Metabolic Abnormalities (metabolic + abnormality)

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Distribution within Medical Sciences

Selected Abstracts

Indinavir did not further increase mean triglyceride levels in HIV-infected patients treated with nucleoside reverse transcriptase inhibitors: An analysis of three randomized clinical trials

Carlos Rojas MD
Abstract Objectives Metabolic abnormalities including hyperlipidemia have developed in patients infected with the human immunodeficiency virus (HIV) after treatment with protease inhibitor drugs. It is unclear whether the deleterious effects on plasma triglyceride concentrations observed in patients receiving highly active antiretroviral therapy are a class effect of protease inhibitors. Hypertriglyceridemia may constitute a risk factor for cardiovascular disease. The purpose of this retrospective analysis of HIV-infected patients enrolled in three randomized, double-blind trials of indinavir therapy was to determine whether indinavir use was associated with a larger increase in triglyceride levels than treatment without a protease inhibitor. Methods Using a mixed-effects model, we compared average changes in nonfasting plasma triglyceride levels among randomized treatment groups for each protocol separately. Results The median increase in triglyceride levels during the 1st year of antiretroviral monotherapy was less with indinavir than with either zidovudine or stavudine. The combination of indinavir and nucleoside-analogue reverse-transcriptase inhibitors (NRTI) resulted in smaller increments in triglyceride levels than NRTI monotherapy. Indinavir also augmented the reduction in triglyceride levels observed with combination therapy using zidovudine and lamivudine in persons with far advanced HIV-infection. However, up to 7% of patients receiving a NRTI and indinavir experienced elevations of nonfasting triglyceride levels in excess of 750,mg/dl. Conclusions On average, the combination of indinavir and NRTI therapy was not associated with a greater elevation of non-fasting triglyceride levels in HIV-infected men with at least moderately advanced immunosuppression than treatment with NRTI drugs alone. Copyright © 2003 John Wiley & Sons, Ltd. [source]

AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives

B. Viollet
Abstract As the liver is central in the maintenance of glucose homeostasis and energy storage, knowledge of the physiology as well as physiopathology of hepatic energy metabolism is a prerequisite to our understanding of whole-body metabolism. Hepatic fuel metabolism changes considerably depending on physiological circumstances (fed vs. fasted state). In consequence, hepatic carbohydrate, lipid and protein synthesis/utilization are tightly regulated according to needs. Fatty liver and hepatic insulin resistance (both frequently associated with the metabolic syndrome) or increased hepatic glucose production (as observed in type 2 diabetes) resulted from alterations in substrates oxidation/storage balance in the liver. Because AMP-activated protein kinase (AMPK) is considered as a cellular energy sensor, it is important to gain understanding of the mechanism by which hepatic AMPK coordinates hepatic energy metabolism. AMPK has been implicated as a key regulator of physiological energy dynamics by limiting anabolic pathways (to prevent further ATP consumption) and by facilitating catabolic pathways (to increase ATP generation). Activation of hepatic AMPK leads to increased fatty acid oxidation and simultaneously inhibition of hepatic lipogenesis, cholesterol synthesis and glucose production. In addition to a short-term effect on specific enzymes, AMPK also modulates the transcription of genes involved in lipogenesis and mitochondrial biogenesis. The identification of AMPK targets in hepatic metabolism should be useful in developing treatments to reverse metabolic abnormalities of type 2 diabetes and the metabolic syndrome. [source]

Active immunization against (Pro3)GIP improves metabolic status in high-fat-fed mice

I. A. Montgomery
Aim: Ablation of gastric inhibitory polypeptide (GIP) receptor signalling can prevent many of the metabolic abnormalities associated with dietary-induced obesity-diabetes. The present study was designed to assess the ability of active immunization against (Pro3)GIP to counter metabolic dysfunction associated with diet-induced obesity in high-fat-fed mice. Methods: Normal male Swiss NIH mice were injected (s.c.) once every 14 days for 98 days with complexed (Pro3)GIP peptide, with transfer to a high-fat diet on day 21. Results: Active immunization against (Pro3)GIP resulted in circulating GIP antibody production and significantly (p < 0.05 p < 0.01) reduced circulating blood glucose concentrations compared to high-fat control mice from day 84 onwards. Glucose levels were not significantly different from lean controls. The glycaemic response to i.p. glucose was correspondingly improved (p < 0.01) in (Pro3)GIP-immunized mice. Furthermore, circulating and glucose-stimulated plasma insulin levels were significantly (p < 0.01 to p < 0.001) depressed compared to high-fat control mice. Liver triglyceride, pancreatic insulin and circulating LDL-cholesterol levels were also significantly reduced in (Pro3)GIP-immunized mice. These changes were independent of any effects on food intake or body weight. The glucose-lowering effect of native GIP was annulled in (Pro3)GIP-immunized mice consistent with the induction of biologically effective GIP-specific neutralizing antibodies. Conclusion: These results suggest that immunoneutralization of GIP represents an effective means of countering the disruption of metabolic processes induced by high-fat feeding. [source]

Cardiovascular metabolic syndrome , an interplay of, obesity, inflammation, diabetes and coronary heart disease

J. S. Rana
Cardiovascular disease is currently one of the biggest causes of morbidity and mortality facing humanity. Such a paradigm shift of disease pattern over the last century has only worsened due to the alarming global prevalence of obesity and type 2 diabetes. In recent years there is increasing focus on inflammation as one of the key players in the patho-physiology of these disorders. In addition to these overt risk factors new research is unraveling the significance of a constellation of early metabolic abnormalities that include weight gain, insulin resistance, prehypertension and a specific pattern of dyslipidaemia. There exists a complex interrelationship of these various metabolic disorders and their effect on cardiovascular system. Simplified explanation can be that inflammation increases insulin resistance, which in turn leads to obesity while perpetuating diabetes, high blood pressure, prothrombotic state and dyslipidaemia. While inflammation and insulin resistance have direct adverse effects on cardiac muscle, these metabolic abnormalities as a whole cause causes cardiovascular complications; warranting a multi pronged therapeutic and preventive approach for the ,Cardiovascular Metabolic Syndrome' as an entity. [source]

