Metabolism - Clinical and Experimental - Articles in Press

The contribution of race and diabetes status to metabolic flexibility in humans - Corrected Proof

April J. Stull, Jose E. Galgani, William D. Johnson, William T. Cefalu — 2010-02-03

Abstract: Factors controlling metabolic flexibility (MF), the ability of the body to switch from fat to carbohydrate oxidation in response to feeding or with insulin administration, are being actively investigated. We sought to determine the effects of race (African American vs Caucasian) and diabetes status (nondiabetic vs type 2 diabetes mellitus individuals) on MF to glucose in humans. Respiratory quotient (RQ) and macronutrient substrate utilization were evaluated by indirect calorimetry during baseline (fasting) and hyperinsulinemic-euglycemic clamp (insulin infusion of 120 mU·m−2·min−1); ΔRQ (MF) = clamp RQ − fasting RQ. The study included 168 human subjects of different races (55 African Americans, 113 Caucasians), sex (73 men, 95 women), ages (18-73 years), body mass index (19.3-47.7 kg/m2), and diabetes status (89 nondiabetic, 79 type 2 diabetes mellitus subjects). Metabolic flexibility was negatively correlated (P < .01) with age (r = − 0.41), fasting RQ (r = −0.22), fasting glucose (r = −0.55), insulin (r = −0.40), and triglyceride (r = −0.44) concentrations; whereas a positive association was observed with insulin sensitivity (r = 0.69, P < .0001). Insulin sensitivity, fasting RQ, triglyceride concentrations, diabetes status, and race accounted for 71% of the variability in MF with insulin sensitivity being the main determinant factor (model R2 = 0.48, P < .0001). After controlling for the significant predictors, MF was higher in African Americans vs Caucasians (mean ± SEM 0.080 ± 0.004 vs 0.069 ± 0.002, P = .008) and in nondiabetic vs type 2 diabetes mellitus subjects (P = .003). This study confirms that insulin sensitivity is the major contributor to MF in humans, but provides the novel findings that African Americans have significantly greater MF than Caucasians even after adjusting for insulin sensitivity and diabetes status.

Human epicardial adipokine messenger RNAs: comparisons of their expression in substernal, subcutaneous, and omental fat - Corrected Proof

2010-02-01

Abstract: We compared the gene expression of inflammatory and other proteins by real-time quantitative polymerase chain reaction in epicardial, substernal (mediastinal) and subcutaneous sternal, upper abdominal, and leg fat from coronary bypass patients and omental (visceral) fat from extremely obese women undergoing bariatric surgery. We hypothesized that (1) epicardial fat would exhibit higher expression of inflammatory messenger RNAs (mRNAs) than substernal and subcutaneous fat and (2) epicardial mRNAs would be similar to those in omental fat. Epicardial fat was clearly different from substernal fat because there was a far higher expression of haptoglobin, prostaglandin D2 synthase, nerve growth factor β, the soluble vascular endothelial growth factor receptor (FLT1), and α1 glycoprotein but not of inflammatory adipokines such as monocyte chemoattractant protein–1, interleukin (IL)-8, IL-1β, tumor necrosis factor α, serum amyloid A, plasminogen activator inhibitor–1, or adiponectin despite underlying coronary atherosclerosis. However, the latter inflammatory adipokines as well as most other mRNAs were overexpressed in epicardial fat as compared with the subcutaneous depots except for IL-8, fatty acid binding protein 4, the angiotensin II receptor 1, IL-6, and superoxide dismutase–2. Relative to omental fat, about one third of the genes were expressed at the same levels, whereas monocyte chemoattractant protein–1, cyclooxygenase-2, plasminogen activator inhibitor–1, IL-1β, and IL-6 were expressed at far lower levels in epicardial fat. In conclusion, epicardial fat does not appear to be a potentially more important source of inflammatory adipokines than substernal mediastinal fat. Furthermore, the expression of inflammatory cytokines such as IL-6 and IL-1β is actually higher in omental fat from obese women without coronary atherosclerosis. The data do not support the hypothesis that most of the inflammatory adipokines are expressed at high levels in epicardial fat of humans.

Influence of acute aerobic exercise on adiponectin oligomer concentrations in middle-aged abdominally obese men - Corrected Proof

2010-01-27

Abstract: Exercise intensity may induce changes in total adiponectin and adiponectin oligomer levels. However, the effects of acute aerobic exercise on total adiponectin and adiponectin oligomers in middle-aged abdominally obese men remain unknown. The purpose of this study was to investigate the influence of aerobic exercise intensity on changes in the concentrations of total adiponectin and adiponectin oligomers (high–molecular weight [HMW] and middle– plus low–molecular weight [MLMW] adiponectin), and the endocrine mechanisms involved in exercise-induced changes in adiponectin oligomer profiles in middle-aged abdominally obese men. Using a crossover design, 9 middle-aged abdominally obese men (age, 54.1 ± 2.4 years; body mass index, 27.9 ± 0.6 kg/m2) underwent 2 trials that consisted of 60 minutes of stationary cycle exercise at either moderate-intensity (ME) or high-intensity (HE) aerobic exercise (50% or 70% of peak oxygen uptake, respectively). Blood samples were collected to measure the concentrations of adiponectin oligomers, hormones (catecholamines, insulin, and growth hormone), metabolites (free fatty acid, glycerol, triglyceride, and glucose), and cytokines (interleukin-6 and tumor necrosis factor–α). After exercise, plasma catecholamine concentrations were higher during HE than during ME (P < .05). Total adiponectin concentration decreased at the end of HE (P < .05), but remained unchanged after ME. The HMW adiponectin concentration did not change at either intensity, whereas the MLMW concentration decreased at the end of HE (P < .05). The ratio of HMW to total adiponectin concentration increased significantly (P < .05), whereas the ratio of MLMW to total adiponectin concentration decreased significantly (P < .05), at the end of HE. The percentage changes in epinephrine concentration from baseline to the end of exercise were correlated with the percentage changes in total adiponectin concentration (r = −0.67, P < .05) and MLMW adiponectin concentration (r = −0.82, P < .05) from baseline to the end of HE. Our results indicate that the change in total adiponectin was mainly due to a change in MLMW adiponectin concentration during high-intensity exercise in middle-aged abdominally obese men. Epinephrine may partially regulate the decrease in total and MLMW adiponectin concentrations during high-intensity exercise.

Chronic fatigue syndrome is associated with metabolic syndrome: results from a case-control study in Georgia - Corrected Proof

Elizabeth M. Maloney, Roumiana S. Boneva, Jin-Mann S. Lin, William C. Reeves — 2010-01-27

Abstract: We hypothesized that persons with chronic fatigue syndrome (CFS) would have a higher prevalence of metabolic syndrome compared with well controls, and that unwell persons with insufficient symptoms or fatigue for CFS (termed ISF) would have a prevalence of metabolic syndrome intermediate between those with CFS and the controls. We also sought to examine the relationship between metabolic syndrome and measures of functional impairment, fatigue, and other symptoms. Our analysis was based on a population-based case-control study conducted in metropolitan, urban, and rural areas of Georgia, United States, between September 2004 and July 2005. There were 111 persons with CFS, 259 with ISF, and 123 controls. Metabolic syndrome was determined based on having at least 3 of 5 standard risk components (abdominal obesity, high triglycerides, high blood pressure, elevated fasting glucose, and decreased high-density lipids) according to the National Cholesterol Education Program Adult Treatment Panel III definition. Persons with CFS were 2-fold as likely to have metabolic syndrome (odds ratio = 2.12, confidence interval = 1.06, 4.23) compared with the controls. There was a significant graded relationship between the number of metabolic syndrome factors and CFS; each additional factor was associated with a 37% increase in likelihood of having CFS. The association of ISF with metabolic syndrome was weaker (odds ratio = 1.72, confidence interval = 0.94-3.16). Among persons with CFS, the number of metabolic syndrome factors was significantly correlated with worse fatigue on a standardized summary measure of fatigue (r = 0.20, P = .04). In conclusion, CFS was associated with metabolic syndrome, which further exacerbated fatigue.

Metabolic response to endotoxin in vivo in the conscious mouse: role of interleukin-6 - Corrected Proof

2010-01-27

Abstract: Inflammation and insulin resistance are characteristics of endotoxemia. Although the role of interleukin (IL)-6 in insulin-resistant states has been characterized, little is known of its role in the metabolic response to inflammation. To study the role of IL-6, conscious chronically catheterized mice were used. Five days before being studied, catheters were implanted in the carotid artery and jugular vein. After a 5-hour fast, Escherichia coli (250 μg per mouse) lipopolysaccharide (LPS) was injected in IL-6−/− (KO, n = 13) and IL-6+/+ (WT, n = 10) littermates. The IL-6 response to LPS was simulated in an additional group of KO mice (KO + IL-6, n = 10). Interleukin-6 increased in WT (15 ± 0.7 ng/mL) 4 hours after LPS and was undetectable in KO. Interleukin-6 replacement in the KO restored circulating IL-6 to levels observed in the WT group (14 ± 0.3 ng/mL). Tumor necrosis factor–α increased more rapidly in WT than in both KO and KO + IL-6 mice. The KO mice exhibited a more profound glucose excursion 30 minutes after LPS injection and no apparent hypoglycemia at 4 hours (95 ± 5 vs 70 ± 8 mg/dL, KO vs WT), despite having a blunted glucagon and epinephrine response. Glucose levels in KO + IL-6 mice, while decreased (93 ± 4 mg/dL) at 4 hours, remained higher than those in WT mice. In summary, the absence of IL-6 protected against LPS-induced hypoglycemia. Acute restoration of the IL-6 response to LPS did not potentiate hypoglycemia but partially restored the glucagon response. Thus, although IL-6 promotes glucose intolerance in insulin-resistant states, IL-6 promotes hypoglycemia during acute inflammation.

