RESUMO
Increased glycolysis is a metabolic trait of activated innate immune cells and supports functional changes including cytokine production. Insulin drives glycolysis in nonimmune cells, yet its metabolic effects on human innate immune cells remain unexplored. Potential effects of insulin on immune cell metabolism may occur acutely after a postprandial increase in plasma insulin levels or as a consequence of chronically elevated insulin levels as observed in obese insulin-resistant individuals and patients with diabetes. Here, we investigated the effects of acute and chronic exposure to insulin on metabolism and function of primary human monocytes. Insulin acutely activated the PI3K/Akt/mTOR pathway in monocytes and increased both oxygen consumption and glycolytic rates. Functionally, acute exposure to insulin increased LPS-induced IL-6 secretion and reactive oxygen species production. To model chronically elevated insulin levels in patients with diabetes, we exposed monocytes from healthy individuals for 24 h to insulin. Although we did not find any changes in expression of metabolic genes that are regulated by insulin in non-immune cells, chronic exposure to insulin increased LPS-induced TNFα production and enhanced MCP-1-directed migration. Supporting this observation, we identified a positive correlation between plasma insulin levels and macrophage numbers in adipose tissue of overweight individuals. Altogether, insulin acutely activates metabolism of human monocytes and induces a shift toward a more proinflammatory phenotype, which may contribute to chronic inflammation in patients with diabetes.
Assuntos
Glicólise/efeitos dos fármacos , Insulina/farmacocinética , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Tecido Adiposo/imunologia , Adulto , Citocinas/metabolismo , Feminino , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Insulina/metabolismo , Masculino , Sobrepeso/metabolismo , FenótipoRESUMO
AIM: Diabetes is associated with a high risk of adverse pregnancy outcomes. Optimal glycaemic control is fundamental and is traditionally monitored with self-measured glucose profiles and periodic HbA1c measurements. We investigated the effectiveness of additional use of retrospective continuous glucose monitoring (CGM) in diabetic pregnancies. MATERIAL AND METHODS: We performed a nationwide multicentre, open label, randomized, controlled trial to study pregnant women with type 1 or type 2 diabetes who were undergoing insulin therapy at gestational age < 16 weeks, or women who were undergoing insulin treatment for gestational diabetes at gestational age < 30 weeks. Women were randomly allocated (1:1) to intermittent use of retrospective CGM or to standard treatment. Glycaemic control was assessed by CGM for 5-7 days every 6 weeks in the CGM group, while self-monitoring of blood glucose and HbA1c measurements were applied in both groups. Primary outcome was macrosomia, defined as birth weight above the 90th percentile. Secondary outcomes were glycaemic control and maternal and neonatal complications. RESULTS: Between July 2011 and September 2015, we randomized 300 pregnant women with type 1 (n = 109), type 2 (n = 82) or with gestational (n = 109) diabetes to either CGM (n = 147) or standard treatment (n = 153). The incidence of macrosomia was 31.0% in the CGM group and 28.4% in the standard treatment group (relative risk [RR], 1.06; 95% CI, 0.83-1.37). HbA1c levels were similar between treatment groups. CONCLUSIONS: In diabetic pregnancy, use of intermittent retrospective CGM did not reduce the risk of macrosomia. CGM provides detailed information concerning glycaemic fluctuations but, as a treatment strategy, does not translate into improved pregnancy outcome.
Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Gestacional/sangue , Macrossomia Fetal/prevenção & controle , Monitorização Ambulatorial , Gravidez em Diabéticas/sangue , Adulto , Terapia Combinada , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/terapia , Diabetes Gestacional/fisiopatologia , Diabetes Gestacional/terapia , Feminino , Macrossomia Fetal/epidemiologia , Macrossomia Fetal/etiologia , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Incidência , Recém-Nascido , Análise de Intenção de Tratamento , Perda de Seguimento , Masculino , Países Baixos/epidemiologia , Pacientes Desistentes do Tratamento , Gravidez , Gravidez em Diabéticas/fisiopatologia , Gravidez em Diabéticas/terapia , RiscoRESUMO
BACKGROUND: Fatigue in type 1 diabetes is prevalent and persistent, but so far, no evidence-based treatments are available. We aimed to investigate the efficacy of cognitive behavioural therapy (CBT) in reducing fatigue severity in patients with type 1 diabetes. METHODS: We did a multicentre randomised controlled trial at one university medical centre and four large teaching hospitals in the Netherlands. Eligible patients were aged 18-70 years and had type 1 diabetes for at least 1 year and chronic fatigue for at least 6 months. We randomly assigned patients (1:1) to CBT or waiting list using computer-generated blocked randomisation, stratified by type of enrolment. The CBT intervention (Dia-Fit) was given for 5 months in blended form, consisting of face-to-face and web-based sessions. The primary outcome was fatigue severity assessed 5 months after randomisation, directly after the intervention or waiting list period, with the Checklist Individual Strength fatigue severity subscale. Secondary outcomes were functional impairment (assessed with the total score of the Sickness Impact Profile-8), glycaemic control (HbA1c), and glucose variability. Analyses were done by intention to treat. This trial is registered with the Nederlands Trial Register, number NTR4312. FINDINGS: Between Feb 6, 2014, and March 24, 2016, we randomly assigned 120 eligible patients to either CBT (n=60) or waiting list (n=60), all of whom were included in the intention-to-treat analyses. Compared with patients in the waiting list group, those in the CBT group had significantly lower fatigue severity scores (mean difference 13·8, 95% CI 10·0-17·5; p<0·0001) and significantly lower scores for functional impairment (mean difference 513, 95% CI 340-686; p<0·0001) after 5 months. HbA1c and glucose variability did not change after treatment and there was no difference between groups. Five patients in the CBT group and seven in the waiting list group reported adverse events; none were deemed to be related to the study intervention. INTERPRETATION: Although our findings need to be confirmed in larger and longer-term studies, they suggest that CBT can effectively reduce fatigue severity and functional impairment in type 1 diabetes. FUNDING: Dutch Diabetes Research Foundation (Diabetes Fonds).
Assuntos
Terapia Cognitivo-Comportamental , Diabetes Mellitus Tipo 1/complicações , Síndrome de Fadiga Crônica/terapia , Adolescente , Adulto , Idoso , Síndrome de Fadiga Crônica/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Innate immunity plays a pivotal role in obesity-induced low-grade inflammation originating from adipose tissue. Key receptors of the innate immune system including Toll-like receptors-2 and -4 (TLRs) are triggered by nutrient excess to promote inflammation. The role of other TLRs in this process is largely unknown. In addition to double-stranded viral mRNA, TLR-3 can also recognize mRNA from dying endogenous cells, a process that is frequently observed within obese adipose tissue. Here, we identified profound expression of TLR-3 in adipocytes and investigated its role during diet-induced obesity. Human adipose tissue biopsies (n=80) and an adipocyte cell-line were used to study TLR-3 expression and function. TLR-3-/- and WT animals were exposed to a high-fat diet (HFD) for 16 weeks to induce obesity. Expression of TLR-3 was significantly higher in human adipocytes compared to the non-adipocyte cells part of the adipose tissue. In vitro, TLR-3 expression was induced during differentiation of adipocytes and stimulation of the receptor led to elevated expression of pro-inflammatory cytokines. In vivo, TLR-3 deficiency did not significantly influence HFD-induced obesity, insulin sensitivity or inflammation. In humans, TLR-3 expression in adipose tissue did not correlate with BMI or insulin sensitivity (HOMA-IR). Together, our results demonstrate that TLR-3 is highly expressed in adipocytes and functionally active. However, TLR-3 appears to play a redundant role in obesity-induced inflammation and insulin resistance.
