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AIM: To assess the effects of Roux-en-Y gastric bypass surgery (RYGB)-related changes in glucagon-like peptide-1 (GLP-1) on cerebral resting-state functioning in obese women. MATERIALS AND METHODS: In nine obese females aged 40-54 years in the fasted state, we studied the effects of RYGB and GLP-1 on five a priori selected networks implicated in food- and reward-related processes as well as environment monitoring (default mode, right frontoparietal, basal ganglia, insula/anterior cingulate and anterior cingulate/orbitofrontal networks). RESULTS: Before surgery, GLP-1 receptor blockade (using exendin9-39) was associated with increased right caudate nucleus (basal ganglia network) and decreased right middle frontal (right frontoparietal network) connectivity compared with placebo. RYGB resulted in decreased right orbitofrontal (insula/anterior cingulate network) connectivity. In the default mode network, after surgery, GLP-1 receptor blockade had a larger effect on connectivity in this region than GLP-1 receptor blockade before RYGB (all PFWE < .05). Results remained similar after correction for changes in body weight. Default mode and right frontoparietal network connectivity changes were related to changes in body mass index and food scores after RYGB. CONCLUSIONS: These findings suggest GLP-1 involvement in resting-state networks related to food and reward processes and monitoring of the internal and external environment, pointing to a potential role for GLP-1-induced changes in resting-state connectivity in RYGB-mediated weight loss and appetite control.
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Derivação Gástrica , Receptor do Peptídeo Semelhante ao Glucagon 1 , Adulto , Feminino , Peptídeo 1 Semelhante ao Glucagon , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Obesidade/cirurgiaRESUMO
Type 2 diabetes (T2DM) is associated with structural cortical and subcortical alterations, although it is insufficiently clear if these alterations are driven by obesity or by diabetes and its associated complications. We used FreeSurfer5.3 and FSL-FIRST to determine cortical thickness, volume and surface area, and subcortical gray matter volume in a group of 16 normoglycemic obese subjects and 28 obese T2DM patients without clinically manifest micro- and marcoangiopathy, and compared them to 31 lean normoglycemic controls. Forward regression analysis was used to determine demographic and clinical correlates of altered (sub)cortical structure. Exploratively, vertex-wise correlations between cortical structure and fasting glucose and insulin were calculated. Compared with controls, obese T2DM patients showed lower right insula thickness and lower left lateral occipital surface area (PFWE < 0.05). Normoglycemic obese versus controls had lower thickness (PFWE < 0.05) in the right insula and inferior frontal gyrus, and higher amygdala and thalamus volume. Thalamus volume and left paracentral surface area were also higher in this group compared with obese T2DM patients. Age, sex, BMI, fasting glucose, and cholesterol were related to these (sub)cortical alterations in the whole group (all P < 0.05). Insulin were related to temporal and frontal structural deficits (all PFWE < 0.05). Parietal/occipital structural deficits may constitute early T2DM-related cerebral alterations, whereas in normoglycemic obese subjects, regions involved in emotion, appetite, satiety regulation, and inhibition were affected. Central adiposity and elevated fasting glucose may constitute risk factors.
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Adiposidade/fisiologia , Glicemia , Encéfalo/diagnóstico por imagem , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Insulina/sangue , Obesidade/diagnóstico por imagem , Adulto , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicações , Tamanho do ÓrgãoRESUMO
Type 2 diabetes mellitus (T2DM) is characterized by obesity, hyperglycemia and insulin resistance. Both T2DM and obesity are associated with cerebral complications, including an increased risk of cognitive impairment and dementia, however the underlying mechanisms are largely unknown. In the current study, we aimed to determine the relative contributions of obesity and the presence of T2DM to altered white matter structure. We used diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) to measure white matter integrity and volume in obese T2DM patients without micro- or macrovascular complications, age- gender- and BMI-matched normoglycemic obese subjects and age- and gender-matched normoglycemic lean subjects. We found that obese T2DM patients compared with lean subjects had lower axial diffusivity (in the right corticospinal tract, right inferior fronto-occipital tract, right superior longitudinal fasciculus and right forceps major) and reduced white matter volume (in the right inferior parietal lobe and the left external capsule region). In normoglycemic obese compared with lean subjects axial diffusivity as well as white matter volume tended to be reduced, whereas there were no significant differences between normoglycemic obese subjects and T2DM patients. Decreased white matter integrity and volume were univariately related to higher age, being male, higher BMI, HbA1C and fasting glucose and insulin levels. However, multivariate analyses demonstrated that only BMI was independently related to white matter integrity, and age, gender and BMI to white matter volume loss. Our data indicate that obese T2DM patients have reduced white matter integrity and volume, but that this is largely explained by BMI, rather than T2DM per se.
