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HIV has classically been a wasting disease. However, in the United States, obesity is increasingly common among HIV-infected individuals receiving effective antiviral treatment. The risks of obesity are unclear in HIV, although the increased prevalence of diabetes and cardiovascular disease in the presence or absence of obesity causes growing concern. This study aimed to assess the effects of weight loss (through energy restriction combined with aerobic and resistance exercise) on body composition, body fat distribution, resting energy expenditure, quality of life (QOL), strength and fitness, and metabolic risk factors in obese, HIV-infected women. Eighteen HIV-infected women with a body mass index of 30 or more completed a 12-week weight loss program. Before and after the intervention, body composition and fat distribution by dual energy x-ray absorptiometry and whole-body magnetic resonance imaging, resting energy expenditure by indirect calorimetry, QOL, strength, and fitness were measured. Insulin sensitivity by intravenous glucose tolerance test and circulating cardiovascular risk factors (including lipids, tissue plasminogen activator, and plasminogen activator inhibitor 1) were measured in a subset (n = 9). Daily food intake and total body weight decreased (mean +/- SD) by 3195 +/- 477 kJ and 6.7 +/- 4.2 kg, respectively. Weight lost was 95.5% fat by dual energy x-ray absorptiometry or 6.2 L of subcutaneous adipose tissue, 0.7 L visceral adipose tissue, and 0.8 L skeletal muscle by magnetic resonance imaging. Resting energy expenditure fell approximately 419 kJ, strength and fitness increased by 28.9% +/- 18.5% and 36.8% +/- 41.6%, respectively, and QOL improved in 11 of 13 dimensions. There was significant insulin resistance in the subset with metabolic measurements at baseline, and at follow-up there was no improvement in fasting glucose, insulin, or insulin sensitivity, nor was there any change in fasting lipids, tissue plasminogen activator, or plasminogen activator inhibitor 1. There was no significant change in CD4 count or HIV viral load. In conclusion, moderate weight loss achieved by a short-term program of diet and exercise in obese HIV-positive women appears safe and induces loss of adiposity in both the subcutaneous adipose tissue and visceral adipose tissue regions. Despite reduced food intake, weight and fat loss, as well as improvements in strength, fitness, and QOL, the lack of improvement in metabolic parameters suggests that additional interventions may be necessary to reduce the risk of diabetes and cardiovascular disease in this population.
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PMID:Body composition and metabolic effects of a diet and exercise weight loss regimen on obese, HIV-infected women. 1697 3

We previously identified a common set of genes, termed atrogenes, whose expression is coordinately induced or suppressed in muscle during systemic wasting states (fasting, cancer cachexia, renal failure, diabetes). To determine whether this transcriptional program also functions during atrophy resulting from loss of contractile activity and whether atrogene expression correlates with the rate of muscle weight loss, we used cDNA microarrays and RT-polymerase chain reaction to analyze changes in mRNA from rat gastrocnemius during disuse atrophy induced by denervation or spinal cord isolation. Three days after Den or SI, the rate of muscle weight loss was greatest, and 78% of the atrogenes identified during systemic catabolic states were induced or repressed. Of particular interest were the large inductions of key ubiquitin ligases, atrogin-1 (35- to 44-fold) and MuRF1 (12- to 22-fold), and the suppression of PGC-1alpha and PGC-1beta coactivators (15-fold). When atrophy slowed (day 14), the expression of 92% of these atrogenes returned toward basal levels. At 28 days, the atrophy-inducing transcription factor, FoxO1, was still induced and may be important in maintaining the "atrophied" state. Thus, 1) the atrophy associated with systemic catabolic states and following disuse involves similar transcriptional adaptations; and 2) disuse atrophy proceeds through multiple phases corresponding to rapidly atrophying and atrophied muscles that involve distinct transcriptional patterns.
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PMID:Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases. 1711 44

