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OBJECTIVE: The main objective of this study is to better understand the effects of diet-induced weight loss on brain connectivity in response to changes in glucose levels in individuals with obesity. METHODS: A total of 25 individuals with obesity, among whom 9 had a diagnosis of type 2 diabetes, underwent functional magnetic resonance imaging (fMRI) scans before and after an 8-week low-calorie diet. We used a two-step hypereuglycemia clamp approach to mimic the changes in glucose levels observed in the postprandial period in combination with task-mediated fMRI intrinsic connectivity distribution (ICD) analysis. RESULTS: After the diet, participants lost an average of 3.3% body weight. Diet-induced weight loss led to a decrease in leptin levels, an increase in hunger and food intake, and greater brain connectivity in the parahippocampus, right hippocampus, and temporal cortex (limbic-temporal network). Group differences (with vs. without type 2 diabetes) were noted in several brain networks. Connectivity in the limbic-temporal and frontal-parietal brain clusters inversely correlated with hunger. CONCLUSIONS: A short-term low-calorie diet led to a multifaceted body response in patients with obesity, with an increase in connectivity in the limbic-temporal network (emotion and memory) and hormone and eating behavior changes that may be important for recovering the weight lost.
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Encéfalo , Restricción Calórica , Diabetes Mellitus Tipo 2 , Hambre , Imagen por Resonancia Magnética , Obesidad , Pérdida de Peso , Humanos , Obesidad/fisiopatología , Obesidad/dietoterapia , Masculino , Femenino , Pérdida de Peso/fisiología , Adulto , Persona de Mediana Edad , Hambre/fisiología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Leptina/sangre , Glucemia/metabolismo , Ingestión de Alimentos/fisiologíaRESUMEN
OBJECTIVE: Obesity is associated with alterations in eating behavior and neurocognitive function. In this study, we investigate the effect of obesity on brain energy utilization, including brain glucose transport and metabolism. METHODS: A total of 11 lean participants and 7 young healthy participants with obesity (mean age, 27 years) underwent magnetic resonance spectroscopy scanning coupled with a hyperglycemic clamp (target, ~180 mg/dL) using [1-13C] glucose to measure brain glucose uptake and metabolism, as well as peripheral markers of insulin resistance. RESULTS: Individuals with obesity demonstrated an ~20% lower ratio of brain glucose uptake to cerebral glucose metabolic rate (Tmax/CMRglucose) than lean participants (2.12 ± 0.51 vs. 2.67 ± 0.51; p = 0.04). The cerebral tricarboxylic acid cycle flux (VTCA) was similar between the two groups (p = 0.64). There was a negative correlation between total nonesterified fatty acids and Tmax/CMRglucose (r = -0.477; p = 0.045). CONCLUSIONS: We conclude that CMRglucose is unlikely to differ between groups due to similar VTCA, and, therefore, the glucose transport Tmax is lower in individuals with obesity. These human findings suggest that obesity is associated with reduced cerebral glucose transport capacity even at a young age and in the absence of other cardiometabolic comorbidities, which may have implications for long-term brain function and health.
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Encéfalo , Glucosa , Resistencia a la Insulina , Obesidad , Humanos , Adulto , Obesidad/metabolismo , Masculino , Femenino , Glucosa/metabolismo , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Adulto Joven , Glucemia/metabolismo , Espectroscopía de Resonancia Magnética , Ciclo del Ácido Cítrico , Transporte Biológico , Técnica de Clampeo de la Glucosa , Metabolismo Energético , Ácidos Grasos no Esterificados/sangre , Ácidos Grasos no Esterificados/metabolismo , Imagen por Resonancia MagnéticaRESUMEN
In the century since the discovery of insulin, diabetes has changed from an early death sentence to a manageable chronic disease. This change in longevity and duration of diabetes coupled with significant advances in therapeutic options for patients has fundamentally changed the landscape of diabetes management, particularly in patients with type 1 diabetes mellitus. However, hypoglycemia remains a major barrier to achieving optimal glycemic control. Current understanding of the mechanisms of hypoglycemia has expanded to include not only counter-regulatory hormonal responses but also direct changes in brain glucose, fuel sensing, and utilization, as well as changes in neural networks that modulate behavior, mood, and cognition. Different strategies to prevent and treat hypoglycemia have been developed, including educational strategies, new insulin formulations, delivery devices, novel technologies, and pharmacologic targets. This review article will discuss current literature contributing to our understanding of the myriad of factors that lead to the development of clinically meaningful hypoglycemia and review established and novel therapies for the prevention and treatment of hypoglycemia.