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Encéfalo/diagnóstico por imagem , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Obesidade/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Imagem de Tensor de Difusão , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Tamanho do ÓrgãoRESUMO
AIMS/HYPOTHESIS: The central nervous system (CNS) is a major player in the regulation of food intake. The gut hormone glucagon-like peptide-1 (GLP-1) has been proposed to have an important role in this regulation by relaying information about nutritional status to the CNS. We hypothesised that endogenous GLP-1 has effects on CNS reward and satiety circuits. METHODS: This was a randomised, crossover, placebo-controlled intervention study, performed in a university medical centre in the Netherlands. We included patients with type 2 diabetes and healthy lean control subjects. Individuals were eligible if they were 40-65 years. Inclusion criteria for the healthy lean individuals included a BMI <25 kg/m(2) and normoglycaemia. Inclusion criteria for the patients with type 2 diabetes included BMI >26 kg/m(2), HbA1c levels between 42 and 69 mmol/mol (6.0-8.5%) and treatment for diabetes with only oral glucose-lowering agents. We assessed CNS activation, defined as blood oxygen level dependent (BOLD) signal, in response to food pictures in obese patients with type 2 diabetes (n = 20) and healthy lean individuals (n = 20) using functional magnetic resonance imaging (fMRI). fMRI was performed in the fasted state and after meal intake on two occasions, once during infusion of the GLP-1 receptor antagonist exendin 9-39, which was administered to block actions of endogenous GLP-1, and on the other occasion during saline (placebo) infusion. Participants were blinded for the type of infusion. The order of infusion was determined by block randomisation. The primary outcome was the difference in BOLD signal, i.e. in CNS activation, in predefined regions in the CNS in response to viewing food pictures. RESULTS: All patients were included in the analyses. Patients with type 2 diabetes showed increased CNS activation in CNS areas involved in the regulation of feeding (insula, amygdala and orbitofrontal cortex) in response to food pictures compared with lean individuals (p ≤ 0.04). Meal intake reduced activation in the insula in response to food pictures in both groups (p ≤ 0.05), but this was more pronounced in patients with type 2 diabetes. Blocking actions of endogenous GLP-1 significantly prevented meal-induced reductions in bilateral insula activation in response to food pictures in patients with type 2 diabetes (p ≤ 0.03). CONCLUSIONS/INTERPRETATION: Our findings support the hypothesis that endogenous GLP-1 is involved in postprandial satiating effects in the CNS of obese patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT 01363609. Funding The study was funded in part by a grant from Novo Nordisk.
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Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Período Pós-Prandial , Recompensa , Resposta de Saciedade , Adulto , Idoso , Estudos Cross-Over , Diabetes Mellitus Tipo 2/psicologia , Feminino , Alimentos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hemoglobinas Glicadas/análise , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Oxigênio/sangue , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/uso terapêutico , Estimulação LuminosaRESUMO
BACKGROUND: Older patients with type 2 diabetes mellitus (T2D) have an increased risk of hypoglycaemic episodes when using sulphonylureas or insulin. In the Netherlands, guidelines exist for reducing glucose-lowering medication in older patients. However, evidence is lacking that a medication reduction in older patients can be safely pursued. Here, we will examine if promoting the deprescribing of insulin/sulphonylureas with a deprescribing programme (DPP) in general practice affects T2D-complications in older overtreated patients. METHODS: We will perform a 1:1 cluster randomised controlled trial in 86 general practices in the Netherlands. The DPP will consist of education sessions with general practitioners and practice nurses about reducing glucose-lowering medication in older patients (≥ 70 years). Topics of the sessions include the necessity of deprescribing, tools to initiate deprescribing and strategies to discuss deprescribing with patients (shared decision making). The DPP further includes a support programme with practice visits. The study will employ a selection tool to identify possibly overtreated older patients from the electronic medical records of the general practitioner. Eligibility for enrolment in the study will be based on HbA1c targets indicated by the Dutch guidelines, which depend on age, diabetes duration, presence of frailty, and life expectancy. The control group will provide usual care. We aim to include 406 patients. The follow-up period will be 2 years. For the primary outcome, the effect of the DPP on T2D-complications will be assessed by counting the cumulative incidence of events related to under- and overtreatment in T2D as registered in the electronic medical records. We shall perform an intention-to-treat analysis and an analysis including only patients for whom deprescribing was initiated. The implementation of the DPP in general practice will be evaluated quantitatively and qualitatively using the Extended Normalisation Process Theory (ENPT) and the Reach, Efficacy - Adoption, Implementation and Maintenance (RE-AIM) model. Other secondary outcomes include quality of life, cognitive functioning, events related to overtreatment or undertreatment, biomarkers of health, amount of blood glucose-lowering medication prescriptions, and cost-effectiveness. DISCUSSION: This study will provide insight into the safety and feasibility of a programme aimed at deprescribing sulphonylureas/insulin in older people with T2D who are treated in general practice. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN50008265 , registered 09 March, 2023.