CB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy balance, metabolism, and cardiovascular health

Daniela Cota
Abstract Insulin resistance, dyslipidaemia and obesity are the major cardiometabolic risk factors contributing to the development of type 2 diabetes and cardiovascular disease (CVD). Owing to the increasing prevalence of obesity, type 2 diabetes, and CVD, new and effective pharmacologic therapies are urgently needed. In this regard, the endogenous cannabinoid system (ECS), a neuromodulatory system involved in the regulation of various aspects of energy balance and eating behaviour through central and peripheral mechanisms, may present the potential to meet this need. In the central nervous system (CNS), cannabinoid type 1 (CB1) receptors and their respective ligands, the endocannabinoids, have a significant role in the modulation of food intake and motivation to consume palatable food. CB1 receptors have also been found in organs involved in the regulation of metabolic homeostasis, such as liver, white adipose tissue, muscle and pancreas. Dysregulation of the ECS has been associated with the development of dyslipidaemia, glucose intolerance, and obesity, and CB1 receptor blockade may have a role in ameliorating these metabolic abnormalities. Thus, pharmacologic options targeting the ECS may provide a novel, effective approach to the prevention and management of CVD, type 2 diabetes and obesity. Copyright © 2007 John Wiley & Sons, Ltd. [source]

Continuous subcutaneous insulin infusion with short-acting insulin analogues or human regular insulin: efficacy, safety, quality of life, and cost-effectiveness

Régis Pierre Radermecker
Abstract Portable insulin infusion devices are effective and safe insulin delivery systems for managing diabetes mellitus, especially type 1 diabetes. Rapidly absorbed insulin analogues, such as insulin lispro or insulin aspart, may offer an advantage over regular human insulin for insulin pumps. Several open-label randomised crossover trials demonstrated that continuous subcutaneous insulin infusion (CSII) with insulin lispro provided a better control of postprandial hyperglycaemia and a slightly but significantly lower glycated haemoglobin level, with lower daily insulin requirement and similar or even less hypoglycaemic episodes. A CSII study comparing insulin lispro and insulin aspart demonstrated similar results with the two analogues, and better results than those with regular insulin. Because these analogues have a quicker onset and a shorter duration of action than regular insulin, one might expect an earlier and greater metabolic deterioration in case of CSII interruption, but a more rapid correction of metabolic abnormalities after insulin boluses when reactivating the pump. These expectations were confirmed in randomised protocols comparing the metabolic changes occurring during and after CSII interruption of various durations when the pump infused either insulin lispro or regular insulin. The extra cost resulting from the use of CSII and insulin analogues in diabetes management should be compensated for by better metabolic control and quality of life. In conclusion, CSII delivering fast-acting insulin analogues may be considered as one of the best methods to replace insulin in a physiological manner by mimicking meal and basal insulin requirements, without higher risk of hypoglycaemia or ketoacidosis in well-educated diabetic patients. Copyright © 2004 John Wiley & Sons, Ltd. [source]

Insulin resistance in type 2 diabetes: role of fatty acids,

Peter Arner
Abstract Insulin resistance is one of the key factors responsible for hyperglycaemia in type 2 diabetes and can result in a number of metabolic abnormalities associated with cardiovascular disease (insulin resistance syndrome), even in the absence of overt diabetes. The mechanisms involved in the development of insulin resistance are multifactorial and are only partly understood, but increased availability of free fatty acids (FFAs) is of particular importance for the liver and skeletal muscle. The role of FFAs in type 2 diabetes is most evident in obese patients who have several abnormalities in FFA metabolism. Because of a mass effect, the release of FFAs from the total adipose tissue depot to the blood stream is increased and the high concentration of circulating FFAs impairs muscle uptake of glucose by competitive inhibition. In upper-body obesity, which predisposes individuals to type 2 diabetes, the rate of lipolysis is accelerated in visceral adipose tissue. This results in a selective increase in FFA mobilisation to the portal vein, which connects visceral fat to the liver. A high ,portal' FFA concentration has undesirable effects on the liver, resulting in dyslipidaemia, hyperinsulinaemia, hyperglycaemia and hepatic insulin resistance. Recently, a new class of antidiabetic agents, the thiazolidinediones (TZDs) or ,glitazones' has been developed. A prominent effect of these agents is the lowering of circulating FFA levels and it is believed, but not yet proven, that this interaction with FFAs constitutes a major mechanism behind the glucose-lowering effect of the TZDs. Copyright © 2002 John Wiley & Sons, Ltd. [source]

Weight reduction, but not a moderate intake of fish oil, lowers concentrations of inflammatory markers and PAI-1 antigen in obese men during the fasting and postprandial state

A. Jellema
Abstract Background, In obese subjects, chronic low-grade inflammation contributes to an increased risk of metabolic abnormalities, which are reversed by weight loss. Sustained weight loss, however, is difficult to achieve and more insight into dietary approaches on anti-inflammatory responses in obese subjects is needed. In this respect, fish oil deserves attention. Material and methods, Eleven obese men (BMI: 30,35 kg m,2) received daily fish oil (1·35 g n-3 fatty acids) or placebo capsules in random order for 6 weeks. Eight subjects continued with a weight reduction study that lasted 8 weeks. Mean weight loss was 9·4 kg. At the end of each experimental period a postprandial study was performed. Results, Relative to fasting concentrations, interleukin-6 (IL-6) levels increased by 75% 2 h and by 118% 4 h after the meal (P < 0·001), when subjects consumed the control capsules. In contrast, C-reactive protein (C-RP) concentrations decreased slightly by 0·7% and 6·6% (P = 0·046), and those of plasminogen activator inhibitor-1 (PAI-1) antigen by, respectively, 26% and 53% (P < 0·001). Tumour necrosis factor-, (TNF-,; P = 0·330) and soluble TNF-receptor concentrations (sTNF-R55 and sTNF-R75; P = 0·451 and P = 0·108, respectively) did not change. Changes relative to fasting concentrations were not significantly affected by either fish oil or weight reduction. Absolute IL-6, C-RP, sTNF-R55, sTNF-R75, and PAI-1 antigen concentrations, however, were consistently lower after weight reduction, but not after fish oil consumption. Conclusion, For slightly obese subjects a moderate intake of fish oil does not have the same favourable effects on markers for a low-grade inflammatory state as weight reduction. [source]