The sodium(Na)- and potassium(K)-activated adenosine-triphosphatase (Na,K-ATPase) is a membrane enzyme that energizes the Na-pump by hydrolysing adenosine triphosphate and wasting energy as heat, so playing a role in thermogenesis and energy balance. Na,K-ATPase regulation by insulin is controversial; in tissue of hyperglycemic-hyperinsulinemic ob/ob mice, we reported a reduction, whereas in streptozotocin-treated hypoinsulinemic-diabetic Swiss and ob/ob mice we found an increased activity, which is against a genetic defect and suggests a regulation by hyperinsulinemia. In human adipose tissue from obese patients, Na,K-ATPase activity was reduced and negatively correlated with body mass index, oral glucose tolerance test-insulinemic area and blood pressure. We hypothesized that obesity is associated with tissue Na,K-ATPase reduction, apparently linked to hyperinsulinemia, which may repress or inactivate the enzyme, thus opposing thyroid hormones and influencing thermogenesis and obesity development. Insulin action on Na,K-ATPase, in vivo, might be mediated by the high level of non-esterified fatty acids, which are circulating enzyme inhibitors and increase in obesity, diabetes and hypertension. In this paper, we analyse animal and human tissue Na,K-ATPase, its level, and its regulation and behaviour in some hyperinsulinemic and insulin-resistant states; moreover, we discuss the link of the enzyme with non-esterified fatty acids and attempt to interpret and organize in a coherent view the whole body of the exhaustive literature on this complicated topic.
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PMID:Animal and human tissue Na,K-ATPase in normal and insulin-resistant states: regulation, behaviour and interpretative hypothesis on NEFA effects. 1744 65

Protein-energy malnutrition (PEM) is highly prevalent among peritoneal dialysis (PD) patients and is a strong predictor of morbidity and mortality. A wide range of factors can lead to PEM and associated wasting (PEM/W) in PD patients, but persistent inflammation and the presence of diabetes have been identified as the two main reasons. An important body of literature has been reporting studies of methods suitable for detecting malnutrition in its early phase so that appropriate intervention can be provided. Although assessment of nutrition status has been substantially improved, no definitive single method of assessing nutrition status has been decided. Rather, several different markers of nutrition should be evaluated together. Because of the complexity of treating malnutrition in PD patients, nontraditional strategies such as appetite stimulants, anti-inflammatory diets, and anti-inflammatory pharmacologic agents are recommended to be combined with more traditional forms of nutritional support, so as to provide a better chance of recovery. The present review briefly discusses the causes of PEM/W, the methods most commonly used to identify the condition, and the new management strategies available.
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PMID:Identifying and managing malnutrition stemming from different causes. 1755 12

Accretion of muscle mass is dependent upon faster rates of protein synthesis than degradation. When an animal is deprived of dietary protein, loss of body weight and negative nitrogen balance ensue. Likewise, refeeding accelerates protein synthesis and results in resumption of positive nitrogen balance. Amino acids and anabolic hormones both interact to maximally enhance rates of protein synthesis acutely during refeeding through an acceleration of the messenger RNA (mRNA) translation initiation. The review will illuminate the molecular mechanisms responsible for increasing mRNA translation initiation in striated muscle. The hastening of mRNA translation initiation most likely results from a stimulation of mammalian target of rapamycin (mTOR) acting through its downstream effector proteins eukaryotic initiation factors (eIF)4E binding protein1 and possibly eIF4G to enhance assembly of eIF4G with eIF4E and 70-kDa ribosomal S6 kinase1. Amino acids and leucine in particular are as effective as a complete meal in stimulating mRNA translation initiation by targeting these specific signal transduction systems. The physiologic importance lies in the potential ability of amino acids as specific nutrients designed to counteract the accelerated host protein wasting associated with a number of disease entities, including cancer, HIV infection, sepsis, and diabetes, and to improve nutrition to maintain muscle mass in aging populations and ensure muscle growth in neonatal populations.
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PMID:Nutrient signaling components controlling protein synthesis in striated muscle. 1763 51

