely ill children presenting to hospitals in low-income countries are associated with mortality. Adrenal insufficiency with low cortisol levels may contribute to low blood glucose concentrations. Understanding the association between low cortisol and low blood glucose may assist in improving guidelines for management of severely ill children. The study aimed to determine the association between low serum cortisol and low blood glucose in severely ill children. A matched case-control study of children aged 1 month to 15 years was conducted at two tertiary hospitals in Malawi. Cases were children with blood glucose < 5 mmol/L. Two age-matched controls with blood glucose of ≥ 5-15 mmol/L were enrolled per case. Low cortisol was defined as serum cortisol of < 25 µg/dL (690 nmol/L) and adrenal insufficiency as serum cortisol of < 10 µg/dL (276 nmol/L). A total of 54 cases and 108 controls were enrolled with, median age of 2.8 years (interquartile range [IQR]: 1.7-4.4). The median cortisol level was 58.7 µg/dL (IQR: 42.3-61.8) in cases and 40.9 µg/dL (IQR: 33.7-51.2) in controls (P = 0.911). The proportion of low cortisol was 4/54 (7.4%) in cases and 9/108 (8.3%) in controls. Logistic regression shows no association between low cortisol and low blood glucose (adjusted odds ratio: 0.33; 95% confidence interval, 0.04-3.02). Results suggest that there is no association between low cortisol and low blood glucose among severely ill children presenting to hospitals in Malawi. The reason for low blood glucose needs further investigation.


Assuntos
Insuficiência Adrenal/epidemiologia , Glicemia/metabolismo , Estado Terminal , Hidrocortisona/sangue , Hipoglicemia/epidemiologia , Adolescente , Insuficiência Adrenal/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Serviço Hospitalar de Emergência , Feminino , Humanos , Hipoglicemia/sangue , Hipoglicemia/metabolismo , Lactente , Malaui/epidemiologia , Masculino , Índice de Gravidade de Doença , Centros de Atenção Terciária
8.
Eur J Endocrinol ; 185(2): R35-R47, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34048365

RESUMO

The aim of the study is to find possible explanations for vanishing juvenile hypoglycemia in growth hormone receptor deficiency (GHRD) in human patients and animal models. We reviewed parameters of glucose metabolism in distinct age groups into two human cohorts (Israeli and Ecuadorian) of Laron syndrome (LS) patients, a mouse model (Ghr-KO mouse) and provided additional data for a porcine model (GHR-KO pig). Juvenile hypoglycemia is a common symptom of GHRD and vanishes in adulthood. In the Israeli cohort, developing metabolic syndrome is associated with decreasing insulin sensitivity, insulinopenia and glucose intolerance, and increasing glucose levels with age. In the Ecuadorian patients and both animal models, insulin sensitivity is preserved or even enhanced. Alterations in food intake and energy consumption do not explain the differences in glucose levels; neither is the accumulation of body fat associated with negative effects in the Ecuadorian cohort nor in the animal models. A reduced beta-cell mass and resulting insulin secretory capacity is common and leads to glucose intolerance in Ghr-KO mice, while glucose tolerance is preserved in Ecuadorian patients and the GHR-KO pig. In human patients and the GHR-KO pig, a simultaneous occurrence of normoglycemia with the onset of puberty is reported. Reduced gluconeogenesis in GHRD is discussed to cause juvenile hypoglycemia and a counter-regulatory stimulation of gluconeogenesis can be hypothesized. A coherent study assessing endogenous glucose production and beta-cell capacity in the hypoglycemic and normoglycemic age group is needed. This can be performed in GHR-KO pigs, including castrated animals.


Assuntos
Hipoglicemia , Síndrome de Laron , Fatores Etários , Animais , Animais Geneticamente Modificados , Estudos de Coortes , Modelos Animais de Doenças , Equador/epidemiologia , Humanos , Hipoglicemia/epidemiologia , Hipoglicemia/etiologia , Hipoglicemia/metabolismo , Hipoglicemia/patologia , Israel/epidemiologia , Síndrome de Laron/complicações , Síndrome de Laron/epidemiologia , Síndrome de Laron/metabolismo , Síndrome de Laron/patologia , Camundongos , Camundongos Knockout , Receptores da Somatotropina/genética , Transdução de Sinais/fisiologia , Suínos
9.
Nat Commun ; 12(1): 2745, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980856