Endothelial function in individuals with coronary artery disease with and without type 2 diabetes mellitus - Corrected Proof

2010-01-27

Abstract: The goal of this study was to determine if individuals with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) had greater endothelial dysfunction (ED) than individuals with only CAD. Flow-mediated dilation (FMD), calculated as percentage increase in brachial artery diameter in response to postischemic blood flow, was measured after an overnight fast in 2 cohorts. The first cohort included 76 participants in the Northern Manhattan Study with CAD; 25 also had T2DM. The second cohort was composed of 27 individuals with both T2DM and CAD who were participants in a study of postprandial lipemia. Combined, we analyzed 103 patients with CAD: 52 with T2DM (T2DM+) and 51 without T2DM (T2DM−). The 52 CAD T2DM+ subjects had a mean FMD of 3.9% ± 3.2%, whereas the 51 CAD T2DM− subjects had a greater mean FMD of 5.5% ± 4.0% (P < .03). An investigation of various confounders known to affect FMD identified age and body mass index as the only significant covariates in a multiple regression model. Adjusting for age and body mass index, we found that FMD remained lower in T2DM+ subjects compared with T2DM− subjects (difference, −1.99%; P < .03). In patients with CAD, the concomitant presence of T2DM is independently associated with greater ED, as measured by FMD. This finding may be relevant to the greater early and late morbidity and mortality observed in patients with both CAD and T2DM.

Effects of C358A missense polymorphism of the degrading enzyme fatty acid amide hydrolase on weight loss, adipocytokines, and insulin resistance after 2 hypocaloric diets - Corrected Proof

2010-01-27

Abstract: It has been demonstrated that the polymorphism 385 C/A of fatty acid amide hydrolase was associated with obesity. We decided to investigate the role of a polymorphism (cDNA 385 C->A) on insulin resistance and weight loss secondary to a low-fat vs a low-carbohydrate diet. A population of 248 patients with obesity was analyzed. Basal measurements were performed, and values were compared to those at the end of a 3-month period in which subjects received either diet I (low fat) or diet II (low carbohydrate). One hundred seventy-eight patients (71.8%) had the genotype C358C (wild-type group), and 70 (28.2%) patients had the genotype C358A (62 patients, 25%) or A358A (8 patients, 3.2%) (mutant-type group). With diet I, body mass index, weight, fat mass, waist circumference, and systolic blood pressures decreased in the wild-type and mutant-type groups. With diet II, body mass index, weight, fat mass, waist circumference, and systolic blood pressures decreased in both genotypes. With diet I, leptin, glucose, total cholesterol, triglyceride, insulin, and homeostasis model assessment for insulin sensitivity (HOMA) decreased in the wild-type group. In the mutant-type group, only cholesterol decreased in a significant way. With diet II, leptin, interleukin-6, glucose, total cholesterol, low-density lipoprotein cholesterol, insulin, HOMA, and C-reactive protein decreased in the wild-type genotype. The allele A358 of fatty acid amide hydrolase was associated with a lack of improvement on glucose insulin, HOMA, and leptin levels in both diets after weight loss.

Serum concentrations of high–molecular weight adiponectin and their association with sex steroids in premenopausal women - Corrected Proof

Gabriele S. Merki-Feld, Bruno Imthurn, Marinella Rosselli, Katharina Spanaus — 2010-01-25

Abstract: At present, the association between adiponectin and sex hormones in women is controversial. Recent studies suggest that it is high–molecular weight (HMW) adiponectin and the HMW to total adiponectin ratio rather than total adiponectin that are associated with antiatherogenic activities, insulin sensitivity, metabolic syndrome, and prediction of cardiovascular events. The present study aimed to investigate whether measuring HMW adiponectin and the HMW to total adiponectin ratio rather than total adiponectin might be more useful to detect an association between circulating female sex steroids and adipocytokines. In a clinical trial, we investigated the associations of total adiponectin, HMW adiponectin, and the HMW to adiponectin ratio with several androgens and estradiol in 36 healthy premenopausal women with regular cycles. No association between the investigated sex hormones and adiponectin was observed. The HMW adiponectin was negatively correlated with estradiol after adjustment for age and body mass index. The HMW to total adiponectin ratio was significantly negatively associated with testosterone, free testosterone, and androstenedione. The testosterone to estradiol ratio, as a parameter for the estrogen-androgen balance, was not associated with adiponectin or the HMW isoform. In conclusion, there is a negative association between estradiol and HMW adiponectin, and between testosterone, free testosterone, and androstenedione and the HMW to adiponectin ratio. Thus, one mechanism whereby female sex steroids may influence the cardiovascular risk of women could be alteration of the relationship between HMW and total adiponectin concentrations in plasma.

Microalbuminuria in nondiabetic patients with nonalcoholic fatty liver disease: association with liver fibrosis - Corrected Proof

2010-01-25

Abstract: Recent evidence has suggested an association between microalbuminuria and ultrasound-diagnosed nonalcoholic fatty liver disease (NAFLD) in patients with diabetes and prediabetes. However, few data are available on the occurrence of microalbuminuria in nondiabetic subjects with histologically proven NAFLD. We thus evaluated the relationships between microalbuminuria and liver histology in a hospital-based sample of 87 adults with biopsy-proven NAFLD from Turkey. An albumin excretion rate less than 30 mg/d was considered within the reference range, whereas an albumin excretion rate from 30 to 300 mg/d was considered to indicate microalbuminuria. Compared with those without microalbuminuria (n = 73), NAFLD patients with microalbuminuria (n = 14) had significantly higher homeostasis model assessment of insulin resistance values (3.9 ± 1.3 vs 5.8 ± 3.7, P < .001). There were no differences in the prevalence of microalbuminuria in patients with definite nonalcoholic steatohepatitis, borderline nonalcoholic steatohepatitis, and simple fatty liver. In the entire study cohort, mean fibrosis scores were significantly higher in patients with microalbuminuria than in those without (1.27 ± 0.26 vs 0. 80 ± 0.11, P < .05). This difference persisted after adjustment for potential confounders. These results indicate the presence of a significant association between the severity of insulin resistance and microalbuminuria in patients with NAFLD. In addition, microalbuminuria may identify NAFLD patients with higher fibrosis scores.

Hyperinsulinemia and metabolic syndrome at mean age of 10 years in black and white schoolgirls and development of impaired fasting glucose and type 2 diabetes mellitus by mean age of 24 years - Corrected Proof

2010-01-25

Abstract: The objective of the study was to evaluate preteen insulin and metabolic syndrome (MS) as independent predictors of impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM) in black and white females by mean age of 24 years. This was a prospective cohort study. There were 8 measures of fasting glucose and insulin from mean age of 10 years through mean age of 24 years, and insulin also at mean age of 25 years. Childhood MS was defined by at least 3 abnormal values among waist circumference, triglyceride, high-density lipoprotein cholesterol, blood pressure, and glucose. Hyperinsulinemia was defined by insulin greater than or equal to race-specific 75th percentile. Patients with type 1 diabetes mellitus were excluded. The study was held in schools and in an outpatient clinical center. Participants were schoolgirls (260 white, 296 black). There was no intervention. The outcome measures were IFG (fasting glucose of at least 100 to 125 mg/dL) and T2DM (fasting glucose of at least 126 mg/dL). By the age of 24 years, there were 11 cases of T2DM (2%) and 108 cases of IFG (19%). By the age of 24 years, IFG + T2DM was present in 18% of women (73/412) who had normal insulin–no MS at the age of 10 years vs 28% (34/122) of those with high insulin–no MS at the age of 10 years (P = .014) and 67% (10/15) of those with high insulin + MS at the age of 10 years (P < .0001). By stepwise logistic regression, significant, independent, positive predictors of IFG + T2DM were first insulin measure in childhood, age at last sampling, childhood MS, change in body mass index over 15 years, and, separately, initial glucose of at least 100 mg/dL and average of all insulin quartile ranks over 15 years. The correlation between childhood insulin z score and insulin z score 15 years later was r = .30, P < .0001. Insulin and MS at a mean age of 10 years plus change in body mass index over 15 years, and 15-year average insulin rank independently predict IFG + T2DM by mean age of 24 years, suggesting avenues for primary prevention.

Effects of glucose or fat calories in total parenteral nutrition on fat metabolism and systemic inflammation in rats - Corrected Proof

2010-01-25

Abstract: This study compared the effects of total parenteral nutrition (TPN) by central vein with or without fat provided at maintenance energy requirement on fatty acid metabolism, de novo lipogenesis, and the risk of hepatic and systemic inflammation in rats. Study 1 was conducted in 2 groups: high glucose (HG), where fat-free TPN was given at maintenance levels of 180 kcal/(kg d), and low glucose (LG), where fat-free TPN containing 30% fewer calories at 126 kcal/(kg d) was provided by reducing 54 kcal/(kg d) from parenteral glucose. Study 2 contained 3 TPN groups: 1 LG group at 126 kcal/(kg d) and 2 groups at 180 kcal/(kg d) with 30% of total calories (54 kcal/[kg d]) either from soybean or fish oil emulsion. In both studies, animals fed a chow diet ad libitum were included. Plasma and hepatic triglyceride and phospholipid fatty acid profiles, enzymes indicating hepatic injury, and C-reactive protein levels (CRP) reflecting systemic injury were measured. In study 1, evidence of de novo lipogenesis was noted in LG and was more prominent in HG with elevation of CRP in HG. In study 2, de novo lipogenesis was reduced by adding either fat to LG to achieve maintenance energy levels. Moreover, adding fat as soybean oil but not fish oil significantly increased plasma and hepatic triglyceride and also elevated aspartate aminotransferase and CRP levels, reflecting inflammation. Thus, in rats, either hypocaloric feeding as glucose-based TPN or TPN provided at maintenance energy levels with the addition of fish oil limits hepatic lipid accumulation and prevents the evidence of hepatic and systemic injury found with maintenance level TPN as glucose only or glucose plus soybean oil.

