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PubMed2007

Neonatal streptozotocin-induced glucose intolerance: different consequences in Lyon normotensive and hypertensive rats.

BACKGROUND: Lyon hypertensive (LH) rats exhibit a mild hypertension associated with excessive body weight, spontaneous hyperlipidemia, elevated insulin/glucose ratio and exaggerated urinary protein excretion. AIMS: We aimed to develop, in LH rats and their normotensive control (LL) rats, a moderate non-insulin-dependent diabetic model to study the different consequences on metabolic and renal functions. METHODS: Non-insulin-dependent diabetes was induced by intraperitoneal injection of streptozotocin (STZ) at 2 days of age (50, 75 or 100 mg/kg for LH and 75, 100 or 125 mg/kg for LL rats). The evolution, with age, of glycemia, glucose tolerance (glucose 2 g/kg by gavage), blood pressure, plasma lipids and urinary protein and albumin excretions were studied in control and STZ-treated LH and LL rats. RESULTS: Although fasting glycemia was not significantly changed, the neonatal administration of STZ increased non-fasting glycemia and induced a marked glucose intolerance that were comparable between LH rats receiving 75 mg/kg and LL rats receiving 100 mg/kg of STZ. Interestingly, in treated LH rats only, the impaired glucose tolerance was accompanied by further metabolic and renal dysfunctions characterized by additional increases in plasma cholesterol (+28%) and triglycerides (+105%) and accelerated progression of proteinuria (+36%) and albuminuria (+48%). CONCLUSIONS: These observations indicate that susceptibility to diabetic metabolic disorders and renal diseases may be linked to the genetic predisposition to hypertension. This new model offers a reasonable reflection of the human situation, where hypertension and non-insulin-dependent diabetes often coincide, suitable for molecular, biochemical and pharmacological investigations.

Animals↗

PubMed2004

Acute effect of oral steroids on muscle function in chronic obstructive pulmonary disease.

Prospective data to support the hypothesis that corticosteroids are a significant cause of muscle weakness in patients with chronic obstructive pulmonary disease (COPD) are lacking. The authors studied respiratory and quadriceps muscle function, using both volitional techniques and magnetic nerve stimulation, as well as measuring metabolic parameters during incremental cycle ergometry, in 25 stable COPD patients. The forced expiratory volume in one second was 37.6 +/- 21.4% predicted, before and after a 2-week course of o.d. prednisolone 30 mg. Quadriceps strength was also assessed in 15 control patients on two occasions. Only two patients met the British Thoracic Society definition of steroid responsiveness. There was no change either in sniff transdiaphragmatic pressure (pre: 96.8 +/- 19.7 cmH2O; post: 98.6 +/- 22.4 cmH2O) or in twitch transdiaphragmatic pressure elicited by bilateral anterolateral magnetic phrenic-nerve stimulation (pre: 16.8 +/- 9.1 cmH2O; post: 17.9 +/- 10 cmH2O). Quadriceps twitch force did not change significantly either in the steroid group (pre: 9.5 +/- 3.1 kg; post: 8.9 +/- 3.7 kg) or in the control patients (pre: 8.1 +/- 2.7 kg; post: 7.9 +/- 2.2 kg). There were no changes in either peak or isotime ventilatory and metabolic parameters during exercise. In conclusion, in stable patients with chronic obstructive pulmonary disease, a 2-week course of 30 mg prednisolone daily does not cause significant skeletal muscle dysfunction or alter metabolic parameters during exercise.

Adrenal Cortex Hormones↗

PubMed2000

17Beta-hydroxysteroid dehydrogenase type 2 and dehydroepiandrosterone sulfotransferase in the human liver.

