RESUMEN
Increasing levels of physical inactivity is a global burden for mankind and is also an emerging problem in companion dogs. In both humans and dogs, insufficient physical activity is associated with increased risk for noncommunicable diseases and impaired quality of life (QoL). The aim of the current pilot study was to evaluate effects of a joint outdoor exercise program for dog owners (n = 22) and dogs (n = 22) with focus on QoL and body measurements. Results indicate that an eight-week exercise intervention alone, with a target distance of at least 2 km twice a week, may be sufficient to significantly increase self-reported QoL and acceptance of bodily appearance in dog owners despite no reductions in body measurements. In dogs, a significantly reduced body condition score (BCS) was registered, despite no considerable changes in feeding. The increased owner motivation for continued joint exercise suggests potential for lifestyle changes, which could be investigated in future studies including control groups and long-term follow-ups. The importance of the human-animal bond as a success factor for increased mutual physical activity and health benefits in both dog owners and dogs is recommended to be studied in a more in-depth manner.
Asunto(s)
Ejercicio Físico , Calidad de Vida , Perros , Animales , Proyectos Piloto , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Vínculo Humano-Animal , Mascotas/psicología , Condicionamiento Físico Animal , PropiedadRESUMEN
Automated quantification of tissue morphology and tracer uptake in PET/MR images could streamline the analysis compared to traditional manual methods. To validate a single atlas image segmentation approach for automated assessment of tissue volume, fat content (FF) and glucose uptake (GU) from whole-body [18F]FDG-PET/MR images. Twelve subjects underwent whole-body [18F]FDG-PET/MRI during hyperinsulinemic-euglycemic clamp. Automated analysis of tissue volumes, FF and GU were achieved using image registration to a single atlas image with reference segmentations of 18 volume of interests (VOIs). Manual segmentations by an experienced radiologist were used as reference. Quantification accuracy was assessed with Dice scores, group comparisons and correlations. VOI Dice scores ranged from 0.93 to 0.32. Muscles, brain, VAT and liver showed the highest scores. Pancreas, large and small intestines demonstrated lower segmentation accuracy and poor correlations. Estimated tissue volumes differed significantly in 8 cases. Tissue FFs were often slightly but significantly overestimated. Satisfactory agreements were observed in most tissue GUs. Automated tissue identification and characterization using a single atlas segmentation performs well compared to manual segmentation in most tissues and will be valuable in future studies. In certain tissues, alternative quantification methods or improvements to the current approach is needed.
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Procesamiento de Imagen Asistido por Computador/métodos , Imagen de Cuerpo Entero/métodos , Anciano , Algoritmos , Fenómenos Bioquímicos , Encéfalo/fisiología , Femenino , Fluorodesoxiglucosa F18 , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Hígado/fisiología , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Imagen Multimodal/métodos , Tomografía de Emisión de Positrones/métodos , Reproducibilidad de los Resultados , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND: The aims of this study were to estimate the risk for diabetic retinopathy (DR) and to identify risk factors. We investigated a nationwide population-based cohort with diabetes diagnosed at age 15-34years. PATIENTS AND METHODS: Of 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) 444 (56%) patients with retinal photos available for classification of retinopathy participated in a follow-up study 15-19 (median 17) years after diagnosis. Mean age was 42.3±5.7years, BMI 26.1±4.1kg/m2, 62% were male and 91% had type 1 diabetes. A sub-study was performed in 367 patients with retinal photos from both the 9 and 17year follow up and the risk for development of retinopathy between 9 and 17years of follow up was calculated. RESULTS: After median 17years 324/444 (73%, 67% of T1D and 71% of T2D), had developed any DR but only 5.4% proliferative DR. Male sex increased the risk of developing retinopathy (OR 1.9, 95% CI 1.2-2.9). In the sub-study obesity (OR 1.2, 95% CI 1.04-1.4), hyperglycemia (OR 2.5, 95% CI 1.6-3.8) and tobacco use (OR 2.9, 95% CI 1.1-7.3) predicted onset of retinopathy between 9 and 17years after diagnosis of diabetes. CONCLUSION: The number of patients with severe retinopathy after 17years of diabetes disease was small. The risk of developing retinopathy with onset between 9 and 17years after diagnosis of diabetes was strongly associated to modifiable risk factors such as glycemic control, obesity and tobacco use.