Periodontal and coronary heart disease in patients undergoing coronary angiography - Corrected Proof

2010-01-25

Abstract: Periodontal inflammation has been implicated in atherosclerosis and coronary heart disease (CHD). Coronary angiography (CA) is used in the assessment of CHD; only a few studies have evaluated periodontal disease (PD) and angiographic measures of coronary atherosclerosis. The aim of this study was to investigate the association between CHD and PD. In this prospective epidemiologic study, 466 patients underwent CA and were assessed for PD. All patients underwent physical, laboratory, cardiac, and dental examination including dental x-rays. Periodontal disease and coronary angiograms were evaluated blindly by a dentist and 2 cardiologists, respectively. A coronary stenosis greater than 50% was ruled as CHD. Periodontal disease was defined and measured with the Community Periodontal Index of Treatment Needs (CPITN); and if at least 2 sextants (segments dividing mandible and maxilla into 6) were recorded as having CPITN of at least 3 (signifying that sextant had periodontal pocket depth ≥3.5 mm), the patient was coded as having PD. Three-hundred forty-nine patients (74.9%) had CHD assessed by CA The CHD patients had PD in 55.6% vs 41.9% in the non-CHD patients (P < .01). The CPITN scores were significantly higher in patients with vs without CHD, 2.43 vs 2.16, respectively (P = .023). After adjusting for age, sex, and risk factors for atherosclerosis with additional inclusion of C-reactive protein and erythrocyte sedimentation rate, PD remained significantly related to CHD (odds ratio = 1.9; 95% confidence interval, 1.2-3.1). Other predictors for CHD were male sex, age, high-density lipoprotein cholesterol, and diabetes. Our results demonstrate an increased odds ratio for angiographically determined CHD in patients with PD and that CHD and PD may cluster in particular groups of a population. Our data indicate that PD represents a potentially modifiable risk factor that is both preventable and treatable with predictable treatments that pose negligible risk.

The effect on the blood lipid profile of soy foods combined with a prebiotic: a randomized controlled trial - Corrected Proof

2010-01-25

Abstract: The value of soy protein as part of the cholesterol-lowering diet has been questioned by recent studies. The apparent lack of effect may relate to the absence of dietary factors that increase colonic fermentation and potentiate the cholesterol-lowering effect of soy. Therefore, unabsorbable carbohydrates (prebiotics) were added to the diet with the aim of increasing colonic fermentation and so potentially increasing the hypocholesterolemic effect of soy. Twenty-three hyperlipidemic adults (11 male, 12 female; 58 ± 7 years old; low-density lipoprotein cholesterol [LDL-C], 4.18 ± 0.58 mmol/L) completed three 4-week diet intervention phases—a low-fat dairy diet and 10 g/d prebiotic (oligofructose-enriched inulin, a fermentable carbohydrate), a soy food–containing diet (30 g/d soy protein, 61 mg/d isoflavones from soy foods) and 10 g/d placebo (maltodextrin), and a soy food–containing diet with 10 g/d prebiotic—in a randomized controlled crossover study. Intake of soy plus prebiotic resulted in greater reductions in LDL-C (−0.18 ± 0.07 mmol/L, P = .042) and in ratio of LDL-C to high-density lipoprotein cholesterol (−0.28 ± 0.11, P = .041) compared with prebiotic. In addition, high-density lipoprotein cholesterol was significantly increased on soy plus prebiotic compared with prebiotic (0.06 ± 0.02 mmol/L, P = .029). Differences in bifidobacteria, total anaerobes, aerobes, and breath hydrogen did not reach significance. Soy foods in conjunction with a prebiotic resulted in significant improvements in the lipid profile, not seen when either prebiotic or soy alone was taken. Coingestion of a prebiotic may potentiate the effectiveness of soy foods as part of the dietary strategy to lower serum cholesterol.

Ethnic differences in serum lipoproteins and their determinants in South African women - Corrected Proof

2010-01-25

Abstract: The objective of the study was to characterize ethnic differences in lipid levels and low-density lipoprotein (LDL) particle size and subclasses in black and white South African women and to explore the associations with insulin sensitivity (SI), body composition, and lifestyle factors. Fasting serum lipids and LDL size and subclasses, body composition (dual-energy x-ray absorptiometry), and SI (frequently sampled intravenous glucose tolerance test) were measured in normal-weight (body mass index <25 kg/m2) black (n = 15) and white (n = 15), and obese (body mass index >30 kg/m2) black (n = 13) and white (n = 13) women. Normal-weight and obese black women had lower triglycerides (0.59 ± 0.09 and 0.77 ± 0.10 vs 0.89 ± 0.09 and 0.93 ± 0.10 mmol/L, P < .05) and high-density lipoprotein cholesterol (1.2 ± 0.1 and 1.1 ± 0.1 vs 1.7 ± 0.1 and 1.6 ± 0.3 mmol/L, P < .01) than white women. The LDL particle size was not different, but obese black women had more LDL subclass IV (17.3% ± 1.0% vs 12.5% ± 1.0%, P < .01). In white women, triglycerides and LDL particle size correlated with SI (P < .01), whereas cholesterol levels correlated with body fat (P < .05). Low socioeconomic status, low dietary protein intake, and injectable contraceptive use were the major determinants of unfavorable lipid profiles in black women. Black women had lower triglyceride and high-density lipoprotein cholesterol levels and more small dense LDL particles than white women. The major determinants of serum lipids in black women were socioeconomic status and lifestyle factors, whereas in white women, SI and body composition most closely correlated with serum lipids.

Novel compound heterozygous mutations in the fructose-1,6-bisphosphatase gene cause hypoglycemia and lactic acidosis - Corrected Proof

2010-01-25

Abstract: Fructose-1,6-bisphosphatase (FBPase) deficiency is an autosomal recessive disorder caused by a mutation of the fructose-1,6-bisphosphatase 1 (FBP1) gene and results in impaired gluconeogenesis. We describe a male patient with typical FBPase deficiency who presented with hypoglycemia and lactic acidosis. The FBPase activity in his peripheral leukocytes and liver was very low. We amplified and sequenced the entire FBP1 coding region of the patient and his family members. Direct and allele-specific sequence analysis of the FBP1 gene revealed that the proband had a compound heterozygote for the G164S and 838delT, which he inherited from his carrier parents. His father and mother had heterozygous 838delT and G164S mutations, respectively, without any symptoms of hypoglycemia. Gene tracking within the family revealed that his elder sister had a heterozygous G164S mutation without symptoms of hypoglycemia. A G164S mutation of FBP1 in a heterozygous pattern (G164S and InsG960_961) has been reported previously, but the heterozygous 838delT mutation is novel. Transient transfection studies using COS-7 cells demonstrated that FBPase proteins with G164S or 838delT mutations were enzymatically inactive. In conclusion, we report a new case of molecular diagnosis of FBPase deficiency and provide evidence that impaired FBPase activity may be caused by novel compound heterozygous mutations in the FBP1 gene.

Postprandial plasma adiponectin response is reduced in prepubertal premature pubarche girls - Corrected Proof

2010-01-22

Abstract: The association between premature pubarche (PP) and metabolic syndrome is controversial and not supported by some authors. The aim of this study was to determine insulin resistance syndrome, plasma adiponectin, and fatty acid profile in PP girls to discern potential confounder variables and markers of metabolic disturbances. We studied 22 prepubertal girls with a diagnosis of PP and 20 healthy controls who differed in body mass index (BMI) (19.33 ± 0.71 vs 17.30 ± 0.60). We evaluated insulin resistance syndrome components and postprandial response of adiponectin, nonesterified fatty acids, and fatty acid profile after consumption of a standardized breakfast. No lipid disturbances were detected in the PP group. High-density lipoprotein to low-density lipoprotein cholesterol ratio tended to be lower in PP girls (P = .052), but this effect disappeared when data were adjusted for both BMI and age (P = .480). Insulin levels tended to be higher at 2 hours in PP girls, who showed significantly higher C-peptide area under the curve. In contrast, adiponectin at 3 hours after the meal and postprandial adiponectin area under the curve were significantly lower. The PP girls showed significantly higher percentages of eicosapentaenoic acid in total plasma and plasma phospholipids. No differences were found in the postprandial fatty acid clearance rate. In conclusion, PP girls and controls differed in postprandial plasma adiponectin response and in postprandial plasma C-peptide response after both BMI and age adjustment. Cholesterol plasma disturbances were mainly attributable to their higher BMI, although n-3 polyunsaturated fatty acids were higher because of the PP.

Further exploration of the possible influence of polymorphisms in HTR2C and 5HTT on body weight - Corrected Proof

2010-01-21

Abstract: Receptors of the 5-HT2C subtype are of importance for the influence of serotonin on food intake, and 2 single nucleotide polymorphisms in this gene (HTR2C)—Cys23Ser (rs6318) and −759C>T (rs3813929)—have been reported to be associated with weight and/or antipsychotic-induced weight gain. The present study aimed to replicate these associations; in addition, the 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) was assessed. The polymorphisms were genotyped in subjects recruited from the normal population (n = 510), and possible associations between genotype and body mass index (BMI) were assessed. The Ser23 allele was more common in underweight subjects (BMI <20) than in normal- and overweight (BMI ≥20) subjects (P = .006). The T allele of the −759C/T polymorphism was less common in the overweight group (BMI ≥25) (P = .007). Homozygosity for the short allele of 5-HTTLPR was more frequent in underweight subjects (P = .015). Our results are in agreement with previous studies, suggesting polymorphisms in HTR2C to be associated with body weight, particularly in women; and they also suggest that 5-HTTLPR may influence this phenotype. Further studies on the importance of the investigated genes for eating disorders and drug-induced weight gain are warranted.

Role of protein kinase C in pitavastatin-induced human paraoxonase I expression in Huh7 cells - Corrected Proof

2010-01-21

Abstract: We have demonstrated that pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, enhanced human serum paraoxonase (PON1) gene promoter activity and that protein kinase C (PKC) activated PON1 expression through Sp1 in cultured HepG2 cells. We investigated whether PKC was involved in pitavastatin-induced PON1 expression. PON1 gene promoter activity was assessed by a reporter gene assay using cultured Huh7 cells. PON1 protein expression and PKC activation were measured by Western blotting. The binding activity of Sp1 to the PON1 gene upstream was analyzed by electrophoretic mobility shift assay. Both PON1 gene promoter activity and PON1 protein expression were elevated by pitavastatin stimulation. The effects of pitavastatin on PON1 promoter activity and PON1 protein expression were attenuated by both bisindolylmaleimide IX (Ro-31-8220) and bisindolylmaleimide I. Electrophoretic mobility shift assay showed that pitavastatin increased the Sp1-PON1 DNA binding, and this effect was attenuated by Ro-31-8220. Pitavastatin activated atypical PKC, but never conventional or novel PKC. Myristoylated pseudosubstrate peptide inhibitor of PKCζ abolished the pitavastatin-increased PON1 promoter activity; however, calphostin C and Gö6976 (PKC inhibitors except for PKCζ) did not influence the promoter activity. In addition, an overexpression of dominant negative form of PKCζ expression vector obviously decreased pitavastatin-induced PON1 promoter activation. These observations suggest that pitavastatin activates PKC, especially PKCζ isoform, which increases the binding intensity of Sp1 to PON1 DNA promoter responsible for enhanced transcription of PON1 gene and increased PON1 protein expression in Huh7 cells.