The liver plays important roles in the clearance and metabolism of sex steroids. Its dysfunction is considered to influence the metabolic pathways of sex steroids, and to result in gynecomastia and other abnormalities of sex steroids. However, the details of its mechanism have not been well-characterized. We therefore examined the enzymes involved in the hepatic clearance and/or metabolism of sex steroids in human liver and its disorders using immunohistochemistry to determine whether there are any abnormalities of expression of these enzymes in human liver disorders. These enzymes are 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 2, an enzyme that catalyzes the biologically active estrogen, estradiol (E2), to inactive estrogen, estrone (El), and dehydroepiandrosterone sulfotransferase (DHEA-ST), which catalyzes sulfonation of dehydroepiandrosterone (DHEA) to form biologically inactive DHEA-S. A total of 162 cases including normal liver (n=31), chronic hepatitis (n=41), liver cirrhosis (n = 21), hepatocellular carcinoma (n = 47), cholangiocellular carcinoma (n = 22) and fetal liver (n = 4) were examined by immunohistochemistry. Both enzymes were expressed in the hepatocytes around portal area and central vein in normal liver. Immunopositive area for DHEA-ST was significantly larger in chronic hepatitis than in normal liver, but that of 17beta-HSD type 2 in chronic hepatitis was not different from normal liver. There were no significant differences in the immunopositive area for both enzymes between liver cirrhosis and normal liver. In hepatocellular carcinoma, immunoreactivity for both enzymes were categorized into Group A, or low positive group, and Group B, or high positive group. The latter tended to be poorly differentiated carcinoma. In cholangiocellular carcinoma, immunopositive areas of both enzymes were significantly smaller than those of normal liver. These findings indicate that the amount of expression of the enzymes involved in metabolism and/or clearance of sex steroids per hepatocyte did not decrease in liver cirrhosis. Therefore, sex steroids' abnormalities may be due to the decreased quantity of hepatocytes associated with liver cirrhosis. In hepatocellular carcinoma, some poorly differentiated cases were associated with increased expression of 17beta-HSD type 2 but its biological significance needs to be determined by further studies.

17-Hydroxysteroid Dehydrogenases↗

PubMed2007

Severity of erectile dysfunction in married impotent patients: interrelationship with anthropometry, hormones, metabolic profiles and lifestyle.

OBJECTIVE: This study was designed to evaluate the effects of risk factors for erectile dysfunction (ED) or cardiovascular disease on the disease severity in impotent men. METHODS: A total of 87 men, 25-75 years old (mean age, 53.4) were included in the study. Patients were evaluated with anthropometry, hormones, metabolic profiles and lifestyle. Baseline erectile function (EF) was evaluated using the International Index of Erectile Function (IIEF). The severity of ED was classified into the following four grades based on the six-item EF domain of the IIEF: severe (6-10); moderate (11-16); mild to moderate (17-21); and mild (22-25). Patients were deemed to have metabolic syndrome (MS) if they had three or more of five criteria according to National Cholesterol Education Program, with some modification. RESULTS: Of 87 patients, 15 patients (17.2%) had mild, 11 (12.6%) had mild to moderate, 33 (37.9%) had moderate and 28 (32.3%) had severe ED. There was no correlation between scores of IIEF or EF domain and continuous parameters. On the multivariate model used, hypertensive patients had 26-fold higher risk (odds ratio, 26.195; 95% confidence interval, 1.463-46.072; P = 0.027) of severe ED than those without hypertension. Other factors were not significant. CONCLUSION: The results of the study indicate that MS might not influence the severity of ED in impotent men. However, our findings suggest that hypertension plays a role in the disease severity in these patients.

Adult↗

PubMed2025

GHSR suppression in neurons protects against aging-associated metabolic and cognitive impairments.

Aging is accompanied by progressive declines in metabolic and cognitive functions. Growth hormone secretagogue receptor (GHSR), a receptor for the gut hormone ghrelin, is highly expressed in neurons and plays a crucial role in metabolic regulation. We previously reported that aged global GHSR-ablated mice are lean and insulin-sensitive, and that neuronal GHSR-deleted mice (Syn1-cre;Ghsrf/f) completely prevent diet-induced obesity. However, the role of neuronal GHSR in metabolic and cognitive aging has not been elucidated. The current study aims to determine the roles of neuronal GHSR in aging metabolism and cognitive dysfunction. Syn1-cre;Ghsrf/f mice were subjected to cold stress, glucose- and insulin-tolerance tests, behavioral tests, and tissue analysis. Aging is accompanied by glycemic dysregulation and insulin resistance; old Syn1-cre;Ghsrf/f mice showed improved glucose tolerance and insulin sensitivity. Aging is associated with thermogenic impairment and cognitive decline; old Syn1-cre;Ghsrf/f mice showed better cold resistance and retained better recognition memory. Noticeably, there were increased expression of thermogenic makers (PGC1α and UCP1) and elevated sympathetic innervation markers (tyrosine hydroxylase and synaptophysin) in brown adipose tissue of old Syn1-cre;Ghsrf/f mice. Lastly, old Syn1-cre;Ghsrf/f mice exhibited decreased pro-inflammatory cytokines and increased neural plasticity-related markers (brain-derived neurotrophic factor, synaptophysin, and tyrosine hydroxylase) in metabolic and cognitive-relevant brain regions such as hypothalamus, cortex, and hippocampus. In conclusion, neuronal inhibition of GHSR promotes a healthy aging phenotype showing improved energy metabolism and cognitive function, which is likely contributed to the improved thermogenesis and insulin sensitivity, reduced inflammation, and restored neuronal plasticity.

