RESUMEN
Nonalcoholic fatty liver disease (NAFLD) is a severe liver disease causing serious liver complications, including nonalcoholic steatohepatitis (NASH). Nuclear receptor PPARα (peroxisome proliferator-activated receptor α) has drawn special attention recently as a potential developmental drug target to treat type-2 diabetes and related diseases due to its unique functions in regulating lipid metabolism, promoting triglyceride oxidation, and suppressing hepatic inflammation, raising interest in PPARα agonists as potential therapies for NAFLD. However, how PPARα coordinates potential treatment of NAFLD and NASH between various metabolic pathways is still obscure. Here, we show that the DY series of novel selective PPARα modulators activate PPARα by up-regulating PPARα target genes directly involved in NAFLD and NASH. The design, synthesis, docking studies, and in vitro and in vivo evaluation of the novel DY series of PPARα agonists are described.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , PPAR alfa/agonistas , Animales , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Homeostasis , Metabolismo de los Lípidos , Ratones , Ratones Endogámicos C57BL , Regulación hacia ArribaRESUMEN
OBJECTIVE: Insulin resistance is a powerful risk factor for Type 2 diabetes and a constellation of chronic diseases, and is most commonly associated with obesity. We examined if factors other than obesity are more substantial predictors of insulin sensitivity under baseline, nonstimulated conditions. METHODS: Metabolic assessment was performed in healthy dogs (n = 90). Whole-body sensitivity from euglycemic clamps (SICLAMP ) was the primary outcome variable, and was measured independently by IVGTT (n = 36). Adiposity was measured by MRI (n = 90), and glucose-stimulated insulin response was measured from hyperglycemic clamp or IVGTT (n = 86 and 36, respectively). RESULTS: SICLAMP was highly variable (5.9-75.9 dl/min per kg per µU/ml). Despite narrow range of body weight (mean, 28.7 ± 0.3 kg), adiposity varied approximately eight-fold and was inversely correlated with SICLAMP (P < 0.025). SICLAMP was negatively associated with fasting insulin, but most strongly associated with insulin clearance. Clearance was the dominant factor associated with sensitivity (r = 0.53, P < 0.00001), whether calculated from clamp or IVGTT. CONCLUSIONS: These data suggest that insulin clearance contributes substantially to insulin sensitivity, and may be pivotal in understanding the pathogenesis of insulin resistance. We propose the hyperinsulinemia due to reduction in insulin clearance is responsible for insulin resistance secondary to changes in body weight.
Asunto(s)
Resistencia a la Insulina/fisiología , Insulina/sangre , Animales , Glucemia/metabolismo , Composición Corporal , Índice de Masa Corporal , Peso Corporal , Diabetes Mellitus Tipo 2/sangre , Perros , Ayuno , Técnica de Clampeo de la Glucosa/métodos , Hiperinsulinismo , Hígado/metabolismo , Imagen por Resonancia Magnética , Masculino , Obesidad/sangreRESUMEN
Digestion and absorption of a meal are time-intensive processes. To optimize digestion and absorption, transit of the meal through the gastrointestinal tract is regulated by a complex integration of neuropeptidergic signals generated as the jejunal brake and ileal brake response to nutrients. Mediators involved in the slowing of transit responses include peptide YY (PYY), chemosensitive afferent neurons, intestinofugal nerves, noradrenergic nerves, myenteric serotonergic neurons, and opioid neurons. The activation of this circuitry modifies the peristaltic reflex to convert the intestinal motility pattern from propagative to segmenting. Fat is the most potent trigger of these transit control mechanisms. The integrated circuitry of gut peptides and neurons involved in transit control in response to nutrients is described in this review.
Asunto(s)
Digestión/fisiología , Tránsito Gastrointestinal/fisiología , Íleon/fisiología , Absorción Intestinal/fisiología , Animales , Carbohidratos de la Dieta/metabolismo , Grasas de la Dieta/metabolismo , Proteínas en la Dieta/metabolismo , Humanos , Absorción Intestinal/efectos de los fármacos , Yeyuno/fisiología , Periodo Posprandial/fisiología , Serotonina/farmacología , Síndrome del Intestino Corto/fisiopatologíaRESUMEN
Similar to that of all mammals, the human gastrointestinal tract is colonized by 100 trillion bacteria shortly after birth. Remarkably, in the open-tube arrangement of the intestine, this bacterial population is tightly compartmentalized to the distal gut. Contamination of the small intestine with colonic bacterial flora or small intestinal bacterial overgrowth (SIBO) has been understood previously as a complication of uncommon conditions associated with obvious intestinal stasis. However, SIBO has also been found in 78% to 84% of patients with the common condition of irritable bowel syndrome (IBS). In this paper, the diagnostic and treatment approaches to SIBO are reconsidered within the larger framework of the patient with IBS.