A cross-sectional study of impaired glucose metabolism was carried out in 48 beta-thalassemic patients receiving hypertransfusions. An oral glucose tolerance test (OGTT) was performed using the method and criteria of the American Diabetes Association (ADA). Diabetes mellitus was diagnosed in two patients, and impaired glucose tolerance was found in four patients, giving a prevalence of impaired glucose metabolism of 12.5% in our patient population. The significant clinical characteristics associated with the diagnosis of impaired glucose metabolism were wasting (-2.15/-0.86 SDS, p = 0.025), stunting (-2.69/-1.22 SDS, p = 0.03), higher ferritin levels (8679/4710 microg/L, p = 0.005), splenectomy (50/9.5%, p = 0.012), and lower area under curve (AUC) of insulin secretion after OGTT (40.0/77.7, p = 0.002). The significant decrease of AUC insulin in thalassemic patients with an impaired glucose tolerance test suggests that the pathogenesis may originate from pancreatic beta-cell damage rather than from insulin resistance. In conclusion, the prevalence of impaired glucose tolerance in our population of thalassemic patients receiving hypertransfusions with suboptimal iron chelating therapy was 12.5%. The clinical characteristics of thalassemic patients who developed impaired glucose tolerance were wasting, stunting, higher ferritin levels, splenectomy, and lower AUC insulin.
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PMID:Prevalence of impaired glucose metabolism in beta-thalassemic children receiving hypertransfusions with a suboptimal dosage of iron-chelating therapy. 1789 88

The metabolism of K and Mg is closely linked. Mg deficiency may arise together with and contribute to the persistence of K deficiency. Isolated disturbances of K balance do not produce secondary abnormalities in Mg homeostasis. In contrast, primary disturbances in Mg balance, particularly Mg depletion, produce secondary K depletion. This appears to result from an inability of the cell to maintain the normally high intracellular concentration of K, perhaps as a result of an increase in membrane permeability to K and / or inhibition of Na+-K+-ATPase. Cases of Mg deficiency accompanying with Mg-dependent or -independent K deficiency are not uncommon among the general population. K and Mg deficiencies are found in patients with chronic alcoholism, cardiac diseases, diabetes mellitus (type II), genetic forms of renal potassium and magnesium wasting (Gitelman's and Bartter's syndromes), severe diarrhea and vomiting, malnutrition, during therapy with some kind of drugs. Various K-Mg salts allowing simultaneously eliminating deficiency of Mg and K are described in the literature. K-Mg aspartate is most distributed among K-Mg salts. It can be used as adjuvant therapy in ischaemic heart disease (in angina pectoris and conditions after myocardial infarction), prophylaxis and adjuvant therapy of cardiac arrhythmia (e.g. prevention of toxic symptoms during therapy with digoxin). Differences in metabolism and utilisation of D- and L-amino acids probably may effect on pharmacological properties of K-Mg L- and D-aspartates, and what is more pharmacological doses of Mg and K salts may induce toxicity which differs according to the nature of the anions. In our research it was established, that L-aspartate salts are better delivery forms for cations such as Mg and K than D-aspartate salts. K-Mg L-aspartate can be more beneficial in the treatment of several forms of primary Mg and K deficiency than K-Mg DL-aspartate and K-Mg D-aspartate.
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PMID:[Potassium magnesium homeostasis: physiology, pathophysiology, clinical consequences of deficiency and pharmacological correction]. 1831 67

One of the long-term consequences of Type I diabetes is weight loss with muscle atrophy, the hallmark phenotype of cachexia. A number of disorders that result in cachexia are associated with immune deficiency. However, whether immune deficiency is a cause or an effect of cachexia is not known. This study examines the non-obese diabetic mouse, the mouse model for spontaneous Type I diabetes, as a potential model to study lymphopenia in cachexia, and to determine whether lymphopenia plays a role in the development of cachexia. The muscle atrophy seen in patients with Type I diabetes involves active protein degradation by activation of the ubiquitin-proteasome pathway, indicating cachexia. Evidence of cachexia in the non-obese diabetic mouse was determined by measuring skeletal muscle atrophy, activation of the ubiquitin-proteasome pathway, and apoptosis, a state also described in some models of cachexia. CD4+ T-cell subset lymphopenia was measured in wasting and non-wasting diabetic mice. Our data show that the mechanism of wasting in diabetic mice involves muscle atrophy, a significant increase in ubiquitin conjugation, and upregulation of the ubiquitin ligases, muscle RING finger 1 (MuRF1) and muscle atrophy F box/atrogin-1 (MAFbx), indicating cachexia. Moreover, fragmentation of DNA isolated from atrophied muscle tissue indicates apoptosis. While CD4+ T-cell lymphopenia is evident in all diabetic mice, CD4+ T cells that express a very low density of CD44 were significantly lost in wasting, but not non-wasting, diabetic mice. These data suggest that CD4+ T-cell subsets are not equally susceptible to cachexia-associated lymphopenia in diabetic mice.
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PMID:Cachexia in the non-obese diabetic mouse is associated with CD4+ T-cell lymphopenia. 1839 74