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Glicemia , Desprescrições , Diabetes Mellitus Tipo 2 , Controle Glicêmico , Hipoglicemiantes , Ensaios Clínicos Controlados Aleatórios como Assunto , Compostos de Sulfonilureia , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/efeitos adversos , Idoso , Compostos de Sulfonilureia/uso terapêutico , Compostos de Sulfonilureia/efeitos adversos , Países Baixos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Resultado do Tratamento , Insulina/uso terapêutico , Fatores Etários , Biomarcadores/sangue , Fatores de Tempo , Estudos Multicêntricos como Assunto , Hemoglobinas Glicadas/metabolismo , Educação de Pacientes como Assunto/métodos , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Hipoglicemia/sangueRESUMO
AIMS: We investigated if individuals with higher emotional eating scores are less sensitive to the effects of a GLP-1RA on central responses to food cues. Additionally, we investigated the associations of higher external and restraint eating scores with the sensitivity to the central effects of GLP-1RA. METHODS: This secondary analysis of a randomized crossover study in people with obesity and type 2 diabetes, consisted of two periods of 12-week treatment with liraglutide or insulin glargine. Using functional MRI, we assessed the relation between baseline eating behavior and the effects of the GLP-1RA liraglutide compared with insulin after 10 days and 12 weeks of treatment on brain responses to food cues. RESULTS: After 10 days, higher emotional eating scores were associated with less pronounced GLP-1RA induced reductions in brain responses to food pictures in the amygdala, insula and caudate nucleus. In addition, higher emotional eating scores tended to be associated with less pronounced GLP-1RA increases in brain responses to chocolate milk receipt in the caudate nucleus and insula. After 12 weeks, there were no significant associations between emotional eating scores and liraglutide-induced changes in brain responses to food cues. After 10 days, baseline external eating scores were associated with less pronounced GLP-1RA induced reductions in brain responses to food pictures in the insula, amygdala and orbitofrontal cortex. After 12 weeks, baseline restraint eating scores were associated with more GLP-1RA induced reductions in brain responses to food pictures in the insula and caudate nucleus, and with more GLP-1RA induced reductions in brain responses to the anticipation of chocolate milk in the caudate nucleus. CONCLUSIONS: Our findings indicate that individuals with higher baseline emotional eating scores are less sensitive to the central effect of GLP-1RA treatment. Additionally, external eating may also decrease, whereas restraint eating may increase the sensitivity to the treatment effects of GLP-1RAs. These insights may help to optimize treatment strategies for obesity and to select patient groups with better efficacy of GLP-1RA treatment.
