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PubMed2000

Changes in microsomal activity in alcoholism and obesity.

BACKGROUND: Liver damage is more prevalent among obese alcoholics, and cytochrome P-4502E1(CYP2E1) induction is involved in its pathogenesis. OBJECTIVES: The study was undertaken to assess microsomal function, in alcoholic and nonalcoholic male subjects with different body compositions, through pharmacokinetics of chlorzoxazone (CLZ). We also intended to study the relationship between CLZ hydroxylation and urinary levels of 8-hydroxydiguanosine, and between CLZ levels and liver histology. METHODS: Serial measurements of CLZ serum concentration, after a 750 mg dose, were performed in 17 alcoholics (9 normal weight and 8 obese) and 21 nonalcoholic subjects (10 normal weight and 11 obese). Concentration of 6-hydroxy-chlorzoxazone (6-OH-CLZ) was determined at the second hour. Anthropometry, clinical laboratory tests, and urinary 8-hydroxydiguanosine concentrations were measured. Liver biopsies were performed in alcoholics. RESULTS: Five biopsies revealed severe lesions, one in normal-weight and four in obese patients (p = NS). Area under the curve (AUC) of CLZ was higher in normal-weight controls compared with the rest of the groups (ANOVA p = 0.001). This parameter correlated negatively with adiposity in nonalcoholic subjects and did not correlate with liver histology. 6-OH-CLZ/CLZ ratio was lower in normal-weight controls, compared with obese subjects and normal-weight alcoholics (p = 0.02). Both alcoholism and obesity were included as predictors of CLZ AUC in a multiple regression analysis. The two-factor ANOVA showed an additive effect of centripetal body fat distribution and alcoholism. Urinary 8-hydroxydiguanosine levels were extremely variable. CONCLUSIONS: Centripetal adiposity and alcoholism are associated with induction of CYP2E1. This may explain the higher prevalence of liver damage among obese alcoholics and also nonalcoholic steatohepatitis.

Adult↗
PubMed2002

Higher serum leptin level in women than in men with type 1 diabetes.

Leptin is the protein product of the obese (ob) gene, a lipostatic hormone that contributes to body weight regulation through suppressing appetite and/or stimulating energy expenditure in humans and/or rodents. In humans, serum leptin concentrations are increased in relation to increased body fat content. Studies have shown a higher leptin level in women compared with men. However, the gender influence on serum leptin concentrations has never been evaluated in patients with type 1 diabetes. In this study, serum leptin levels and percentage body fat mass were measured in men and women with type 1 diabetes. Fasting serum leptin levels were higher in women (16.7 + 11.6 ng/mL) than in men (3.0 +/- 1.5 ng/mL; P < 0.05) and were independent of exogenous insulin intake and of glucose control. Percentage body fat and fat mass were significant determinants of leptin concentration, whereas age and duration of diabetes were not related to leptin concentration. Subgroups of men (n = 12) and women (n = 11) with total body fat between 20 and 30% were compared. Leptin levels were also higher in women compared with men (13.5 +/- 8.3 ng/mL versus 3.2 +/- 1.7 ng/mL; P < 0.05, respectively). In conclusion, our findings indicate that gender is an important determinant of serum leptin concentration in type 1 diabetics, this gender difference is partly explained by body fat distribution and that type 1 diabetic women may be more resistant than type 1 diabetic men to leptin's alleged lipostatic actions.

Adipose Tissue↗
PubMed2004

Metabolic complications associated with the use of highly active antiretroviral therapy in HIV-1-infected adults.

The availability of highly active antiretroviral therapy (HAART) has resulted in dramatic declines in morbidity and mortality in patients infected with human immunodeficiency virus-1 (HIV-1). However, the success of HAART has been tempered by the recognition of adverse metabolic effects clearly associated with its use. These "metabolic complications" include dyslipidemia, changes in body fat distribution, insulin resistance and glucose intolerance, metabolic bone disease, and lactic acidosis. Guidelines to assist clinicians in the management of these complications have been put forth by various organizations, including the International AIDS Society, the HIV Medicine Association of the Infectious Disease Society of America, and the Adult AIDS Clinical Trials Group.