Under various pathophysiological muscle-wasting conditions, such as diabetes and starvation, a family of ubiquitin ligases, including muscle-specific RING-finger protein 1 (MuRF1), are induced to target muscle proteins for degradation via ubiquitination. We have generated transgenic mouse lines over-expressing MuRF1 in a skeletal muscle-specific fashion (MuRF1-TG mice) in an attempt to identify the in vivo targets of MuRF1. MuRF1-TG lines were viable, had normal fertility and normal muscle weights at eight weeks of age. Comparison of quadriceps from MuRF1-TG and wild type mice did not reveal elevated multi-ubiquitination of myosin as observed in human patients with muscle wasting. Instead, MuRF1-TG mice expressed lower levels of pyruvate dehydrogenase (PDH), a mitochondrial key enzyme in charge of glycolysis, and of its regulator PDK2. Furthermore, yeast two-hybrid interaction studies demonstrated the interaction of MuRF1 with PDH, PDK2, PDK4, PKM2 (all participating in glycolysis) and with phosphorylase beta (PYGM) and glycogenin (both regulating glycogen metabolism). Consistent with the idea that MuRF1 may regulate carbohydrate metabolism, MuRF1-TG mice had twofold elevated insulin blood levels and lower hepatic glycogen contents. To further examine MuRF1's role for systemic carbohydrate regulation, we performed glucose tolerance tests (GTT) in wild type and MuRF1-TG mice. During GTT, MuRF1-TG mice developed striking hyperinsulinaemia and hepatic glycogen stores, that were depleted at basal levels, became rapidly replenished. Taken together, our data demonstrate that MuRF1 expression in skeletal muscle re-directs glycogen synthesis to the liver and stimulates pancreatic insulin secretion, thereby providing a regulatory feedback loop that connects skeletal muscle metabolism with the liver and the pancreas during metabolic stress.
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PMID:MuRF1-dependent regulation of systemic carbohydrate metabolism as revealed from transgenic mouse studies. 1846 20

This study is to evaluate the associations between adiponectin level and noncardiovascular death and to test a hypothesis that adiponectin level reflects the degree of systemic wasting that precedes death. A nested case-control study was conducted involving 5243 subjects, drawn from 12490 subjects of the Jichi Medical School Cohort Study, whose blood samples had been drawn between 1992 and 1995. Over an average of 10.8 years of follow-up, 103 cases with noncardiovascular death and 565 controls without history/event/death of any cardiovascular disease were identified. Odds ratios (ORs) were estimated relative to the lowest quintile of adiponectin level. The risks for noncardiovascular death of the second lowest quintile and the highest quintile of adiponectin level were significantly higher than that of the lowest quintile when adjusted for age and sex (model 1) (OR, 2.38 [95% confidence interval (CI), 1.12-5.06] and 2.16 [1.01-4.80]). All the statistical significances disappeared when adjusted further for body mass index and C-reactive protein level (model 2). When excluding cases with cancer death, the odds for death in the highest 2 quintiles were significantly higher than those in the lowest quintile in model 1 (OR, 2.80 [95% CI, 1.04-7.59] and 3.74 [1.38-10.18]). The significant difference between the highest vs the lowest quintile remained significant in model 2 and even after adjusting further for smoking, diabetes, and total cholesterol level (model 3) (OR, 3.28 [95% CI, 1.02-10.51] and 3.98 [1.21-13.13]). Adiponectin levels had linear associations with the risks of noncardiovascular noncancer death in models 1, 2, and 3 (OR per 1 SD increase in log-adiponectin, 1.72 [95% CI, 1.23-2.40], 1.89 [1.23-2.91], and 2.01 [1.29-3.15]). Adiponectin is an independent indicator of noncardiovascular mortality that may relate with systemic wasting.
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PMID:Adiponectin and noncardiovascular death: a nested case-control study. 1850 64


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