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Diabetes Mellitus Tipo 1 , Hipoglucemia , Humanos , Hipoglucemia/etiología , Hipoglucemia/terapia , Diabetes Mellitus Tipo 1/terapia , Insulina/uso terapéutico , Glucosa , Glucemia , Hipoglucemiantes/uso terapéuticoRESUMEN
CONTEXT: The neural regulation of appetite and energy homeostasis significantly overlaps with the neurobiology of stress. Frequent exposure to repeated acute stressors may cause increased allostatic load and subsequent dysregulation of the cortico-limbic striatal system leading to inefficient integration of postprandial homeostatic and hedonic signals. It is therefore important to understand the neural mechanisms by which stress generates alterations in appetite that may drive weight gain. OBJECTIVE: To determine glucocorticoid effects on metabolic, neural and behavioral factors that may underlie the association between glucocorticoids, appetite and obesity risk. METHODS: A randomized double-blind cross-over design of overnight infusion of hydrocortisone or saline followed by a fasting morning perfusion magnetic resonance imaging to assess regional cerebral blood flow (CBF) was completed. Visual Analog Scale (VAS) hunger, cortisol and metabolic hormones were also measured. RESULTS: Hydrocortisone relative to saline significantly decreased whole brain voxel based CBF responses in the hypothalamus and related cortico-striatal-limbic regions. Hydrocortisone significantly increased hunger VAS pre-scan, insulin, glucose and leptin, but not other metabolic hormones versus saline CBF groups. Hydrocortisone related increases in hunger were predicted by less reduction of CBF (hydrocortisone minus saline) in the medial OFC, medial brainstem and thalamus, left primary sensory cortex and right superior and medial temporal gyrus. Hunger ratings were also positively associated with plasma insulin on hydrocortisone but not saline day. CONCLUSIONS: Increased glucocorticoids at levels akin to those experienced during psychological stress, result in increased fasting hunger and decreased regional cerebral blood flow in a distinct brain network of prefrontal, emotional, reward, motivation, sensory and homeostatic regions that underlie control of food intake.
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Glucocorticoides , Hambre , Humanos , Glucocorticoides/farmacología , Hambre/fisiología , Apetito/fisiología , Circulación Cerebrovascular , Insulina/metabolismo , Hidrocortisona , Imagen por Resonancia MagnéticaRESUMEN
OBJECTIVE: Maternal obesity increases the incidence of excess adiposity in newborns, resulting in lifelong diabetes risk. Elevated intrauterine fetal adiposity has been attributed to maternal hyperglycemia; however, this hypothesis does not account for the increased adiposity seen in newborns of mothers with obesity who have euglycemia. We aimed to explore the placental response to maternal hyperinsulinemia and the effect of insulin-like growth factor 2 (IGF-2) in promoting fetal adiposity by increasing storage and availability of nutrients to the fetus. METHODS: We used placental villous explants and isolated trophoblasts from normal weight and obese women to assess the effect of insulin and IGF-2 on triglyceride content and insulin receptor signaling. Stable isotope tracer methods were used ex vivo to determine effect of hormone treatment on de novo lipogenesis (DNL), fatty acid uptake, fatty acid oxidation, and esterification in the placenta. RESULTS: Here we show that placentae from euglycemic women with normal weight and obesity both have abundant insulin receptor. Placental depth and triglyceride were greater in women with obesity compared with normal weight women. In syncytialized placental trophoblasts and villous explants, insulin and IGF-2 activate insulin receptor, induce expression of lipogenic transcription factor SREBP-1 (sterol regulatory element-binding protein 1), and stimulate triglyceride accumulation. We demonstrate elevated triglyceride is attributable to increased esterification of fatty acids, without contribution from DNL and without an acceleration of fatty acid uptake. CONCLUSIONS: Our work reveals that obesity-driven aberrations in maternal metabolism, such as hyperinsulinemia, alter placental metabolism in euglycemic conditions, and may explain the higher prevalence of excess adiposity in the newborns of obese women.