Fat redistribution preferentially reflects the anti-inflammatory benefits of pioglitazone treatment - Corrected Proof

2010-01-21

Abstract: Thiazoledinedione is known to have an anti-inflammatory effect besides a hypoglycemic effect. We investigated changes in high-sensitivity C-reactive protein (hsCRP), a proinflammatory marker, after pioglitazone treatment in association with the resulting changes in various metabolic and anthropometric parameters. A total of 93 type 2 diabetes mellitus patients (47 men and 46 women; mean age, 50.0 ± 10.8 years) who were being treated with a stable dose of sulfonylurea or metformin were enrolled in the study. Pioglitazone (15 mg/d) was added to their treatment regimen for 12 weeks, and metabolic and anthropometric measurements were taken before and after pioglitazone treatment. Pioglitazone treatment for 12 weeks decreased serum hsCRP levels (0.83 [1.14] to 0.52 [0.82] mg/L, P < .001) and improved glycemic control (fasting glucose, P < .001; glycosylated hemoglobin, P < .001) and lipid profiles (triglyceride, P = .016; high-density lipoprotein cholesterol, P < .001). Between responders and nonresponders to the hsCRP-lowering effect of pioglitazone, there were significant differences in baseline hsCRP levels and changes in the postprandial glucose and the ratio of visceral fat thickness (VFT) to subcutaneous fat thickness (SFT) (P = .004, .011, and .001, respectively). The percentage change in hsCRP levels after treatment was inversely correlated with baseline hsCRP levels (r = −0.497, P < .001) and directly correlated with the change in postprandial glucose (r = 0.251, P = .021), VFT (r = 0.246, P = .030), and VFT/SFT ratio (r = 0.276, P = .015). Logistic regression analysis revealed that the hsCRP-lowering effect of pioglitazone was affected by baseline hsCRP levels (odds ratio [OR] = 7.929, P = .007) as well as changes in postprandial 2-hour glucose (OR = 0.716, P = .025) and VFT/SFT ratio (OR = 0.055, P = .009). In conclusion, treatment with pioglitazone produced an anti-inflammatory effect, decreasing serum hsCRP levels; and a decrease in the VFT/SFT ratio was independently and most strongly associated with the hsCRP-decreasing effect. These results suggest that abdominal fat redistribution preferentially reflects the anti-inflammatory benefits of pioglitazone treatment.

Telmisartan ameliorates hyperglycemia and metabolic profile in nonobese Cohen-Rosenthal diabetic hypertensive rats via peroxisome proliferator activator receptor–γ activation - Corrected Proof

2010-01-14

Abstract: The importance of hypertension treatment has expanded beyond blood pressure management to include additional risk factors, mainly diabetes. It was considered of interest to test the effect of telmisartan, an angiotensin receptor 1 antagonist and peroxisome proliferator activator receptor–γ partial agonist, on Cohen-Rosenthal diabetic hypertensive nonobese (CRDH) rats, a unique model combining both pathologies. Its effect was examined on fat-derived and inflammatory agents in CRDH. To determine the extent of the drug's peroxisome proliferator activator receptor–γ modulating beneficial metabolic actions, results were compared with those obtained with valsartan and rosiglitazone in CRDH and Cohen diabetic rat (CDR). Telmisartan and valsartan were given in drinking water at 3 and 12 mg/kg/d, whereas rosiglitazone (3 mg/kg/d) was given as food admixture for a period of 5 months. Blood pressure, glucose, insulin, adiponectin, leptin, and tumor necrosis factor α were examined. Telmisartan and valsartan significantly (P < .01) reduced blood pressure, whereas telmisartan and rosiglitazone considerably reduced blood glucose levels to normoglycemic levels (P < .01) in these 2 strains. Insulin levels were not affected by telmisartan and valsartan but were slightly reduced by rosiglitazone in CDR. In contrast to valsartan, adiponectin was significantly (60%, P < .01) increased by telmisartan in both CDR and CRDH, whereas rosiglitazone induced a 60% and 180% increase in CRDH and CDR animals, respectively, on day 30 of treatment. Co-treatment with GW9662 averted telmisartan-induced rise of adiponectin. Tumor necrosis factor α declined in telmisartan-treated rats, less so with rosiglitazone, but not valsartan. Telmisartan also induced downsizing of epididymal adipocytes compared with valsartan. Leptin levels were significantly increased by valsartan (P < .05) but reduced by telmisartan and rosiglitazone. The telmisartan-induced increase in adiponectin was most probably associated with a decrease in glucose and tumor necrosis factor α levels. Therefore, in addition to its hypotensive effect, telmisartan demonstrated beneficial thiazolidinedione-like effects.

Effects of gliclazide on platelet aggregation and the plasminogen activator inhibitor type 1 level in patients with type 2 diabetes mellitus - Corrected Proof

2010-01-13

Abstract: Vascular complications are a common factor determining morbidity and mortality of diabetic patients. In vitro studies have revealed that gliclazide has antiplatelet activities. To clinically assess this action, we measured the effects of gliclazide on platelet activities and abnormal fibrinolysis in patients with type 2 diabetes mellitus. We studied 14 patients aged 38 to 72 years (9 men and 5 women) with type 2 diabetes mellitus who have been treated with glibenclamide in our hospital for more than 6 months. We switched from glibenclamide to gliclazide using the average ratio of the respective doses, 2.5 vs 40 mg. We titrated the dose of gliclazide to keep the glycemic control at the same level as the previous (glibenclamide) treatment. We measured 10 μmol/L serotonin–induced or 0.5 μmol/L adenosine diphosphate (ADP)–induced platelet aggregate formation by particle counting using light scattering at baseline and up to 6 months after the switch. After switching to gliclazide, platelet aggregate formation induced by serotonin was significantly reduced (P < .05, compared with the levels observed after glibenclamide treatment). The body mass index, fasting plasma glucose, immunoreactive insulin, homeostasis model assessment of insulin resistance, hemoglobin A1c (HbA1c), total cholesterol, triglycerides, high-density lipoprotein cholesterol, prothrombin time, activated partial thromboplastin time, fibrinogen, thrombin-antithrombin III complex, plasmin-α2-plasmin inhibitor complex, and plasma plasminogen activator inhibitor type 1 (PAI-1) were not changed. In the group with improved HbA1c (n = 5), ADP-induced platelet aggregate formation and plasma PAI-1 level were significantly reduced (P < .05, compared with the group with aggravated HbA1c, n = 9). Multiple regression analysis showed that percentage change of ADP-induced platelet aggregate formation (standardized β = 0.540, P < .05) was independently associated with percentage change of plasma PAI-1 level in addition to percentage change of HbA1c (standardized β = 0.657, P < .05) (R = 0.939, P < .05) after switching to gliclazide. The other independent variants, like the final dose of gliclazide, homeostasis model assessment of insulin resistance, percentage change of prothrombin time, activated partial thromboplastin time, and total cholesterol, were not significantly associated with the percentage change of plasma PAI-1 level. These results indicate that gliclazide inhibits platelet aggregation via the serotonin pathway, independently of the metabolic control per se. Furthermore, in the patients with improved glycemic control, gliclazide could inhibit ADP-induced platelet aggregation and reduce PAI-I level. Taken together, the results show that gliclazide may be more useful for the prevention of diabetic vascular complications than glibenclamide.

Preliminary report: Zn-alpha2-glycoprotein genotype and serum levels are associated with serum lipids - Corrected Proof

2010-01-13

Abstract: Zn-alpha2-glycoprotein (ZAG) is a serum protein implicated in cancer cachexia and lipolysis. Our aim was to investigate serum levels of ZAG and polymorphisms in the ZAG gene in relation to serum lipids in man. Serum levels of ZAG correlated with serum levels of cholesterol (P = .00088) in healthy subjects and during weight loss (P = .059). The ZAG genotype was associated with total cholesterol (P = .014) and low-density lipoprotein cholesterol (P = .026) in healthy subjects, and the associations were replicated in an additional cohort (P = .0017 and P = .060, respectively). Our data indicate that ZAG plays a role in lipid metabolism.

Dietary fat intake promotes the development of hepatic steatosis independently from excess caloric consumption in a murine model - Corrected Proof

2010-01-08

Abstract: Nonalcoholic fatty liver disease results from overconsumption and is a significant and increasing cause of liver failure. The type of diet that is conducive to the development of this disease has not been established, and evidence-based treatment options are currently lacking. We hypothesized that the onset of hepatic steatosis is linked to the consumption of a diet with a high fat content, rather than related to excess caloric intake. In addition, we also hypothesized that fully manifested hepatic steatosis could be reversed by reducing the fat percentage in the diet of obese mice. C57BL/6J male mice were fed either a purified rodent diet containing 10% fat or a diet with 60% of calories derived from fat. A pair-feeding design was used to distinguish the effects of dietary fat content and caloric intake on dietary-induced hepatic lipid accumulation and associated injury. Livers were analyzed by quantitative reverse transcriptase polymerase chain reaction for lipid metabolism-related gene expression. After 9 weeks, mice on the 60%-fat diet exhibited more weight gain, insulin resistance, and hepatic steatosis compared with mice on a 10%-fat diet with equal caloric intake. Furthermore, mice with established metabolic syndrome at 9 weeks showed reversal of hepatic steatosis, insulin resistance, and obesity when switched to a 10%-fat diet for an additional 9 weeks, independent of caloric intake. Quantitative reverse transcriptase polymerase chain reaction revealed that transcripts related to both de novo lipogenesis and increased uptake of free fatty acids were significantly up-regulated in mice pair-fed a 60%-fat diet compared with 10%-fat–fed animals. Dietary fat content, independent from caloric intake, is a crucial factor in the development of hepatic steatosis, obesity, and insulin resistance in the C57BL/6J diet-induced obesity model caused by increased uptake of free fatty acids and de novo lipogenesis. In addition, once established, all these features of the metabolic syndrome can be successfully reversed after switching obese mice to a diet low in fat. Low-fat diets deserve attention in the investigation of a potential treatment of patients with nonalcoholic fatty liver disease.