Animals↗

PubMed2002

Inborn errors presenting with liver dysfunction.

In neonates, inborn errors of metabolism can produce all the major signs of liver dysfunction - jaundice, coagulopathy, hepatomegaly, splenomegaly, ascites and encephalopathy. The significance of encephalopathy in the neonate is different from that in older patients; it is usually due to a specific abnormality such as hypoglycaemia rather than being a non-specific indicator of liver failure. Attention is focused on five neonatal presentations: unconjugated hyperbilirubinaemia, cholestatic jaundice with otherwise good liver function, severe liver dysfunction (jaundice, coagulopathy persisting after vitamin K, and ascites), hepatomegaly with hypotonia+/- cardiomyopathy; and hepatosplenomegaly. The metabolic disorders presenting in these ways are listed alongside specific clinical features that can aid differential diagnosis and tests that can be used to confirm or refute the diagnosis. Diagnosis is important because treatment can be dramatically effective, e.g. withdrawal of galactose in galactosaemia. Even when treatment is not effective it is often possible to offer prenatal diagnosis for future pregnancies.

Diagnosis, Differential↗

PubMed2026

cGAS-STING signaling in aging and age-related diseases: therapeutic promise and precaution.

Endogenous cytoplasmic DNA (cytoDNA) is increasingly recognized as a mediator of tissue dysfunction and disease progression during aging. As a major cytosolic DNA-sensing pathway, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway can translate aging-associated cytoDNA accumulation into innate immune and inflammatory programs. This review summarizes the evolutionary and signaling features of the cGAS-STING cascade and critically discusses its crosstalk with aging-associated intracellular molecular threats, including nuclear genomic and chromatin stress, mitochondrial dysfunction, oxidative-metabolic stress, and defective clearance of nucleic acids or damaged organelles. We further synthesize evidence linking dysregulated cGAS-STING activation to inflammatory remodeling, senescence-associated changes, cell injury, fibrosis, and tissue dysfunction, while highlighting the context-dependent roles of this pathway across physiological aging and ARDs. Finally, we discuss the therapeutic potential and limitations of cGAS-STING modulation, emphasizing that successful translation will require context-defined therapeutic windows, tissue- and cell-specific targeting, subcellular compartmentalization, and long-term safety assessment.

Humans↗

PubMed1990

Thyroid hormones and thermogenesis: a microcalorimetric study of overall cell metabolism in lymphocytes from patients with different degrees of thyroid dysfunction.

We used microcalorimetry to measure lymphocyte heat production rate in patients with clinical and laboratory hyperthyroidism (serum TSH decreases, serum FT4 increases, serum FT3 increases), subclinical hyperthyroidism (serum TSH decreases, serum FT1 increases, serum FT3 =), and subclinical hypothyroidism (serum TSH increases, serum FT4 decreases, serum FT3 =) compared with healthy controls (N = 13). The lymphocyte heat production rate was significantly correlated to the free thyroxine level (r = 0.53, p less than 0.01) and to the free triiodothyronine level (r = 0.51, p less than 0.01) when calculated from pooled data for the three patients groups. The hyperthyroid patients (N = 8) had a significantly increased lymphocyte heat production rate, 3.43 +/- 0.25 pW/cell, as compared with 2.31 +/- 0.12 pW/cell in the control group (p less than 0.001). The groups with subclinical hyperthyroidism (N = 7) and subclinical hypothyroidism (N = 9) had lymphocyte heat production rates of 2.14 +/- 0.11 and 2.56 +/- 0.15 pW/cell, respectively, not significantly different from that in the controls. Consistently, there was no significant difference between patients with subclinical hyperthyroidism (N = 5) and controls (N = 5) with regard to lymphocyte energy production as calculated from separately measured oxygen consumption rates in vitro, 1.36 +/- 0.20 and 1.56 +/- 0.12 pW/cell, respectively. Thus microcalorimetry seems to be suitable for studying the influence of thyroid hormones on cellular metabolism. Subclinical thyroid dysfunction does not seem to alter the overall rate of lymphocyte metabolism.