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Hiperinsulinismo , Obesidad Materna , Adiposidad , Ácidos Grasos/metabolismo , Femenino , Feto/metabolismo , Humanos , Hiperinsulinismo/metabolismo , Recién Nacido , Insulina/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Masculino , Obesidad/metabolismo , Placenta/metabolismo , Embarazo , Receptor de Insulina/metabolismo , Triglicéridos/metabolismoRESUMEN
AIMS/HYPOTHESIS: We have previously shown that individuals with uncontrolled type 2 diabetes have a blunted rise in brain glucose levels measured by 1H magnetic resonance spectroscopy. Here, we investigate whether reductions in HbA1c normalise intracerebral glucose levels. METHODS: Eight individuals (two men, six women) with poorly controlled type 2 diabetes and mean ± SD age 44.8 ± 8.3 years, BMI 31.4 ± 6.1 kg/m2 and HbA1c 84.1 ± 16.2 mmol/mol (9.8 ± 1.4%) underwent 1H MRS scanning at 4 Tesla during a hyperglycaemic clamp (~12.21 mmol/l) to measure changes in cerebral glucose at baseline and after a 12 week intervention that improved glycaemic control through the use of continuous glucose monitoring, diabetes regimen intensification and frequent visits to an endocrinologist and nutritionist. RESULTS: Following the intervention, mean ± SD HbA1c decreased by 24.3 ± 15.3 mmol/mol (2.1 ± 1.5%) (p=0.006), with minimal weight changes (p=0.242). Using a linear mixed-effects regression model to compare glucose time courses during the clamp pre and post intervention, the pre-intervention brain glucose level during the hyperglycaemic clamp was significantly lower than the post-intervention brain glucose (p<0.001) despite plasma glucose levels during the hyperglycaemic clamp being similar (p=0.266). Furthermore, the increases in brain glucose were correlated with the magnitude of improvement in HbA1c (r = 0.71, p=0.048). CONCLUSION/INTERPRETATION: These findings highlight the potential reversibility of cerebral glucose transport capacity and metabolism that can occur in individuals with type 2 diabetes following improvement of glycaemic control. Trial registration ClinicalTrials.gov NCT03469492.
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Diabetes Mellitus Tipo 2 , Hiperglucemia , Adulto , Glucemia/metabolismo , Automonitorización de la Glucosa Sanguínea , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Glucosa , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Cinética , Masculino , Persona de Mediana EdadRESUMEN
Glucose is the primary energy source for the brain, and exposure to both high and low levels of glucose has been associated with numerous adverse central nervous system (CNS) outcomes. While a large body of work has highlighted the impact of hyperglycemia on peripheral and central measures of oxidative stress, cognitive deficits, and vascular complications in Type 1 and Type 2 diabetes, there is growing evidence that glycemic variability significantly drives increased oxidative stress, leading to neuroinflammation and cognitive dysfunction. In this review, the latest data on the impact of glycemic variability on brain function and neuroinflammation will be presented. Because high levels of oxidative stress have been linked to dysfunction of the blood-brain barrier (BBB), special emphasis will be placed on studies investigating the impact of glycemic variability on endothelial and vascular inflammation. The latest clinical and preclinical/in vitro data will be reviewed, and clinical/therapeutic implications will be discussed.