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Diabetes Mellitus Tipo 2 , Liraglutida , Estudos Cross-Over , Diabetes Mellitus Tipo 2/complicações , Comportamento Alimentar , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Obesidade/complicaçõesRESUMO
Introduction: Globally, women with dementia have a higher disease burden than men with dementia. In addition, women with diabetes especially are at higher risk for cognitive impairment and dementia compared to men with diabetes. Differences in the influence of diabetes on the cerebral vasculature and brain structure may contribute to these sex-specific differences. We examined sex-specific patterns in the relationship between diabetes and brain structure, as well as diabetes and cognitive function. Methods: In total, 893 patients [age 79 ± 6.6 years, 446 (50%) women] from the Amsterdam Ageing Cohort with available data on brain structures (assessed by an MRI or CT scan) and cognitive function were included. All patients underwent a thorough standardized clinical and neuropsychological assessment (including tests on memory, executive functioning, processing speed, language). Brain structure abnormalities were quantified using visual scales. Results: Cross-sectional multivariable regression analyses showed that diabetes was associated with increased incidence of cerebral lacunes and brain atrophy in women (OR 2.18 (1.00-4.72) but not in men. Furthermore, diabetes was associated with decreased executive function, processing speed and language in women [B -0.07 (0.00-0.13), -0.06 (0.02-0.10) and -0.07 (0.01-0.12) resp.] but not in men. Conclusions: Diabetes is related to increased risk of having lacunes, brain atrophy and impaired cognitive function in women but not in men. Further research is required to understand the time trajectory leading up to these changes and to understand the mechanisms behind them in order to improve preventive health care for both sexes.
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CONTEXT: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) cause less weight loss than expected based on urinary calorie excretion. This may be explained by SGLT2i-induced alterations in central reward and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists are associated with reduced appetite and body weight, mediated by direct and indirect central nervous system (CNS) effects. OBJECTIVE: We investigated the separate and combined effects of dapagliflozin and exenatide on the CNS in participants with obesity and type 2 diabetes. METHODS: This was a 16-week, double-blind, randomized, placebo-controlled trial. Obese participants with type 2 diabetes (nâ =â 64, age 63.5â ±â 0.9 years, BMI 31.7â ±â 0.6 kg/m2) were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice daily 10 µg with dapagliflozin-matched placebo, dapagliflozin and exenatide, or double placebo. Using functional MRI, the effects of treatments on CNS responses to viewing food pictures were assessed after 10 days and 16 weeks of treatment. RESULTS: After 10 days, dapagliflozin increased, whereas exenatide decreased CNS activation in the left putamen. Combination therapy had no effect on responses to food pictures. After 16 weeks, no changes in CNS activation were observed with dapagliflozin, but CNS activation was reduced with dapagliflozin-exenatide in right amygdala. CONCLUSION: The early increase in CNS activation with dapagliflozin may contribute to the discrepancy between observed and expected weight loss. In combination therapy, exenatide blunted the increased CNS activation observed with dapagliflozin. These findings provide further insights into the weight-lowering mechanisms of SGLT2i and GLP-1 receptor agonists.
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Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Compostos Benzidrílicos , Glicemia , Encéfalo/diagnóstico por imagem , Sinais (Psicologia) , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Exenatida , Glucosídeos , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Redução de PesoRESUMO
OBJECTIVES: Excessive sodium intake, despite current dietary advice, remains a global issue with cardiovascular and renal consequences. The aim of this study was to determine whether glucagon-like peptide receptor agonists (GLP-1 RAs), used as antihyperglycemic agents for type 2 diabetes (T2DM) management, may reduce salt cravings as they are known to reduce hedonic feeding behavior and are involved in sodium homeostasis by increasing renal sodium excretion. METHODS: We performed exploratory analyses using data from two randomized, clinical crossover trials, which primarily aimed to assess the effects of GLP-1 RAs on central satiety and reward circuits and subsequent related feeding behavior. In study A, healthy, obese individuals and patients with T2DM were randomly assigned to receive intravenous administration of placebo or GLP-1 RA exenatide with or without concurrent GLP-1 receptor blockade, on separate testing days. In study B, individuals with T2DM randomly received GLP-1 RA liraglutide (titrated up to 1.8 mg daily) or titrated insulin glargine for 12 wk. In both studies, participants received an ad libitum mixed meal that served to calculate sodium