Asunto(s)
Bacterias/crecimiento & desarrollo , Enfermedades Intestinales/diagnóstico , Enfermedades Intestinales/terapia , Intestino Delgado/microbiología , Colon/microbiología , Humanos , Enfermedades Intestinales/microbiologíaRESUMEN
The mechanism by which increased central adiposity causes hepatic insulin resistance is unclear. The "portal hypothesis" implicates increased lipolytic activity in the visceral fat and therefore increased delivery of free fatty acids (FFA) to the liver, ultimately leading to liver insulin resistance. To test the portal hypothesis at the transcriptional level, we studied expression of several genes involved in glucose and lipid metabolism in the fat-fed dog model with visceral adiposity vs. controls (n = 6). Tissue samples were obtained from dogs after 12 wk of either moderate fat (42% calories from fat; n = 6) or control diet (35% calories from fat). Northern blot analysis revealed an increase in the ratio of visceral to subcutaneous (v/s ratio) mRNA expression of both lipoprotein lipase (LPL) and peroxisome proliferator-activated receptor-gamma (PPARgamma). In addition, the ratio for sterol regulatory element-binding transcription factor-1 (SREBP-1) tended to be higher in fat-fed dogs, suggesting enhanced lipid accumulation in the visceral fat depot. The v/s ratio of hormone-sensitive lipase (HSL) increased significantly, implicating a higher rate of lipolysis in visceral adipose despite hyperinsulinemia in obese dogs. In fat-fed dogs, liver SREBP-1 expression was increased significantly, with a tendency for increased fatty acid-binding protein (FABP) expression. In addition, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK) increased significantly, consistent with enhanced gluconeogenesis. Liver triglyceride content was elevated 45% in fat-fed animals vs. controls. Moreover, insulin receptor binding was 50% lower in fat-fed dogs. Increased gene expression promoting lipid accumulation and lipolysis in visceral fat, as well as elevated rate-limiting gluconeogenic enzyme expression in the liver, is consistent with the portal theory. Further studies will need to be performed to determine whether FFA are involved directly in this pathway and whether other signals (either humoral and/or neural) may contribute to the development of hepatic insulin resistance observed with visceral obesity.
Asunto(s)
Tejido Adiposo/metabolismo , Glucosa/metabolismo , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos , Hígado/metabolismo , Modelos Biológicos , Vísceras/metabolismo , Animales , Constitución Corporal/fisiología , Causalidad , Grasas de la Dieta/metabolismo , Perros , Regulación de la Expresión Génica/fisiología , Masculino , Especificidad de Órganos , Estadística como AsuntoRESUMEN
Obesity is highly correlated with insulin resistance and the development of type 2 diabetes. Insulin resistance will result in a decrease in insulin's ability to stimulate glucose uptake into peripheral tissue and will suppress glucose production by the liver. However, the development of peripheral and hepatic insulin resistance relative to one another in the context of obesity-associated insulin resistance is not well understood. To examine this phenomena, we used the moderate fat-fed dog model, which has been shown to develop both subcutaneous and visceral adiposity and severe insulin resistance. Six normal dogs were fed an isocaloric diet with a modest increase in fat content for 12 weeks, and they were assessed at weeks 0, 6, and 12 for changes in insulin sensitivity and glucose turnover. By week 12 of the diet, there was a more than twofold increase in trunk adiposity as assessed by magnetic resonance imaging because of an accumulation in both subcutaneous and visceral fat depots with very little change in body weight. Fasting plasma insulin had increased by week 6 (150% of week 0) and remained increased up to week 12 of the study (170% of week 0). Surprisingly, there appeared to be no change in the rates of insulin-stimulated glucose uptake as measured by euglycemic-hyperinsulinemic clamps throughout the course of fat feeding. However, there was an increase in steady-state plasma insulin levels at weeks 6 and 12, indicating a moderate degree of peripheral insulin resistance. In contrast to the moderate defect seen in the periphery, there was a marked impairment in insulin's ability to suppress endogenous glucose production during the clamp such that by week 12 of the study, there was a complete inability of insulin to suppress glucose production. Our results indicate that a diet enriched with a moderate amount of fat results in the development of both subcutaneous and visceral adiposity, hyperinsulinemia, and a modest degree of peripheral insulin resistance. However, there is a complete inability of insulin to suppress hepatic glucose production during the clamp, suggesting that insulin resistance of the liver may be the primary defect in the development of insulin resistance associated with obesity.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/efectos adversos , Ingestión de Energía , Resistencia a la Insulina , Hígado/fisiopatología , Síndrome Metabólico/etiología , Síndrome Metabólico/fisiopatología , Tejido Adiposo/patología , Animales , Glucemia/análisis , Composición Corporal , Perros , Ayuno/sangre , Ácidos Grasos no Esterificados/sangre , Glucosa/metabolismo , Insulina/sangre , Insulina/metabolismo , Masculino , Síndrome Metabólico/patologíaRESUMEN
We previously developed a canine model of central obesity and insulin resistance by supplementing the normal chow diet with 2 g cooked bacon grease/kg body weight. Dogs fed this fatty diet maintained glucose tolerance with compensatory hyperinsulinemia. The signal(s) responsible for this up-regulation of plasma insulin is unknown. We hypothesized that meal-derived factors such as glucose, fatty acids, or incretin hormones may signal beta-cell compensation in the fat-fed dog. We fed the same fat-supplemented diet for 12 wk to six dogs and compared metabolic responses with seven control dogs fed a normal diet. Fasting and stimulated fatty acid and glucose-dependent insulinotropic peptide concentrations were not increased by fat feeding, whereas glucose was paradoxically decreased, ruling out those three factors as signals for compensatory hyperinsulinemia. Fasting plasma glucagon-like peptide-1 (GLP-1) concentration was 2.5-fold higher in the fat-fed animals, compared with controls, and 3.4-fold higher after a mixed meal. Additionally, expression of the GLP-1 receptor in whole pancreas was increased 2.3-fold in the fat-fed dogs. The increase in both circulating GLP-1 and its target receptor may have increased beta-cell responsiveness to lower glucose. Glucose is not the primary cause of hyperinsulinemia in the fat-fed dog. Corequisite meal-related signals may be permissive for development of hyperinsulinemia.