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Glucemia/metabolismo , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Sistema Nervioso Central/fisiopatología , Hiperglucemia/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Barrera Hematoencefálica/fisiopatología , Encéfalo/metabolismo , Control Glucémico , Humanos , InflamaciónRESUMEN
OBJECTIVE: In this study, we assess the impact of obesity and diabetes on maternal brain and periphery, as well as fetal exposure to insulin and leptin, and two hormones that play an important role in regulating energy homeostasis. STUDY DESIGN: Fasting maternal plasma, fetal cord vein and artery plasma, and maternal cerebrospinal fluid (CSF) were collected in 37 women (12 lean, nondiabetic [prepregnancy body mass index (BMI): 22.9 ± 1.7 kg/m2]; 12 overweight/obese nondiabetic [BMI: 37.8 ± 7.3 kg/m2]; 13 gestational/type 2 diabetes mellitus [BMI: 29.8 ± 7.3 kg/m2]) with uncomplicated singleton pregnancies undergoing elective Cesarean delivery. HbA1C, insulin, glucose, and leptin levels were measured. RESULTS: Compared with lean mothers, mothers with obesity and diabetes mellitus (DM) had significantly lower CSF-to-plasma ratios of insulin. Moreover, mothers with obesity and DM had significantly lower cord arterial and cord venous to maternal plasma ratios of insulin, but not leptin, compared with lean mothers. There were no differences in CSF and cord blood insulin and leptin levels between obese and DM mothers. CONCLUSION: Compared with lean individuals, mothers with obesity and DM have relative deficiencies in insulin exposure. The patterns observed in mothers with obesity and diabetes were similar highlighting the importance of the maternal metabolic environment in obesity and suggesting obese patients warrant further clinical focus.
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Diabetes Gestacional/metabolismo , Insulina/metabolismo , Leptina/metabolismo , Obesidad/metabolismo , Adulto , Peso al Nacer , Glucemia/metabolismo , Índice de Masa Corporal , Diabetes Gestacional/sangre , Diabetes Gestacional/líquido cefalorraquídeo , Femenino , Sangre Fetal/metabolismo , Hemoglobina Glucada/metabolismo , Humanos , Recién Nacido , Obesidad/sangre , Obesidad/líquido cefalorraquídeo , Embarazo , Complicaciones del EmbarazoRESUMEN
The energy-dissipating properties of brown adipose tissue (BAT) have been proposed as therapeutic targets for obesity and diabetes. Little is known about basal BAT activity. Capitalizing on the dense sympathetic innervation of BAT, we have previously shown that BAT can be detected in humans under resting room temperature (RT) conditions by using (S,S)-11C-O-methylreboxetine (MRB), a selective ligand for the norepinephrine transporter (NET). In this study, we determine whether MRB labeling of human BAT is altered by obesity. Fifteen healthy, nondiabetic Caucasian women (nine lean, age 25.6 ± 1.7, BMI 21.8 ± 1.3 kg/m2; six obese age 30.8 ± 8.8 BMI 37.9 ± 6.6 kg/m2) underwent PET-CT imaging of the neck/supraclavicular region using 11C-MRB under RT conditions. The distribution volume ratio (DVR) for 11C-MRB was estimated via multilinear reference tissue model 2 (MRTM2) referenced to the occipital cortex. Two women (one lean and one with obesity) had no detectable BAT. Of the women with detectable BAT, women with obesity had lower 11C-MRB DVR (0.80 ± 0.12 BAT DVR) compared to lean (1.15 ± 0.19 BAT DVR) (p = 0.004). Our findings are consistent with reports that NET is decreased in obesity and suggest that the sympathetic innervation of BAT is altered in obesity.