intake. Moreover, salt craving was scored using a Likert scale. RESULTS: In study A, acute exenatide, parallel to reduced total food intake, reduced sodium intake in all studied groups by up to 30%. In study B, prolonged liraglutide treatment did not affect sodium or total caloric intake. Neither acute exenatide nor prolonged liraglutide treatment affected salt craving as measured by the Likert scale. CONCLUSION: Acute exenatide reduced sodium intake in light of a generalized reduction in food ingestion, while prolonged intervention with liraglutide did not lower sodium intake. Neither intervention affected salt craving. Given the known effects of these drugs on renal sodium excretion, blood pressure, and renal and cardiovascular outcome, it seems plausible to perform dedicated mechanistic studies in humans to assess the effects of GLP-1 RA administration on sodium balance.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Ingestão de Alimentos/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/farmacologia , Sódio na Dieta/análise , Adulto , Idoso , Estudos Cross-Over , Exenatida/farmacologia , Feminino , Humanos , Liraglutida/farmacologia , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The progressive nature of type 2 diabetes (T2D) requires practitioners to periodically evaluate patients and intensify glucose-lowering treatment once glycemic targets are not attained. With guidelines moving away from a one-size-fits-all approach toward setting patient-centered goals and allowing flexibility in choosing a second-/third-line drug from the growing number of U.S. Food and Drug Administration-approved glucose-lowering agents, keen personalized management in T2D has become a challenge for health care providers in daily practice. Among the newer generation of glucose-lowering drug classes, sodium-glucose cotransporter 2 inhibitors (SGLT2is), which enhance urinary glucose excretion to lower hyperglycemia, have made an imposing entrance to the T2D treatment armamentarium. Given their unique insulin-independent mode of action and their favorable efficacy-to-adverse event profile and given their marked benefits on cardiovascular-renal outcome in moderate-to-high risk T2D patients, which led to updates of guidelines and product monographs, the role of this drug class in multidrug regimes is promising. However, despite many speculations based on pharmacokinetic and pharmacodynamic properties, physiological reasoning, and potential synergism, the effects of these agents in terms of glycemic and pleiotropic efficacy when combined with other glucose-lowering drug classes are largely understudied. In this perspective, we review the currently emerging evidence, discuss prevailing hypotheses, and elaborate on necessary future studies to clarify the potential risks and benefits of using an SGLT2i in dual combination with metformin and triple combination with a glucagon-like peptide 1 receptor agonist, dipeptidyl peptidase 4 inhibitor, or other glucose-lowering agent that is recommended by the American Diabetes Association and European Association for the Study of Diabetes (i.e., a sulfonylurea, thiazolidinedione, or insulin) to treat patients with T2D.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Quimioterapia Combinada , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/administração & dosagem , Insulina/efeitos adversos , Metformina/administração & dosagem , Metformina/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/efeitos adversos , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/efeitos adversos , Resultado do TratamentoRESUMO
Obese individuals are characterized by altered brain reward responses to food. Despite the latest discovery of obesity-associated genes, the contribution of environmental and genetic factors to brain reward responsiveness to food remains largely unclear. Sixteen female monozygotic twin pairs with a mean BMI discordance of 3.96 ± 2.1 kg/m2 were selected from the Netherlands Twin Register to undergo functional MRI scanning while watching high- and low-calorie food and non-food pictures and during the anticipation and receipt of chocolate milk. In addition, appetite ratings, eating behavior and food intake were assessed using visual analog scales, validated questionnaires and an ad libitum lunch. In the overall group, visual and taste stimuli elicited significant activation in regions of interest (ROIs) implicated in reward, i.e. amygdala, insula, striatum and orbitofrontal cortex. However, when comparing leaner and heavier co-twins no statistically significant differences in ROI-activations were observed after family wise error correction. Heavier versus leaner co-twins reported higher feelings of hunger (P = 0.02), cravings for sweet food (P = 0.04), body dissatisfaction (P < 0.05) and a trend towards more emotional eating (P = 0.1), whereas caloric intake was not significantly different between groups (P = 0.3). Our results suggest that inherited rather than environmental factors are largely responsible for the obesity-related altered brain responsiveness to food. Future studies should elucidate the genetic variants underlying the susceptibility to reward dysfunction and obesity. CLINICAL TRIAL REGISTRATION NUMBER: NCT02025595.