Adult↗

PubMed2006

Methoxyflurane revisited: tale of an anesthetic from cradle to grave.

Methoxyflurane metabolism and renal dysfunction: clinical correlation in man. By Richard I. Mazze, James R. Trudell, and Michael J. Cousins. Anesthesiology 1971; 35:247-52. Reprinted with permission. Serum inorganic fluoride concentration and urinary inorganic fluoride excretion were found to be markedly elevated in ten patients previously shown to have methoxyflurane induced renal dysfunction. Five patients with clinically evident renal dysfunction had a mean peak serum inorganic fluoride level (190 +/- 21 microm) significantly higher (P < 0.02) than that of those with abnormalities in laboratory tests only (106 +/- 17 microm). Similarly, patients with clinically evident renal dysfunction had a mean peak oxalic acid excretion (286 +/- 39 mg/24 h) significantly greater (P < 0.05) than that of those with laboratory abnormalities only (130 +/- 51 mg/24 h). That patients anesthetized with halothane had insignificant changes in serum inorganic fluoride concentration and oxalic acid excretion indicates that these substances are products of methoxyflurane metabolism. A proposed metabolic pathway to support this hypothesis is presented, as well as evidence to suggest that inorganic fluoride is the substance responsible for methoxyflurane renal dysfunction.

Anesthesiology↗

PubMed2005

Severity of ultrasonographic liver steatosis and metabolic syndrome in Korean men and women.

AIM: To evaluate the association between the severity of liver steatosis and metabolic syndrome in apparently healthy Korean adults. METHODS: We examined 1 022 men and women, aged 30-79 years, who participated in a health screening test. A standard interview, anthropometrics, biochemical studies, and abdominal ultrasonography were conducted for each participant. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III, with a modification for the waist circumference cut-off level. The severity of liver steatosis was evaluated using liver ultrasonography, and serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (gamma-GT) levels were determined. RESULTS: Ultrasonographic liver steatosis was strongly associated with metabolic syndrome and common metabolic abnormalities. Compared with people without steatosis, people with mild, moderate, and severe steatosis had adjusted odds ratios for metabolic syndrome of 1.72 (95%CI, 1.01-2.94), 2.89 (1.75-4.76) and 3.53 (1.25-9.98) in men, and 2.86 (1.64-5.01), 3.19 (1.80-5.65) and 3.70 (0.82-16.73) in women, respectively. The serum AST level was not associated with metabolic syndrome. The serum ALT and gamma-GT levels were significantly associated with metabolic syndrome in men but not in women. CONCLUSION: The occurrence of metabolic syndrome shows a stronger association with the severity of ultrasonographic steatosis than with the serum liver enzyme levels. The degree of fatty infiltration detected on ultrasonography can be used as an indicator of liver dysfunction attributable to metabolic abnormalities.

Adult↗

PubMed2006

Metabolic syndrome and urinary cGMP excretion in general population.

To examine the relationship between metabolic syndrome and endothelial dysfunction, we investigated cross-sectionally the correlation between metabolic risk factors and urinary excretion of cyclic guanosine 3',5'-monophosphate (cGMP), a second messenger of nitric oxide (NO), in 1541 Japanese men and women aged 40-79 years. The 24-h urinary excretion of cGMP was measured using a (125)I-labeled cGMP radioimmunoassay and was adjusted for urinary creatinine excretion (nmol/mmol creatinine). The components of metabolic syndrome were defined based on the following criteria: body mass index (BMI)> or =25.0 kg/m(2), fasting plasma glucose> or =6.11 mmol/l or non-fasting plasma glucose level> or =11.1 mmol/l, systolic blood pressure> or =130 mm Hg or diastolic blood pressure> or =85 mm Hg, high-density lipoprotein (HDL)-cholesterol<1.03 mmol/l for men and <1.29 mmol/l for women, and triglyceride> or =1.69 mmol/l. The number of components of metabolic syndrome correlated inversely with urinary cGMP excretion; means of cGMP excretion for the whole group adjusted for age, sex, and cardiovascular risk factors were 53.6, 48.6, 47.9, 44.4 and 42.3 nmol/mmol for 0, 1, 2, 3, and 4-5 components of metabolic syndrome, respectively (p=0.002). Our data suggest that a reduction of NO bioactivity concur with clustered features of the metabolic syndrome.