Assuntos
Adipócitos/metabolismo , Tecido Adiposo/patologia , Inflamação/complicações , Obesidade/complicações , Transdução de Sinais , Receptor 3 Toll-Like/metabolismo , Adulto , Idoso , Animais , Dieta Hiperlipídica , Feminino , Humanos , Resistência à Insulina , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Receptor 3 Toll-Like/genética , Aumento de PesoRESUMO
Cytokines of the IL-1 family are important modulators of obesity-induced inflammation and the development of systemic insulin resistance. Here we show that IL-1 family member IL-37, recently characterized as an anti-inflammatory cytokine, ameliorates obesity-induced inflammation and insulin resistance. Mice transgenic for human IL-37 (IL-37tg) exhibit reduced numbers of adipose tissue macrophages, increased circulating levels of adiponectin and preserved glucose tolerance and insulin sensitivity after 16 weeks of HFD. In vitro treatment of adipocytes with recombinant IL-37 reduces adipogenesis and activates AMPK signalling. In humans, elevated steady-state IL-37 adipose tissue mRNA levels are positively correlated with insulin sensitivity and a lower inflammatory status of the adipose tissue. These findings reveal IL-37 as an important anti-inflammatory modulator during obesity-induced inflammation and insulin resistance in both mice and humans, and suggest that IL-37 is a potential target for the treatment of obesity-induced insulin resistance and type 2 diabetes.
Assuntos
Adipócitos/efeitos dos fármacos , Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Interleucina-1/metabolismo , Obesidade/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/metabolismo , Adipócitos/patologia , Adiponectina/sangue , Adiponectina/genética , Tecido Adiposo/patologia , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica , Gorduras na Dieta/efeitos adversos , Expressão Gênica , Teste de Tolerância a Glucose , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Insulina/sangue , Insulina/genética , Interleucina-1/genética , Interleucina-1/farmacologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/etiologia , Obesidade/genética , Obesidade/patologia , Cultura Primária de CélulasRESUMO
Obesity is accompanied by the presence of chronic low-grade inflammation manifested by infiltration of macrophages into adipose tissue. Mannose-binding lectin (MBL), a soluble mediator of innate immunity, promotes phagocytosis and alters macrophage function. To assess the function of MBL in the development of obesity, we studied wild-type and MBL(-/-) mice rendered obese using a high-fat diet (HFD). Whereas no gross morphological differences were observed in liver, an HFD provoked distinct changes in the adipose tissue morphology of MBL(-/-) mice. In parallel with increased adipocyte size, MBL(-/-) mice displayed an increased influx of macrophages into adipose tissue. Macrophages were polarized toward an alternatively activated phenotype known to modulate apoptotic cell clearance. MBL deficiency also significantly increased the number of apoptotic cells in adipose tissue. Consistent with these observations, recombinant MBL enhanced phagocytic capacity of the stromal vascular fraction isolated from adipose tissue and modulated uptake of apoptotic adipocytes by macrophages. Despite changes in macrophage abundance and polarity, the absence of MBL did not affect systemic insulin resistance. Finally, in humans, lower levels of circulating MBL were accompanied by enhanced macrophage influx in subcutaneous adipose tissue. We propose a novel role for MBL in the recognition and clearance of apoptotic adipocytes during obesity.
Assuntos
Tecido Adiposo/citologia , Resistência à Insulina/genética , Fígado/metabolismo , Macrófagos/metabolismo , Lectina de Ligação a Manose/genética , Obesidade/metabolismo , Fagocitose/genética , Adipócitos/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Humanos , Lectina de Ligação a Manose/metabolismo , Camundongos Knockout , Obesidade/etiologia , Sobrepeso/etiologia , Sobrepeso/metabolismoRESUMO
OBJECTIVE: The determinants of insulin-associated weight gain in type 2 diabetes mellitus (T2DM) are partly unknown. Therefore, we conducted a prospective study to identify predictors of insulin-associated weight gain. RESEARCH DESIGN AND METHODS: In patients with T2DM, we assessed physical activity by accelerometry and measured diabetes-related distress by questionnaires before and 6 and 12 months after starting insulin therapy. Glycemic control (HbA1c) and insulin dose were monitored. RESULTS: After 12 months of insulin therapy, mean body weight had increased by 3.0 ± 2.5 kg (P < 0.001). The drop in HbA1c was correlated with insulin-associated weight gain. With the use of a multiple linear regression model, a cluster of variables was identified that significantly related to weight gain. Diabetes-related distress, initial insulin dose, and the increase of insulin dose during the course of the study as well as age appeared to be important predictors of weight gain after initiation of insulin therapy. Physical activity (measured as MET) decreased from 1.40 ± 0.04 at baseline to 1.32 ± 0.04 MET (P < 0.05) but was not significantly related to weight changes. CONCLUSIONS: Diabetes-related distress, initial and titration of insulin dose, and age all significantly predict insulin-associated weight gain. After the initiation of insulin therapy, physical activity decreased significantly, but this did not determine weight gain over the first 12 months. Our study findings may have clinical implications.