Acidosis, Lactic↗
PubMed2001

Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection.

BACKGROUND: Changes in body fat distribution are an adverse effect of therapy with HIV protease inhibitors (PI). It has been suggested that nucleoside analogue reverse transcriptase inhibitors (NRTI) may also contribute to this so-called lipodystrophy syndrome, but the relative contribution of the two drug classes is unclear as they are usually administered concomitantly. METHOD: The occurrence of lipodystrophy, as reported by physicians using no standardized criteria, was followed in patients randomly assigned to treatment with either a PI alone or a PI combined with an NRTI. The patients were part of a multicenter, open-label, randomized comparison of ritonavir (RTV)/saquinavir (SQV) with or without the addition of stavudine (d4T) in HIV-1-infected patients without prior PI and d4T experience (the Prometheus study). RESULTS: Lipodystrophy was reported in 29 of 175 (17%) patients during 96 weeks of follow up. Overall, it was reported significantly more frequently in patients who were randomized to RTV/SQV/d4T (22/88; 25%), than in patients randomized to RTV/SQV alone (7/87; 8%) (P = 0.003). When the analysis was limited to patients without any prior antiretroviral experience, lipodystrophy likewise was significantly more frequent in patients randomized to RTV/SQV/d4T (12/50; 24%) than in those randomized to RTV/SQV (2/44; 5%) (P = 0.008). CONCLUSION: This randomized clinical trial, in spite of not having been blinded, supports a contributory role of NRTI in the development of antiretroviral therapy-associated lipodystrophy. The low incidence of lipodystrophy in patients with no or limited NRTI exposure supports further evaluation of NRTI-sparing regimens as alternatives to current antiretroviral regimens.

Anti-HIV Agents↗
PubMed2003

Effect of exercise and strength training on cardiovascular status in HIV-infected patients receiving highly active antiretroviral therapy.

A routine evaluation of lipid metabolism and body fat distribution along with a careful cardiovascular risk stratification according to international guidelines are required for HIV-infected patients receiving highly active antiretroviral therapy. Intervention includes evaluation of patients for both epidemiological and clinical factors, and for anthropometric and biochemical parameters. Diet counseling, prescription of antihyperlipidemic drugs and exercise training are the cornerstones of programs devoted to protecting patients from side effects of therapies that compromise quality of life and the functions of organs like the pancreas and heart that are involved in lipid disorders.

Antiretroviral Therapy, Highly Active↗
PubMed1992

Comparison of nomogram- and ultrasound-determined renal depths for calculation of glomerular filtration rates in spinal cord injury patients.

In an informal survey, poor correlation was found between 24-hour creatinine levels and glomerular filtration rates calculated from nuclear medicine studies in spinal cord injury patients. It was speculated that the discrepancies were because the nomograms used in the calculations did not take into account differences in body fat distribution for this patient group. Twenty-five chronic spinal cord injury patients were prospectively studied to compare glomerular filtration rates (GFR) using the nomograms based on height and weight and those using renal depth determined by ultrasound. It was found that the renal depth determined by nuclear medicine was significantly less than that determined sonographically. The mean difference between the total nuclear medicine-based GFR and total ultrasound-based GFR was 17.576 ml +/- 15.449 ml (P < or = 0.001). It was found that there was a significant difference between calculated GFRs based on renal depths as determined by the different methods. In addition, calculated GFRs based on ultrasound-determined depths corresponded more closely to 24-hour creatine clearance levels and with a smaller degree of error than those using renal depths determined by the nuclear medicine nomograms.

Adipose Tissue↗
PubMed1991

Lipid metabolism and hyperandrogenism.