Asunto(s)
Glucemia/metabolismo , Complicaciones de la Diabetes/etiología , Retinopatía Diabética/etiología , Hiperglucemia/complicaciones , Sobrepeso/complicaciones , Uso de Tabaco/efectos adversos , Adolescente , Adulto , Estudios de Cohortes , Complicaciones de la Diabetes/epidemiología , Retinopatía Diabética/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Hiperglucemia/fisiopatología , Masculino , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: 11ß-hydroxysteroid dehydrogenase type I (11ß-HSD1), a target for Type 2 diabetes mellitus, converts inactive glucocorticoids into bioactive forms, increasing tissue concentrations. We have compared the pharmacokinetic-pharmacodynamic (PK/PD) relationship of target inhibition after acute and repeat administration of inhibitors of 11ß-HSD1 activity in human, rat and mouse adipose tissue (AT). EXPERIMENTAL APPROACH: Studies included abdominally obese human volunteers, rats and mice. Two specific 11ß-HSD1 inhibitors (AZD8329 and COMPOUND-20) were administered as single oral doses or repeat daily doses for 7-9 days. 11ß-HSD1 activity in AT was measured ex vivo by conversion of (3) H-cortisone to (3) H-cortisol. KEY RESULTS: In human and rat AT, inhibition of 11ß-HSD1 activity was lost after repeat dosing of AZD8329, compared with acute administration. Similarly, in rat AT, there was loss of inhibition of 11ß-HSD1 activity after repeat dosing with COMPOUND-20 with continuous drug cover, but effects were substantially reduced if a 'drug holiday' period was maintained daily. Inhibition of 11ß-HSD1 activity was not lost in mouse AT after continuous cover with COMPOUND-20 for 7 days. CONCLUSIONS AND IMPLICATIONS: Human and rat AT, but not mouse AT, exhibited tachyphylaxis for inhibition of 11ß-HSD1 activity after repeat dosing. Translation of observed efficacy in murine disease models to human for 11ß-HSD1 inhibitors may be misleading. Investigators of the effects of 11ß-HSD1 inhibitors should confirm that desired levels of enzyme inhibition in AT can be maintained over time after repeat dosing and not rely on results following a single dose.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Tejido Adiposo/enzimología , Benzoatos/farmacología , Dipéptidos/farmacología , Pirazoles/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Animales , Benzoatos/sangre , Benzoatos/farmacocinética , Dipéptidos/sangre , Dipéptidos/farmacocinética , Humanos , Masculino , Ratones , Pirazoles/sangre , Pirazoles/farmacocinética , Ratas , TaquifilaxisRESUMEN
AIMS: The main objective of this study was to estimate the occurrence of diabetic nephropathy in a population-based cohort of patients diagnosed with diabetes as young adults (15-34 years). METHODS: All 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) were invited to a follow-up study 15-19 years after diagnosis, and 468 (58%) participated. Analysis of islet antibodies was used to classify type of diabetes. RESULTS: After median 17 years of diabetes, 15% of all patients, 14% T1DM and 25% T2DM, were diagnosed with diabetic nephropathy. Ninety-one percent had microalbuminuria and 8.6% macroalbuminuria. Older age at diagnosis (HR 1.05; 95% CI 1.01-1.10 per year) was an independent and a higher BMI at diabetes diagnosis (HR 1.04; 95% CI 1.00-1.09 per 1 kg/m²), a near-significant predictor of development of diabetic nephropathy. Age at onset of diabetes (p = 0.041), BMI (p = 0.012) and HbA1c (p < 0.001) were significant predictors of developing diabetic nephropathy between 9 and 17 years of diabetes. At 17 years of diabetes duration, a high HbA1c level (OR 1.06; 95% CI 1.03-1.08 per 1 mmol/mol increase) and systolic blood pressure (OR 1.08; 95% CI 1.05 1.12 per 1 mmHg increase) were associated with DN. CONCLUSIONS: Patients with T2DM diagnosed as young adults seem to have an increased risk to develop diabetic nephropathy compared with those with T1DM. Older age and higher BMI at diagnosis of diabetes were risk markers for development of diabetic nephropathy. In addition, poor glycaemic control but not systolic blood pressure at 9 years of follow-up was a risk marker for later development of diabetic nephropathy.