Assuntos
Envelhecimento/fisiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/psicologia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Aumento de Peso/fisiologia , Adulto , Idoso , Peso Corporal/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Valor Preditivo dos Testes , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
AIMS/HYPOTHESIS: The best treatment strategy for a patient with type 2 diabetes who shows pronounced weight gain after the introduction of insulin treatment is unclear. We determined whether addition of a glucagon-like peptide-1 (GLP-1) analogue could reverse pronounced insulin-associated weight gain while maintaining glycaemic control, and compared this with the most practised strategy, continuation and intensification of standard insulin therapy. METHODS: In a 26-week, randomised controlled trial (ELEGANT), conducted in the outpatient departments of one academic and one large non-academic teaching hospital in the Netherlands, adult patients with type 2 diabetes with ≥ 4% weight gain during short-term (≤ 16 months) insulin therapy received either open-label addition of liraglutide 1.8 mg/day (n = 26) or continued standard therapy (n = 24). A computer-generated random number list was used to allocate treatments. Participants were evaluated every 4-6 weeks for weight, glycaemic control and adverse events. The primary endpoint was between-group weight difference after 26 weeks of treatment (intention to treat). RESULTS: Of 50 randomised patients (mean age 58 years, BMI 33 kg/m(2), HbA1c 7.4% [57 mmol/mol]), 47 (94%) completed the study; all patients were analysed. Body weight decreased by 4.5 kg with liraglutide and increased by 0.9 kg with standard therapy (mean difference -5.2 kg [95% CI -6.7, -3.6 kg]; p < 0.001). The respective changes in HbA1c were -0.77% (-8.4 mmol/mol) and +0.01% (+0.1 mmol/mol) (difference -0.74% [-8.1 mmol/mol]) ([95% CI -1.08%, -0.41%] [-11.8, -4.5 mmol/mol]; p < 0.001); respective changes in insulin dose were -29 U/day and +5 U/day (difference -33 U/day [95% CI -41, -25 U/day]; p < 0.001). In five patients (19%), insulin could be completely discontinued. Liraglutide was well tolerated; no severe adverse events or severe hypoglycaemia occurred. CONCLUSIONS/INTERPRETATION: In patients with pronounced insulin-associated weight gain, addition of liraglutide to their treatment regimen reverses weight, decreases insulin dose and improves glycaemic control, and hence seems a valuable therapeutic option compared with continuation of standard insulin treatment. Trial registration ClinicalTrials.gov NCT01392898. Funding The study was funded by Novo Nordisk.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/uso terapêutico , Aumento de Peso/efeitos dos fármacos , Idoso , Feminino , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Humanos , Liraglutida , Masculino , Pessoa de Meia-IdadeRESUMO
Chronic low-grade inflammation in adipose tissue often accompanies obesity, leading to insulin resistance and increasing the risk for metabolic diseases. MAP3K8 (TPL2/COT) is an important signal transductor and activator of pro-inflammatory pathways that has been linked to obesity-induced adipose tissue inflammation. We used human adipose tissue biopsies to study the relationship of MAP3K8 expression with markers of obesity and expression of pro-inflammatory cytokines (IL-1ß, IL-6 and IL-8). Moreover, we evaluated obesity-induced adipose tissue inflammation and insulin resistance in mice lacking MAP3K8 and WT mice on a high-fat diet (HFD) for 16 weeks. Individuals with a BMI >30 displayed a higher mRNA expression of MAP3K8 in adipose tissue compared to individuals with a normal BMI. Additionally, high mRNA expression levels of IL-1ß, IL-6 and IL-8, but not TNF -α, in human adipose tissue were associated with higher expression of MAP3K8. Moreover, high plasma SAA and CRP did not associate with increased MAP3K8 expression in adipose tissue. Similarly, no association was found for MAP3K8 expression with plasma insulin or glucose levels. Mice lacking MAP3K8 had similar bodyweight gain as WT mice, yet displayed lower mRNA expression levels of IL-1ß, IL-6 and CXCL1 in adipose tissue in response to the HFD as compared to WT animals. However, MAP3K8 deficient mice were not protected against HFD-induced adipose tissue macrophage infiltration or the development of insulin resistance. Together, the data in both human and mouse show that MAP3K8 is involved in local adipose tissue inflammation, specifically for IL-1ß and its responsive cytokines IL-6 and IL-8, but does not seem to have systemic effects on insulin resistance.