Sleep and the metabolic syndrome

Robert Wolk
The metabolic syndrome represents a clustering of several interrelated risk factors of metabolic origin that are thought to increase cardiovascular risk. It is still uncertain whether this clustering results from multiple underlying risk factors or whether it has a single cause. One metabolic abnormality that may underlie several clinical characteristics of the metabolic syndrome is insulin resistance. This review discusses the evidence that sleep disturbances (obstructive sleep apnoea, sleep deprivation and shift work) may independently lead to the development of both insulin resistance and individual clinical components of the metabolic syndrome. The converse may also be true, in that metabolic abnormalities associated with the metabolic syndrome and insulin resistance may potentially exacerbate sleep disorders. The notion that sleep disturbances exert detrimental metabolic effects may help explain the increasing prevalence of the metabolic syndrome and insulin resistance in the general population and may have important implications for population-based approaches to combat the increasing epidemic of metabolic and cardiovascular disease. [source]

The backbone of oral glucose-lowering therapy: time for a paradigm shift?

Jochen Seufert
Abstract The complex array of metabolic abnormalities associated with type 2 diabetes provides a number of new targets for therapeutic intervention. Although the established oral glucose-lowering therapies, metformin and the sulfonylureas, continue to provide the backbone of therapeutic approaches, the thiazolidinediones (TZDs) also play an important role. Further, a new class of oral agents, the dipeptidyl peptidase-IV (DPP-IV) inhibitors, has recently become available with apparent utility in decreasing postprandial glucose excursions. This review examines how the TZDs and the DPP-IV inhibitors might integrate into current treatment strategies, considering not only glycemic goals, but also longer-term benefits such as durability of glycemic control, effect on metabolic parameters and cardiovascular outcomes. A practical approach is taken, reflecting potential clinical situations in which therapeutic intervention is required. [source]

Axonal integrity in the absence of functional peroxisomes from projection neurons and astrocytes

GLIA, Issue 13 2010
Astrid Bottelbergs
Abstract Ablation of functional peroxisomes from all neural cells in Nestin-Pex5 knockout mice caused remarkable neurological abnormalities including motoric and cognitive malfunctioning accompanied by demyelination, axonal degeneration, and gliosis. An oligodendrocyte selective Cnp-Pex5 knockout mouse model shows a similar pathology, but with later onset and slower progression. Until now, the link between these neurological anomalies and the known metabolic alterations, namely the accumulation of very long-chain fatty acids (VLCFA) and reduction of plasmalogens, has not been established. We now focused on the role of peroxisomes in neurons and astrocytes. A neuron-specific peroxisome knockout model, NEX-Pex5, showed neither microscopic nor metabolic abnormalities indicating that the lack of functional peroxisomes within neurons does not cause axonal damage. Axonal integrity and normal behavior was also preserved when peroxisomes were deleted from astrocytes in GFAP-Pex5,/, mice. Nevertheless, peroxisomal metabolites were dysregulated in brain including a marked accumulation of VLCFA and a slight reduction in plasmalogens. Interestingly, despite minor targeting of oligodendrocytes in GFAP-Pex5,/, mice, these metabolic perturbations were also present in isolated myelin indicating that peroxisomal metabolites are shuttled between different brain cell types. We conclude that absence of peroxisomal metabolism in neurons and astrocytes does not provoke the neurodegenerative phenotype observed after deleting peroxisomes from oligodendrocytes. Lack of peroxisomal metabolism in astrocytes causes increased VLCFA levels in myelin, but this has no major impact on neurological functioning. © 2010 Wiley-Liss, Inc. [source]

The prevalence of lipodystrophy in an ambulant HIV-infected population: it all depends on the definition

HIV MEDICINE, Issue 3 2001
VM Carter
Objectives This study's objective was to determine the prevalence of body shape changes and metabolic abnormalities in an ambulant population with HIV infection. Three different definitions of lipodystrophy were used to assess these changes. Patients' anthropometric measures and dual-energy X-ray absorptiometry (DEXA) scans were compared in order to estimate fat distribution in this population. We sought to evaluate potential predictors for lipodystrophy according to each of the three definitions. Methods We performed a cross-sectional study in the outpatient clinic of a tertiary referral hospital in Melbourne, Australia. We enrolled a total of 167 HIV-infected ambulatory patients over 3 months in mid-1998. Data on 159 males, 149 of whom were receiving triple combination antiretroviral therapy, were evaluated. Anthropometric measures, clinical examination, self-report of body shape changes, biochemical measures and DEXA scan were used to assess lipodystrophy and risk factors for cardiovascular disease. Patients described body shape changes in the face, trunk, arms and legs. Laboratory parameters measured included fasting triglyceride (TG), cholesterol, high-density lipoproteins (HDL), glucose, insulin, CD4 cell count and plasma HIV RNA. Current and past antiretroviral therapies were ascertained. Results According to one proposed Australian national definition of lipodystrophy (LDNC), the prevalence of lipodystrophy in this population was 65%. This definition included an objective assessment with major and minor criteria. Patient-defined lipodystrophy (LDP), which involved a subjective assessment of thinning arms and legs and central adiposity, occurred in 19%. Patient-defined lipoatrophy (LAP), which involved a subjective assessment of thinning arms and legs without central adiposity, occurred in 21.3%. No change in body habitus was noted by 37% of the cohort. Hypercholesterolaemia was recorded in 44%, hypertriglyceridaemia in 52% and elevated insulin levels in 23%. Anthropometry was predictive of the per cent total body fat recorded by DEXA scan, but produced consistently lower values. In multivariate analysis, LDP and LAP were significantly associated with stavudine (d4T) use, while LAP was also associated with zidovudine (ZDV) treatment. There were no treatment associations with LDNC. Protease inhibitor (PI) exposure was associated with metabolic changes but not patient perceived body shape changes, while d4T and ZDV exposure was associated with increased triglycerides and reduced peripheral fat stores. Conclusions The prevalence of body shape changes in a single population varied depending on the definition applied. The LDNC definition overestimated body shape abnormalities in comparison with patient perception. LAP was associated with significantly lower fat stores measured by anthropometry and DEXA scan than those identified under the LDNC definition. In contrast to LDNC, LAP was associated with d4T exposure, nucleoside reverse transcriptase inhibitor (NRTI) and ZDV duration of use, but not PI use. Until a consensus definition for lipodystrophy is developed, including agreement on objective measurement and thresholds for abnormality, careful description of the individual components of the syndrome is required to enable cohort comparisons so that predictors of the syndrome can be assessed more accurately and outcome studies made feasible. [source]