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Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/epidemiología , Sobrepeso/complicaciones , Insuficiencia Renal/epidemiología , Adolescente , Adulto , Edad de Inicio , Albuminuria/etiología , Índice de Masa Corporal , Estudios Transversales , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/terapia , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/fisiopatología , Nefropatías Diabéticas/prevención & control , Femenino , Estudios de Seguimiento , Hemoglobina Glucada/análisis , Humanos , Hiperglucemia/prevención & control , Incidencia , Masculino , Insuficiencia Renal/complicaciones , Insuficiencia Renal/fisiopatología , Insuficiencia Renal/prevención & control , Factores de Riesgo , Índice de Severidad de la Enfermedad , Suecia/epidemiología , Adulto JovenRESUMEN
BACKGROUND: New-onset diabetes after transplantation is associated with an increase in risk of graft failure, cardiovascular disease, and mortality. Therefore, it compromises the overall beneficial outcome of organ transplantation. CASE REPORT: A patient with new-onset diabetes after renal transplantation showed glucose and lipid metabolism improvements after switching immunosuppressant from everolimus to cyclosporin A. A subcutaneous adipose tissue biopsy displayed changes in gene and protein expression that could contribute to the clinical improvement of hyperglycemia and dyslipidemia.
Asunto(s)
Tejido Adiposo/metabolismo , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Sirolimus/análogos & derivados , Anciano , Diabetes Mellitus/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Everolimus , Femenino , Glucosa , Humanos , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
Cyclosporine A (CsA) and sirolimus (SRL) are immunosuppressive agents (IA) associated with new-onset diabetes after transplantation (NODAT). This study aims to evaluate the effects of 3-weeks of treatment with either CsA (5 mg/kg BW/day) or SRL (1 mg/kg BW/day) on insulin signaling and expression of markers involved in glucose metabolism in insulin-sensitive tissues, in Wistar rats. Although no differences were observed in fasting glucose, insulin or C-peptide levels, both treated groups displayed an impaired glucose excursion during both glucose and insulin tolerance tests. These results suggest glucose intolerance and insulin resistance. An increase in glucose-6-phosphatase protein levels (68%, p < 0.05) and in protein-tyrosine phosphatase 1B (163%, p < 0.05), a negative regulator of insulin was observed in the CsA-treated group in the liver, indicating enhanced gluconeogenesis and increased insulin resistance. On the other hand, glucokinase protein levels were decreased in the SRL group (35%, p < 0.05) compared to vehicle, suggesting a decrease in glucose disposal. SRL treatment also reduced peroxisome proliferator-activated receptor γ coactivator 1 alpha protein expression in muscle (~50%, p < 0.05), while no further protein alterations were observed in muscle and perirenal adipose tissue nor with the CsA treatment. Moreover, the phosphorylation of key proteins of the insulin signaling cascade was suppressed in the SRL group, but was unchanged by the CsA treatment. Taken together, these data suggest that CsA treatment enhances gluconeogenic factors in liver, while SRL treatment impairs insulin signaling in peripheral tissues, which can contribute to the development of insulin resistance and NODAT associated with immunosuppressive therapy.
Asunto(s)
Ciclosporina/farmacología , Gluconeogénesis/efectos de los fármacos , Inmunosupresores/farmacología , Insulina/metabolismo , Sirolimus/farmacología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Péptido C/sangre , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Glucógeno/metabolismo , Glucosuria/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Proteína Tirosina Fosfatasa no Receptora Tipo 1/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
OBJECTIVE: Simple methods for the evaluation of dynamic b-cell function in epidemiological and clinical studies of patients with type 2 diabetes (T2D) are needed. The aim of this study was to evaluate the dynamic beta-cell function in young patients with T2D with different disease durations and treatments. METHODS: Overall, 54 subjects with T2D from the Diabetes Incidence Study in Sweden (DISS) and 23 healthy control participants were included in this cross-sectional study. Beta-cell function was assessed by intravenous (i.v.) administration of arginine followed by i.v. glucose. The acute insulin and C-peptide responses to arginine (AIRarg and Ac-pepRarg, respectively) and to glucose (AIRglu and Ac-pepRglu, respectively)were estimated.Homeostasis model assessment of b-cell function(HOMA-b) andCpeptide assessments were also used for comparisons between patients with T2D and control participants. RESULTS: AIRarg and Ac-pepRarg, but not AIRglu and Ac-pepRglu, could differentiate between patients with different disease durations. AIRglu values were 89% (P < 0.001) lower and AIRarg values were 29% (P < 0.01) lower in patients with T2D compared with control participants. HOMA-b and fasting plasma C-peptide levels did not differ between the T2D and control groups. CONCLUSION: In young patients with T2D, the insulin secretory response to i.v. glucose is markedly attenuated, whereas i.v. arginine-stimulated insulin release is better preserved and can distinguish between patients with different disease duration and antidiabetic therapies. This suggests that the i.v. arginine stimulation test may provide an estimate of functional beta-cell reserve.
