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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth hormone (GH) deficiency in adults is characterized by central obesity, dyslipidemia, coagulopathy and glucose intolerance, all features of the "metabolic syndrome", explaining the increased cardiovascular morbidity and mortality associated with GH deficiency in adults. Employing the 2-step euglycemic-hyperinsulinemic clamp, we have demonstrated severe insulin resistance in GH-deficient adults, with a reduction in insulin-mediated glucose utilization of -50%. Basal glucose turnover and partitioning of whole body glucose utilization into glycolytic flux (GF) and glycogen synthesis/glucose storage (GS) pathways are normal, but insulin activation of these 2 pathways is reduced, predominantly in the GS pathway. Activation of muscle glycogen synthase by insulin is markedly decreased, as is glycogen content of muscle. Insulin-induced muscle hexokinase activity appears also to be attenuated in GH-deficient adults with raised intramuscular cellular glucose and normal-reduced concentrations of glucose-6-phosphate. Beta-cell function is not excessive in GH-deficient adults and is inappropriately low for the insulin resistance. Following treatment of GH-deficient adults with recombinant GH (rhGH), the insulin resistance is either unchanged or more pronounced by 3, 6 or 24 months of treatment, despite the significant reduction in general and central obesity. The GF and GS pathways and muscle glycogen synthase and hexokinase activities remain severely impaired. Abnormalities in free fatty acid (FFA) metabolism are present in rhGH-treated GH-deficient adults and correlate significantly with the degree of insulin resistance as do the concentrations of rhGH-induced insulin-like growth factor (IGF)-I, the post-basal insulinemia and the duration of the GHD, but is independent of obesity. In conclusion, long-term rhGH treatment in GH-deficient adults results in persistent insulin resistance and abnormalities in the GF and GS pathways due to reduced glycogen synthase and hexokinase activities, in the presence of an ongoing reduction of central obesity. We postulate that the insulin resistance is due to chronic rhGH-induced alterations in FFA metabolism, non-physiological levels of IGF-I and chronic basal hyperinsulinemia.
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PMID:Insulin sensitivity in growth hormone (GH)-deficient adults and effect of GH replacement therapy. 1044 67

Insulin resistance seems to be a metabolic aberration associated with obesity. Impaired insulin action is also central to a cluster of diseases including non-insulin dependent diabetes, hypertension, dyslipidemias and atherosclerosis. Body fat distribution, especially upper body segment obesity is related to insulin-resistance. Glucose uptake is insulin dependent in skeletal muscle and adipose tissue. From a quantitative standpoint, skeletal muscle has the greater impact on whole body glucose economy, therefore the cause of altered insulin sensitivity has been looked for in this tissue. The skeletal muscle is composed of different types of fibers with specific metabolic and circulatory characteristics; type IIB fibers are less insulin-sensitive and their proportion has been related to obesity and insulin resistance. The different factors that may impair insulin action and alter glucose uptake in skeletal muscle are: lower blood flow to muscle, produced by either decreased vasodilation or by increased sympathetic nerve activity; augmented diffusion distance from capillaries to muscle due to a decrease in capillary number or to enlarged muscle cells; decrease of insulin receptors; change in the fatty acid profile of major membrane structural phospholipids; decrease in glucose transporters (GLUT 4) and/or hexokinase; impairment in metabolic routes of glucose in muscle as reduction in glycogen synthase. Also, the high rate of lipolysis present in obesity and in insulin resistance could lead to an impaired glucose oxidation in muscle.
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PMID:[Obesity, insulin resistance and skeletal muscle characteristics]. 1051 36

