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

The diaphragm is the primary muscle of inspiration, and as such uncompromised function is essential to support the ventilatory and gas exchange demands associated with physical activity. The normal healthy diaphragm may fatigue during intense exercise, and diaphragm function is compromised with aging and obesity. However, more insidiously, respiratory diseases such as emphysema mechanically disadvantage the diaphragm, sometimes leading to muscle failure and death. Based on metabolic considerations, recent evidence suggests that specific regions of the diaphragm may be or may become more susceptible to failure than others. This paper reviews the regional differences in mechanical and metabolic activity within the diaphragm and how such heterogeneities might influence diaphragm function in health and disease. Our objective is to address five principal areas: 1) Regional diaphragm structure and mechanics (GAF). 2) Regional differences in blood flow within the diaphragm (WLS). 3) Structural and functional interrelationships within the diaphragm microcirculation (DCP). 4) Nitric oxide and its vasoactive and contractile influences within the diaphragm (MBR). 5) Metabolic and contractile protein plasticity in the diaphragm (SKP). These topics have been incorporated into three discrete sections: Functional Anatomy and Morphology, Physiology, and Plasticity in Health and Disease. Where pertinent, limitations in our understanding of diaphragm function are addressed along with potential avenues for future research.
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PMID:Diaphragm structure and function in health and disease. 921 1

The JCR:LA-corpulent rat is an animal model that, if homozygous for the cp gene (cp/cp), spontaneously exhibits obesity and a severe insulin resistance, with a resultant hyperinsulinemia and hypertriglyceridemia. The obese male rats show defective nitric oxide-mediated vascular relaxation, advanced atherosclerosis, and ischemic myocardial lesions. Benfluorex has both anorectic and metabolic effects that lower body weight and improve insulin sensitivity in obesity and type 2 diabetes. Male cp/cp rats that were treated with benfluorex (or pair-fed to the treated animals) from the time of weaning, at 3 weeks of age, showed a marked delay in the development of postprandial hyperinsulinemia. At 12 weeks of age benfluorex-treated cp/cp rats did not show the extreme insulin response to a test meal that was observed in untreated or pair-fed rats. Both benfluorex-treated and pair-fed rats had a significant increase in sensitivity to acetylcholine-induced (nitric oxide-mediated) vascular relaxation. Corpulent male rats were also treated from 6 to 39 weeks of age with benfluorex in the feed at a dose of approximately 36 mg/kg/day at 12 weeks of age and decreasing to 23 mg/kg/day at 39 weeks to determine the effects on cardiovascular outcomes. The rats showed a sustained decrease in food consumption and body weight, although they exhibited 50% of the excess body weight of the controls and were grossly obese. Both fasting insulin concentrations and the hyperplasia of the islets of Langerhans were decreased by approximately 50%. Serum triglyceride concentrations were decreased by 44%, and free cholesterol and cholesteryl esters by 30%. The severity of the atherosclerotic lesions on the aortic arch was decreased (P < 0.05). There was also a decrease in the size of early ischemic myocardial lesions that are characterized by cell lysis and chronic inflammatory cell infiltration. Mature, scarred myocardial lesions were essentially absent in the hearts of 39-week-old benfluorex-treated rats. Long-term major food restriction (18 g/day) decreased the body weights of obese rats to essentially those of lean control animals, with similar beneficial effects on the insulin resistance and hyperlipidemia. While myocardial lesion frequency was reduced in these much thinner animals, lesions remained and the apparent effect was not statistically significant. This evidence shows that the beneficial metabolic effects of benfluorex are associated with long-term effects on the vessel wall and delay the onset of insulin resistance and cardiovascular disease in an animal model.
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PMID:Antiatherogenic effects of long-term benfluorex treatment in male insulin resistant JCR:LA-cp rats. 924 64

Despite the increase in body fat and obesity that occurs with aging, there is a linear decrease in food intake over the life span. This conundrum is explained by decreased physical activity and altered metabolism with aging. Thus, older persons fail to adequately regulate food intake and develop a physiologic anorexia of aging. This physiologic anorexia depends not only on decreased hedonic qualities of feeding with aging (an area that remains controversial) but also on altered hormonal and neurotransmitter regulation of food intake. Findings in older animals and humans have provided clues to the causes of the anorexia of aging. An increase in circulating concentrations of the satiating hormone, cholecystokinin, occurs with aging in humans. In addition, animal studies suggest a decrease in the opioid (dynorphin) feeding drive and possibly in neuropeptide Y and nitric oxide. The physiologic anorexia of aging puts older persons at high risk for developing protein-energy malnutrition when they develop either psychologic or physical disease processes. Despite its high prevalence, however, protein-energy malnutrition in older persons is rarely recognized and even more rarely treated appropriately. Screening tools for the early detection of protein-energy malnutrition in older persons have been developed. Multiple treatable causes of pathologic anorexia have been identified. There is increasing awareness of the importance of depression as a cause of severe weight loss in older persons. Approaches to the management of anorexia and weight loss in older persons are reviewed. Although many drugs exist that can enhance appetite, none of these are ideal for use in older persons currently.
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PMID:Anorexia of aging: physiologic and pathologic. 973 60