Current concepts in triglyceride metabolism, pathophysiology, and treatment - Corrected Proof

2010-01-08

Abstract: It is becoming more evident that age, gender, and race play a significant role in the metabolic profiles that are seen among individuals in a clinical setting. It is important to understand these variances in metabolic profiles; and with these variances in mind it is now possible to understand why a single diet might not decrease cardiovascular disease risk profiles uniformly for everyone. Much is now understood about triglyceride metabolism and its contribution to energy storage. In this review we will focus on triglycerides; their production, metabolism and influence on daily life, as well as the various methods for the treatment of hypertryglyceridemia and prevention of its sequelae.

Sedentary behavior, physical activity, and concentrations of insulin among US adults - Corrected Proof

2010-01-08

Abstract: Time spent watching television has been linked to obesity, metabolic syndrome, and diabetes, all conditions characterized to some degree by hyperinsulinemia and insulin resistance. However, limited evidence relates screen time (watching television or using a computer) directly to concentrations of insulin. We examined the cross-sectional associations between time spent watching television or using a computer, physical activity, and serum concentrations of insulin using data from 2800 participants aged at least 20 years of the 2003-2006 National Health and Nutrition Examination Survey. The amount of time spent watching television and using a computer as well as physical activity was self-reported. The unadjusted geometric mean concentration of insulin increased from 6.2 μU/mL among participants who did not watch television to 10.0 μU/mL among those who watched television for 5 or more hours per day (P = .001). After adjustment for age, sex, race or ethnicity, educational status, concentration of cotinine, alcohol intake, physical activity, waist circumference, and body mass index using multiple linear regression analysis, the log-transformed concentrations of insulin were significantly and positively associated with time spent watching television (P = < .001). Reported time spent using a computer was significantly associated with log-transformed concentrations of insulin before but not after accounting for waist circumference and body mass index. Leisure-time physical activity but not transportation or household physical activity was significantly and inversely associated with log-transformed concentrations of insulin. Sedentary behavior, particularly the amount of time spent watching television, may be an important modifiable determinant of concentrations of insulin.

Association between serum vaspin concentrations and visceral adipose tissue in Korean subjects - Corrected Proof

Hye Mi Chang, Hye Soon Park, Cheol-Young Park, Young Sook Song, Yeon Jin Jang — 2010-01-08

Abstract: Adipokines modulate multiple signaling pathways of insulin resistance via endocrine, paracrine, or autocrine mechanisms. Visceral adipose tissue (VAT)–derived serpin (vaspin) is a novel adipokine with potential insulin-sensitizing effects. We investigated the association between serum vaspin concentrations and abdominal adiposity. We recruited subjects (N = 150) aged 20 to 69 years who visited our hospital for regular health examinations. Abdominal VAT and subcutaneous adipose tissue areas were assessed by computed tomography. We measured serum vaspin concentrations by enzyme-linked immunosorbent assay. Statistical analysis was performed after stratification, using a homeostasis model for insulin resistance (HOMA-IR). Serum vaspin concentrations correlated positively with age (r = 0.196) when data from all subjects were analyzed. In the higher–HOMA-IR group, serum vaspin levels correlated more prominently with age (r = .344) and VAT area (r = .327) although these associations were not found in the lower–HOMA-IR group. In multivariate linear regression analysis, the VAT area was independently correlated with serum vaspin concentrations in the higher–HOMA-IR group. The association between serum vaspin concentrations and VAT differs according to insulin resistance. Insulin resistance might influence the correlation between serum vaspin concentration and VAT in human subjects.

Differential impact of serum glucose, triglycerides, and high-density lipoprotein cholesterol on cardiovascular risk factor burden in nondiabetic, obese African American women: implications for the prevalence of metabolic syndrome - Corrected Proof

Trudy Gaillard, Dara Schuster, Kwame Osei — 2010-01-06

Abstract: Metabolic syndrome (MetS) as defined by the Adult Treatment Panel (ATP) III criteria includes 3 metabolic parameters: serum glucose, triglycerides, and high-density lipoprotein cholesterol (HDL-C) measurements. However, the impact of each of the 3 metabolic parameters on cardiovascular disease (CVD) risk in African American women (AAW) is unknown. Therefore, we investigated CVD risk clusters associated with each of the 3 metabolic components of MetS in adult nondiabetic, overweight/obese AAW. We studied the clinical and metabolic CVD risk factors of 258 AAW (mean age, 42.4 ± 8.4 years; mean body mass index, 33.4 ± 8.0 (kg/m2). Fasting serum insulin, glucose, and C-peptide levels were obtained in each subject. Waist circumference and systolic and diastolic blood pressure were measured. Insulin sensitivity (Bergman minimal model method) and insulin resistance (homeostasis model assessment) were calculated. We examined the prevalence of MetS and its components associated with each of the 3 metabolic components (ie, serum glucose, HDL-C, and triglycerides) of the MetS as defined by ATP III. Worsening of any of the 3 metabolic parameters was associated with increasing waist circumference but not with age and body mass index nor with insulin, C-peptide, homeostasis model assessment of insulin resistance, and insulin sensitivity. As a group, the prevalence of MetS was 35.5% in our AAW. The prevalence of MetS increased 3-fold from first to third tertiles of serum glucose (14.1% and 42.3%, respectively). Worsening of serum HDL-C from tertiles 3 to 1 was associated with significant increases in the prevalence of MetS (1.2% vs 42.3%, respectively). Comparing first with third tertile of triglycerides, there was no significant increase in MetS in our AAW (7% vs 17%). Contrasting the 3 metabolic components, the prevalence of MetS was higher in the third tertile of glucose (43.2%) and first tertile of HDL-C (42.3%) and least with the third tertile of triglycerides (17%). In summary, each of the metabolic components of MetS was associated with different degrees of the clustering of CVD risk factors in AAW. We found that alterations in serum glucose and HDL-C were more predictive of MetS, each yielding approximately 40% of the prevalence of MetS in our nondiabetic, obese AAW. We found that triglycerides had the least impact on MetS in our AAW. We propose (1) that the 3 metabolic parameters for MetS defined by ATP III should be weighted differently with respect to their potential for CVD risks and perhaps outcomes and (2) that nondiabetic AAW in our third tertile of serum glucose (>100 mg/dL) and/or first tertile of HDL-C (<40 mg/dL) should be targeted for screening for MetS.

Metabolic signs of vitamin B12 deficiency in humans: computational model and its implications for diagnostics - Corrected Proof

Sergey N. Fedosov — 2010-01-06

Abstract: Early diagnostics of cobalamin (Cbl, vitamin B12) deficiency is primarily based on measurements of the relevant metabolic markers in blood plasma—total B12, specific Cbl-saturated transporter holo-transcobalamin (holoTC), and substrates of Cbl-dependent enzymatic reactions methylmalonic acid (MMA) and homocysteine (Hcy). Concentrations of B12 and holoTC decrease whereas MMA and Hcy increase under deficiency. Yet, the results of individual tests are often contradictory and do not guarantee unambiguous diagnosis. The current work describes the metabolic manifestation of vitamin B12 deficiency in terms of flux equations fitted to data sets from literature. The model mathematically connects all the markers and presents 4 independent measurements as a single point (x, y) in the combined coordinates x = (holoTC·B12)½ and y = ½log10(MMA·Hcy). Pairwise averaging compensates for the individual fluctuations of the markers caused by (1) irregular spikes of holoTC, (2) delayed change of the total plasma B12 buffered by an internal Cbl depot, and (3) variations in the production/excretion velocities of MMA and Hcy. Bivariate distribution of the marker combinations (x, y) reveals several peaks of frequency in the analyzed mixed population. The peaks seem to represent the reference subgroups with different B12 physiology and characteristic values of “wellness parameter”: w = log10(holoTCn) + log10(B12n) − log10(MMAn) − log10(Hcyn), where concentrations are normalized (eg, MMAn = MMA/MMAnormal). Dynamic response of the organism to B12 intake is quantified and described as an additional analytical tool when classifying uncertain cases. The discussed mathematical approaches are of general applicability in diagnostics.

Suppressed glucose metabolism in acinar cells might contribute to the development of exocrine pancreatic insufficiency in streptozotocin-induced diabetic mice - Corrected Proof

Junying Han, Ye Q. Liu — 2010-01-06

Abstract: High prevalence of exocrine pancreatic insufficiency has been observed in diabetic patients. However, the underlying mechanisms are not well known. Reduced cytosolic Ca2+ signals in pancreatic acinar cells may contribute to lower digestive enzyme secretion. It is well known that adenosine triphosphate (ATP) regulates cytosolic Ca2+ signals in acinar cells; however, little is known as to whether diabetes impairs glucose metabolism that produces ATP in acinar cells. Streptozotocin (STZ)-induced diabetic C57BL/6 mouse model was used. Four weeks after being diabetic, pancreatic acinar cells were isolated; and amylase secretion and contents, glucose utilization and oxidation, the activities of several key enzymes for glucose metabolism, and ATP and nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) contents were determined. Compared with controls, diabetic mice had lower body weight. Cholecystokinin-8– and acetylcholine-stimulated amylase secretion was significantly impaired, and total amylase activity in acinar cells of STZ-diabetic mice was markedly reduced. Glucose utilization and oxidation were suppressed; measured enzyme activities for glucose metabolism and the ATP and NADPH contents were significantly reduced. These data indicate that glucose metabolism and ATP and NADPH productions are very important for maintaining acinar cell normal function. Reduction of ATP (reduces cytosolic Ca2+ signals) and NADPH (reduces cell capability for antioxidative stress) productions may contribute to the development of exocrine pancreatic insufficiency in STZ-diabetic mice.