RESUMO

In mice, time of day strongly influences lethality in response to LPS, with survival greatest at the beginning compared to the end of the light cycle. Here we show that feeding, rather than light, controls time-of-day dependent LPS sensitivity. Mortality following LPS administration is independent of cytokine production and the clock regulator BMAL1 expressed in myeloid cells. In contrast, deletion of BMAL1 in hepatocytes globally disrupts the transcriptional response to the feeding cycle in the liver and results in constitutively high LPS sensitivity. Using RNAseq and functional validation studies we identify hepatic farnesoid X receptor (FXR) signalling as a BMAL1 and feeding-dependent regulator of LPS susceptibility. These results show that hepatocyte-intrinsic BMAL1 and FXR signalling integrate nutritional cues to regulate survival in response to innate immune stimuli. Understanding hepatic molecular programmes operational in response to these cues could identify novel pathways for targeting to enhance endotoxemia resistance.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Comportamento Alimentar/fisiologia , Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Sepse/mortalidade , Fatores de Transcrição ARNTL/genética , Animais , Ritmo Circadiano/genética , Modelos Animais de Doenças , Resistência à Doença , Hepatócitos/metabolismo , Hipoglicemia/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Knockout , Receptores Citoplasmáticos e Nucleares/genética , Sepse/induzido quimicamente , Sepse/genética , Sepse/metabolismo , Transdução de Sinais
11.
Am J Physiol Endocrinol Metab ; 320(5): E891-E897, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33813879

RESUMO

Pancreatic insulin secretion produces an insulin gradient at the liver compared with the rest of the body (approximately 3:1). This physiological distribution is lost when insulin is injected subcutaneously, causing impaired regulation of hepatic glucose production and whole body glucose uptake, as well as arterial hyperinsulinemia. Thus, the hepatoportal insulin gradient is essential to the normal control of glucose metabolism during both fasting and feeding. Insulin can regulate hepatic glucose production and uptake through multiple mechanisms, but its direct effects on the liver are dominant under physiological conditions. Given the complications associated with iatrogenic hyperinsulinemia in patients treated with insulin, insulin designed to preferentially target the liver may have therapeutic advantages.


Assuntos
Glucose/metabolismo , Controle Glicêmico/métodos , Insulina/administração & dosagem , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Vias de Administração de Medicamentos , Gluconeogênese/efeitos dos fármacos , Controle Glicêmico/efeitos adversos , Humanos , Hiperinsulinismo/induzido quimicamente , Hiperinsulinismo/metabolismo , Hipoglicemia/induzido quimicamente , Hipoglicemia/metabolismo , Insulina/efeitos adversos , Sistemas de Infusão de Insulina , Secreção de Insulina/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo
12.
Sci Rep ; 11(1): 9057, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33907279

RESUMO

The contribution of endogenous insulin secretion to glycemic variability (GV) may differ between patients with impaired insulin secretion and those with preserved secretion. Our objective was to determine the linearity of the relationship between fasting C-peptide (CPR) as a marker of endogenous insulin secretion and GV in type 2 diabetes (T2DM), regardless of the type of antidiabetic treatment. We conducted a prospective observational study using continuous glucose monitoring obtained from 284 Japanese outpatients with T2DM with various HbA1c values and antidiabetic treatment. We constructed a prediction curve of base-line CPR versus coefficient of variation (CV) and identified the clinical factors associated with CV using multiple regression analysis. Fasting CPR showed a significant negative log-linear relationship with CV (P < 0.0001), and the latter being strikingly high in the low-CPR group. The multiple regression analysis showed that low CPR was an independent predictor of high CV (P < 0.0001). The significant correlations were sustained in both patients with/without insulin treatment. The contribution of endogenous insulin secretion to GV depends on the extent of insulin secretion impairment. Fasting CPR may represent a useful indicator of GV instability in T2DM.