Adult↗

PubMed2004

RSK4 and PAK5 are novel candidate genes in diabetic rat kidney and brain.

The orphan hepatic nuclear factor (HNF) HNF4alpha is of pivotal importance for liver development and hepatocellular differentiation and plays an essential role in a regulatory circuitry to control a wide range of metabolic processes. It also targets genes in other organs, including pancreas, kidney, intestine, and colon; promotes expression of an epithelial phenotype; triggers de novo formation of functional tight junctions; and contributes to epithelial cell polarity. In particular, HNF4alpha dysfunction leads to metabolic disorders, including diabetes. We used the chromatin immunoprecipitation (ChIP) cloning procedure and a bioinformatic approach to search for candidate genes associated with impaired liver, pancreas, and kidney function. We identified two novel targets regulated by HNF4alpha, which participate in the control, at least in part, in cell-cycle regulation and are members of the mitogen-activated kinase pathway. In multiple ChIP assays, ribosomal S6 kinase 4 (RSK4) and p21-activated kinase 5 (PAK5) were confirmed, and in vitro binding of HNF4alpha was evidenced by electrophoretic mobility shift assays (EMSA) using oligonucleotides, which harbor novel binding sites. We also used EMSA to probe for binding sites in promoters of HNF1alpha, apolipoprotein B, alpha1-antitrypsin, and angiotensinogen. We further studied RSK4 and PAK5 kinase expression in streptozotocin-induced diabetic rat kidney and brain and observed significant repression of HNF4alpha, RSK4, and PAK5 as determined by quantitative real-time reverse transcriptase-polymerase chain reaction. RSK4 and PAK5 may provide a molecular rationale for late-stage complications in disease, and further studies are warranted to explore these targets for the treatment of diabetic nephro- and neuropathy, frequently seen in patients with HNF4alpha dysfunction.

Animals↗

PubMed1986

Computerized tomography, magnetic resonance imaging, and positron emission tomography in the study of brain trauma. Preliminary observations.

Results of computerized tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), xenon-133 measurement of cerebral blood flow (CBF), and neuropsychological assessments are described in three head-injured patients. The patients were selected because they presented with intracranial hemorrhage diagnosed by CT. Two of the patients were studied acutely and again approximately 6 months later. In the acute stage, MRI was superior to CT in identifying the precise location and extent of intracranial hemorrhage and associated edema. Small subdural hematomas diagnosed on MRI were missed with CT scanning. The extent of apparent encephalomalacia in the chronic stages of injury was also better defined with MRI. Positron emission tomography showed disturbances of glucose metabolism that extended beyond the structural abnormalities demonstrated by MRI and CT; anterior temporal lobe dysfunction was particularly evident in all three patients. Regional CBF studies failed to detect a number of the abnormalities seen on MRI and CT, and even ignored the metabolic dysfunction evident on PET that should have been accompanied by changes in regional CBF. The neuropsychological studies localized frontal lesions, but did not reveal abnormalities attributable to the structural lesions and the reduced metabolism in the anterior temporal lobes.

Adult↗

PubMed1998

Influence of metabolic control and duration of disease on microvascular dysfunction in diabetes assessed by laser Doppler anemometry.