Plasma apelin levels in subjects with nonalcoholic fatty liver disease - Corrected Proof

2010-01-04

Abstract: Nonalcoholic fatty liver disease (NAFLD), one of the most common forms of chronic liver disease, is closely associated with obesity and insulin resistance. Recent studies suggest that apelin, a newly described adipokine, is associated with hyperinsulinemia and inflammation. The aim of the study was to investigate plasma apelin concentrations in biopsy-proven NAFLD patients who had no metabolic confounders and also to search for the association of apelin with adiponectin, body mass index (BMI), and insulin sensitivity. Fifty male patients with NAFLD and 30 healthy male controls were enrolled. Apelin was measured along with BMI, lipids, glucose, insulin, adiponectin, and homeostasis model assessment (HOMA) of insulin resistance indexes. Plasma apelin levels were significantly higher and adiponectin levels were lower in NAFLD patients when compared with the controls (P < .001 and P = .013, respectively). In multivariate analysis adjusted for BMI and HOMA indexes, the differences in apelin and adiponectin disappeared in the 2 groups (P = .3 and P = .1, respectively). In addition, apelin levels were positively correlated with BMI (r = 0.29, P = .05) and HOMA indexes (r = 0.4, P = .008) in subjects with NAFLD. The results of this preliminary study suggest that plasma apelin levels are not altered in nondiabetic and normotensive male subjects with NAFLD.

Effects of acute ethionine injection on plasma ghrelin and obestatin levels in trained male rats - Corrected Proof

Abbass Ghanbari-Niaki, Rahelah Soltani, Afsaneh Shemshaki, Robert R. Kraemer — 2010-01-04

Abstract: Ghrelin and obestatin are orexigenic and anorexigenic peptides, respectively, that are secreted from the stomach mucosa into the circulation. These peptides have opposing actions on food intake, weight gain, and adiposity. It is thought that ghrelin is sensitive to a negative energy environment and also plays a considerable role in short- and long-term energy balance and glucose homeostasis. It has been suggested that the levels of ghrelin and obestatin are upregulated by fasting, hypoglycemic status, and a physical-exercise–induced energy deficit. Ethionine (ETH), the ethyl analogue of methionine, has been shown to increase food intake, decrease adenosine triphosphate (ATP) and glycogen levels, and inhibit protein synthesis in the liver. The purpose of this study was to examine the effect of a single dose of ETH (0.7 mg/g of body weight) injection on resting plasma total ghrelin and obestatin concentrations in male trained rats. Thirty-two adult Wistar male rats weighing 180 to 200 g were randomly assigned to control (n = 16) and training (n =16) groups. The training group was exercised for 10 weeks (25 m/min, 0% grade, 60 minutes, and 5 d/wk). Seventy-two hours after the last exercise session, rats were injected with either saline (NaCl) or ETH and then killed. Ethionine compared with a NaCl injection resulted in significant (P < .013) reductions in resting hepatic ATP and glycogen levels, and in a significant (P < .001) increase in concentrations of plasma total ghrelin but not obestatin. The results indicate that ETH-induced liver ATP and glycogen deficiency could exert a powerful regulatory influence on plasma total ghrelin, but this is not the case for obestatin. Findings demonstrate the short-term energy-regulating capacity of ghrelin.

Role of FADS1 and FADS2 polymorphisms in polyunsaturated fatty acid metabolism - Corrected Proof

Claudia Glaser, Joachim Heinrich, Berthold Koletzko — 2010-01-04

Abstract: Tissue availability of polyunsaturated fatty acids (PUFAs) depends on dietary intake and metabolic turnover and has a major impact on human health. Strong associations between variants in the human genes fatty acid desaturase 1 (FADS1, encoding Δ-5 desaturase) and fatty acid desaturase 2 (FADS2, encoding Δ-6 desaturase) and blood levels of PUFAs and long-chain PUFAs (LC-PUFAs) have been reported. The most significant associations and the highest proportion of genetically explained variability (28%) were found for arachidonic acid (20:4n-6), the main precursor of eicosanoids. Subjects carrying the minor alleles of several single nucleotide polymorphisms had a lower prevalence of allergic rhinitis and atopic eczema. Therefore, blood levels of PUFAs and LC-PUFAs are influenced not only by diet, but to a large extent also by genetic variants common in a European population. These findings have been replicated in independent populations. Depending on genetic variants, requirements of dietary PUFA or LC-PUFA intakes to achieve comparable biological effects may differ. We recommend including analyses of FADS1 and FADS2 polymorphism in future cohort and intervention studies addressing biological effects of PUFAs and LC-PUFAs.

Methionine restriction effects on mitochondrial biogenesis and aerobic capacity in white adipose tissue, liver, and skeletal muscle of F344 rats - Corrected Proof

2010-01-04

Abstract: Methionine restriction increases life span in rats and mice and reduces age-related accretion of adipose tissue in Fischer 344 rats. Recent reports have shown that adipose tissue mitochondrial content and function are associated with adiposity; therefore, the expression of genes involved in mitochondrial biogenesis and oxidative capacity was examined in white adipose tissue, liver, and skeletal muscle from Fischer 344 rats fed control (0.86% methionine) or methionine-restricted (0.17% methionine) diets for 3 months. Methionine restriction induced transcriptional changes of peroxisome proliferator-activated receptors, peroxisome proliferator-activated receptor coactivators 1α and 1β, and some of their known target genes in all of these tissues. In addition, tissue-specific responses were elicited at the protein level. In inguinal adipose tissue, methionine restriction increased protein levels of peroxisome proliferator-activated receptor and peroxisome proliferator-activated receptor coactivator target genes. It also induced mitochondrial DNA copy number, suggesting mitochondrial biogenesis and corresponding with the up-regulation of citrate synthase activity. In contrast, methionine restriction induced changes in mitochondrial glycerol-3-phosphate dehydrogenase activity and stearoyl–coenzyme A desaturase 1 protein levels only in liver and uncoupling protein 3 and cytochrome c oxidase subunit IV protein levels only in skeletal muscle. No increase in mitochondrial DNA copy number was observed in liver and skeletal muscle despite an increase in mitochondrial citrate synthase activity. The results indicate that adiposity resistance in methionine-restricted rats is associated with mitochondrial biogenesis in inguinal adipose tissue and increased mitochondrial aerobic capacity in liver and skeletal muscle.

The cortisol awakening response and the metabolic syndrome in a population-based sample of middle-aged men and women - Corrected Proof

2010-01-04

Abstract: The objective was to explore the relationship between the cortisol awakening response (CAR) and the metabolic syndrome (MetS) as defined by the National Cholesterol Education Program criteria. The final study sample consisted of 91 women (14 with MetS) and 84 men (15 with MetS), aged 45 to 70 years, from a general population sample. The only exclusion criteria were no consent, pregnancy, or insufficient cortisol testing. On the day of measurement (weekday), salivary cortisol was sampled at awakening and 15 minutes after awakening. Relative CAR (CAR%) and the MetS were the main variables studied. Results showed that, in women with the MetS, cortisol at awakening was significantly lower (mean, 8.92 vs 12.33 nmol/L; P = .05) and the CAR was significantly higher (91.4% vs 36.5%, P < .001) than in women without the syndrome. Significant difference in the relative CAR was also present between men and women with MetS (38.5% and 91.4%, respectively; P = .02). No difference was seen in the awakening response comparing men with and without the MetS. In a regression model, the response to awakening was dependent on the MetS in women (F1,89 = 13.19, P < .001); but the model was not significant in men. Furthermore, the awakening response was associated with more depressive symptoms in women (F1,80 = 8.12, P = .01) and with weekday/weekend cortisol sampling in men (F1,82 = 4.63, P = .03). The association between the relative CAR and the MetS remained significant but somewhat attenuated after adjusting for depressive symptoms (P = .01). Results indicate a sex difference in the CAR% in the presence of the MetS independent of depressive symptoms, a known correlate of the MetS.

Glucose-transporter–mediated positive inotropic effects in human myocardium of diabetic and nondiabetic patients - Corrected Proof

2010-01-04

Abstract: Insulin causes inotropic effects via Ca2+-dependent and Ca2+-independent pathways. The latter one is potentially glucose dependent. We examined inotropic responses and signal transduction of insulin in human atrial myocardium of diabetic and nondiabetic patients to test for the role of glucose transporters. Experiments were performed in isolated atrial myocardium of 88 patients undergoing cardiac surgery and 28 ventricular muscle samples of explanted hearts. Influence of insulin (0.02 μmol/L) on isometric twitch force was examined with and without blocking glucose transporter (GLUT) 4 translocation (latrunculin), sodium-coupled glucose transporter (SGLT) 1 (phlorizin, T-1095A), or PI3-kinase (wortmannin). Experiments were performed in Tyrode solution containing glucose or pyruvate as energetic substrate. Messenger RNA expression of glucose transporters (GLUT1, GLUT4, SGLT1, SGLT2) was analyzed in atrial and ventricular myocardium of both diabetic and nondiabetic patients. Developed force increases after insulin (to 117.8% ± 2.4% and 115.8% ± 1.9%) in trabeculae from patients with and without diabetes. Inotropic effect was reduced after displacing glucose with pyruvate as well as after PI3-kinase inhibition (to 103% ± 2%) or inhibition of glucose transporters GLUT4 (to 105% ± 2%) and SGLT1 (phlorizin to 106% ± 2%, T-1095A to 105% ± 2%), without differences between the 2 groups. In glucose-free pyruvate-containing solution, only inhibition of PI3-kinase but not blocking glucose transporters resulted in further inhibitory effects. Messenger RNA expression did not show significant differences between patients with or without diabetes. Insulin exerts positive inotropic effects in human atrial myocardium. These effects are mediated via a PI3-kinase–sensitive and a glucose-transport–sensitive pathway. Differences in functional effects or messenger RNA expression of glucose transporters were not detectable between patients with and without diabetes.