Asunto(s)
Arginina , Péptido C , Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina/metabolismo , Insulina , Administración Intravenosa , Adulto , Arginina/administración & dosificación , Arginina/análisis , Arginina/metabolismo , Péptido C/sangre , Péptido C/metabolismo , Fenómenos Fisiológicos Celulares/efectos de los fármacos , Estudios Transversales , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Glucosa/administración & dosificación , Glucosa/metabolismo , Humanos , Hipoglucemiantes/farmacología , Insulina/sangre , Insulina/metabolismo , Insulina/farmacología , Secreción de Insulina , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
Cyclosporin A (CsA) and sirolimus (SRL) are immunosuppressive agents (IAs) associated with dyslipidemia, insulin resistance and new onset diabetes after transplantation (NODAT). However, the molecular mechanisms involved are not fully understood. We investigated the effects of six-week treatment of either CsA or SRL on glucose and lipid metabolism in Wistar rats. The results show that, compared with vehicle-treated rats, SRL-treated rats were significantly lighter starting at week 5. CsA or SRL caused glucose intolerance, increased storage of lipids in the liver and skeletal muscle, and decreased the insulin-stimulated glucose uptake in isolated adipocytes. Furthermore, these agents significantly decreased genes involved in insulin action and glucose uptake, such as, IRS-1, Glut4 and Glut1, and increased genes and/or proteins involved in hepatic lipogenesis and gluconeogenesis, while decreasing them in adipose tissue. After either treatment PGC1α gene expression was down regulated in skeletal muscle, an important player in fatty acid oxidation. Moreover, there was an increase in IL-6 gene expression in adipose tissue in the SRL-treated rats, suggesting stimulation of lipolysis. The results of the present study suggest that CsA and SRL lead to metabolic alterations in liver, muscle and adipose tissue, which may contribute to the development of dyslipidemia and insulin resistance associated with immunosuppressive therapy.
Asunto(s)
Tejido Adiposo/metabolismo , Ciclosporina/metabolismo , Glucosa/metabolismo , Metabolismo de los Lípidos/fisiología , Músculo Esquelético/metabolismo , Sirolimus/metabolismo , Tejido Adiposo/efectos de los fármacos , Animales , Ciclosporina/farmacología , Inmunosupresores/metabolismo , Inmunosupresores/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Músculo Esquelético/efectos de los fármacos , Ratas , Ratas Wistar , Sirolimus/farmacologíaRESUMEN
AIM: Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight or obese men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor. METHODS: Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 h after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying. RESULTS: Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at the end of treatment. With AZD7687 doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea. CONCLUSIONS: Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.
Asunto(s)
Acetatos/uso terapéutico , Fármacos Antiobesidad/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Diarrea/inducido químicamente , Obesidad/tratamiento farmacológico , Pirazinas/uso terapéutico , Acetatos/efectos adversos , Adulto , Fármacos Antiobesidad/efectos adversos , Diacilglicerol O-Acetiltransferasa/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Vaciamiento Gástrico/efectos de los fármacos , Péptido 1 Similar al Glucagón/efectos de los fármacos , Humanos , Absorción Intestinal/efectos de los fármacos , Masculino , Persona de Mediana Edad , Péptido YY/efectos de los fármacos , Pirazinas/efectos adversos , Resultado del Tratamiento , Pérdida de Peso/efectos de los fármacosRESUMEN
The measurement of tissue lipid and glycogen contents and the establishment of normal levels of variability are important when assessing changes caused by pathology or treatment. We measured hepatic and skeletal muscle lipid and glycogen levels using (1)H and (13)C MRS at 3 T in groups of subjects with and without type 2 diabetes. Within-visit reproducibility, due to repositioning and instrument errors was determined from repeat measurements made over 1 h. Natural variability was assessed from separate measurements made on three occasions over 1 month. Hepatic lipid content was greater in subjects with diabetes relative to healthy subjects (p = 0.03), whereas levels of hepatic and skeletal muscle glycogen, and of intra- and extra-myocellular lipid, were similar. The single-session reproducibility values (coefficient of variation, CV) for hepatic lipid content were 12% and 7% in groups of subjects with and without diabetes, respectively. The variability of hepatic