Assuntos
Biomarcadores/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Hiperglicemia/epidemiologia , Hipoglicemia/epidemiologia , Idoso , Glicemia/análise , Automonitorização da Glicemia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Hemoglobina A Glicada/análise , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hipoglicemia/metabolismo , Hipoglicemia/patologia , Incidência , Secreção de Insulina , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
13.
Nat Commun ; 12(1): 1823, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33758197

RESUMO

The body naturally and continuously secretes sweat for thermoregulation during sedentary and routine activities at rates that can reflect underlying health conditions, including nerve damage, autonomic and metabolic disorders, and chronic stress. However, low secretion rates and evaporation pose challenges for collecting resting thermoregulatory sweat for non-invasive analysis of body physiology. Here we present wearable patches for continuous sweat monitoring at rest, using microfluidics to combat evaporation and enable selective monitoring of secretion rate. We integrate hydrophilic fillers for rapid sweat uptake into the sensing channel, reducing required sweat accumulation time towards real-time measurement. Along with sweat rate sensors, we integrate electrochemical sensors for pH, Cl-, and levodopa monitoring. We demonstrate patch functionality for dynamic sweat analysis related to routine activities, stress events, hypoglycemia-induced sweating, and Parkinson's disease. By enabling sweat analysis compatible with sedentary, routine, and daily activities, these patches enable continuous, autonomous monitoring of body physiology at rest.


Assuntos
Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Regulação da Temperatura Corporal/fisiologia , Microfluídica/métodos , Suor/metabolismo , Sudorese/fisiologia , Dispositivos Eletrônicos Vestíveis , Corpo Humano , Humanos , Concentração de Íons de Hidrogênio , Hipoglicemia/metabolismo , Levodopa/metabolismo , Microfluídica/instrumentação , Doença de Parkinson/metabolismo , Descanso/fisiologia , Estresse Fisiológico/fisiologia , Suor/fisiologia , Caminhada/fisiologia
14.
Biomed Pharmacother ; 138: 111464, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33725590

RESUMO

Encapsulation systems promote targeted delivery to the gastrointestinal tract. An oil-in-water (O/W) nanoemulsion was covered using new delivery system composition based on zein and sodium alginate. The impact of aqueous phase (distilled water and cooked pumpkin puree), pH (2-4), and zein-alginate concentration solution (0.05-0.20% w/v) was investigated on particle size, zeta potential, incorporation efficiency (IE), stability, viscosity, and glucose release from single-layer (SLN) and double-layer nanoemulsion (DLN). DLNs showed a larger droplet size and zeta potential. The slow gradual release of glucose proved effective application of zein/alginate as delivery system for nanoemulsion. Moreover, cooked pumpkin and 0.12% of zein exhibited more delayed release of glucose than distilled water as an aqueous phase of DLN and as a delivery system respectively. Up-to-49% IE, up-to-50% stability in a period of 7-day storage, and controlled-release glucose for 240 min under in vitro gastrointestinal conditions were obtained in DLN. The results of the current study revealed that SLN covered by zein at 0.12% of concentration can be an ideal delivery system composition for patients with hypoglycemia and clinical problems.


Assuntos
Cucurbita , Diabetes Mellitus/metabolismo , Emulsões/metabolismo , Glucose/metabolismo , Hipoglicemia/metabolismo , Nanopartículas/metabolismo , Animais , Cucurbita/química , Cucurbita/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/metabolismo , Diabetes Mellitus/prevenção & controle , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Emulsões/síntese química , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Glucose/antagonistas & inibidores , Humanos , Hipoglicemia/prevenção & controle , Nanopartículas/administração & dosagem , Nanopartículas/química , Suínos
15.
Am J Physiol Endocrinol Metab ; 320(5): E914-E924, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33779306

RESUMO

Iatrogenic hypoglycemia is a prominent barrier to achieving optimal glycemic control in patients with diabetes, in part due to dampened counterregulatory hormone responses. It has been demonstrated that elevated liver glycogen content can enhance these hormonal responses through signaling to the brain via afferent nerves, but the role that hypoglycemia in the brain plays in this liver glycogen effect remains unclear. During the first 4 h of each study, the liver glycogen content of dogs was increased by using an intraportal infusion of fructose to stimulate hepatic glucose uptake (HG; n = 13), or glycogen was maintained near fasting levels with a saline infusion (NG; n = 6). After a 2-h control period, during which the fructose/saline infusion was discontinued, insulin was infused intravenously for an additional 2 h to bring about systemic hypoglycemia in all animals, whereas brain euglycemia was maintained in a subset of the HG group by infusing glucose bilaterally into the carotid and vertebral arteries (HG-HeadEu; n = 7). Liver glycogen content was markedly elevated in the two HG groups (43 ± 4, 73 ± 3, and 75 ± 7 mg/g in NG, HG, and HG-HeadEu, respectively). During the hypoglycemic period, arterial plasma glucose levels were indistinguishable between groups (53 ± 2, 52 ± 1, and 51 ± 1 mg/dL, respectively), but jugular vein glucose levels were kept euglycemic (88 ± 5 mg/dL) only in the HG-HeadEu group. Glucagon and epinephrine responses to hypoglycemia were higher in HG compared with NG, whereas despite the increase in liver glycogen, neither increased above basal in HG-HeadEu. These data demonstrate that the enhanced counterregulatory hormone secretion that accompanies increased liver glycogen content requires hypoglycemia in the brain.NEW & NOTEWORTHY It is well known that iatrogenic hypoglycemia is a barrier to optimal glycemic regulation in patients with diabetes. Our data confirm that increasing liver glycogen content 75% above fasting levels enhances hormonal responses to insulin-induced hypoglycemia and demonstrate that this enhanced hormonal response does not occur in the absence of hypoglycemia in the brain. These data demonstrate that information from the liver regarding glycogen availability is integrated in the brain to optimize the counterregulatory response.