Metabolic differences between Asian and Caucasian patients on clozapine treatment

Mythily Subramaniam
Abstract Objective To establish if there are ethnic differences in the various metabolic disturbances that are common with clozapine treatment. Method Forty subjects (20 Asians and 20 Caucasians) with a diagnosis of schizophrenia were recruited for the study. Clozapine blood levels as well as fasting blood glucose, lipid levels, and liver function tests were established. Other clinical parameters such as blood pressure and Body Mass Index (BMI) were recorded for each patient. Results The mean clozapine dose was significantly higher in the Caucasian subjects (432.5,±,194.7,mg) as compared to the Asian subjects (175.6,±,106.9,mg) (p,<,0.001) while the mean weight-corrected dose for Asian patients was lower (3.0,±,1.9 and 5.0,±,2.1,mg/kg, respectively, p,=,0.005). There were, however, no ethnic differences in the mean plasma clozapine concentration (415.3,±,185.8,ng/ml in Caucasians and 417.1,±,290.8,ng/ml in Asians). BMI were significantly higher in Caucasians, as were the number of subjects with hypertension; levels of hepatic enzymes were higher in the Asian group. Conclusions Not only are there pharmacokinetic differences between Asian and Caucasian patients receiving clozapine, but there may also be differential emergence of certain metabolic abnormalities like hypertension and weight gain in these two ethnic groups. However, the effects of life style including diet and exercise cannot be excluded. Copyright © 2007 John Wiley & Sons, Ltd. [source]

Screening of glucose/insulin metabolic alterations in men with multiple skin tags on the neck

Emilio Sudy
Summary Multiple skin tags appear associated with abnormalities in glucose/insulin metabolism. Clinical and metabolic glucose/insulin characteristics of men with multiple (8 or more) skin tags on the neck were compared with a control group with few or none. Both groups were divided in two subgroups according to normal or abnormal laboratory findings. In the study subgroup with normal laboratory findings the number of skin tags varied from 8,33, whereas in those with abnormal laboratory findings the range was 9,65. Eight or more skin tags were related with statistically significant laboratory glucose/insulin abnormalities: basal hyperinsulinemia (p<0.002), postprandial hyperinsulinemia (p<0.003), and postprandial hyperglycemia (p<0.01). In the multiple skin tag group 77 % had diverse laboratory abnormalities, including insulin resistance, basal hyperinsulinemia, postprandial hyperinsulinemia, glucose intolerance or type 2 diabetes, in contrast with the control group, where only 33 % showed laboratory abnormalities. One-third of the study group had acanthosis nigricans. Only 15 % of patients with metabolic abnormalities did not show any cutaneous expression of glucose/insulin alterations (9 or more skin tags on the neck, acanthosis nigricans, or waist circumference greater than 95 cm). Multiple skin tags were more sensitive than acanthosis nigricans in identifying those with alterations in the glucose/insulin metabolism (77 vs. 32 % respectively), although less specific (68 vs.100%). Multiple skin tags should raise suspicion of insulin resistance or hyperinsulinemia. [source]

Pathogenesis and Pathophysiology of the Cardiometabolic Syndrome

Erik P. Kirk PhD
The cardiometabolic syndrome represents a cluster of metabolic abnormalities that are risk factors for cardiovascular disease. The mechanism(s) responsible for developing the cardiometabolic syndrome is not known, but it is likely that multi-organ insulin resistance, which is a common feature of the cardiometabolic syndrome, is involved. Insulin resistance is an important risk factor for type 2 diabetes and can cause vasoconstriction and renal sodium reabsorption, leading to increased blood pressure. Alterations in adipose tissue fatty acid and adipokine metabolism are involved in the pathogenesis of insulin resistance. Excessive rates of fatty acid release into the bloodstream can impair the ability of insulin to stimulate muscle glucose uptake and suppress hepatic glucose production. Noninfectious systemic inflammation associated with adipocyte and adipose tissue macrophage cytokine production can also cause insulin resistance. In addition, increased free fatty acid delivery to the liver can stimulate hepatic very low-density lipoprotein triglyceride production, leading to dyslipidemia. [source]

Early versus late enteral nutritional support in adults with burn injury: a systematic review