lipid content over 1 month was greater than the reproducibility, with CV = 22% (p = 0.08) and CV = 44% (p = 0.004) in subjects with and without diabetes, respectively. Similarly, levels of variation in basal hepatic glycogen concentrations (subjects with diabetes, CV = 38%; healthy volunteers, CV = 35%) were significantly larger than single-session reproducibility values (CV = 17%, p = 0.02 and CV = 13%, p = 0.05, respectively), indicating substantial biological changes in basal concentrations over 1 month. There was a decreasing correlation in measurements of both hepatic lipid and glycogen content with increasing time between scans. Levels of variability in intra- and extra-myocellular lipid in the soleus muscle, and glycogen concentrations in the gastrocnemius muscle, tended to be larger than expected from single-session reproducibility, although these did not reach significance.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Ayuno/metabolismo , Glucógeno/metabolismo , Metabolismo de los Lípidos , Hígado/metabolismo , Espectroscopía de Resonancia Magnética , Músculo Esquelético/metabolismo , Isótopos de Carbono , Femenino , Humanos , Glucógeno Hepático/metabolismo , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Protones , Reproducibilidad de los ResultadosRESUMEN
This study explored sex differences in 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity and gene expression in isolated adipocytes and adipose tissue (AT), obtained via subcutaneous biopsies from non-diabetic subjects [58 M, 64 F; age 48.3 ± 15.3 years, body mass index (BMI) 27.2 ± 3.9 kg/m²]. Relationships with adiposity and insulin resistance (IR) were addressed. Males exhibited higher 11ß-HSD1 activity in adipocytes than females, but there was no such difference for AT. In both men and women, adipocyte 11ß-HSD1 activity correlated positively with BMI, waist circumference, % body fat, adipocyte size and with serum glucose, triglycerides and low-density lipoprotein:high-density lipoprotein (LDL:HDL) ratio. Positive correlations with insulin, HOMA-IR and haemoglobin A1c (HbA1c) and a negative correlation with HDL-cholesterol were significant only in males. Conversely, 11ß-HSD1 activity in AT correlated with several markers of IR and adiposity in females but not in males, but the opposite pattern was found with respect to 11ß-HSD1 mRNA expression. This study suggests that there are sex differences in 11ß-HSD1 regulation and in its associations with markers of obesity and IR.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adiposidad , Regulación Enzimológica de la Expresión Génica , Resistencia a la Insulina , Sobrepeso/metabolismo , Grasa Subcutánea/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Biomarcadores/sangre , Biomarcadores/metabolismo , Biopsia , Índice de Masa Corporal , Tamaño de la Célula , Células Cultivadas , Femenino , Hemoglobina Glucada/análisis , Humanos , Hiperlipidemias/etiología , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Sobrepeso/complicaciones , Sobrepeso/patología , Sobrepeso/fisiopatología , ARN Mensajero/metabolismo , Caracteres Sexuales , Grasa Subcutánea/enzimología , Grasa Subcutánea/patologíaRESUMEN
Allostatic load (AL) has been shown to be a useful marker of physiological strain during chronic stress and burnout in non-clinical working populations. The usability of the AL index for a clinical population with severe stress-related exhaustion was tested in this study. Thirteen biomarkers assembled as an AL index were analysed using blood samples from 90 patients with stress-related exhaustion (43 men and 47 women, age 31-61 years) and 90 healthy controls (46 men and 44 women, age 25-56 years). The AL scores did not differ between patients and controls. For men, some indication of higher cardiovascular risk was seen in the patient group: male patients had higher body mass index and waist-hip ratio and a poorer blood lipid status than male controls. We found lower plasma glucose concentrations in both female and male patients than those in controls. The male patients also showed increased fasting serum insulin concentrations. Further analysis using homeostasis model assessment for insulin resistance and ß-cell function showed indications of insulin resistance in the patient group, particularly in the males, and an increased insulin secretion in both male and female patients. In conclusion, AL index does not seem to capture plausible physiological strain in patients diagnosed with stress-related exhaustion. The finding of lower plasma glucose concentrations, probably due to higher insulin secretion, in patients with severe stress-related exhaustion, needs to be further investigated, including mechanisms and the clinical relevance.