In Western countries 25-35% of the population have insulin resistance syndrome characteristics. The defects most likely to explain the insulin resistance of the insulin resistance syndrome include: 1) the glucose transport system of skeletal muscle (GLUT-4) and its different signalling proteins and enzymes; 2) glucose phosphorylation by hexokinase; 3) glycogen synthase activity and 4) competition between glucose and fatty acid oxidation (glucose-fatty acid cycle). High carbohydrate/low fat diets deteriorate insulin sensitivity on the short term. However, on the long term, high fat/low carbohydrate diets have a lower satiating power, induce low leptin levels and eventually lead to higher energy consumption, obesity and more insulin resistance. Moderately high-carbohydrate (45-55% of the daily calories)/low-fat diets seem to be a good choice with regard to the prevention of diabetes and cardiovascular risk factors as far as the carbohydrates are rich in fibers. Long-term interventions with regular exercise programs show a 1/3 decrease in the appearance of overt diabetes in glucose intolerant subjects. Furthermore, diet and exercise interventions "normalise" the mortality rate of patients with impared glucose tolerance. Therefore, moderately high carbohydrate/low fat diets are most likely to prevent obesity and type 2 diabetes. Triglycerides should be monitored and, in some cases, a part of the carbohydrates could be replaced by fat rich in monounsaturated fatty acids. However, total caloric intake is of utmost importance, as weight gain is the major determinant for the onset of insulin resistance and glucose intolerance. Regular (when possible daily) exercise, decreases cardiovascular risk. With regard to insulin resistance, resistance training seems to offer some advantages over aerobic endurance activities.
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PMID:Interaction of physical activity and diet: implications for insulin-glucose dynamics. 1061 74

Type 2 diabetes is characterized by a susceptibility to beta-cell failure. However, subjects at risk of developing type 2 diabetes, such as those with obesity or a family history of diabetes, have been shown to display hyperinsulinemia. Although this hyperinsulinemia may be an adaptive response to insulin resistance, the possibility that insulin hypersecretion may be a primary defect has not been thoroughly investigated. The DBA/2 mouse is a model of pancreatic islet susceptibility. Unlike the resistant C57BL/6 mouse strain, the DBA/2 mouse islet fails when stressed with insulin resistance or when exposed to chronic high glucose concentrations. The aim of this study was to compare insulin secretory function in the DBA/2 and C57BL/6 strains in the absence of insulin resistance or high glucose. Insulin secretion was assessed in vivo using the iv glucose tolerance test and in vitro using isolated islets in static incubations. It was shown that DBA/2 mice hypersecreted insulin in vivo, compared with C57BL/6 mice, at 1 d and at 4 and 10 wk of age. This hypersecretion was not attributable to insulin resistance (as assessed by the insulin tolerance test) or increased parasympathetic nervous system outflow. Insulin hypersecretion was also demonstrated in vitro. This was associated with higher glycolysis and glucose oxidation, and elevated activity (but not protein levels) of islet glucokinase and hexokinase. Furthermore, GLUT2 protein levels were higher, which may explain an increase in glucokinase activity in DBA/2 mouse islets. In summary, the DBA/2 mouse, a model of islet failure, has increased glucose-mediated insulin secretion from a very early age, which is associated with an increase in glucose utilization. Further studies will determine whether there is a link between insulin hypersecretion and subsequent beta-cell failure.
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PMID:Comparison of insulin secretory function in two mouse models with different susceptibility to beta-cell failure. 1202 Nov 73

Specialized neurons utilize glucose as a signaling molecule to alter their firing rate. Glucose-excited (GE) neurons increase and glucose-inhibited (GI) neurons reduce activity as ambient glucose levels rise. Glucose-induced changes in the ATP-to-ADP ratio in GE neurons modulate the activity of the ATP-sensitive K(+) channel, which determines the rate of cell firing. The GI glucosensing mechanism is unknown. We postulated that glucokinase (GK), a high-Michaelis constant (K(m)) hexokinase expressed in brain areas containing populations of GE and GI neurons, is the controlling step in glucosensing. Double-label in situ hybridization demonstrated neuron-specific GK mRNA expression in locus ceruleus norepinephrine and in hypothalamic neuropeptide Y, pro-opiomelanocortin, and gamma-aminobutyric acid neurons, but it did not demonstrate this expression in orexin neurons. GK mRNA was also found in the area postrema/nucleus tractus solitarius region by RT-PCR. Intracarotid glucose infusions stimulated c-fos expression in the same areas that expressed GK. At 2.5 mmol/l glucose, fura-2 Ca(2+) imaging of dissociated ventromedial hypothalamic nucleus neurons demonstrated GE neurons whose intracellular Ca(2+) oscillations were inhibited and GI neurons whose Ca(2+) oscillations were stimulated by four selective GK inhibitors. Finally, GK expression was increased in rats with impaired central glucosensing (posthypoglycemia and diet-induced obesity) but was unaffected by a 48-h fast. These data suggest a critical role for GK as a regulator of glucosensing in both GE and GI neurons in the brain.
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PMID:Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons. 1208 33