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Tejido Adiposo Pardo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Obesidad , Tejido Adiposo Pardo/diagnóstico por imagen , Tejido Adiposo Pardo/metabolismo , Adulto , Radioisótopos de Carbono/farmacocinética , Femenino , Humanos , Obesidad/diagnóstico por imagen , Obesidad/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones , Reboxetina/farmacocinética , Adulto JovenRESUMEN
CONTEXT: Individuals with type 1 diabetes mellitus (T1DM) have alterations in brain activity that have been postulated to contribute to the adverse neurocognitive consequences of T1DM; however, the impact of T1DM and hypoglycemic unawareness on the brain's resting state activity remains unclear. OBJECTIVE: To determine whether individuals with T1DM and hypoglycemia unawareness (T1DM-Unaware) had changes in the brain resting state functional connectivity compared to healthy controls (HC) and those with T1DM and hypoglycemia awareness (T1DM-Aware). DESIGN: Observational study. SETTING: Academic medical center. PARTICIPANTS: 27 individuals with T1DM and 12 HC volunteers participated in the study. INTERVENTION: All participants underwent blood oxygenation level dependent (BOLD) resting state functional magnetic brain imaging during a 2-step hyperinsulinemic euglycemic (90 mg/dL)-hypoglycemic (60 mg/dL) clamp. OUTCOME: Changes in resting state functional connectivity. RESULTS: Using 2 separate methods of functional connectivity analysis, we identified distinct differences in the resting state brain responses to mild hypoglycemia between HC, T1DM-Aware, and T1DM-Unaware participants, particularly in the angular gyrus, an integral component of the default mode network (DMN). Furthermore, changes in angular gyrus connectivity also correlated with greater symptoms of hypoglycemia (r = 0.461, P = 0.003) as well as higher scores of perceived stress (r = 0.531, P = 0.016). CONCLUSION: These findings provide evidence that individuals with T1DM have changes in the brain's resting state connectivity patterns, which may be further associated with differences in awareness to hypoglycemia. These changes in connectivity may be associated with alterations in functional outcomes among individuals with T1DM.
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Encéfalo/patología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemia/patología , Hipoglucemiantes/efectos adversos , Vías Nerviosas/patología , Adulto , Biomarcadores/análisis , Encéfalo/efectos de los fármacos , Mapeo Encefálico , Estudios de Casos y Controles , Conectoma , Diabetes Mellitus Tipo 1/patología , Femenino , Estudios de Seguimiento , Humanos , Hipoglucemia/inducido químicamente , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/efectos de los fármacos , PronósticoRESUMEN
PURPOSE: Changes in blood glucose levels have been shown to influence eating in healthy individuals; however, less is known about effects of glucose on food intake in individuals who are obese (OB). The goal of this study was to determine the predictive effect of circulating glucose levels on eating in free-living OB and normal weight (NW) individuals. METHODS: Interstitial glucose levels, measured with a continuous glucose monitor (CGM) system, were obtained from 15 OB and 16 NW volunteers (age: 40 ± 14 and 37 ± 12 years; weight: 91 ± 13 and 68 ± 12 kg; hemoglobin A1c: 5.1% ± 0.7% and 5.2% ± 0.4%, respectively). While wearing the CGM, participants filled out a food log (mealtime, hunger rating, and amount of food). Glucose profiles were measured in relation to their meals [macro program (CGM peak and nadir analysis) using Microsoft® Excel]. RESULTS: OB and NW individuals showed comparable CGM glucose levels: mean [OB = 100 ± 8 mg/dL; NW = 99 ± 13 mg/dL; P = nonsignificant (NS)] and SD (OB = 18 ± 5 mg/dL, NW = 18 ± 4 mg/dL; P = NS). Obesity was associated with slower postprandial rate of changing glucose levels (P = 0.04). Preprandial nadir glucose levels predicted hunger and food intake in both groups (P < 0.0001), although hunger was associated with greater food intake in OB individuals than in NW individuals (P = 0.008 for group interaction). CONCLUSIONS: Premeal glucose nadir predicted hunger and food intake in a group of free-living, healthy, nondiabetic NW and OB individuals; however for a similar low glucose level stimulus, hunger-induced food intake was greater in OB than NW individuals.