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Índice de Massa Corporal , Encéfalo/fisiologia , Ingestão de Alimentos/fisiologia , Alimentos , Recompensa , Percepção Visual/fisiologia , Antecipação Psicológica/fisiologia , Encéfalo/diagnóstico por imagem , Dieta Hiperlipídica , Ingestão de Alimentos/psicologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Oxigênio/sangue , Gêmeos MonozigóticosRESUMO
OBJECTIVE: It has been suggested that weight reduction and improvements in satiety after Roux-en-Y gastric bypass (RYGB) are partly mediated via postoperative neuroendocrine changes. Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted after food ingestion and is associated with appetite and weight reduction, mediated via effects on the central nervous system (CNS). Secretion of GLP-1 is greatly enhanced after RYGB. We hypothesized that postoperative elevated GLP-1 levels contribute to the improved satiety regulation after RYGB via effects on the CNS. RESEARCH DESIGN AND METHODS: Effects of the GLP-1 receptor antagonist exendin 9-39 (Ex9-39) and placebo were assessed in 10 women before and after RYGB. We used functional MRI to investigate CNS activation in response to visual food cues (pictures) and gustatory food cues (consumption of chocolate milk), comparing results with Ex9-39 versus placebo before and after RYGB. RESULTS: After RYGB, CNS activation was reduced in the rolandic operculum and caudate nucleus in response to viewing food pictures (P = 0.03) and in the insula in response to consumption of palatable food (P = 0.003). GLP-1 levels were significantly elevated postoperatively (P < 0.001). After RYGB, GLP-1 receptor blockade resulted in a larger increase in activation in the caudate nucleus in response to food pictures (P = 0.02) and in the insula in response to palatable food consumption (P = 0.002). CONCLUSIONS: We conclude that the effects of RYGB on CNS activation in response to visual and gustatory food cues may be mediated by central effects of GLP-1. Our findings provide further insights into the mechanisms underlying the weight-lowering effects of RYGB.
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Sistema Nervoso Central/fisiologia , Sinais (Psicologia) , Derivação Gástrica , Peptídeo 1 Semelhante ao Glucagon/sangue , Período Pós-Operatório , Adulto , Idoso , Apetite/fisiologia , Índice de Massa Corporal , Estudos Cross-Over , Ingestão de Alimentos/fisiologia , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Receptor do Peptídeo Semelhante ao Glucagon 1/sangue , Humanos , Pessoa de Meia-Idade , Redução de PesoRESUMO
OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with reduced appetite and body weight. We investigated whether these effects could be mediated by the central nervous system (CNS). RESEARCH DESIGN AND METHODS: We performed a randomized crossover study in obese patients with type 2 diabetes (n = 20, mean age 59.3 ± 4.1 years, mean BMI 32 ± 4.7 kg/m(2)), consisting of two periods of 12-week treatment with either liraglutide 1.8 mg or insulin glargine. Using functional MRI, we determined the effects of treatment on CNS responses to viewing food pictures in the fasted condition and 30 min after meal intake. RESULTS: After 12 weeks, the decrease in HbA1c was larger with liraglutide versus insulin glargine (Δ-0.7% vs. -0.2%, P < 0.001). Body weight decreased during liraglutide versus insulin glargine (Δ-3.3 kg vs. 0.8 kg, P < 0.001). After 10 days, patients treated with liraglutide, compared with insulin glargine, showed decreased responses to food pictures in insula and putamen (P ≤ 0.02). In addition, liraglutide enhanced the satiating effect of meal intake on responses in putamen and amygdala (P ≤ 0.05). Differences between liraglutide and insulin glargine were not observed after 12 weeks. CONCLUSIONS: Compared with insulin, liraglutide decreased CNS activation significantly only after short-term treatment, suggesting that these effects of GLP-1RA on the CNS may contribute to the induction of weight loss, but not necessarily to its maintenance, in view of the absence of an effect of liraglutide on CNS activation in response to food pictures after longer-term treatment.