Dietary fatty acid recommendations for patients with diabetes mellitus may be neither similar to, nor extrapolated from, those for the normal population; some evidence suggests that diabetes prevalence may be correlated with the dietary ratio of n-6 to n-3 fatty acids. In human experiments, n-3 fatty acids may improve many of the metabolic sequelae of insulin resistance by lowering blood pressure and triacylglycerol concentrations. In animals, n-3 fatty acids may cause less weight gain than other fats; however, they may raise low-density-lipoprotein concentrations, increase hepatic glucose output, and decrease insulin secretion in non-insulin-dependent diabetes mellitus. In a minority of patients with insulin-dependent diabetes mellitus, glycemic control may be adversely affected n-6 Fatty acids lower plasma cholesterol but may increase lipoprotein oxidation. Glucose in the presence of transition metals may produce free radicals and result in pancreatic damage and the formation of glycosylation products that inhibit nitric oxide-mediated smooth muscle relaxation; fish oil may counter these effects. High-carbohydrate, low-fat diets, once recommended for diabetes mellitus, appear to aggravate hypertriglyceridemia and are inferior to diets high in monounsaturated fatty acids (MUFAs) if saturated fats are kept to a minimum. MUFA-rich diets improve lipid profiles and may also have antioxidant properties. However, high-fat diets-whatever their composition-promote obesity. Current advice individualizes carbohydrate and fat requirements to optimize blood glucose and lipid concentrations in a lifestyle program to control obesity, exercise, smoking, and blood pressure. Fatty acid modifications may fine-tune the diet if proper balance is kept between the different long-chain polyunsaturated fatty acids and antioxidant requirements.
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PMID:Dietary fatty acids in the management of diabetes mellitus. 932 79

We present a new hypothesis to explain the development of salt-dependent hypertension in humans. We propose that hypertension has two phases: an early phase in which elevations in blood pressure (BP) are mainly episodic and are mediated by a hyperactive sympathetic nervous or renin-angiotensin system, and a second phase in which BP is persistently elevated and that is primarily mediated by an impaired ability of the kidney to excrete salt (NaCl). We propose that the transition from the first phase to the second occurs as a consequence of catecholamine-induced elevations in BP that preferentially damage regions of the kidney (juxtamedullary and medullary regions) that do not autoregulate well to changes in renal perfusion pressure. The catecholamine response is associated with both an increase in peritubular capillary pressure and a reduction in peritubular capillary plasma flow, resulting in injury to the peritubular capillaries with ischemia to the tubules and interstitium. The local injury triggers the release or activation (angiotensin II, adenosine, renal sympathetic nerves) or inhibition (nitric oxide, prostaglandins, dopamine) of vasoactive mediators that further augment ischemia and result in abnormal tubuloglomerular feedback and enhanced NaCl reabsorption. The peritubular capillary injury with rarefaction simultaneously blunts the pressure natriuresis mechanism. The combined effect of enhanced tubuloglomerular feedback and impaired pressure natriuresis results in a defect in NaCl excretion which, on the exposure to salt, results in the development of persistent hypertension. Evidence is provided to suggest that this may be the major mechanism for the development of salt-dependent hypertension, and particularly for the hypertension associated with blacks, aging and obesity. Thus, essential hypertension may be a type of acquired tubulointerstitial renal disease.
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PMID:Hypothesis: the role of acquired tubulointerstitial disease in the pathogenesis of salt-dependent hypertension. 935 Jun 40