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BACKGROUND: Aging is a complex physiological phenomenon, intricately associated with cardiovascular pathologies, where platelets play a central pathophysiological role. Although antiplatelets are commonly employed to prevent and treat major adverse cardiovascular events, aging associated intraplatelet changes remain largely unexplored. METHODS: Platelets were studied in high cardiovascular risk patients (aged 40-100â¯years) comparing them to younger healthy subjects. This was followed by cross sectional and longitudinal mice studies. Flow cytometry, biochemical and molecular assays were used to study platelets comprehensively. FINDINGS: CVD Patients were categorized in the age groups 40-59, 60-79, and 80-100â¯years. Progressive decline in platelet health was observed in the 40-79â¯years age cohort, marked by increase in oxidative stress, hyperactivation and apoptotic markers. Paradoxically, this was reversed in patients aged above 79â¯years and the improved platelet phenotype was associated with lower oxidative damage. The platelets from the very old (80-100â¯year) group were found to be preloaded with increased antioxidants, which also contributed to higher resistance against induced redox insults. Cross sectional mouse studies excluded the effect of comorbidities and medications. Longitudinal mouse studies implicate an adaptive increase in antioxidant levels as the mechanism. INTERPRETATION: We report a novel age associated, non-linear redox regulation in platelets in both humans and mice. In advanced age, there occurs an adaptive increase in platelet antioxidants, reducing the intracellular ROS and leading to a healthier platelet phenotype. Clinically, our results advocate the use of less aggressive antiplatelet therapies for CVD in the elderly population. FUND: Study funded by NIH-NHLBI, RO1-HL122815 and RO1-HL115247.
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Envejecimiento/metabolismo , Plaquetas/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Adaptación Fisiológica , Factores de Edad , Anciano , Anciano de 80 o más Años , Envejecimiento/sangre , Animales , Antioxidantes/metabolismo , Apoptosis , Biomarcadores , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/metabolismo , Comorbilidad , Modelos Animales de Enfermedad , Femenino , Homeostasis , Humanos , Masculino , Ratones , Persona de Mediana Edad , Activación Plaquetaria , Adhesividad Plaquetaria , Especies Reactivas de Oxígeno/metabolismo , Medición de Riesgo , Factores de RiesgoAsunto(s)
Antibacterianos/uso terapéutico , Tirantes , Fiebre/etiología , Linfadenopatía/diagnóstico , Dolor de Cuello/etiología , Tortícolis/diagnóstico , Niño , Femenino , Fiebre/tratamiento farmacológico , Humanos , Linfadenopatía/fisiopatología , Linfadenopatía/terapia , Dolor de Cuello/tratamiento farmacológico , Tomografía Computarizada por Rayos X , Tortícolis/fisiopatología , Tortícolis/terapiaRESUMEN
The impact of glycemic variability on brain glucose transport kinetics among individuals with type 1 diabetes mellitus (T1DM) remains unclear. Fourteen individuals with T1DM (age 35 ± 4 years; BMI 26.0 ± 1.4 kg/m2; HbA1c 7.6 ± 0.3) and nine healthy control participants (age 32 ± 4; BMI 23.1 ± 0.8; HbA1c 5.0 ± 0.1) wore a continuous glucose monitor (Dexcom) to measure hypoglycemia, hyperglycemia, and glycemic variability for 5 days followed by 1H MRS scanning in the occipital lobe to measure the change in intracerebral glucose levels during a 2-h glucose clamp (target glucose concentration 220 mg/dL). Hyperglycemic clamps were also performed in a rat model of T1DM to assess regional differences in brain glucose transport and metabolism. Despite a similar change in plasma glucose levels during the hyperglycemic clamp, individuals with T1DM had significantly smaller increments in intracerebral glucose levels (P = 0.0002). Moreover, among individuals with T1DM, the change in brain glucose correlated positively with the lability index (r = 0.67, P = 0.006). Consistent with findings in humans, streptozotocin-treated rats had lower brain glucose levels in the cortex, hippocampus, and striatum compared with control rats. These findings that glycemic variability is associated with brain glucose levels highlight the need for future studies to investigate the impact of glycemic variability on brain glucose kinetics.