J. Wasiak
Abstract Background Burn injury increases the body's metabolic demands, and therefore nutritional requirements. Provision of an adequate supply of nutrients is believed to lower the incidence of metabolic abnormalities, thus reducing septic morbidity, and improving survival rates. Enteral nutrition support is the best feeding method in a patient who is unable to achieve an adequate oral intake, but optimal timing of its introduction after burn injury (i.e. early versus late) needs to be established. The purpose of this review is to examine evidence for the effectiveness and safety of early versus late enteral nutrition support in adults with burn injury. Methods An examination of randomized and controlled clinical trials using various medical databases such as The Cochrane Library (Issue 3, 2006), MEDLINE (from 1950), CINHAL (from 1982) and EMBASE (from 1980). Results The trial evidence about the benefit of early enteral nutritional support on standardized clinical outcomes such as length of hospital stay and mortality remained inconclusive. Similarly, the question of whether early enteral feeding influenced or decreased metabolic rate, reduced septic and other complications remained uncertain. Conclusions Promising results suggest early enteral nutrition support may blunt the hypermetabolic response to thermal injury, but it is insufficient to provide clear guidelines for practice. Further research incorporating larger sample sizes and rigorous methodology that utilizes valid and reliable outcome measures is essential. [source]

Abnormalities of whole body protein turnover, muscle metabolism and levels of metabolic hormones in patients with chronic heart failure

Abstract. Objective., It is well known that chronic heart failure (CHF) is associated with insulin resistance and cachexia, but little is known about the underlying substrate metabolism. The present study was undertaken to identify disturbances of basal glucose, lipid and protein metabolism. Design., We studied eight nondiabetic patients with CHF (ejection fraction 30 ± 4%) and eight healthy controls. Protein metabolism (whole body and regional muscle fluxes) and total glucose turnover were isotopically assayed. Substrate oxidation were obtained by indirect calorimetry. The metabolic response to exercise was studied by bicycle ergometry exercise. Results., Our data confirm that CHF patients have a decreased lean body mass. CHF patients are characterised by (i) decreased glucose oxidation [glucose oxidation (mg kg,1 min,1): 1.25 ± 0.09 (patients) vs. 1.55 ± 0.09 (controls), P < 0.01] and muscle glucose uptake [a , v diffglucose (,mol L,1): ,10 ± 25 (patients) vs. 70 ± 22 (controls), P < 0.01], (ii) elevated levels of free fatty acids (FFA) [FFA (mmol L,1): 0.72 ± 0.05 (patients) vs. 0.48 ± 0.03 (controls), P < 0.01] and 3-hydroxybutyrate and signs of elevated fat oxidation and muscle fat utilization [a , v diffFFA (mmol L,1): 0.12 ± 0.02 (patients) vs. 0.05 ± 0.01 (controls), P < 0.05] and (iii) elevated protein turnover and protein breakdown [phenylalanine flux (,mol kg,1 h,1): 36.4 ± 1.5 (patients) vs. 29.6 ± 1.3 (controls), P < 0.01]. Patients had high circulating levels of noradrenaline, glucagon, and adiponectin, and low levels of ghrelin. We failed to observe any differences in metabolic responses between controls and patients during short-term exercise. Conclusions., In the basal fasting state patients with CHF are characterized by several metabolic abnormalities which may contribute to CHF pathophysiology and may provide a basis for targeted intervention. [source]

Protein tyrosine phosphatase 1B: a new target for the treatment of obesity and associated co-morbidities

O. Ukkola
Abstract.,Ukkola O, Santaniemi M (University of Oulu, Oulu, Finland). Protein tyrosine phosphatase 1B: a new target for the treatment of obesity and associated co-morbidities (Review). J Intern Med 2002; 251: 467,475. Impaired insulin action is important in the pathophysiology of multiple metabolic abnormalities such as obesity and type 2 diabetes. Protein tyrosine phosphatase 1B (PTP1B) is considered a negative regulator of insulin signalling. This is best evidenced by studies on knockout mice showing that lack of PTP1B is associated with increased insulin sensitivity as well as resistance to obesity and in vitro studies whilst studies in animals and humans have given contradictory results. However, several studies support the notion that insulin signalling can be enhanced by the inhibition of PTP1B providing an attractive target for therapy against type 2 diabetes and obesity. In addition, recent genetic studies support the association between PTP1B with insulin resistance. The development of PTP1B inhibitors has already begun although it has become clear that is not easy to find both a selective, safe and effective PTP1B inhibitor. The objective of this paper is to review the current evidence of PTP1B in the pathophysiology of obesity, type 2 diabetes and cancer as well as in the treatment of these disorders. [source]

1H magnetic resonance spectroscopy in human hydrocephalus

Kees P.J. Braun MD
Abstract Purpose To evaluate cerebral metabolism in clinical hydrocephalus with 1H magnetic resonance spectroscopy (MRS). Materials and Methods In 24 children and adults with progressive, arrested, or normal pressure hydrocephalus, long-echo time 1H MR spectra were acquired from periventricular white matter and intraventricular cerebrospinal fluid (CSF). Metabolite ratios, and the presence of lactate, were compared with 38 age-matched controls. Results Metabolite ratios of patients were within the 95% confidence interval (CI) of controls. A small lactate resonance was detected in 20% of control and hydrocephalic subjects. Lactate was consistently visible in CSF spectra, though lactate concentrations were normal. The CSF lactate T2 was long in comparison with the known intracellular metabolite T2 relaxation times. In three neonates with hydrocephalus and spina bifida, 3-hydroxybutyrate was detected in CSF in vivo. Conclusion Within the limits of the present methods, 1H MRS could not detect cerebral metabolic abnormalities in human hydrocephalus and provided no additional diagnostic information. The long T2 of lactate in CSF explains its high visibility. Hence, the detection of lactate in spectra acquired from voxels that contain CSF does not necessarily imply cerebral ischemia. J. Magn. Reson. Imaging 2003;17:291,299. © 2003 Wiley-Liss, Inc. [source]

Nerve Tissue-Specific (GLUD2) and Housekeeping (GLUD1) Human Glutamate Dehydrogenases Are Regulated by Distinct Allosteric Mechanisms