Asunto(s)
Alostasis/fisiología , Glucemia/metabolismo , Fatiga/metabolismo , Fatiga/psicología , Insulina/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Adulto , Biomarcadores , Presión Sanguínea/fisiología , Índice de Masa Corporal , Proteína C-Reactiva/metabolismo , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Análisis por Conglomerados , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hidrocortisona/metabolismo , Lipoproteínas LDL/sangre , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Pruebas de Función Pancreática , Triglicéridos/sangre , Relación Cintura-CaderaRESUMEN
AIMS: This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamic effects of the glucokinase activator (GKA) AZD6370 in non-diabetic subjects, using the euglycaemic clamp to avoid the risk of hypoglycaemia. METHODS: Oral single ascending doses of AZD6370 10-650 mg or subcutaneous short-acting insulin 4 or 12 U were given to healthy fasting subjects. AZD6370 safety, tolerability and pharmacokinetics were assessed. Pharmacodynamic effects on serum (S)-insulin and glucose infusion rate (GIR) were investigated with euglycaemic clamp. AZD6370 10-20 mg was also assessed when taken with food without euglycaemic clamp. RESULTS: AZD6370 was well tolerated and no safety concerns were raised. AZD6370 was rapidly absorbed and eliminated, and plasma concentration was proportional to dose. Both S-insulin and GIR increased following AZD6370 administration. The observed increase in GIR correlated with increasing AZD6370 area under the plasma concentration vs. time curve, demonstrating a dose-concentration-dependent pharmacodynamic effect. AZD6370 at doses of 50 and 80 mg had similar effects to short-acting insulin 4 U on peripheral S-insulin levels but greater effects on GIR, suggesting an effect beyond the increase of peripheral S-insulin levels at lower doses. In the food interaction part of the study, performed without euglycaemic clamp, dose escalation was stopped at a low dose (20 mg) because of hypoglycaemia. CONCLUSION: The euglycaemic clamp was successfully used to avoid hypoglycaemia and to demonstrate pharmacodynamic effects, that is, markedly increased insulin secretion and glucose utilisation, following administration of AZD6370 in healthy fasting subjects. In addition to the effect on pancreatic insulin secretion, the data support an extra-pancreatic (hepatic) component of GKA action.
Asunto(s)
Benzamidas/farmacología , Glucemia/efectos de los fármacos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Insulina de Acción Corta/farmacología , Sulfonas/farmacología , Administración Oral , Adulto , Benzamidas/administración & dosificación , Benzamidas/farmacocinética , Glucemia/fisiología , Relación Dosis-Respuesta a Droga , Ayuno , Técnica de Clampeo de la Glucosa , Humanos , Hipoglucemiantes/farmacocinética , Insulina de Acción Corta/administración & dosificación , Masculino , Sulfonas/administración & dosificación , Sulfonas/farmacocinética , Suecia , Resultado del TratamientoRESUMEN
AIMS: Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which catalyses the final step in triacylglycerol (TAG) assembly, is suggested as a treatment for type 2 diabetes and obesity based on animal data indicating insulin sensitization and weight reduction. This first-time-in-human single ascending dose study explored the safety, tolerability, pharmacokinetics and pharmacodynamics of the selective DGAT1 inhibitor AZD7687. METHODS: Eighty healthy male subjects were enrolled. In each of 10 cohorts, six subjects received the same dose of AZD7687 orally (range across cohorts 1-60 mg) and two placebo. Plasma AZD7687 exposure was measured repeatedly. Postprandial serum TAG excursion was measured during 8 h after a standardized mixed meal with fat energy content of 60% (SMM 60%; five cohorts, 1-20 mg), before (baseline) and after dosing, to assess effects on gut DGAT1 activity. RESULTS: AZD7687 markedly reduced postprandial TAG excursion with a steep concentration-effect relationship. Incremental TAG AUC (area under the serum concentration vs. time curve) following SMM 60% was decreased >75% from baseline at doses ≥5 mg (p < 0.0001 vs. placebo). Serum levels of diacylglycerol, specifically measured with mass spectrometry, did not increase after AZD7687 administration. Nausea, vomiting and diarrhoea were reported with increasing doses and they limited dose escalation. Lowering of SMM fat content to 45 or 30% in five cohorts gradually reduced the frequency of gastrointestinal symptoms at a given dose of AZD7687. CONCLUSIONS: The attenuating effect of AZD7687 on postprandial TAG excursion provides proof of mechanism with respect to gut DGAT1 inhibition. However, dose and diet-related gastrointestinal side effects may impact further development of DGAT1 inhibitors.