Asunto(s)
Glucemia/metabolismo , Grasas de la Dieta/administración & dosificación , Hiperinsulinismo/sangre , Hiperinsulinismo/etiología , Fragmentos de Péptidos/sangre , Animales , Northern Blotting , Perros , Ayuno , Ácidos Grasos no Esterificados/sangre , Expresión Génica , Glucagón , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Péptidos Similares al Glucagón , Glucosa/farmacología , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Resistencia a la Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/fisiopatología , Cinética , Imagen por Resonancia Magnética , Masculino , Obesidad/sangre , Receptores de Glucagón/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Despite the well-described association between obesity and insulin resistance, the physiologic mechanisms that link these two states are poorly understood. The present study was performed to elucidate the role of visceral adipose tissue in whole-body glucose homeostasis. Dogs made abdominally obese with a moderately elevated fat diet had catheters placed into the superior mesenteric artery so that the visceral adipose bed could be insulinized discretely. Omental insulin infusion was extracted at approximately 27%, such that systemic insulin levels were lower than in control (portal vein) insulin infusions. Omental infusion did not lower systemic free fatty acid levels further than control infusion, likely because of the resistance of the omental adipose tissue to insulin suppression and the confounding lower systemic insulin levels. The arteriovenous difference technique showed that local infusion of insulin did suppress omental lipolysis, but only at extremely high insulin concentrations. The median effective dose for suppression of lipolysis was almost fourfold higher in the visceral adipose bed than for whole-body suppression of lipolysis. Thus, the omental adipose bed represents a highly insulin-resistant depot that drains directly into the portal vein. Increased free fatty acid flux to the liver may account for hepatic insulin resistance in the moderately obese state.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/fisiología , Resistencia a la Insulina , Animales , Arterias , Glucemia/metabolismo , Grasas de la Dieta/administración & dosificación , Perros , Ácidos Grasos no Esterificados/sangre , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Glicerol/sangre , Homeostasis , Insulina/administración & dosificación , Insulina/sangre , Lipólisis/efectos de los fármacos , Hígado/metabolismo , Epiplón , Vena Porta , VíscerasRESUMEN
Only in the last decade did modeling studies predict, and knockout experiments confirm, that type 2 diabetes is a "2-hit" disease in which insulin resistance is necessarily accompanied by beta-cell defect(s) preventing the compensatory upregulation of insulin secretion. This long- delayed insight was associated with the development of a constant, the "disposition index," describing the beta-cell sensitivity-secretion relationship as a rectangular hyperbola. Shifts in insulin sensitivity are accompanied by compensatory alterations in beta-cell sensitivity to glucose. Insulin-sensitive subjects do not require a massive insulin response to exogenous glucose to maintain a normal blood glucose. But if their insulin sensitivity decreases by 80%, as in late pregnancy, they need a fivefold greater insulin response to achieve an identical disposition index. Women with gestational diabetes have an insulin response similar to that of normal volunteers; at first glance, this suggests similar islet function, but the utility of the disposition index is to normalize this response to the amplitude of third trimester insulin resistance, revealing severe beta-cell deficiency. The index is a quantitative, convenient, and accurate tool in analyzing epidemiologic data and identifying incipient impaired glucose tolerance. Separate major issues remain, however: the causes of insulin resistance, the causes of the failure of adequate beta-cell compensation in type 2 diabetes, and the nature of the signal(s) from insulin-resistant tissues that fail to elicit the appropriate beta-cell increment in sensitivity to glucose and other stimuli. The disposition index is likely to remain the most accurate physiologic measure for testing hypotheses and solutions to these challenges in whole organisms.