Endogenous red blood cell membrane fatty acids and sudden cardiac arrest - Corrected Proof

2010-01-04

Abstract: Little is known of the associations of endogenous fatty acids with sudden cardiac arrest (SCA). We investigated the associations of SCA with red blood cell membrane fatty acids that are end products of de novo fatty acid synthesis: myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1 n7), vaccenic acid (18:1 n7), stearic acid (18:0), oleic acid (18:1 n9), and a related fatty acid, cis-7 hexadecenoic acid (16:1 n9). We used data from a population-based case-control study where cases, aged 25 to 74 years, were out-of-hospital SCA patients attended by paramedics in Seattle, WA (n = 265). Controls, matched to cases by age, sex, and calendar year, were randomly identified from the community (n = 415). All participants were free of prior clinically diagnosed heart disease. We observed associations of higher red blood cell membrane levels of 16:0, 16:1n-7, 18:1n-7, and 16:1n-9 with higher risk of SCA. In analyses adjusted for traditional SCA risk factors and trans- and n-3 fatty acids, a 1-SD–higher level of 16:0 was associated with 38% higher risk of SCA (odds ratio, 1.38; 95% confidence interval, 1.12-1.70) and a 1-SD–higher level of 16:1n-9 with 88% higher risk (odds ratio, 1.88; 95% confidence interval, 1.27-2.78). Several fatty acids that are end products of fatty acid synthesis are associated with SCA risk. Further work is needed to investigate if conditions that favor de novo fatty acid synthesis, such as high-carbohydrate/low-fat diets, might also increase the risk of SCA.

Effects of a 6-month lifestyle modification intervention on the cardiometabolic risk factors and health-related qualities of life in women with metabolic syndrome - Corrected Proof

2010-01-04

Abstract: Although therapeutic lifestyle modification (TLM) has been recommended as a cornerstone treatment of metabolic syndrome (MetS), little is known about the biobehavioral effects of a TLM program for patients in a community. The purpose of this study was to examine the effects of a 6-month TLM program on MetS risk factors and health-related qualities of life (HRQOL) among middle-aged and older women in a community in Korea. Fifty-two women (mean age, 62.7 ± 9.0 years) with MetS were recruited from 3 community health centers and were randomly assigned to the intervention (n = 31) or control (n = 21) groups. The patients in the intervention group participated in supervised TLM sessions for 6 months. The TLM program included health monitoring, counseling, health education, exercise, and dieting. Metabolic risk factors and HRQOL were measured at baseline, during the study (month 3), at completion (month 6), and postcompletion (month 12) of the TLM program. Compared with the control group, the TLM group showed significantly greater reductions in body weight (P < .001) and waist circumference (P < .001); these effects were sustained for 6 months after intervention. With regard to HRQOL, the TLM group showed greater improvements in physical function (P = .017), general health (P < .001), vitality (P = .008), and mental health (P = .027). These improvements, however, were not sustained after the intervention. The results indicate that a nurse-led systematic TLM program may be an effective strategy for managing middle-aged and older women with MetS at a community level.

Association of central adiposity with prediabetes and decreased insulin sensitivity in rural Chinese normal-weight and overweight women - Corrected Proof

2010-01-04

Abstract: This study investigated whether high central adiposity was associated with prediabetes and decreased insulin sensitivity (IS) in both normal-weight (body mass index [BMI] <23 kg/m2) and overweight (BMI ≥23 kg/m2) rural Chinese women. Adipose variables measured by dual-energy x-ray absorptiometry (percentage body fat, percentage lower-body fat [%LF], and percentage trunk fat [%TF]) and general adipose variables (BMI and waist circumference) were used for examining the association of adiposity with prediabetes among 4071 rural Chinese women aged 20 to 60 years. Furthermore, the association of adiposity with IS was tested in both normal- and overweight women with normal glucose tolerance. BMI was highly correlated with percentage body fat and waist circumference, but was weakly correlated with %LF and %TF. Both high %TF (top quartile of %TF) and low %LF (lower 3 quartiles of %LF) were associated with higher prevalence of prediabetes in both normal- and overweight women. Compared with normal-weight women in low %TF, the odds of prediabetes were similarly increased for women with high %TF regardless of whether they were overweight (odds ratio [95% confidence interval] = 1.6 [1.3-2.0]) or not (odds ratio [95% confidence interval] = 1.5 [1.2-2.0]). Similarly, among 3280 women with normal glucose tolerance, high %TF was associated with increased fasting insulin, 2-hour oral glucose tolerance test insulin, and homeostasis model assessment of insulin resistance regardless of weight status (normal or overweight). Among relatively lean, rural Chinese women, high %TF was associated with increased odds of prediabetes and lower IS regardless of weight status (normal or overweight).

Preliminary report: circulating levels of the adipokine vaspin in gestational diabetes mellitus and preeclampsia - Corrected Proof

2010-01-04

Abstract: The objective of the study was to investigate serum levels of the insulin-sensitizing adipokine vaspin in patients with gestational diabetes mellitus (GDM) and preeclampsia (PE) as compared with healthy controls of similar gestational age. Vaspin serum levels were quantified by enzyme-linked immunosorbent assay in control (n = 102), GDM (n = 40), and PE (n = 22) subjects. Median maternal vaspin concentrations were not significantly different in GDM, PE, and control subjects. Furthermore, vaspin did not significantly correlate to clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation. Circulating vaspin levels are not significantly different between GDM, PE, and control subjects and do not correlate with insulin sensitivity in pregnant subjects.

The characterization of Abelson helper integration site–1 in skeletal muscle and its links to the metabolic syndrome - Corrected Proof

2010-01-04

Abstract: The human Abelson helper integration site–1 (AHI1) gene is associated with both neurologic and hematologic disorders; however, it is also located in a chromosomal region linked to metabolic syndrome phenotypes and was identified as a type 2 diabetes mellitus susceptibility gene from a genomewide association study. To further define a possible role in type 2 diabetes mellitus development, AHI1 messenger RNA expression levels were investigated in a range of tissues and found to be highly expressed in skeletal muscle as well as displaying elevated levels in brain regions and gonad tissues. Further analysis in a rodent polygenic animal model of obesity and type 2 diabetes mellitus identified increased Ahi-1 messenger RNA levels in red gastrocnemius muscle from fasted impaired glucose–tolerant and diabetic rodents compared with healthy animals (P < .002). Moreover, elevated gene expression levels were confirmed in skeletal muscle from fasted obese and type 2 diabetes mellitus human subjects (P < .02). RNAi-mediated suppression of Ahi-1 resulted in increased glucose transport in rat L6 myotubes in both the basal and insulin-stimulated states (P < .01). Finally, single nucleotide polymorphism association studies identified 2 novel AHI1 genetic variants linked with fasting blood glucose levels in Mexican American subjects (P < .037). These findings indicate a novel role for AHI1 in skeletal muscle and identify additional genetic links with metabolic syndrome phenotypes suggesting an involvement of AHI1 in the maintenance of glucose homeostasis and type 2 diabetes mellitus progression.

Diet-genotype interactions in the early development of obesity and insulin resistance in mice with a genetic deficiency in tumor necrosis factor–α - Corrected Proof

Brenda Bouter, Nori Geary, Wolfgang Langhans, Lori Asarian — 2010-01-04

Abstract: The onset of insulin resistance, the sites of action, and the mechanisms through which tumor necrosis factor–α (TNF-α) exacerbates the increase in adiposity and the development of insulin resistance in mice fed high-fat (HF) diet remain unclear. Here we investigated the effect of TNF-α deficiency on adiposity and insulin resistance during the initial 1 to 4 weeks of HF feeding. We examined body weight; the distribution of white adipose tissue (WAT); homeostasis model assessment; and levels of leptin, resistin, and adiponectin in the initial 4 weeks of HF feeding in TNF-α knockout (KO) mice and wild-type (WT) controls. Through 4 weeks of HF feeding, KO mice, unlike WT mice, maintained normal insulin sensitivity. Although WT-HF and KO-HF mice had similar levels of WAT at this time, KO-HF mice had more subcutaneous and less epididymal fat than WT-HF mice. The KO-HF mice also had less liver fat than the WT-HF mice. Finally, KO-HF mice had lower plasma levels of resistin than WT-HF mice. These data demonstrate that genetic lack of TNF-α protects insulin sensitivity during the early phase of HF feeding in the absence of altered total WAT. The data also suggest that the mechanism maintaining insulin sensitivity in the absence of TNF-α may involve redirection of the fat deposition to the metabolically more inert subcutaneous depot or decreases in circulating resistin and resultant decrease in liver fat deposition. The efficacy of therapeutic measures designed to counteract the effects of TNF-α may be increased during the early stages of obesity and insulin resistance.

Age-dependent associations of smoking and drinking with non–high-density lipoprotein cholesterol - Corrected Proof

Ichiro Wakabayashi, Klaus Groschner — 2010-01-04

Abstract: Serum high-density lipoprotein (HDL) cholesterol levels are influenced by habitual smoking and drinking. Non-HDL cholesterol is known to be a potent predictor of cardiovascular disease. However, it remains to be determined whether the associations of non-HDL cholesterol with smoking and drinking differ with age. The objectives of this study were to investigate relationships among smoking, drinking, and non-HDL cholesterol and to investigate interactions of age with smoking and drinking regarding serum non-HDL cholesterol levels. Subjects (54,020 Japanese men aged 20-69 years) were divided into drinkers and nondrinkers or into smokers and nonsmokers and were further divided into 5 age groups with 10-year intervals. Subjects in each age group were divided into 3 subgroups according to alcohol or cigarette consumption. The mean levels of serum non-HDL cholesterol calculated after adjustment for age and body mass index were compared among the groups. In nondrinkers, non-HDL cholesterol levels of subjects in their 40s or older were significantly higher in heavy smokers than in nonsmokers, whereas non-HDL cholesterol levels of subjects in their 20s and 30s were not significantly different among non-, light, and heavy smokers. In drinkers, non-HDL cholesterol levels of subjects in all age groups were not higher in light and heavy smokers than in nonsmokers. In nonsmokers, non-HDL cholesterol in subjects in their 30s or older was significantly lower in light and heavy drinkers than in nondrinkers, whereas this difference was not observed in subjects in their 20s. In smokers, non-HDL cholesterol levels of subjects in all age groups were significantly lower in light and heavy drinkers than in nondrinkers, and the differences in non-HDL cholesterol between drinkers and nondrinkers tended to increase with advance of age. The difference in non-HDL cholesterol between drinkers and nondrinkers tended to be greater in smokers than in nonsmokers. Thus, the associations of non-HDL cholesterol with smoking and drinking were modified by drinking and smoking, respectively. Smoking is associated with high non-HDL cholesterol in nondrinkers, and drinking is associated with low non-HDL cholesterol in nonsmokers; these associations are shown at middle and elderly ages but not at young ages.