Like obese humans, Zucker diabetic fatty (ZDF) rats exhibit early beta cell compensation for insulin resistance (4-fold beta cell hyperplasia) followed by decompensation (>50% loss of beta cells). In prediabetic and diabetic ZDF islets, apoptosis measured by DNA laddering is increased 3- and >7-fold, respectively, compared with lean ZDF controls. Ceramide, a fatty acid-containing messenger in cytokine-induced apoptosis, was significantly increased (P < 0.01) in prediabetic and diabetic islets. Free fatty acids (FFAs) in plasma are high (>1 mM) in prediabetic and diabetic ZDF rats; therefore, we cultured prediabetic islets in 1 mM FFA. DNA laddering rose to 19.6% vs. 4.6% in lean control islets, preceded by an 82% increase in ceramide. C2-Ceramide without FFA induced DNA laddering, but fumonisin B1, a ceramide synthetase inhibitor, completely blocked FFA-induced DNA laddering in cultured ZDF islets. [3H]Palmitate incorporation in [3H]ceramide in ZDF islets was twice that of controls, but [3H]palmitate oxidation was 77% less. Triacsin C, an inhibitor of fatty acyl-CoA synthetase, and troglitazone, an enhancer of FFA oxidation in ZDF islets, both blocked DNA laddering. These agents also reduced inducible nitric oxide (NO) synthase mRNA and NO production, which are involved in FFA-induced apoptosis. In ZDF obesity, beta cell apoptosis is induced by increased FFA via de novo ceramide formation and increased NO production.
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PMID:Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. 948 14

1. Metabolic disorders, such as obesity and non-insulin-dependent diabetes mellitus, and cardiovascular disorders, such as essential hypertension, congestive cardiac failure and atherosclerosis, have two features in common, namely relative resistance to insulin-mediated glucose uptake and vascular endothelial dysfunction. 2. Significant increases in limb blood flow occur in response to systemic hyperinsulinaemia, although there is marked variation in the results due to a number of confounding factors, including activation of the sympathetic nervous system. Local hyperinsulinaemia has a less marked vasodilator action despite similar plasma concentrations, but this can be augmented by co-infusing D-glucose. 3. Insulin may stimulate endothelial nitric oxide production or may act directly on vascular smooth muscle via stimulation of the Na+-H+ exchanger and Na+/K+-ATPase, leading to hyperpolarization of the cell membrane and consequent closure of voltage-gated Ca2+ channels. 4. There is evidence both for and against the existence of a functional relationship between insulin-mediated glucose uptake (insulin sensitivity) and insulin-mediated vasodilation (which can be regarded as a surrogate measure for endothelial function). 5. If substrate delivery is the rate-limiting step for insulin-mediated glucose uptake (in other words, if skeletal muscle blood flow is a determinant of glucose uptake), then endothelial dysfunction, resulting in a relative inability of mediators, including insulin, to stimulate muscle blood flow, may be the underlying mechanism accounting for the association of atherosclerosis and other cardiovascular disorders with insulin resistance. 6. Glucose uptake may determine peripheral blood flow via stimulation of ATP-dependent ion pumps with consequent vasorelaxation. 7. A 'third factor' may cause both insulin resistance and endothelial dysfunction in cardiovascular disease. Candidates include skeletal muscle fibre type and capillary density, distribution of adiposity and endogenous corticosteroid production. 8. A complex interaction between endothelial dysfunction, abnormal skeletal muscle blood flow and reduced insulin-mediated glucose uptake may be central to the link between insulin resistance, blood pressure, impaired glucose tolerance and the risk of cardiovascular disease. An understanding of the primary mechanisms resulting in these phenotypes may reveal new therapeutic targets in metabolic and cardiovascular disease.
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PMID:Insulin as a vascular hormone: implications for the pathophysiology of cardiovascular disease. 959 May 66

Insulin resistance is associated with a decreased vasodilator response to insulin. Because insulin's vasodilator effect is nitric oxide dependent, this impairment may reflect endothelial dysfunction. Troglitazone, an insulin-sensitiser, might thus improve insulin-dependent and/or endothelium-dependent vascular function in insulin resistant obese subjects. For 8 weeks, fifteen obese subjects were treated with either 400 mg troglitazone once daily or placebo, in a randomised, double-blind, cross-over design. At the end of each treatment period, we measured forearm vasodilator responses (plethysmography) to intra-arterial administered acetylcholine and sodium nitroprusside; insulin sensitivity and insulin-induced vascular and neurohumoral responses (clamp); vasoconstrictor responses to NC-monomethyl-L-arginine (L-NMMA) during hyperinsulinaemia; and ambulatory 24-h blood pressure (ABPM). Baseline data (placebo) of obese subjects were compared with those obtained in lean control subjects. Obese subjects were insulin resistant compared with leans (whole-body glucose uptake: 26.8+/-3.0 vs. 53.9+/-4.3 [tmol kgl min-, p < 0.001). Troglitazone improved whole-body glucose uptake (to 31.9+/-3.3 micromol x kg(-1) x min(-1) , p=0.028), and forearm glucose uptake (from 1.09+/-0.54 to 2.31+/-0.69 micromol dL(-1) x min(-1), p=0.006). Insulin-induced vasodilatation was blunted in obese subjects (percent increase in forearm blood flow (FBF) in lean 66.5+/-23.0%, vs. 10.1+/-11.3% in obese, p=0.04), but did not improve during troglitazone. Vascular responses to acetylcholine, sodium nitroprusside and L-NMMA did not differ between the obese and lean group, nor between both treatment periods in the obese individuals. In conclusion, in insulin resistant obese subjects, endothelial vascular function is normal despite impaired vasodilator responses to insulin. Troglitazone improved insulin sensitivity but it had no effects on endothelium-dependent and -independent vascular responses. These data do not support an association between insulin resistance and endothelial function.
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PMID:Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone. 962 75