Assuntos
Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Proteínas Sanguíneas/análise , Inflamação/etiologia , MAP Quinase Quinase Quinases/metabolismo , MAP Quinase Quinase Quinases/fisiologia , Obesidade/complicações , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/fisiologia , Tecido Adiposo/metabolismo , Animais , Western Blotting , Índice de Massa Corporal , Células Cultivadas , Dieta Hiperlipídica , Teste de Tolerância a Glucose , Humanos , Técnicas Imunoenzimáticas , Inflamação/metabolismo , Inflamação/patologia , Insulina/metabolismo , Resistência à Insulina , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , MAP Quinase Quinase Quinases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Obesidade/patologia , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are typically overweight and have an increased liver fat content (LFAT). High LFAT may be explained by an increased efflux of free fatty acids from the adipose tissue, which is partly instigated by inflammatory changes. This would imply an association between inflammatory features of the adipose tissue and liver fat content. OBJECTIVE: To analyse associations between inflammatory features of the adipose tissue and liver fat content. DESIGN: A cross-sectional study. PATIENTS: Twenty-seven obese patients with insulin-treated T2DM were studied. MEASUREMENTS: LFAT content was measured by proton magnetic resonance spectroscopy. A subcutaneous (sc) fat biopsy was obtained to determine morphology and protein levels within adipose tissue. In addition to fat cell size, the percentage of macrophages and the presence of crown-like structures (CLSs) within sc fat were assessed by CD68-immunohistochemical staining. RESULTS: Mean LFAT percentage was 11·1 ± 1·7% (range: 0·75-32·9%); 63% of the patients were diagnosed with an elevated LFAT (upper range of normal ≤5·5%). Whereas adipocyte size did not correlate with LFAT, 3 of 4 subjects with CLSs in sc fat had elevated LFAT and the percentage of macrophages present in sc adipose tissue was positively associated with LFAT. Protein concentrations of adiponectin within adipose tissue negatively correlated with LFAT. Adipose tissue protein levels of the key inflammatory adipokine plasminogen activator inhibitor-1 (PAI-1) were positively associated with LFAT. CONCLUSIONS: Several pro-inflammatory changes in sc adipose tissue associate with increased LFAT content in obese insulin-treated patients with T2DM. These findings suggest that inflammatory changes at the level of the adipose tissue may drive liver fat accumulation.
Assuntos
Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Gorduras/metabolismo , Inflamação/metabolismo , Fígado/metabolismo , Gordura Subcutânea/imunologia , Gordura Subcutânea/metabolismo , Tecido Adiposo/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Insulina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismoRESUMO
The Na(v)1.7 sodium channel is preferentially expressed in nocioceptive dorsal root ganglion and sympathetic ganglion neurons. Gain-of-function mutations in Na(v)1.7 produce the nocioceptor hyperexcitability underlying inherited erythromelalgia, characterized in most kindreds by early-age onset of severe pain. Here we describe a mutation (Na(v)1.7-G616R) in a pedigree with adult-onset of pain in some family members. The mutation shifts the voltage-dependence of channel fast-inactivation in a depolarizing direction in the adult-long, but not in the neonatal-short splicing isoform of Na(v)1.7 in dorsal root ganglion neurons. Altered inactivation does not depend on the age of the dorsal root ganglion neurons in which the mutant is expressed. Expression of the mutant adult-long, but not the mutant neonatal-short, isoform of Na(v)1.7 renders dorsal root ganglion neurons hyperexcitable, reducing the current threshold for generation of action potentials, increasing spontaneous activity and increasing the frequency of firing in response to graded suprathreshold stimuli. This study shows that a change in relative expression of splice isoforms can contribute to time-dependent manifestation of the functional phenotype of a sodium channelopathy.