Obese individuals are more likely to suffer from diseases termed the "metabolic syndrome," which includes type 2 diabetes. It is now recognized that early life dietary experiences play an important role in the etiology of such diseases. In this context, the consequences of a high carbohydrate (HC) dietary intervention in neonatal rats is being studied in our laboratory. Artificial rearing of 4-day-old rat pups on a HC milk formula up to Day 24 results in the immediate onset of hyperinsulinemia, which persists throughout the period of dietary intervention. Several adaptations at the biochemical, cellular, and molecular levels in the islets of these HC rats support the onset and persistence of the hyperinsulinemic condition during this period. Some of these adaptations include a distinct leftward shift in the insulin secretory capacity, increased hexokinase activity, increased gene expression of preproinsulin and related transcription factors and specific kinases in 12-day-old HC islets, and alterations in the number and size of islets. These adaptations are programmed and expressed in adulthood thereby sustain the hyperinsulinemic condition in the postweaning period and form the basis for adult-onset obesity. HC females spontaneously transmit the HC phenotype (chronic hyperinsulinemia and adult-onset obesity) to their progeny. Collectively, our results indicate that even a mere switch in the nature of the source of calories (from fat rich in rat milk to carbohydrate rich in the HC milk formula) during critical phases of early development in the rat results in metabolic programming of islet functions leading to chronic hyperinsulinemia (throughout life) and adult-onset obesity. This metabolic programming, once established, forms a vicious cycle because HC female rats spontaneously transmit the HC phenotype to their progeny. The results from our laboratory in the context of metabolic programming due to neonatal nutritional experiences are discussed in this review.
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PMID:Neonatal nutrition: metabolic programming of pancreatic islets and obesity. 1252 68

Neonatal female rat pups that were raised artificially on a high-carbohydrate (HC) milk formula during their suckling period developed hyperinsulinemia immediately, maintained chronic hyperinsulinemia in the postweaning period on laboratory diet, and developed obesity in adulthood. Pups (second-generation HC [2-HC]) born to such female rats (first-generation HC [1-HC]) spontaneously developed chronic hyperinsulinemia and adult-onset obesity (HC phenotype) without the requirement for any dietary intervention in their suckling period. Leftward shift in the insulin secretory response to a glucose stimulus, increase in hexokinase activity, and increased preproinsulin gene transcription were observed in islets from 28-day-old 2-HC rats, and these adaptations are similar to those reported for islets from 12-day-old and 100-day-old 1-HC rats. Unlike 1-HC islets, the ability to secrete moderate amounts of insulin in the absence of glucose and calcium and the incretin input for augmentation of insulin secretion were not observed in 2-HC islets. These results show that a dietary modification in the early postnatal life of the 1-HC female rat sets up a vicious cycle of spontaneous transfer of the HC phenotype to its progeny, implicating a new component to the growing list of factors that contribute to the fetal origins of adult-onset diseases.
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PMID:Programming of islet functions in the progeny of hyperinsulinemic/obese rats. 1266 70

The purpose of the present study was to investigate the relationship between intra-abdominal-obesity susceptibility and the adaptation of skeletal muscle metabolic and histochemical characteristics when fed a high-fat diet (HFD) for a short period of time. Twenty-four male Wistar rats were fed a HFD (39.7% calories of fat) for 5 wk. After the 5-wk dietary period, the rats were sacrificed and divided into intra-abdominal-obesity-prone (OP) or obesity-resistant (OR) groups according to the total intra-abdominal fat pads (epididymal, mesenteric, and perirenal) weights. A superficial portion of the Muscle (M.) gastrocnemius tissue obtained from 2 groups before and after feeding the HFD were analyzed to determine their hexokinase (HK), (beta-hydroxyacyl CoA dehydrogenase (beta-HAD), and citrate synthase (CS) activities. Muscle fiber composition and capillary density were examined in the deep portion of the M. gastrocnemius, soleus, and extensor digitorum longus (EDL) gained after the HFD. While the OP group had more intra-abdominal fat pads and a heavier final body weight than the OR group, there was no significant difference in the energy intake between the two. Due to the HFD, the OP group showed significant increases in beta-HAD and CS activities, while the OR group did not. Change of beta-HAD activity by HFD in the OP group was significantly greater than that in the OR group. The ratio of fat oxidation, expressed as beta-HAD/CS, significantly increased in the OP group, but not in the OR group. No differences were found in either the muscle fiber composition or capillarization. These results suggest that intra-abdominal-obesity-susceptive rats may have a higher adaptation degree in muscle oxidative enzyme activities as characteristic in the early stage of intra-abdominal adipose accumulation.
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PMID:Adaptation of skeletal muscle characteristics to a high-fat diet in rats with different intra-abdominal-obesity susceptibilities. 1459 10