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Encéfalo/efeitos dos fármacos , Sinais (Psicologia) , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Obesidade/tratamento farmacológico , Saciação/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/fisiologia , Estudos Cross-Over , Diabetes Mellitus Tipo 2/complicações , Jejum , Feminino , Alimentos , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Insulina Glargina/uso terapêutico , Liraglutida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/fisiopatologiaRESUMO
CONTEXT: Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonist treatment in type 2 diabetes (T2DM) reduce blood glucose and food intake. It has been suggested that these effects are partly mediated through central GLP-1 receptors (GLP-1Rs). The rodent and nonhuman primate hypothalamus show clear GLP-1R expression. However, a detailed description of GLP-1R expression in the human hypothalamus is lacking, and it is unknown whether this expression is altered in T2DM patients. OBJECTIVE: The objective of the study was to investigate the GLP-1R distribution in the human postmortem hypothalamus and to determine whether hypothalamic GLP-1R expression is altered in T2DM patients. DESIGN: We investigated the distribution of GLP-1R expression throughout the human hypothalamus by means of in situ hybridization. We also performed quantifications of GLP-1R mRNA expression in two hypothalamic nuclei (ie, the paraventricular nucleus [PVN] and infundibular nucleus [IFN]), comparing patients with T2DM and control subjects. RESULTS: We found that GLP-1R mRNA was expressed in a number of hypothalamic nuclei including the PVN and the IFN, both involved in the regulation of energy metabolism. We observed sporadic colocalization of the GLP-1R in the IFN with the orgexigenic neuropeptide Y, agouti-related peptide, or proopiomelanocortin transcripts. Comparison of GLP-1R mRNA in the PVN and IFN between T2DM patients and control subjects revealed a decreased expression in T2DM patients. CONCLUSIONS: Our studies show that GLP-1R is widely expressed throughout the human hypothalamus. The decreased expression of GLP-1R in the PVN and IFN of T2DM patients may be related to the dysregulation of feeding behavior and glucose homeostasis in T2DM.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hipotálamo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Diabetes Mellitus Tipo 2/genética , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismoRESUMO
Glucagon-like peptide-1 (GLP1) affects appetite, supposedly mediated via the central nervous system (CNS). In this study, we investigate whether modulation of CNS responses to palatable food consumption may be a mechanism by which GLP1 contributes to the central regulation of feeding. Using functional MRI, we determined the effects of endogenous GLP1 and treatment with the GLP1 analogue liraglutide on CNS activation to chocolate milk receipt. Study 1 included 20 healthy lean individuals and 20 obese patients with type 2 diabetes (T2DM). Scans were performed on two occasions: during infusion of the GLP1 receptor antagonist exendin 9-39 (blocking actions of endogenous GLP1) and during placebo infusion. Study 2 was a randomised, cross-over intervention study carried out in 20 T2DM patients, comparing treatment with liraglutide to insulin, after 10 days and 12 weeks. Compared with lean individuals, T2DM patients showed reduced activation to chocolate milk in right insula (P = 0.04). In lean individuals, blockade of endogenous GLP1 effects inhibited activation in bilateral insula (P ≤ 0.03). Treatment in T2DM with liraglutide, vs insulin, increased activation to chocolate milk in right insula and caudate nucleus after 10 days (P ≤ 0.03); however, these effects ceased to be significant after 12 weeks. Our findings in healthy lean individuals indicate that endogenous GLP1 is involved in the central regulation of feeding by affecting central responsiveness to palatable food consumption. In obese T2DM, treatment with liraglutide may improve the observed deficit in responsiveness to palatable food, which may contribute to the induction of weight loss observed during treatment. However, no long-term effects of liraglutide were observed.
Assuntos
Sistema Nervoso Central/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Ingestão de Alimentos/fisiologia , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Obesidade/fisiopatologia , Apetite , Glicemia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Liraglutida , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicações , Fragmentos de PeptídeosRESUMO
OBJECTIVE: The neural correlates and pathophysiology of emotional eating are insufficiently known. Glucagon-like peptide-1 (GLP-1), a postprandial hormone, plays a role in feeding behavior by signaling satiety to the brain. GLP-1 receptor agonists, used for treatment of type 2 diabetes (T2DM), promote weight loss. This study investigated the association between emotional eating and responses to food-cues in brain areas involved in satiety and reward processing, as well as GLP-1 receptor agonist-induced effects on these brain responses. METHODS: T2DM patients with obesity, normoglycemic individuals with obesity, and lean individuals (n = 48) were studied in a randomized placebo-controlled crossover study. Using functional MRI, we determined the relation between emotional eating and regional brain responses to visual food stimuli and acute effects of intravenous administration of the GLP-1 receptor agonist exenatide on these responses. RESULTS: Emotional eating scores positively correlated with responses to food-cues in lean subjects in the insula, in normoglycemic subjects with obesity in the insula, and in T2DM patients in the amygdala, orbitofrontal cortex, and insula. Emotional eating scores negatively correlated with exenatide-induced reductions in responses to food-cues in normoglycemic subjects with obesity in the amygdala and in T2DM patients in the insula. CONCLUSIONS: Our findings indicate that emotional eaters have altered brain responses to food-cues and are less sensitive to the central effects of GLP-1 receptor activation.