Implications for Biologic Function
Abstract: Human glutamate dehydrogenase (GDH), an enzyme central to the metabolism of glutamate, is known to exist in housekeeping and nerve tissue-specific isoforms encoded by the GLUD1 and GLUD2 genes, respectively. As there is evidence that GDH function in vivo is regulated, and that regulatory mutations of human GDH are associated with metabolic abnormalities, we sought here to characterize further the functional properties of the two human isoenzymes. Each was obtained in recombinant form by expressing the corresponding cDNAs in Sf9 cells and studied with respect to its regulation by endogenous allosteric effectors, such as purine nucleotides and branched chain amino acids. Results showed that L-leucine, at 1.0 mM, enhanced the activity of the nerve tissue-specific (GLUD2-derived) enzyme by ,1,600% and that of the GLUD1-derived GDH by ,75%. Concentrations of L-leucine similar to those present in human tissues (,0.1 mM) had little effect on either isoenzyme. However, the presence of ADP (10-50 ,M) sensitized the two isoenzymes to L-leucine, permitting substantial enzyme activation at physiologically relevant concentrations of this amino acid. Nonactivated GLUD1 GDH was markedly inhibited by GTP (IC50 = 0.20 ,M), whereas nonactivated GLUD2 GDH was totally insensitive to this compound (IC50 > 5,000 ,M). In contrast, GLUD2 GDH activated by ADP and/or L-leucine was amenable to this inhibition, although at substantially higher GTP concentrations than the GLUD1 enzyme. ADP and L-leucine, acting synergistically, modified the cooperativity curves of the two isoenzymes. Kinetic studies revealed significant differences in the Km values obtained for ,-ketoglutarate and glutamate for the GLUD1- and the GLUD2-derived GDH, with the allosteric activators differentially altering these values. Hence, the activity of the two human GDH is regulated by distinct allosteric mechanisms, and these findings may have implications for the biologic functions of these isoenzymes. [source]

Review article: the treatment of non-alcoholic steatohepatitis with thiazolidinediones

Summary It is generally accepted that non-alcoholic fatty liver disease will be the most frequent liver disease in the near future and that the management of patients with non-alcoholic fatty liver disease will be a challenge for hepatologists in the next decades. Non-alcoholic fatty liver disease is considered the hepatic manifestation of the metabolic syndrome, in which insulin resistance plays a crucial role. Although steatosis will often not progress to severe liver disease, in some patients, it results in cirrhosis and even hepatocellular carcinoma. Therefore, it is important to identify those patients at risk for developing fibrosis. Age, diabetes, obesity and hypertriglyceridaemia are independent risk factors for fibrosis in patients with elevated serum alanine aminotransferase levels and steatosis on ultrasound. The presence of multiple metabolic disorders increases the risk. Apart from diet, exercise and correction of underlying metabolic abnormalities, no specific treatment is available at the moment. Theoretically, thiazolidinediones are an attractive way to treat non-alcoholic fatty liver disease, because they improve insulin resistance. Some preliminary studies with thiazolidinediones were encouraging, as steatosis, inflammation and fibrosis improved in a substantial number of patients. Although no serious side effects occurred in the pilot studies, we should look vigilantly for hepatotoxicity, as the first generation thiazolidinediones proved to be toxic for the liver. [source]

Non-alcoholic fatty liver disease , a common and benign finding in octogenarian patients

Nadya Kagansky
Kagansky N, Levy S, Keter D, Rimon E, Taiba Z, Fridman Z, Berger D, Knobler H, Malnick S. Non-alcoholic fatty liver disease , a common and benign finding in octogenarian patients. Liver International 2004: 24: 588,594. © Blackwell Munksgaard 2004 Abstract: Background: Non-alcoholic fatty liver disease (NAFLD), a common entity in the general population, has been shown to be linked with insulin resistance and metabolic syndrome. Several of the components of the metabolic syndrome are more common in the aged population. The aims of the current study were to determine in the aged, the prevalence and the clinical presentation of NAFLD, as well as the relation to the underlying metabolic abnormalities. Method: In this prospective study, we evaluated 91 octogenarians with a mean age of 85.56±3.76 years, who were admitted to the rehabilitation departments of a geriatric hospital. Clinical evaluation included: abdominal ultrasound (US), fasting glucose and lipid levels, serum liver enzymes, ferritin, iron and transferrin saturation. Elderly patients with NAFLD were compared with 46 young patients with NAFLD. Results: NAFLD diagnosed by US was a common finding in this aged population, is present in 42/91 patients (46.2%). No significant differences were observed between the patients with or without NAFLD in the following: age, gender, chronic illnesses, anthropometric parameters, lipid profile, fasting glucose levels, metabolic syndrome prevalence, serum levels of transaminases, ferritin and iron. Young patients with NAFLD had significantly higher serum levels of triglycerides and a significantly higher prevalence of glucose intolerance, obesity and the metabolic syndrome compared with the elderly patients with NAFLD. Conclusions: NAFLD was a common finding in our group of elderly patients and the prevalence was higher than reported in the general population. In contrast to the well-described association between the metabolic syndrome and NAFLD in the general population, we did not find this association in the aged group. In addition, none of the patients had stigmata of advanced liver disease. These data suggest that NAFLD is a common and benign finding in the elderly population, but is not associated with the metabolic syndrome. [source]

Do stress reactions cause abdominal obesity and comorbidities?