Assuntos
Encéfalo/metabolismo , Hipoglicemia/metabolismo , Hipoglicemiantes/farmacologia , Glicogênio Hepático/fisiologia , Animais , Glicemia/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Cães , Feminino , Gluconeogênese/efeitos dos fármacos , Glucose/deficiência , Glucose/metabolismo , Técnica Clamp de Glucose , Glicogênio/metabolismo , Hipoglicemia/induzido quimicamente , Hipoglicemia/patologia , Insulina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino
16.
Diabetes ; 70(6): 1265-1277, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33674408

RESUMO

While Roux-en-Y gastric bypass (RYGB) surgery in obese individuals typically improves glycemic control and prevents diabetes, it also frequently causes asymptomatic hypoglycemia. Previous work showed attenuated counterregulatory responses following RYGB. The underlying mechanisms as well as the clinical consequences are unclear. In this study, 11 subjects without diabetes with severe obesity were investigated pre- and post-RYGB during hyperinsulinemic normo-hypoglycemic clamps. Assessments were made of hormones, cognitive function, cerebral blood flow by arterial spin labeling, brain glucose metabolism by 18F-fluorodeoxyglucose (FDG) positron emission tomography, and activation of brain networks by functional MRI. Post- versus presurgery, we found a general increase of cerebral blood flow but a decrease of total brain FDG uptake during normoglycemia. During hypoglycemia, there was a marked increase in total brain FDG uptake, and this was similar for post- and presurgery, whereas hypothalamic FDG uptake was reduced during hypoglycemia. During hypoglycemia, attenuated responses of counterregulatory hormones and improvements in cognitive function were seen postsurgery. In early hypoglycemia, there was increased activation post- versus presurgery of neural networks in brain regions implicated in glucose regulation, such as the thalamus and hypothalamus. The results suggest adaptive responses of the brain that contribute to lowering of glycemia following RYGB, and the underlying mechanisms should be further elucidated.


Assuntos
Encéfalo/fisiologia , Derivação Gástrica , Obesidade Mórbida , Adolescente , Adulto , Glicemia/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Cognição/fisiologia , Feminino , Derivação Gástrica/efeitos adversos , Glucose/farmacocinética , Humanos , Hipoglicemia/etiologia , Hipoglicemia/metabolismo , Hipoglicemia/psicologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neurônios/fisiologia , Obesidade Mórbida/metabolismo , Obesidade Mórbida/psicologia , Obesidade Mórbida/cirurgia , Tomografia por Emissão de Pósitrons , Fluxo Sanguíneo Regional/fisiologia , Adulto Jovem
17.
Lancet Child Adolesc Health ; 5(4): 265-273, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33577770