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Encéfalo/metabolismo , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/metabolismo , Glucosa/metabolismo , Adulto , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Femenino , Hemoglobina Glucada , Humanos , Hiperglucemia/sangre , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Hipoglucemiantes/uso terapéutico , Masculino , Modelos Teóricos , Ratas , Ratas Sprague-DawleyAsunto(s)
Lesiones Encefálicas , Disfunción Cognitiva , Hipoglucemia , Encéfalo , Humanos , Hipoglucemiantes , VerapamiloRESUMEN
Context: Hypoglycemia, one of the major factors limiting optimal glycemic control in insulin-treated patients with diabetes, elicits a brain response to restore normoglycemia by activating counterregulation. Animal data indicate that local release of norepinephrine (NE) in the hypothalamus is important for triggering hypoglycemia-induced counterregulatory (CR) hormonal responses. Objective: To examine the potential role of brain noradrenergic (NA) activation in humans during hypoglycemia. Design: A hyperinsulinemic-hypoglycemic clamp was performed in conjunction with positron emission tomographic imaging. Participants: Nine lean healthy volunteers were studied during the hyperinsulinemic-hypoglycemic clamp. Design: Participants received intravenous injections of (S,S)-[11C]O-methylreboxetine ([11C]MRB), a highly selective NE transporter (NET) ligand, at baseline and during hypoglycemia. Results: Hypoglycemia increased plasma epinephrine, glucagon, cortisol, and growth hormone and decreased [11C]MRB binding potential (BPND) by 24% ± 12% in the raphe nucleus (P < 0.01). In contrast, changes in [11C]MRB BPND in the hypothalamus positively correlated with increments in epinephrine and glucagon levels and negatively correlated with glucose infusion rate (all P < 0.05). Furthermore, in rat hypothalamus studies, hypoglycemia induced NET translocation from the cytosol to the plasma membrane. Conclusions: Insulin-induced hypoglycemia initiated a complex brain NA response in humans. Raphe nuclei, a region involved in regulating autonomic output, motor activity, and hunger, had increased NA activity, whereas the hypothalamus showed a NET-binding pattern that was associated with the individual's CR response magnitude. These findings suggest that NA output most likely is important for modulating brain responses to hypoglycemia in humans.
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Encéfalo/metabolismo , Hipoglucemia/metabolismo , Norepinefrina/metabolismo , Adulto , Glucemia , Encéfalo/diagnóstico por imagen , Epinefrina/sangre , Femenino , Glucagón/sangre , Hormona de Crecimiento Humana/sangre , Humanos , Hidrocortisona/sangre , Hipoglucemia/diagnóstico por imagen , Masculino , Tomografía de Emisión de PositronesRESUMEN
Blood glucose levels influence brain regulation of food intake. This study assessed the effect of mild physiological hyperglycemia on brain response to food cues in individuals with obesity (OB) versus normal weight individuals (NW). Brain responses in 10 OB and 10 NW nondiabetic healthy adults [body mass index: 34 (3) vs. 23 (2) kg/m2, means (SD), P < 0.0001] were measured with functional MRI (blood oxygen level-dependent contrast) in combination with a two-step normoglycemic-hyperglycemic clamp. Participants were shown food and nonfood images during normoglycemia (~95 mg/dl) and hyperglycemia (~130 mg/dl). Plasma glucose levels were comparable in both groups during the two-step clamp ( P = not significant). Insulin and leptin levels were higher in the OB group compared with NW, whereas ghrelin levels were lower (all P < 0.05). During hyperglycemia, insula activity showed a group-by-glucose level effect. When compared with normoglycemia, hyperglycemia resulted in decreased activity in the hypothalamus and putamen in response to food images ( P < 0.001) in the NW group, whereas the OB group exhibited increased activity in insula, putamen, and anterior and dorsolateral prefrontal cortex (aPFC/dlPFC; P < 0.001). These data suggest that OB, compared with NW, appears to have disruption of brain responses to food cues during hyperglycemia, with reduced insula response in NW but increased insula response in OB, an area involved in food perception and interoception. In a post hoc analysis, brain activity in obesity appears to be associated with dysregulated motivation (striatum) and inappropriate self-control (aPFC/dlPFC) to food cues during hyperglycemia. Hyperstimulation for food and insensitivity to internal homeostatic signals may favor food consumption to possibly play a role in the pathogenesis of obesity.