The JCR:LA-cp rat is a unique strain that, if homozygous for the autosomal recessive cp gene, is obese and exhibits the metabolic syndrome of insulin resistance, hyperinsulinemia, and hypertriglyceridemia. Obese male rats spontaneously develop advanced atherosclerosis and ischemic myocardial lesions. The angiotensin-converting enzyme inhibitor, captopril, was administered to obese rats at 30 mg/kg body weight from 6 to 39 weeks of age. There were no significant changes in food consumption or body weights of the treated animals. Insulin sensitivity was not improved. Plasma insulin levels were unaltered, but the volume density of the islets of Langerhans was halved, reflecting both reduced hyperplasia and a more normal islet structure. Triglyceride concentrations were not reduced, but unesterified cholesterol and cholesteryl esters decreased by 50% and 34%, respectively (p < 0.01). The impaired nitric oxide-mediated vascular relaxation of the obese rats was not improved, and the relaxant sensitivity to acetylcholine as indicated by the median effective concentration (EC50) was reduced. In vitro, captopril significantly reduced the basal tension of aortic rings from untreated rats, antagonized the contractile effects of norepinephrine, and induced complete relaxation of the contraction in response to 10(-7) M norepinephrine. The severity of spontaneous, raised atherosclerotic lesions of the aortic arch at age 39 weeks was not significantly decreased by captopril treatment. In contrast, the frequency of ischemic myocardial lesions was reduced by 78% (p < 0.01). The protective effects of captopril on the heart and pancreas in this animal model of type II diabetes and atherosclerosis are probably the result of its bradykinin-enhancing effects.
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PMID:Inhibition of myocardial lesions in the JCR:LA-corpulent rat by captopril. 964 85

1. The effects of nitric oxide (NO) on vascular reactivity and platelet function in the obese (cp/cp) and lean (+/?) JCR:LA-cp rats were investigated. 2. Phenylephrine (PE; 0.1 nM-10 microM) induced contraction of isolated aortic rings in both genotypes (cp/cp and +/?) of JCR:LA-cp rats. The sensitivity to contraction with PE was enhanced in cp/cp compared with +/? rings. Rings from both genotypes showed an increased contraction upon removal of the endothelium. 3. Acetylcholine (ACh; 0.1 nM-10 microM)-induced endothelium-dependent relaxation of rings was not significantly different in the two genotypes. Both were inhibited to a similar extent by NG-nitro-L-arginine methyl ester (L-NAME; 0.01-1 mM) when administered in vitro. 4. The nitric oxide synthase (NOS) inhibitor (L-NAME; 0.3, 1 or 3 mg ml(-1), p.o.) when administered in vivo increased blood pressure in cp/cp rats but not in +/? rats. 5. L-NAME resulted in greater inhibition of ACh-induced relaxation in cp/cp rings compared with +/? rings. 6. L-NAME treatment in vivo caused a decrease in cyclic GMP and NOS activity in rings from cp/cp but not +/? rats. 7. The NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP; 0.1 nM-10 microM)-induced relaxation of rings from +/? rats, an effect enhanced by the treatment with L-NAME in vivo. 8. Oral administration of L-NAME did not enhance the vasorelaxant effect of SNAP on rings of aorta from cp/cp animals. 9. Platelet aggregation and NOS activity were similar in both genotypes and were not modified by oral administration of L-NAME. 10. These results show that unimpaired generation of NO is crucial for maintenance of vascular tone particularly under conditions of vascular insult exemplified by insulin resistance, obesity and dyslipidemia detected in cp/cp rats.
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PMID:Inhibition of nitric oxide generation unmasks vascular dysfunction in insulin-resistant, obese JCR:LA-cp rats. 964 54


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