Assuntos
Encéfalo/fisiologia , Emoções/fisiologia , Comportamento Alimentar/fisiologia , Comportamento Alimentar/psicologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Estudos Cross-Over , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Peptídeo 1 Semelhante ao Glucagon/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Metabolic syndrome (MetS) is characterized by central obesity, insulin resistance, dysglycemia, and a pro-atherogenic plasma lipid profile. MetS creates a high risk for development of type 2 diabetes (T2DM) and cardiovascular disease (CVD), presumably by altering inflammatory responses. Presently, it is unknown how the chronic metabolic disturbances in acute hyperglycemia, MetS and T2DM affect the immune activity of peripheral blood cells. METHODS: We performed genome-wide expression analysis of peripheral blood cells obtained from patients with T2DM (n = 6) and age-, sex- , BMI- and blood pressure-matched obese individuals with MetS (n = 4) and lean healthy normoglycemic controls (n = 3), both under fasting conditions and after controlled induction of acute hyperglycemia during a 70 min hyperglycemic clamp. Differential gene expression during fasting conditions was confirmed by real-time PCR, for which we included additional age-, sex-, BMI-, and blood pressure-matched obese individuals with (n = 4) or without (n = 4) MetS. RESULTS: Pathway and Gene ontology analysis applied to baseline expression profiles of peripheral blood cells from MetS and T2DM patients revealed metabolic changes, highly similar to a reoviral infection gene signature in T2DM patients. Transcription factor binding site analysis indicated that increased HIF-1α activity, a transcription factor induced by either hypoxia or oxidative stress, is responsible for this aberrant metabolic profile in peripheral blood cells from T2DM patients. Acute hyperglycemia in healthy controls resulted in reduced expression of cytotoxicity-related genes, representing NK- and CD8(+) cells. In obese controls, MetS and especially T2DM patients, baseline expression of genes involved in cytotoxicity was already low, compared to healthy controls and did not further decrease upon acute hyperglycemia. CONCLUSIONS: The reduced activity of cytotoxic genes in T2DM is explained by chronic hyperglycemia, but its acute effects are restricted to healthy controls. Genome expression of circulating leukocytes from T2DM patients differs from MetS individuals by a specific reovirus signature. Our data thus suggest a role for suppressed anti-viral capacity in the etiology of diabetes.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Síndrome Metabólica/sangue , Reoviridae/genética , Idoso , Pressão Sanguínea , Índice de Massa Corporal , Doenças Cardiovasculares/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/virologia , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Técnica Clamp de Glucose , Humanos , Inflamação/metabolismo , Lipídeos/sangue , Masculino , Síndrome Metabólica/genética , Pessoa de Meia-Idade , Obesidade Abdominal/genética , Obesidade Abdominal/metabolismo , Análise de Sequência com Séries de OligonucleotídeosRESUMO
Gut-derived hormones, such as GLP-1, have been proposed to relay information to the brain to regulate appetite. GLP-1 receptor agonists, currently used for the treatment of type 2 diabetes (T2DM), improve glycemic control and stimulate satiety, leading to decreases in food intake and body weight. We hypothesized that food intake reduction after GLP-1 receptor activation is mediated through appetite- and reward-related brain areas. Obese T2DM patients and normoglycemic obese and lean individuals (n = 48) were studied in a randomized, crossover, placebo-controlled trial. Using functional MRI, we determined the acute effects of intravenous administration of the GLP-1 receptor agonist exenatide, with or without prior GLP-1 receptor blockade using exendin 9-39, on brain responses to food pictures during a somatostatin pancreatic-pituitary clamp. Obese T2DM patients and normoglycemic obese versus lean subjects showed increased brain responses to food pictures in appetite- and reward-related brain regions (insula and amygdala). Exenatide versus placebo decreased food intake and food-related brain responses in T2DM patients and obese subjects (in insula, amygdala, putamen, and orbitofrontal cortex). These effects were largely blocked by prior GLP-1 receptor blockade using exendin 9-39. Our findings provide novel insights into the mechanisms by which GLP-1 regulates food intake and how GLP-1 receptor agonists cause weight loss.