Hyperandrogenism and lipid metabolism were shown to be related intimately. Any discussion of the nature of their relationship must include other clinical and metabolic variables such as hyperinsulinemia and UBO. Despite the many correlations among each of these factors, the appropriate sequence in the pathogenesis of these conditions has not been defined. Do conditions that result in insulin resistance (e.g., genetic defects, insulin receptor antibodies, and obesity) also lead to the development of hyperandrogenemia by direct or indirect ovarian stimulation by insulin? Does hyperandrogenism of ovarian or adrenal origin cause abnormal upper body fat distribution, in turn leading to lipid abnormalities and insulin resistance? Regardless of the issue of mechanism of causality, women with hyperandrogenism are thought to be at greater risk for cardiovascular morbidity and mortality than their normoandrogenic counterparts. These women often are obese, hypertensive, and sedentary; ingest diets high in saturated fats; and have glucose intolerance and/or insulin resistance. All these abnormalities are well known independent risk factors for the development of lipid abnormalities and cardiovascular disease. Whether hyperandrogenism is a secondary consequence of any of these or whether it is an independent contributor to lipid aberrations requires future study. Treatment strategies for hyperandrogenic women, however, should not only be directed toward alleviation of the cosmetic problem of hirsutism but also toward the prevention and treatment of cardiovascular morbidity using modalities aimed at eradicating hyperinsulinemia, hypertension, and dyslipidemia. These modalities should include modifications in diet, exercise, and weight in addition to pharmacologic and/or surgical manipulation. Weight reduction will reduce many cardiovascular risk factors. Obesity is easier to target because of the many risk factors that result in it.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗
PubMed1997

Can the blood pressure predict cognitive task performance in a healthy population sample?

OBJECTIVES: To study the relation between the blood pressure and the neurocognitive function within the full adult age range in a large population sample. DESIGN: A cross-sectional study of 936 healthy adults who were recruited from a register of family practices, stratified for age (24-81 years), sex, and occupational level, who took part in a medical and neurocognitive test program. METHODS: The blood pressure status was studied in relation to five measures of cognitive ability, including verbal memory and speed of information processing. Other vascular risk factors were treated as control variables and included smoking, alcohol intake, body mass index, and body fat distribution. The blood pressure was measured five times using an automatic recording technique (with a Dinamap 8100 device). RESULTS: After adjustment for age, sex, and educational level in a hierarchical regression analysis, we found no unequivocal association between the mean systolic and diastolic blood pressures (or any other studied vascular risk factor) and cognitive test performance both for the whole group and for the subgroup of subjects who were not being administered antihypertensive medication and whose medical history did not include cardiovascular events. Stratified analysis within four age levels revealed no age-specific associations between the blood pressure and the cognitive function. Subjects whose blood pressure was within the hypertensive range performed worse than did matched controls at letter digit copying, but not according to other cognitive measures. CONCLUSIONS: With a population-based sample unselected for blood pressure status we found no linear relationship between the actual blood pressure level and various aspects of cognitive performance. Prospective studies are needed to investigate the possibility that the systemic blood pressure load over time is associated with a decline in specific cognitive abilities.

Adult↗
PubMed1996

Risk factors for cardiovascular disease among women.

The studies of risk factors for cardiovascular disease among women have changed over the past few years because of: (1) the further development and evaluation of noninvasive methods of measuring subclinical atherosclerosis, (2) the availability of potent drugs that substantially lower LDL-cholesterol levels, (3) improvement in the methods of measuring factors related to clotting and fibrinolysis and inflammation, (4) better methods of quantifying obesity, fatness and body fat distribution, (5) increasing interest in the interrelationship between endogenous sex-steroid hormone metabolism, risk factors and disease, (6) the relationship of new metabolic risk factors and cardiovascular disease and (7) the use of molecular genetics to identify specific genotypes of risk factors.

Adolescent↗
PubMedDate not supplied

Cyclic progestin administration increases energy expenditure and decreases body fat mass in perimenopausal women.