Asunto(s)
Acetatos/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Resistencia a la Insulina , Absorción Intestinal/efectos de los fármacos , Pirazinas/farmacología , Triglicéridos/metabolismo , Acetatos/administración & dosificación , Adulto , Área Bajo la Curva , Estudios de Cohortes , Diabetes Mellitus Tipo 2/sangre , Diglicéridos/sangre , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Espectrometría de Masas , Periodo Posprandial , Pirazinas/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Hyperalimentation for 4 weeks is associated with raised liver enzymes and liver fat content (LFC), which are two common features found in individuals with diabetes. AIM: We evaluated the effect of two mixed meal challenges on LFC, liver enzymes and serum bio-markers of liver injury and fibrosis in 16 healthy volunteers (HV) and subjects with type 2 diabetes (T2DM). METHODS: Subjects (HV: 9 male, 7 female, aged 57.9 ± 1.7 years, body mass index (BMI) 27.1 kg/m(2); and T2DM: 11 male, 5 female, aged 62.1 ± 1.3 years, BMI 28.0 ± 0.4 kg/m(2)) consumed two meals at 1 h (884 kcal) and at 6 h (1,096 kcal). LFC determined by (1)H magnetic resonance spectroscopy, serum levels of liver enzymes, hyaluronic acid (HA), procollagen III N-terminal peptide (P3NP) and tissue inhibitor metalloproteinase-1 (TIMP-1) were estimated at time 0 (fasting) and 9 h (postprandial). RESULTS: Fasting LFC was higher in the T2DM group 7.6 % (4.9, 15.4) [median (inter-quartile range)] than in the HV group 2.3 % (0.8, 5.1) (p < 0.05) while levels of HA, P3NP and TIMP-1 were similar. Following the meal challenge there was no significant change in LFC. Subjects with T2DM had higher post-prandial rise in alanine transaminase (ALT) (p = 0.014), serum HA (p = 0.007) and P3NP (p = 0.015) compared with HV. Fasting LFC correlated with a greater post-prandial increase in P3NP levels in all subjects (Pearson correlation r = 0.53, p = 0.001). CONCLUSIONS: In subjects with T2DM, a mixed meal challenge is associated with a significant elevation in the serum levels of ALT, HA and P3NP without significant changes in LFC. These markers should be performed in the fasted state.
Asunto(s)
Alanina Transaminasa/sangre , Biomarcadores/sangre , Diabetes Mellitus Tipo 2/sangre , Ingestión de Alimentos , Cirrosis Hepática/sangre , Glucemia/análisis , Diabetes Mellitus Tipo 2/enzimología , Femenino , Humanos , Ácido Hialurónico/sangre , Insulina/sangre , Cirrosis Hepática/enzimología , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Procolágeno/sangre , Estadísticas no Paramétricas , Inhibidor Tisular de Metaloproteinasa-1/sangreRESUMEN
BACKGROUND: Dysregulated autonomic nerve activity may contribute to the development of type 2 diabetes. The aim of this study was to assess the effects of an anticholinergic agent, atropine, and a cholinergic agent, physostigmine, on insulin sensitivity in lean and abdominally obese subjects. SUBJECTS AND METHODS: In a single-blinded three-way crossover study, six lean and six abdominally obese nondiabetic subjects [three males and three females in each group; age, 43.8 ± 14.8 vs. 46.8 ± 4.8 yr (mean ± sd); body mass index, 22.6 ± 1.7 vs. 28.8 ± 1.3 kg/m(2); and waist circumference, 85 ± 2 vs. 99 ± 6 cm, respectively] were given iv infusions with atropine (15 µg/kg bolus, 4 µg/kg · h infusion), physostigmine (0.12 µg/kg · min) or saline (0.9% NaCl) in a randomized treatment order. Infusions were started 30 min before and continued throughout a 120-min euglycemic (5.6 mm) hyperinsulinemic (40 mU/m(2) · min) clamp. RESULTS: Insulin sensitivity (M-value, i.e. glucose infusion rate divided by lean body mass) during the last 60 min of the clamp was higher during infusion with atropine than saline (9.2 ± 1.0 vs. 7.6 ± 1.0 mg/kg lean body mass · min, mean ± sem; P = 0.015) in all subjects. Physostigmine did not differ significantly from saline (8.2 ± 1.0). M-values were significantly higher in lean vs. obese [atropine, 11.6 ± 1.4 vs. 7.6 ± 1.3; physostigmine, 10.8 ± 1.3 vs. 6.3 ± 1.3; and saline, 9.1 ± 1.4 vs. 6.4 ± 1.3, respectively (all P < 0.05)], but the incremental effect of atropine vs. saline did not differ consistently between groups. CONCLUSION: Insulin sensitivity was higher during a short-term atropine infusion compared with saline in both lean and abdominally obese subjects. This insulin-sensitizing effect of cholinergic blockade is unexpected, and the underlying mechanisms should be further investigated.