A reduced and delayed postocclusive reactive hyperaemia has been demonstrated in diabetic patients using videophotometric capillaroscopy and laser Doppler fluxmetry. The aim of the present study was to examine by means of the new technique of laser Doppler anemometry whether impairment of skin microcirculation differs between type 1 and type 2 diabetic patients especially with regard to metabolic control and duration of diabetes. Sixteen type 1 and 19 type 2 diabetic patients were investigated and subdivided in patients with "good" (HbA1c < 7.5%) or "bad" (HbA1c > 7.5%) metabolic control and in patients with a diabetes duration of less or more than 10 years. Two age- and sex-matched groups comprising 16 and 19 non-diabetic subjects served as controls. The capillary blood cell velocity (CBV) was measured in the dorsal middle phalangeal area during rest and after 3-min arterial occlusion. In type 1 diabetic patients we found a reduced peak CBV (0.69 +/- 0.08 mm/s vs. 0.96 +/- 0.07 mm/s, p < 0.05) and a prolonged time to peak CBV (33.8 +/- 4.8 s vs. 13.6 +/- 1.9 s, p < 0.001). The delay of the postocclusive reactive hyperaemia was shown not only in patients with a diabetes duration of more than 10 years and HbA1c values above 7.5% but also in patients with a shorter disease duration and better metabolic control. In type 2 diabetes time to peak CBV (46.8 +/- 8.5 s vs. 16.4 +/- 2.2 s, p < 0.001) was also prolonged already in the first 10 years of the disease. However with regard to metabolic control a reduced peak CBV (0.54 +/- 0.04 mm/ s vs. 0.70 +/- 0.04 mm/s, p < 0.05) and a prolonged time to peak CBV (56.6 +/- 14.8 s vs. 13.7 +/- 2.7 s, p < 0.01) was found in type 2 diabetes only in the group of patients with HbA1c > 7.5%. The results indicate that in type 2 diabetes actual metabolic control might be of greater importance for the microvascular dysfunction than in type 1 diabetes and that the skin capillary circulation is impaired already in the first 10 years of both diabetes types.

Adolescent↗

PubMed1997

Chronic effect of fatty acids on insulin release is not through the alteration of glucose metabolism in a pancreatic beta-cell line (beta HC9).

Hyperinsulinaemia in the fasting state and a blunted insulin secretory response to acute glucose stimulation are commonly observed in obesity associated non-insulin-dependent diabetes mellitus. Hyperlipidaemia is a hallmark of obesity and may play a role in the pathogenesis of this beta-cell dysfunction because glucose metabolism in pancreatic beta cells may be altered by the increased lipid load. We tested this hypothesis by assessing the chronic effect of oleic acid on glucose metabolism and its relationship with glucose-induced insulin release in beta HC9 cells in tissue culture. Our results show: (1) A 4-day treatment with oleic acid caused an enhancement of insulin release at 0-5 mmol/l glucose concentrations while a significant decrease in insulin release occurred when the glucose level was greater than 15 nmol/l; (2) Hexokinase activity was increased and a corresponding left shift of the dose-dependency curve of glucose usage was observed associated with inhibition of glucose oxidation in oleic acid treated beta HC9 cells, yet the presumed glucose-related ATP generation did not parallel the change in insulin release due to glucose; (3) The rate of cellular respiration was markedly increased in oleic acid treated beta HC9 cells both in the absence of glucose and at all glucose concentrations tested. This enhanced oxidative metabolism may explain the increased insulin release at a low glucose level but is clearly dissociated from the blunted insulin secretion at high glucose concentrations. We conclude that a reduction of oxidative metabolism in pancreatic beta cells is unlikely to be the cause of the dramatic effect that high levels of non-esterified fatty acids have on glucose-induced insulin release.

Animals↗

PubMed2006

Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins.