OBJECTIVE: The menopause transition is characterized by luteal phase defect anovulatory cycles, and changes in body weight and body composition. Resting metabolic rate (RMR) is increased in the luteal phase of the menstrual cycle. We evaluated whether progestin administration increases RMR and influences body composition of perimenopausal women. DESIGN: Thirty-six perimenopausal women were randomly allocated to receive either calcium (1 g/day) continuously plus the progestin nomegestrol acetate (NOMAc; 5 mg/day for 10 days x month for 12 months) or calcium alone. Body composition, RMR, energy intake, and climacteric and psychological symptoms were evaluated at baseline and after 12 months. In the NOMAc group, body composition and RMR analyses were performed twice during the first month of treatment. One evaluation was performed after almost 8 days of NOMAc adjunct, and an another before or almost 15 days after NOMAc administration. RESULTS: Resting metabolic rate was increased by NOMAc administration of 54.5 +/- 73.8 kcal/24 h (P < 0.01). In women treated with NOMAc, fat mass decreased by 1.2 +/- 0.6 kg (P < 0.001). In comparison with controls, body weight (P < 0.05) and body mass index (P < 0.05) were also reduced after 12 months of therapy with NOMAc. CONCLUSIONS: In perimenopausal women the use of NOMAc increases RMR. During the menopause transition, cyclic NOMAc administration may contribute to reduce negative modification of body composition.

Adipose Tissue, White↗
PubMedDate not supplied

Menopause, insulin resistance, and risk factors for cardiovascular disease.

OBJECTIVE: In this retrospective analysis of the European Group for the Study of Insulin Resistance database, a clamp data pooling project, a cardiovascular risk score (CVS) was assessed to verify whether hyperinsulinemia and/or insulin resistance were independent cardiovascular risk factors and to investigate how menopause affected CVS and insulin resistance. DESIGN: Information was obtained on whole-body glucose uptake (M), determined by the euglycemic hyperinsulinemic clamp technique, normalized by fat-free mass (FFM), and insulin concentration (I) at a steady state. Body composition was estimated using a labeled water technique or bioimpedance. Other parameters measured included blood pressure, lipid levels, and waist-to-hip ratio. CVS was computed using a structural equation model that included age, body mass index, blood lipids, and blood pressure. The study population included 523 normal and overweight patients. Women were grouped according to fertility status, and men, according to age (cutoff 50 y). RESULTS: M/kg(FFM)/I significantly decreased after menopause (12.41 +/- 3.40 vs 10.96 +/- 3.68; P < 0.01) and in men 50 years and older (11.39 +/- 3.47 vs 10.32 +/- 3.77 micromol x min(-1) x kg(-1) x microUI/mL; P < 0.02). CVS was lowest in fertile women (-0.414 +/- 0.57 vs 0.107 +/- 0.43; P < 0.0001) and highest in men 50 years and older (0.045 +/- 0.455 vs 0.257 +/- 0.51; P < 0.001). CVS significantly correlated with M/kg(FFM)/I in men 49 years and younger (r(o) = -0.27, P < 0.0001) and 50 years and older (r(o) = -0.38, P < 0.0001) and with fasting insulin in fertile women (r(o) = -0.29, P < 0.01) and in the other groups (r(o) ranging from 0.37 to 0.45, P < 0.0001). CONCLUSIONS: Menopause does not seem to strictly relate to a decrease in insulin sensitivity as postmenopausal women had the same insulin sensitivity as age-matched men. In the population studied, the best predictor of CVS was fasting insulin rather than insulin sensitivity.

Adolescent↗
PubMed2026

Refining the Genetic Contribution to Type 2 Diabetes Subtypes.