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Atropina/farmacología , Glucemia/efectos de los fármacos , Resistencia a la Insulina/fisiología , Obesidad Abdominal/fisiopatología , Parasimpatolíticos/farmacología , Adulto , Estudios Cruzados , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Insulina/farmacología , Masculino , Persona de Mediana Edad , Método Simple CiegoRESUMEN
Treatment of hypertension with angiotensin receptor blockers has been shown to reduce the risk of developing type 2 diabetes in comparison to thiazide diuretics and beta adrenergic blockers. Therefore, we wanted to study the effect of antihypertensive drugs on adipose tissue with respect to insulin resistance. In the MEDICA (MEchanisms for the DIabetes preventing effects of CAndesartan) study, 22 hypertensive, nondiabetic patients with abdominal obesity (10 men, 12 women) were randomized into 12-week treatment periods with candesartan, hydrochlorothiazide, and placebo according to a 3-way cross-over design. Subcutaneous adipose tissue biopsies were taken after 8 weeks treatment to analyze gene expression, glucose uptake capacity, insulin-signaling, and adipocyte size. Adipose tissue gene expression of serum amyloid A (SAA) was higher after hydrochlorothiazide treatment compared to candesartan (p=0.036), and this was in accordance with our previous finding on circulating SAA levels. Serum levels of E selectin were increased after hydrochlorothiazide compared to candesartan treatment (p=0.002) and lower after candesartan compared to placebo (p=0.002). In adipocytes, there were no significant differences between the treatments with respect to cell size, glucose uptake capacity, or insulin-signaling. In comparison to candesartan, hydrochlorothiazide raised the adipose tissue gene expression of SAA and the serum level of SAA as well as E selectin in hypertensive patients. Less adipose and systemic inflammation may be one explanation why candesartan is favorable in comparison to thiazide diuretics with respect to development of insulin resistance and type 2 diabetes.
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Amiloide/sangre , Antihipertensivos/uso terapéutico , Bencimidazoles/uso terapéutico , Expresión Génica/efectos de los fármacos , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Tetrazoles/uso terapéutico , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Compuestos de Bifenilo , Femenino , Humanos , Hipertensión/genética , Hipertensión/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
Insulin resistance (IR) is found early-on in renal disease. The aim of this study was to prospectively evaluate if a change in glomerular filtration rate (GFR) or in endocrine and inflammatory factors over time alters insulin sensitivity in patients with type 1 diabetes (T1D) or without diabetic nephropathy (DN) at baseline. 20 T1D with (DN+, n = 12) or without DN (DN-, n = 8) were re-examined after 5.0 ± 0.4 years. GFR was determined by 5¹Cr-EDTA clearance. Insulin sensitivity was assessed by hyperinsulinemic (56 mU/m²/min), euglycemic clamp (M-value at steady state during clamp) and calculated per lean body mass. Body composition was determined by bioimpedance. No association was found between change in GFR and change in M-value over time. Instead, change in M-value was associated to change in fat mass (%) and change in IL-6 levels in all subjects taken together (r = -0.55, p = 0.012 and r = -0.62, p = 0.006). These association were verified in the multivariate regression analyses. Findings were similar in DN - and DN +, respectively, but the change in IL-6 was only significantly associated with altered M-value in DN+ subjects. This prospective study indicates that change in amount body fat and levels of inflammatory cytokines, such as IL-6, contribute to change in insulin resistance over time in type 1 diabetes patients with and without diabetic nephropathy.
Asunto(s)
Tejido Adiposo/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Nefropatías Diabéticas/metabolismo , Insulina/sangre , Interleucina-6/sangre , Adulto , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/fisiopatología , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/fisiopatología , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The aim of this study was to measure 11ß-HSD-1 activity in subcutaneous adipose tissue by an ex vivo method in three subgroups; lean, obese, and type 2 diabetes subjects, both in the fasting state and after a mixed meal and to determine the variability and reproducibility of this method. Eighteen subjects were investigated; 6 lean, 6 abdominally obese, and 6 type 2 diabetes subjects (BMI 22 ± 1, 30 ± 3 and 31 ± 3 kg/m², respectively). Needle biopsies were taken repeatedly and an index of 11ß-HSD-1 activity was measured as percent conversion of (3)H-cortisone to (3)H-cortisol/100 mg tissue. For two separate biopsies taken in the fasting state on the same day, the within subjects CV was 16% and the between CV was 36% for 11ß-HSD-1 activity for all subjects. For two biopsies taken in the fasting state at two different days, the total within subjects CV was 38% and the between subjects CV was 46%. Lean subjects had lower 11ß-HSD-1 activity (4.8 ± 1.5% conversion of ³H-cortisone to ³H-cortisol/100 mg tissue) than both obese (14.4 ± 1.6% conversion, p<0.01) and type 2 diabetes subjects (11.7 ± 1.9% conversion, p<0.05) in the fasting state. There was no effect of a meal on 11ß-HSD-1 activity in any of the three groups. The conclusions from this study are: 1) the variation coefficient for the ex vivo adipose tissue 11ß-HSD-1 activity method was â¼25% for repeat measures within subjects; 2) food intake had no major impact on enzyme activity; and 3) 11ß-HSD-1 activity in subcutaneous adipose tissue was significantly increased in obese subjects with or without T2DM compared to lean subjects without diabetes.