P. Björntorp
Summary ,Stress' embraces the reaction to a multitude of poorly defined factors that disturb homeostasis or allostasis. In this overview, the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system have been utilized as objective measurements of stress reactions. Although long-term activation of the sympathetic nervous system is followed by primary hypertension, consequences of similar activation of the HPA axis have not been clearly defined. The focus of this overview is to examine whether or not repeated activation of these two stress centres may be involved in the pathogenesis of abdominal obesity and its comorbidities. In population studies adrenal hormones show strong statistical associations to centralization of body fat as well as to obesity. There is considerable evidence from clinical to cellular and molecular studies that elevated cortisol, particularly when combined with secondary inhibition of sex steroids and growth hormone secretions, is causing accumulation of fat in visceral adipose tissues as well as metabolic abnormalities (The Metabolic Syndrome). Hypertension is probably due to a parallel activation of the central sympathetic nervous system. Depression and ,the small baby syndrome' as well as stress exposure in men and non-human primates are followed with time by similar central and peripheral abnormalities. Glucocorticoid exposure is also followed by increased food intake and ,leptin resistant' obesity, perhaps disrupting the balance between leptin and neuropeptide Y to the advantage of the latter. The consequence might be ,stress-eating', which, however, is a poorly defined entity. Factors activating the stress centres in humans include psychosocial and socioeconomic handicaps, depressive and anxiety traits, alcohol and smoking, with some differences in profile between personalities and genders. Polymorphisms have been defined in several genes associated with the cascade of events along the stress axes. Based on this evidence it is suggested that environmental, perinatal and genetic factors induce neuroendocrine perturbations followed by abdominal obesity with its associated comorbidities. [source]

First phase insulin release and glucose tolerance in children with Fanconi anemia after hematopoietic cell transplantation

Lynda E. Polgreen MD
Abstract Background Fanconi anemia (FA) is an autosomal and X-linked recessive disease of chromosomal instability, which results in bone marrow failure. Children with FA have been shown to have an increased risk of diabetes mellitus (DM). Procedure A cross-sectional study of glucose and insulin metabolism was conducted in 17 children with FA who had undergone hematopoietic cell transplantation (HCT) at the University of Minnesota. First phase insulin release (FPIR) was determined by intravenous glucose tolerance test (IVGTT). Oral glucose tolerance test (OGTT), lipid panel, blood pressure, and medical history were reviewed for additional metabolic abnormalities. Results Seventeen FA participants, median age 11.3 (range 5.5,17.6) years, were evaluated. IVGTT identified three separate groups: low FPIR, normal FPIR, and high FPIR. Those with low FPIR were more likely to have low BMI, but had normal glucose levels. Those with high FPIR, had high BMI, elevated lipids, and body fat. One patient with normal FPIR had impaired glucose tolerance and another with normal FPIR had impaired fasting glucose. No participant was diagnosed with DM by fasting glucose, 2 hr glucose during OGTT, or hemoglobin A1C. Conclusions The majority of children with FA had normal glucose tolerance and normal beta-cell function after HCT. Two small subsets of patients had lower than expected and higher than expected FPIR. The clinical significance of these differences is not yet known given the normal glucose tolerance and fasting glucose levels in these two groups. Pediatr Blood Cancer 2009;53:191,196. © 2009 Wiley-Liss, Inc. [source]

The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial

H. Fallah Huseini
Abstract Oxidative stresses are increasingly implicated in the pathogenesis of diabetic complications which may either cause direct pancreatic , -cell damage or lead to metabolic abnormalities that can induce or aggravate diabetes. The valuable effect of antioxidant nutrients on the glycemic control of diabetic patients has been reported in experimental and clinical studies. The present study was designed to investigate the effects of the herbal medicine, Silybum marianum seed extract (silymarin), which is known to have antioxidant properties on the glycemic profile in diabetic patients. A 4-month randomized double-blind clinical trial was conducted in 51 type II diabetic patients in two well-matched groups. The first group (n = 25) received a silymarin (200 mg) tablet 3 times a day plus conventional therapy. The second group (n = 26) received the same therapy but a placebo tablet instead of silymarin. The patients were visited monthly and glycosylated hemoglobin (HbA1c), fasting blood glucose (FBS), insulin, total cholesterol, LDL and HDL, triglyceride, SGOT and SGPT levels were determined at the beginning and the end of the study. The results showed a significant decrease in HbA1c, FBS, total cholesterol, LDL, triglyceride SGOT and SGPT levels in silymarin treated patients compared with placebo as well as with values at the beginning of the study in each group. In conclusion, silymarin treatment in type II diabetic patients for 4 months has a beneficial effect on improving the glycemic profile. Copyright © 2006 John Wiley & Sons, Ltd. [source]

Electrophysiological evidence for altered early cerebral somatosensory signal processing in schizophrenia

Till D. Waberski
Abstract Various studies have indicated an impairment of sensory signal processing in schizophrenic patients. Anatomical and functional imaging studies have indicated morphological and metabolic abnormalities in the thalamus in schizophrenia. Other results give evidence for an additional role of cortical dysfunction in sensory processing in schizophrenia. Advanced analysis of human median nerve somatosensory evoked potentials (SEPs) reveals a brief oscillatory burst of low-amplitude and high-frequency activity (,600 Hz), the so-called high frequency oscillations (HFOs). The present study explores the behavior of HFOs in a cohort of schizophrenic patients in comparison to a group of controls. HFOs in the group of patients appeared with a delayed latency. In the low-frequency part of the SEPs an increase in amplitude was found. These results are interpreted to reflect a lack of somatosensory inhibition in the somatosensory pathway, either at a thalamic or a cortical level. [source]

Fetal, infant, adolescent and adult phenotypes of polycystic ovary syndrome in prenatally androgenized female rhesus monkeys

David H. Abbott
Abstract Old World monkeys provide naturally occurring and experimentally induced phenotypes closely resembling the highly prevalent polycystic ovary syndrome (PCOS) in women. In particular, experimentally induced fetal androgen excess in female rhesus monkeys produces a comprehensive adult PCOS-like phenotype that includes both reproductive and metabolic dysfunction found in PCOS women. Such a reliable experimental approach enables the use of the prenatally androgenized (PA) female rhesus monkey model to (1) examine fetal, infant and adolescent antecedents of adult pathophysiology, gaining valuable insight into early phenotypic expression of PCOS, and (2) to understand adult pathophysiology from a mechanistic perspective. Elevated circulating luteinizing hormone (LH) levels are the earliest indication of reproductive dysfunction in late gestation nonhuman primate fetuses and infants exposed to androgen excess during early (late first to second trimester) gestation. Such early gestation-exposed PA infants also are hyperandrogenic, with both LH hypersecretion and hyperandrogenism persisting in early gestation-exposed PA adults. Similarly, subtle metabolic abnormalities appearing in young nonhuman primate infants and adolescents precede the abdominal adiposity, hyperliplidemia and increased incidence of type 2 diabetes that characterize early gestation-exposed PA adults. These new insights into the developmental origins of PCOS, and progression of the pathophysiology from infancy to adulthood, provide opportunities for clinical intervention to ameliorate the PCOS phenotype thus providing a preventive health-care approach to PCOS-related abnormalities. For example, PCOS-like traits in PA monkeys, as in PCOS women, can improve with better insulin,glucose homeostasis, suggesting that lifestyle interventions preventing increased adiposity in adolescent daughters of PCOS mothers also may reduce their risk of acquiring many PCOS-related metabolic abnormalities in adulthood. Am. J. Primatol. 71:776,784, 2009. © 2009 Wiley-Liss, Inc. [source]