RESUMO

BACKGROUND: Hyperglycaemia and hypoglycaemia are common in preterm infants and have been associated with increased risk of mortality and morbidity. Interventions to reduce risk associated with these exposures are particularly challenging due to the infrequent measurement of blood glucose concentrations, with the potential of causing more harm instead of improving outcomes for these infants. Continuous glucose monitoring (CGM) is widely used in adults and children with diabetes to improve glucose control, but has not been approved for use in neonates. The REACT trial aimed to evaluate the efficacy and safety of CGM in preterm infants requiring intensive care. METHODS: This international, open-label, randomised controlled trial was done in 13 neonatal intensive care units in the UK, Spain, and the Netherlands. Infants were included if they were within 24 h of birth, had a birthweight of 1200 g or less, had a gestational age up to 33 weeks plus 6 days, and had parental written informed consent. Infants were randomly assigned (1:1) to real-time CGM or standard care (with masked CGM for comparison) using a central web randomisation system, stratified by recruiting centre and gestational age (<26 or ≥26 weeks). The primary efficacy outcome was the proportion of time sensor glucose concentration was 2·6-10 mmol/L for the first week of life. Safety outcomes related to hypoglycaemia (glucose concentrations <2·6 mmol/L) in the first 7 days of life. All outcomes were assessed on the basis of intention to treat in the full analysis set with available data. The study is registered with the International Standard Randomised Control Trials Registry, ISRCTN12793535. FINDINGS: Between July 4, 2016, and Jan 27, 2019, 182 infants were enrolled, 180 of whom were randomly assigned (85 to real-time CGM, 95 to standard care). 70 infants in the real-time CGM intervention group and 85 in the standard care group had CGM data and were included in the primary analysis. Compared with infants in the standard care group, infants managed using CGM had more time in the 2·6-10 mmol/L glucose concentration target range (mean proportion of time 84% [SD 22] vs 94% [11]; adjusted mean difference 8·9% [95% CI 3·4-14·4]), equivalent to 13 h (95% CI 5-21). More infants in the standard care group were exposed to at least one episode of sensor glucose concentration of less than 2·6 mmol/L for more than 1 h than those in the intervention group (13 [15%] of 85 vs four [6%] of 70). There were no serious adverse events related to the use of the device or episodes of infection. INTERPRETATION: Real-time CGM can reduce exposure to prolonged or severe hyperglycaemia and hypoglycaemia. Further studies using CGM are required to determine optimal glucose targets, strategies to obtain them, and the potential effect on long-term health outcomes. FUNDING: National Institute for Health Research Efficacy and Mechanisms Evaluation Programme.


Assuntos
Glicemia/metabolismo , Hiperglicemia/diagnóstico , Hipoglicemia/diagnóstico , Monitorização Fisiológica/métodos , Feminino , Glucose/administração & dosagem , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/terapia , Hipoglicemia/metabolismo , Hipoglicemia/terapia , Hipoglicemiantes/uso terapêutico , Lactente Extremamente Prematuro , Recém-Nascido , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Insulina/uso terapêutico , Unidades de Terapia Intensiva Neonatal , Masculino , Países Baixos , Espanha , Fatores de Tempo , Reino Unido
18.
J Neurochem ; 157(6): 1861-1875, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33025588

RESUMO

The endothelial cells of the blood-brain barrier participate in the regulation of glutamate concentrations in the brain interstitial fluid by taking up brain glutamate. However, endothelial glutamate metabolism has not been characterized, nor is its role in brain glutamate homeostasis and endothelial energy production known. The aim of this study was to investigate endothelial glutamate dehydrogenase (GDH) expression and glutamate metabolism and probe its functional significance. The primary brain endothelial cells were isolated from bovine and mouse brains, and human brain endothelial cells were derived from induced pluripotent stem cells. GDH expression on the protein level and GDH function were investigated in the model systems using western blotting, confocal microscopy, 13 C-glutamate metabolism, and Seahorse assay. In this study, it was shown that GDH was expressed in murine and bovine brain capillaries and in cultured primary mouse and bovine brain endothelial cells as well as in human-induced pluripotent stem cell-derived endothelial cells. The endothelial GDH expression was confirmed in brain capillaries from mice carrying a central nervous system-specific GDH knockout. Endothelial cells from all tested species metabolized 13 C-glutamate to α-ketoglutarate, which subsequently entered the tricarboxylic acid (TCA)-cycle. Brain endothelial cells maintained mitochondrial oxygen consumption rates, when supplied with glutamate alone, whereas glutamate supplied in addition to glucose did not lead to additional oxygen consumption. In conclusion, brain endothelial cells directly take up and metabolize glutamate and utilize the resulting α-ketoglutarate in the tricarboxylic acid cycle to ultimately yield ATP if glucose is unavailable.