Mitochondrial dysfunction during acute metabolic crises is considered an important pathomechanism in inherited disorders of propionate metabolism, i.e. propionic and methylmalonic acidurias. Biochemically, these disorders are characterized by accumulation of propionyl-CoA and metabolites of alternative propionate oxidation. In the present study, we demonstrate uncompetitive inhibition of PDHc (pyruvate dehydrogenase complex) by propionyl-CoA in purified porcine enzyme and in submitochondrial particles from bovine heart being in the same range as the inhibition induced by acetyl-CoA, the physiological product and known inhibitor of PDHc. Evaluation of similar monocarboxylic CoA esters showed a chain-length specificity for PDHc inhibition. In contrast with CoA esters, non-esterified fatty acids did not inhibit PDHc activity. In addition to PDHc inhibition, analysis of respiratory chain and tricarboxylic acid cycle enzymes also revealed an inhibition by propionyl-CoA on respiratory chain complex III and alpha-ketoglutarate dehydrogenase complex. To test whether impairment of mitochondrial energy metabolism is involved in the pathogenesis of propionic aciduria, we performed a thorough bioenergetic analysis in muscle biopsy specimens of two patients. In line with the in vitro results, oxidative phosphorylation was severely compromised in both patients. Furthermore, expression of respiratory chain complexes I-IV and the amount of mitochondrial DNA were strongly decreased, and ultrastructural mitochondrial abnormalities were found, highlighting severe mitochondrial dysfunction. In conclusion, our results favour the hypothesis that toxic metabolites, in particular propionyl-CoA, are involved in the pathogenesis of inherited disorders of propionate metabolism, sharing mechanistic similarities with propionate toxicity in micro-organisms.

Acetyl Coenzyme A↗

PubMed2003

Mechanisms and consequences of large artery rigidity.

In this review paper, the classical and more recently described mechanisms responsible for the structural and functional characteristics of large artery rigidity are described. Mostly important, these characteristics appear to be non-specific to the primary disease process involved in arterial hypertension, diabetes mellitus, dyslipidemia, congestive heart failure, chronic uremia, and perhaps senescence, including vascular dementia. Nonspecific in terms of aetiology, the vasculopathy encountered in these diseases exhibits common structural and functional abnormalities. The identification of such abnormalities could well become the target of potent nonpharmacological and (or) pharmacological interventions capable of preventing or retarding morbidity and mortality. The structural characteristics responsible for large artery rigidity include smooth muscle cell hypertrophy, matrix collagen deposition, and recently described, dysfunction in proteoglycan metabolism. Functional abnormalities, such as bradykinin-dependent hyper-reactivity of smooth muscle cells and vasa vasorum microcirculation network disturbances, also appear to alter aortic wall rigidity. The physiopathology of target organ damage is then revisited, based on endothelial dysfunction, documented in large and resistance arteries, as well as in microcirculation networks, where altered permeability to macromolecules leads to interstitial matrix disorganization and cell damage. The clinical evaluation of large artery rigidity is described, and one of the noninvasive methods, evaluation of pulse-wave velocity, is validated in normal conditions and in disease processes. Finally, non-pharmacological and pharmacological therapeutic measures are presented, and includes physical exercise to reduce insulin resistance, and renin-angiotensin-II-aldosterone modulators.

Animals↗

PubMed2006

Are age, anthropometry and components of metabolic syndrome-risk factors interrelated with lower urinary tract symptoms in patients with erectile dysfunction? A prospective study.

AIM: To evaluate the effects of metabolic profiles on lower urinary tract symptoms (LUTS) in men with erectile dysfunction (ED). METHODS: A total of 75 impotent men aged 25-75 years old (mean 58.1 years) were included in the study on a prospective basis. Patients were evaluated with a complete history, physical examination, anthropometry and metabolic profiles. LUTS were assessed using the International Prostate Symptom Score (IPSS). RESULTS: Overall, there was no correlation between the IPSS and continuous parameters. However, when continuous variables were categorized, some parameters were significantly associated with LUTS. Patients with triglyceride level of 150 mg/dL or higher had more severe symptoms than those with triglyceride levels less than 150 mg/dL (19.4 +/- 2.4 vs. 14.3 +/- 1.1, P = 0.033). When 40 mg/dL was chosen as the high-density lipoprotein (HDL)-cholesterol cut-off level, the IPSS was significantly different between the two groups divided by 40 mg/dL (19.4 +/- 2.6 for HDL-cholesterol < 40 mg/dL vs. 14.4 +/- 1.0 for HDL-cholesterol = or > 40 mg/dL, P = 0.042). The area under the receiver operating characteristic curve (AUROCC) of triglyceride was 65.7% (95% confidence interval [CI], 52.6%-82.3%; P = 0.034) for severe LUTS. However, the AUROCC for 'HDL-cholesterol' was not significant (area, 65.4%; 95% CI, 48.2%-82.7%; P = 0.062). No other factors were determined to be significant in this regard. CONCLUSION: The results of the present study indicate that some metabolic profiles might influence LUTS in men with ED.

Adult↗