BACKGROUND: Type 2 diabetes (T2D) is a complex and highly heterogeneous disease driven in part by genetic predisposition and can be stratified into clinical subgroups to aid disease management. We recently grouped T2D subjects in the Qatar Biobank (QBB) cohort into Severe Insulin-Deficient Diabetes (SIDD), Severe Insulin-Resistant Diabetes (SIRD), Mild Obesity-Related Diabetes (MOD) and Mild Age-Related Diabetes (MARD) subtypes. Herein, we focused on the genetic makeup of these subtypes. METHODS: We used the QBB cohort (n&#x2009;=&#x2009;13,808), of whom 2687 were with T2D, and comprehensively assessed polygenic risk scores (PGS) across T2D subtypes, investigated genetic loci associated with each subtype by leveraging the most recent and largest GWAS for T2D, evaluated SNP associations across T2D genetic clusters, and identified protein interaction pathways associated with these distinct T2D subtypes. RESULTS: MOD showed consistently lower PGS compared with other T2D subtypes across all tested scores. SIDD showed more associations with SNPs mapping to residual glycemic cluster compared with other T2D subtypes. The incremental analysis of PGS004838 demonstrated a high &#x394;AUC of 0.101 for SIDD and a moderate &#x394;AUC of 0.068 for SIRD, but not for MOD and MARD. Protein interaction analyses identified candidate subtype-associated gene networks linked to pathways related to glucose homeostasis in SIDD, insulin signalling and hepatic metabolism in SIRD, body fat distribution in MOD and vascular-related processes in MARD. CONCLUSION: We found heterogeneous genetic architectures across clinically defined T2D subtypes in a Middle Eastern population. Our findings provide evidence supporting differential polygenic burden, subtype genetic associations and subtype-associated biological pathways across T2D subtypes. These observations support the utility of subtype-based genetic analyses for improving biological understanding of T2D heterogeneity.

Humans↗
PubMed1985

Blood glucose, glucose tolerance and manifest diabetes in relation to cardiovascular disease and death in women. A 12-year follow-up of participants in the population study of women in Gothenburg, Sweden.

A longitudinal population study of 1462 women, aged 38-60, was carried out in Gothenburg, Sweden in 1968-69. Women with initially manifest diabetes mellitus had significantly increased 12-year incidence of myocardial infarction and increased mortality while no increased incidence of angina pectoris, ECG changes indicating ischaemic heart disease or stroke was observed. The association to myocardial infarction remained in multivariate analyses and was independent of age, body fat distribution, smoking, serum cholesterol and systolic blood pressure. The association to mortality was independent of these factors and also of serum triglycerides. Women who were diagnosed as "new diabetics" during the 12-year follow-up had a significantly increased 12-year incidence of myocardial infarction but no significant increase was observed for any of the other end-points studied. When women with initially manifest diabetes mellitus were excluded, no association was found between initial fasting blood glucose concentration and the end-points studied. A negative significant association was found between initial fasting blood glucose concentration and smoking.

Adult↗
PubMed1991

High blood pressure and insulin resistance: influence of ethnic background.

Hyperinsulinaemia links non-insulin dependent diabetes (NIDDM), obesity, and hypertension, each an insulin-resistant state in its own right. Insulin resistance predicts the occurrence of NIDDM, and plays a major role in its pathogenesis. We tested the hypothesis that hyperinsulinaemia may also predict hypertension in a sample (n = 2905) of the mixed population of San Antonio, in which hyperinsulinaemia and NIDDM are more prevalent among Mexican-Americans than non-Hispanic whites. Whilst in the whole sample the hypertensives had significantly (P less than 0.001) higher plasma insulin concentrations than the normotensives, high blood pressure was significantly (P less than 0.01) more frequent among non-Hispanic whites than Mexican-Americans regardless of diabetes status. After adjusting for factors (age, sex, body mass, and body fat distribution) known to affect insulin levels, a direct relationship between post-glucose plasma insulin concentrations and prevalence of hypertension was still present in both ethnic groups. In Mexican-Americans, however, the standardized prevalence of hypertension was significantly (P less than 0.001) lower at any given insulin concentration. Post-glucose plasma glucose levels also were directly related to hypertension prevalence in both groups; again, the regression line was shifted downward and, furthermore, less steep (P less than 0.02) in Mexican-Americans, suggesting relative protection against the negative effect of hyperglycaemia on blood pressure. Dyslipidaemia (higher total cholesterol and triglyceride, and lower HDL-cholesterol concentrations) was strongly associated with hyperinsulinaemia and blood pressure in both ethnic groups. After adjusting for plasma insulin, only hypertriglyceridaemia was associated with high blood pressure, with no inter-ethnic difference.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2006

Plasma lipid concentrations after 1.5 years of exposure to nevirapine or efavirenz together with stavudine and lamivudine.