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Encefalopatías/etiología , Alimentos , Hiperglucemia/complicaciones , Hiperglucemia/psicología , Obesidad/complicaciones , Obesidad/psicología , Administración Intravenosa , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Encefalopatías/diagnóstico por imagen , Encefalopatías/fisiopatología , Cognición/fisiología , Señales (Psicología) , Femenino , Glucosa/administración & dosificación , Glucosa/efectos adversos , Humanos , Hiperglucemia/inducido químicamente , Hiperglucemia/diagnóstico , Imagen por Resonancia Magnética , Masculino , Obesidad/diagnóstico , Obesidad/fisiopatología , Estimulación Luminosa , Adulto JovenRESUMEN
BACKGROUND: Among nondiabetic individuals, mild glucose decrements alter brain activity in regions linked to reward, motivation, and executive control. Whether these effects differ in type 1 diabetes mellitus (T1DM) patients with and without hypoglycemia awareness remains unclear. METHODS: Forty-two individuals (13 healthy control [HC] subjects, 16 T1DM individuals with hypoglycemia awareness [T1DM-Aware], and 13 T1DM individuals with hypoglycemia unawareness [T1DM-Unaware]) underwent blood oxygen level-dependent functional MRI brain imaging during a 2-step hyperinsulinemic euglycemic (90 mg/dl)-hypoglycemic (60 mg/dl) clamp for assessment of neural responses to mild hypoglycemia. RESULTS: Mild hypoglycemia in HC subjects altered activity in the caudate, insula, prefrontal cortex, and angular gyrus, whereas T1DM-Aware subjects showed no caudate and insula changes, but showed altered activation patterns in the prefrontal cortex and angular gyrus. Most strikingly, in direct contrast to HC and T1DM-Aware subjects, T1DM-Unaware subjects failed to show any hypoglycemia-induced changes in brain activity. These findings were also associated with blunted hormonal counterregulatory responses and hypoglycemia symptom scores during mild hypoglycemia. CONCLUSION: In T1DM, and in particular T1DM-Unaware patients, there is a progressive blunting of brain responses in cortico-striatal and fronto-parietal neurocircuits in response to mild-moderate hypoglycemia. These findings have implications for understanding why individuals with impaired hypoglycemia awareness fail to respond appropriately to falling blood glucose levels. FUNDING: This study was supported in part by NIH grants R01DK020495, P30 DK045735, K23DK109284, K08AA023545. The Yale Center for Clinical Investigation is supported by an NIH Clinical Translational Science Award (UL1 RR024139).
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Concienciación , Glucemia/metabolismo , Corteza Cerebral , Diabetes Mellitus Tipo 1 , Hipoglucemia , Imagen por Resonancia Magnética , Adolescente , Adulto , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/diagnóstico por imagen , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Humanos , Hipoglucemia/sangre , Hipoglucemia/diagnóstico por imagen , Hipoglucemia/fisiopatología , Masculino , Persona de Mediana EdadRESUMEN
71/F presented with left sided headaches and neck pain with nuchal rigidity progressively worsening over 3 weeks with no other neurologic symptoms. Odontoid osteomyelitis with epidural abscess was discovered on further workup with neuroimaging. Concurrent jugular vein and transverse sinus venous thrombosis was also found and suspected to be secondary to the pyogenic odontoid osteomyelitis. Patient was treated with intravenous antibiotics for the osteomyelitis as well as intravenous heparin for the venous thrombosis. To our knowledge, this is the first case reported in literature of transverse sinus venous thrombosis secondary to odontoid osteomyelitis.