To test whether long-chain fatty acyl-CoA esters link obesity with type 2 diabetes through inhibition of the mitochondrial adenine nucleotide translocator, we applied a system-biology approach, dual modular kinetic analysis, with mitochondrial membrane potential (Deltapsi) and the fraction of matrix ATP as intermediates. We found that 5 mumol/l palmitoyl-CoA inhibited adenine nucleotide translocator, without direct effect on other components of oxidative phosphorylation. Indirect effects depended on how oxidative phosphorylation was regulated. When the electron donor and phosphate acceptor were in excess, and the mitochondrial "work" flux was allowed to vary, palmitoyl-CoA decreased phosphorylation flux by 38% and the fraction of ATP in the medium by 39%. Deltapsi increased by 15 mV, and the fraction of matrix ATP increased by 46%. Palmitoyl-CoA had a stronger effect when the flux through the mitochondrial electron transfer chain was maintained constant: Deltapsi increased by 27 mV, and the fraction of matrix ATP increased 2.6 times. When oxidative phosphorylation flux was kept constant by adjusting the rate using hexokinase, Deltapsi and the fraction of ATP were not affected. Palmitoyl-CoA increased the extramitochondrial AMP concentration significantly. The effects of palmitoyl-CoA in our model system support the proposed mechanism linking obesity and type 2 diabetes through an effect on adenine nucleotide translocator.
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PMID:Modular kinetic analysis of the adenine nucleotide translocator-mediated effects of palmitoyl-CoA on the oxidative phosphorylation in isolated rat liver mitochondria. 1579 31

ASP-deficient mice (C3 KO) have delayed postprandial TG clearance, are hyperphagic, and display increased energy expenditure. Markers of carbohydrate and fatty acid metabolism in the skeletal muscle and heart were examined to evaluate the mechanism. On a high-fat diet, compared with wild-type mice, C3 KO mice have increased energy expenditure, decreased RQ, lower ex vivo glucose oxidation (-39%, P = 0.018), and higher ex vivo fatty acid oxidation (+68%, P = 0.019). They have lower muscle glycogen content (-25%, P < 0.05) and lower activities for the glycolytic enzymes glycogen phosphorylase (-31%, P = 0.005), hexokinase (-43%, P = 0.007), phosphofructokinase (-51%, P < 0.0001), and GAPDH (-15%, P = 0.04). Analysis of mitochondrial enzyme activities revealed that hydroxyacyl-coenzyme A dehydrogenase was higher (+25%, P = 0.004) in C3 KO mice. Furthermore, Western blot analysis of muscle revealed significantly higher fatty acid transporter CD36 (+40%, P = 0.006) and cytochrome c (a marker of mitochondrial content; +69%, P = 0.034) levels in C3 KO mice, whereas the activity of AMP kinase was lower (-48%, P = 0.003). Overall, these results demonstrate a shift in the metabolic potential of skeletal muscle toward increased fatty acid utilization. Whether this is 1) a consequence of decreased adipose tissue storage with repartitioning toward muscle or 2) a direct result of the absence of ASP interaction with the receptor C5L2 in muscle remains to be determined. However, these in vivo data suggest that ASP inhibition could be a potentially viable approach in correcting muscle metabolic dysfunction in obesity.
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PMID:Shift in metabolic fuel in acylation-stimulating protein-deficient mice following a high-fat diet. 1839 12


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