OBJECTIVES: To assess long-term changes in lipids and lipoproteins concentrations associated with exposure to non-nucleoside reverse transcriptase inhibitors. METHODS: Long-term analysis of plasma lipid concentrations was performed in patients starting first-line antiretroviral therapy with stavudine (d4T) and lamivudine, and either nevirapine or efavirenz. RESULTS: Concentrations of total cholesterol, low-density lipoprotein cholesterol and triglycerides continued to increase, while high-density lipoprotein cholesterol showed a slight decrease compared with earlier reported increases after 48 weeks. CONCLUSIONS: Changes in body fat distribution expected to occur with continued exposure to d4T could offer a potential explanation for these findings.

Alkynes↗
PubMed2002

SREBP-1: gene regulatory key to syndrome X?

Combined appearance of different cardiovascular risk factors seems to be more prevalent in individuals with decreased insulin sensitivity and increased visceral obesity, thereby being components of the so-called metabolic syndrome or syndrome X. Alterations in the abundance and activity of transcription factors lead to complex dysregulation of gene expression, which might be a key to understand insulin resistance-associated clinical clustering of coronary risk factors at the cellular or gene regulatory level. Recent examples are members of the nuclear hormone receptor superfamily-for example, peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding proteins (SREBPs). Besides their regulation by metabolites and nutrients, these transcription factors are also targets of hormones (like insulin and leptin), growth factors, inflammatory signals, and drugs. Major signaling pathways coupling transcription factors to extracellular stimuli are the MAP kinase cascades. We have recently shown that SREBPs appear to be substrates of MAP kinases and propose that SREBP-1 might play a role in the development of cellular features belonging to lipid toxicity and possibly syndrome X. Thus, the metabolic syndrome appears to be not only a disease or state of altered glucose tolerance, plasma lipid levels, blood pressure, and body fat distribution, but rather a complex clinical phenomenon of dysregulated gene expression.

Animals↗
PubMed2005

Thermogenic responsiveness to beta-adrenergic stimulation is augmented in exercising versus sedentary adults: role of oxidative stress.

Beta-adrenergic receptor (beta-AR) modulation of resting and postprandial energy expenditure (EE) is augmented in regularly exercising compared with sedentary adults, but the underlying physiological mechanisms are unknown. Differences in thermogenic responsiveness to beta-AR stimulation, perhaps secondary to reactive oxygen species (ROS) bioactivity, may be involved. To determine habitual exercise-related differences in beta-AR thermogenic responsiveness and the possible influence of ROS, we measured the percentage increase in EE (DeltaEE%; indirect calorimetry, ventilated hood method) above resting EE in response to non-specific beta-AR stimulation (intravenous isoproterenol (isoprenaline): 6, 12 and 24 ng (kg fat-free mass)-1 min-1) in 25 sedentary (11 males; 51+/-4 years; body mass index 25.0+/-0.8 kg m-2, maximal oxygen uptake 29+/-1 ml kg-1 min-1 (mean+/-s.e.m.)) and 14 habitually aerobic exercising (9 males, 46+/-6 years, 23.1+/-0.7 kg m-2, 44+/-3 ml kg-1 min-1) healthy adults under normal (control) conditions and during acute intravenous administration of a potent antioxidant, ascorbic acid (vitamin C; 0.04 g (kg fat-free mass)-1). DeltaEE% was greater (P=0.02) in the habitually exercising (8.6+/-1.2, 12.9+/-1.2, 20.0+/-1.4) versus sedentary (6.3+/-0.7, 10.4+/-0.8, 16.0+/-1.0) adults. Ascorbic acid increased (P=0.01) DeltaEE% only in the sedentary adults (to 9.5+/-0.9, 12.4+/-0.7, 18.5+/-0.8), abolishing baseline group differences. DeltaEE% was not related to the amount of body fat, sex, or any other baseline characteristic. Thermogenic responsiveness to beta-AR stimulation is augmented in habitually exercising adults. The mechanism is ascorbic acid dependent, suggesting that it may be linked to decreased ROS bioactivity. Our findings advance a novel mechanism by which habitual physical activity may modulate EE in humans, with potential implications for energy balance and body weight control.

Adolescent↗