REVIEW ARTICLE: Inflammation and Implantation

Nava Dekel
Approximately half of all human embryo implantations result in failed pregnancy. Multiple factors may contribute to this failure, including genetic or metabolic abnormalities of the embryo. However, many of these spontaneous early abortion cases are attributed to poor uterine receptivity. Furthermore, although many fertility disorders have been overcome by a variety of assisted reproductive techniques, implantation remains the rate-limiting step for the success of the in vitro fertilization (IVF) treatments. It has been demonstrated that endometrial biopsies performed either during the spontaneous, preceding cycle, or during the IVF cycle itself, significantly improve the rate of implantation, clinical pregnancies and live births. These observations suggest that mechanical injury of the endometrium may enhance uterine receptivity by provoking the immune system to generate an inflammatory reaction. In strong support of this idea, we recently found that dendritic cells (DCs), an important cellular component of the innate immune system, play a critical role in successful implantation in a mouse model. In this review, we discuss the hypothesis that the injury-derived inflammation in the biopsy-treated patients generates a focus for uterine DCs accumulation that, in turn, enhances the endometrial expression of essential molecules, which facilitate the interaction between the embryo and the uterine epithelium. [source]

Baseline Clinical Characteristics and Midterm Prognosis of STE-ACS and NSTE-ACS Patients with Normal Coronary Arteries

Lukasz Mazurkiewicz M.D.
Objective: We sought to compare clinical profiles and midterm prognosis of patients with normal coronary arteries presenting with ST-elevation ACS (STE-ACS) versus non-ST-elevation ACS (nSTE-ACS). Background: There are limited data regarding ACS in patients with normal coronary arteries, and especially clinical differences between ST-ACS and nSTE-ACS patients have not been evaluated sufficiently. Methods: The study group comprised 190 patients (mean age: 53.2 years, 63.1% males, 63.6% STE-ACS) presenting with ACS and normal coronary angiograms. The participants were evaluated in terms of 42 clinical variables. MACE [cardiac death (CD) and hospitalization for angina (HA)] were the study end points. Results: STE-ACS in comparison to nSTE-ACS patients were younger (P < 0.01), were more frequently males (P < 0.01), had more often infection prior to ACS (P < 0.01), higher hsCRP on admission (P < 0.01), and greater infarct size, measured by maximal troponin I (P < 0.01). By multivariate analysis in this subgroup, predictors of outcome were hsCRP (P = 0.03) and raised troponin I (P = 0.02). nSTE-ACS in comparison to STE-ACS patients were more obese (BMI, P < 0.01), had higher LDL cholesterol (P < 0.01), fasting glucose (P = 0.03). LDL cholesterol (P = 0.02) and fasting glucose (P = 0.03) emerged as independent predictors of outcome in these patients. Mean follow-up period was 25.4 months. STE-ACS patients had twice fewer MACE rate than nSTE-ACS patients [(1-CD, 12-HA; 11%) vs (1-CD, 16-HA; 25%), respectively, log rank P < 0.01]. Conclusions: STE-ACS and nSTE-ACS patients with normal coronary arteriography have different clinical profiles. In nSTE-ACS patients more pronounced metabolic abnormalities were identified, while in STE-ACS patients inflammatory background was more significant. [source]

Emodin, a natural product, selectively inhibits 11,-hydroxysteroid dehydrogenase type 1 and ameliorates metabolic disorder in diet-induced obese mice

Ying Feng
BACKGROUND AND PURPOSE 11,-Hydroxysteroid dehydrogenase type 1 (11,-HSD1) is an attractive therapeutic target of type 2 diabetes and metabolic syndrome. Emodin, a natural product and active ingredient of various Chinese herbs, has been demonstrated to possess multiple biological activities. Here, we investigated the effects of emodin on 11,-HSD1 and its ability to ameliorate metabolic disorders in diet-induced obese (DIO) mice. EXPERIMENTAL APPROACH Scintillation proximity assay was performed to evaluate inhibition of emodin against recombinant human and mouse 11,-HSDs. The ability of emodin to inhibit prednisone- or dexamethasone-induced insulin resistance was investigated in C57BL/6J mice and its effect on metabolic abnormalities was observed in DIO mice. KEY RESULTS Emodin is a potent and selective 11,-HSD1 inhibitor with the IC50 of 186 and 86 nM for human and mouse 11,-HSD1, respectively. Single oral administration of emodin inhibited 11,-HSD1 activity of liver and fat significantly in mice. Emodin reversed prednisone-induced insulin resistance in mice, whereas it did not affect dexamethasone-induced insulin resistance, which confirmed its inhibitory effect on 11,-HSD1 in vivo. In DIO mice, oral administration of emodin improved insulin sensitivity and lipid metabolism, and lowered blood glucose and hepatic PEPCK, and glucose-6-phosphatase mRNA. CONCLUSIONS AND IMPLICATIONS This study demonstrated a new role for emodin as a potent and selective inhibitor of 11,-HSD1 and its beneficial effects on metabolic disorders in DIO mice. This highlights the potential value of analogues of emodin as a new class of compounds for the treatment of metabolic syndrome or type 2 diabetes. [source]