Assuntos
Trifosfato de Adenosina/metabolismo , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Glutamato Desidrogenase/biossíntese , Ácido Glutâmico/metabolismo , Ácidos Tricarboxílicos/metabolismo , Animais , Encéfalo/citologia , Bovinos , Células Cultivadas , Humanos , Hipoglicemia/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
19.
Endocrinology ; 162(3)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33367607

RESUMO

Activation of the adrenergic system in response to hypoglycemia is important for proper recovery from low glucose levels. However, it has been suggested that repeated adrenergic stimulation may also contribute to counterregulatory failure, but the underlying mechanisms are not known. The aim of this study was to establish whether repeated activation of noradrenergic receptors in the ventromedial hypothalamus (VMH) contributes to blunting of the counterregulatory response by enhancing local lactate production. The VMH of nondiabetic rats were infused with either artificial extracellular fluid, norepinephrine (NE), or salbutamol for 3 hours/day for 3 consecutive days before they underwent a hypoglycemic clamp with microdialysis to monitor changes in VMH lactate levels. Repeated exposure to NE or salbutamol suppressed both the glucagon and epinephrine responses to hypoglycemia compared to controls. Furthermore, antecedent NE and salbutamol treatments raised extracellular lactate levels in the VMH. To determine whether the elevated lactate levels were responsible for impairing the hormone response, we pharmacologically inhibited neuronal lactate transport in a subgroup of NE-treated rats during the clamp. Blocking neuronal lactate utilization improved the counterregulatory hormone responses in NE-treated animals, suggesting that repeated activation of VMH ß2-adrenergic receptors increases local lactate levels which in turn, suppresses the counterregulatory hormone response to hypoglycemia.


Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Epinefrina/farmacologia , Hipoglicemia/metabolismo , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Agonistas Adrenérgicos/farmacologia , Neurônios Adrenérgicos/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Regulação para Baixo/efeitos dos fármacos , Técnica Clamp de Glucose , Hipoglicemia/patologia , Ácido Láctico/metabolismo , Masculino , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos/metabolismo , Recidiva , Núcleo Hipotalâmico Ventromedial/metabolismo
20.
Am J Physiol Endocrinol Metab ; 320(3): E425-E437, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33356994

RESUMO

Aerobic exercise in type 1 diabetes (T1D) causes rapid increase in glucose utilization due to muscle work during exercise, followed by increased insulin sensitivity after exercise. Better understanding of these changes is necessary for models of exercise in T1D. Twenty-six individuals with T1D underwent three sessions at three insulin rates (100%, 150%, 300% of basal). After 3-h run-in, participants performed 45 min aerobic exercise (moderate or intense). We determined area under the curve for endogenous glucose production (AUCEGP) and rate of glucose disappearance (AUCRd) over 45 min from exercise start. A novel application of linear regression of Rd across the three insulin sessions allowed separation of insulin-mediated from non-insulin-mediated glucose uptake before, during, and after exercise. AUCRd increased 12.45 mmol/L (CI = 10.33-14.58, P < 0.001) and 13.13 mmol/L (CI = 11.01-15.26, P < 0.001) whereas AUCEGP increased 1.66 mmol/L (CI = 1.01-2.31, P < 0.001) and 3.46 mmol/L (CI = 2.81-4.11, P < 0.001) above baseline during moderate and intense exercise, respectively. AUCEGP increased during intense exercise by 2.14 mmol/L (CI = 0.91-3.37, P < 0.001) compared with moderate exercise. There was significant effect of insulin infusion rate on AUCRd equal to 0.06 mmol/L per % above basal rate (CI = 0.05-0.07, P < 0.001). Insulin-mediated glucose uptake rose during exercise and persisted hours afterward, whereas non-insulin-mediated effect was limited to the exercise period. To our knowledge, this method of isolating dynamic insulin- and non-insulin-mediated uptake has not been previously employed during exercise. These results will be useful in informing glucoregulatory models of T1D. The study has been registered at www.clinicaltrials.gov as NCT03090451.NEW & NOTEWORTHY Separating insulin and non-insulin glucose uptake dynamically during exercise in type 1 diabetes has not been done before. We use a multistep process, including a previously described linear regression method, over three insulin infusion sessions, to perform this separation and can graph these components before, during, and after exercise for the first time.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Exercício Físico/fisiologia , Glucose/farmacocinética , Insulina/fisiologia , Adolescente , Adulto , Glicemia/metabolismo , Feminino , Humanos , Hiperinsulinismo/metabolismo , Hipoglicemia/metabolismo , Insulina/administração & dosagem , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Esforço Físico/fisiologia , Adulto Jovem
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