Common INSIG2 polymorphisms are associated with age-related changes in body size and high-density lipoprotein cholesterol from young adulthood to middle age - Corrected Proof

2010-01-04

Abstract: Insulin-induced gene 2 (INSIG2) plays an important role in the regulation of cholesterol and fatty acids synthesis. A polymorphism, rs7566605, located 10 kilobases upstream of the INSIG2 gene, was identified in a genomewide association study of obesity. We conducted an association study of 12 INSIG2 tag–single nucleotide polymorphisms with longitudinal measures of body size (body mass index and waist circumference) and lipid metabolism (plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides levels). We investigated their interaction with age in 4304 Coronary Artery Risk Development in Young Adults participants (49.5% blacks, 50.5% whites) followed prospectively for 20 years. rs7566605 was not associated with variation in body size or lipid metabolism at any age in either racial group. However, rs1352083 and rs10185316 were associated with age-related decline in high-density lipoprotein cholesterol in whites (P = .0005 and .04, respectively). A similar trend was observed in blacks who consistently maintained a body mass index less than 25 kg/m2 over the study period. These data support a role of INSIG2 sequence variation in the regulation of cholesterol metabolism.

Adipose tissue lamin A/C messenger RNA expression in women - Corrected Proof

2010-01-04

Abstract: Mutations in the lamin A/C gene (LMNA) cause lipodystrophy. However, little data are available on lamin A/C expression in various fat depots in women. We recruited 34 women scheduled for gynecologic surgery. Blood samples were collected on the morning of surgery to obtain a detailed lipid profile. Radiological examinations were performed to measure total body fat mass and abdominal fat accumulation. Fat samples were taken from the subcutaneous (SC) fat depot and from the greater omentum (OM) during the surgical procedure. Whole adipose tissue samples were used for total messenger RNA (mRNA) extraction and real-time polymerase chain reaction quantification of the LMNA transcript. No association was observed between lamin A/C mRNA expression, either in SC or OM fat tissue, and adiposity measures. Women with low SC lamin A/C expression, identified on the basis of the median value of SC lamin A/C mRNA expression, had a significantly altered lipid profile including lower levels of high-density lipoprotein (HDL) cholesterol and HDL2 cholesterol and reduced HDL2 cholesterol to HDL3 cholesterol ratio (P < .05 for all). These women were also characterized by higher cholesterol to HDL cholesterol, low-density lipoprotein–triglycerides, very low-density lipoprotein–apolipoprotein B, and low-density lipoprotein cholesterol to HDL cholesterol (P < .05 for all). Low SC lamin A/C mRNA expression levels were also associated with significantly increased lipolysis in isolated fat cells from this fat depot. Specifically, the response to lipolytic agent isoproterenol was significantly increased at doses ranging from 10−5 to 10−10 mol/L (P < .05). A similar trend was observed in OM fat cells but did not reach significance. In conclusion, low lamin A/C expression in SC adipose tissue is associated with significant alterations in the lipid profile and increased fat cell lipolysis, independent of the level of total or abdominal adiposity.

Common polymorphisms of the peroxisome proliferator-activated receptor–γ (Pro12Ala) and peroxisome proliferator-activated receptor–γ coactivator–1 (Gly482Ser) and the response to pioglitazone in Chinese patients with type 2 diabetes mellitus - Corrected Proof

2010-01-04

Abstract: We investigated the effects of the common polymorphisms in the peroxisome proliferator-activated receptor–γ (PPAR-γ; Pro12Ala) and in PPAR-γ coactivator–1(PGC-1; Gly482Ser) genes on the response to pioglitazone in Chinese with type 2 diabetes mellitus. A total of 250 patients with type 2 diabetes mellitus were treated with pioglitazone (30 mg/d) for 24 weeks without a change in previous medications. All patients were genotyped for the PPAR-γ Pro12Ala and PGC-1 Gly482Ser polymorphisms. The Ala12Ala and Pro12Ala genotypes (26.0% vs 13.5%, P = .025) and Ala allele (15.6% vs 7.3%, P = .008) were significantly more frequent in pioglitazone responders than in nonresponders. The distribution of PGC-1 genotypes and alleles was not significantly different between responders and nonresponders. The decrease in fasting glucose (50.4 ± 52.2 vs 43.3 ± 51.7 mg/dL, P < .001) and hemoglobin A1c (0.57% ± 1.44% vs 0.35% ± 1.10%, P = .004) levels was significantly greater in subjects with the Ala12 carriers (Pro12Ala and Ala12Ala) than in those without the allele (Pro12Pro). Baseline fasting glucose and triglyceride levels were related to the response of pioglitazone. Only the PPAR-γ Pro12Ala polymorphism was found to be associated with the response of pioglitazone by multiple logistic regression analysis. The PPAR-γ Pro12Ala gene polymorphism is associated with the response to pioglitazone in Chinese patients with type 2 diabetes mellitus. These findings may be helpful for targeted treatment of diabetes by identifying patients who are likely to respond to pioglitazone.

High follicular fluid adenosine levels may be pivotal in the metabolism and recycling of adenosine nucleotides in the human follicle - Corrected Proof

2010-01-04

Abstract: This study investigated the biochemical relationship between human follicular/oocyte maturity and the levels of follicular fluid purines. Intrafollicular levels of purine metabolites and creatinine are associated with oocyte presence, and the presence of such high levels of adenosine indicates a privileged site with no adenosine deaminase activity. Subgrouping according to oocyte recovery and fertilization revealed differences in correlation between the purine metabolites: Only where an oocyte was recovered and subsequently fertilized did follicular fluid adenosine, adenine, and hypoxanthine levels correlate with each other. Significantly, purines' correlation with levels of the terminal degradation product, uric acid, could only be seen in failed fertilization samples. Given the established metabolic pathways for adenosine triphosphate/adenosine diphosphate/adenosine monophosphate degradation, the results indicate maximization of 2 purine salvage pathways (from adenine and hypoxanthine) that pivot on the presence of high adenosine levels. Such optimized recovery may be necessary to build a store of salvaged adenosine phosphate for oocyte survival.

The influence of multiple indices of socioeconomic disadvantage across the adult life course on the metabolic syndrome: the Vietnam Experience Study - Corrected Proof

2010-01-04

Abstract: Few studies have explored the relationship between individual and combined multiple indicators of socioeconomic status across the life course and the metabolic syndrome, or attempted to understand the mechanisms underlying any associations. The present study examined the associations between 4 indicators of socioeconomic status, individually and in combination, and metabolic syndrome risk in a study of male US veterans and examined the influence of health behaviors, intelligence, and psychologic distress on these associations. Participants (N = 4253) were drawn from the Vietnam Experience Study. From military service files, telephone interviews, and a medical examination, occupational, sociodemographic, health behavior, intelligence, psychologic, and health data were collected. The 4 indices of socioeconomic status were as follows: education achieved, early adulthood income, household income in midlife, and occupational prestige in midlife. Metabolic syndrome was diagnosed from the following: body mass index, fasting blood glucose or a diagnosis of diabetes, blood pressure—a diagnosis of hypertension or taking antihypertensives, high-density lipoprotein cholesterol, and triglyceride levels. In models that adjusted for age, men in the lower 2 groups on the combined measure of socioeconomic status experienced a higher risk of metabolic syndrome. This association was accounted for mainly by education achieved, household income in midlife, and occupational prestige in midlife. Intelligence appeared to explain much of this association. Combined socioeconomic status measures across the life course were related to metabolic syndrome but in a threshold rather than dose-response manner. Intelligence appeared to mediate this relationship.

Protective effect of caffeic acid on cardiac markers and lipid peroxide metabolism in cardiotoxic rats: an in vivo and in vitro study - Corrected Proof

K. Senthil Kumaran, P. Stanely Mainzen Prince — 2010-01-04

Abstract: Myocardial infarction affects a large population in the world. Lipid peroxide metabolism plays an important role in the pathology of myocardial infarction. This study aims to evaluate the preventive effect of caffeic acid on lipid peroxides, antioxidants, cardiac marker enzymes, and histopathological findings in isoproterenol (ISO)-induced myocardial-infarcted male Wistar rats. Myocardial infarction was induced in rats by subcutaneous injection of ISO (100 mg/kg) at an interval of 24 hours for 2 days. The ISO-induced rats showed significant increase in the levels of thiobarbituric acid reactive substances, lipid hydroperoxides in the heart, plasma uric acid, and serum cardiac marker enzymes, and significant decrease in the activities of heart superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, and the levels of reduced glutathione, vitamin E, and vitamin C in the plasma and heart. Oral pretreatment with caffeic acid (15 mg/kg) daily for 10 days showed significant decrease in the levels of serum cardiac marker enzymes, heart lipid peroxidation products and plasma uric acid and significant increase in the levels of antioxidant system. Histopathology of myocardium also confirmed the protective effect of caffeic acid in myocardial-infarcted rats. In vitro study on total antioxidant activity (2,2'-azinobis-[3-ethylbenzothiazoline-6-sulfonic acid]+ assay) confirmed the strong antioxidant action of caffeic acid. Thus, the present study revealed that caffeic acid ameliorates cardiac damage in ISO-induced myocardial infarction by maintaining lipid peroxide metabolism due to its free radical scavenging and antioxidant effects. A diet containing caffeic acid may be beneficial to myocardial infarction.

Poor prediction of resting energy expenditure in obese women by established equations - Corrected Proof

2010-01-04

Abstract: The objective of the study was to evaluate the accuracy of established prediction equations that calculate resting energy expenditure (REE) in obese women. This was a cross-sectional study. In 273 mildly to severely obese women (age, 41.7 ± 13.2 years; body mass index, 42.8 ± 7.0 kg/m2), REE was measured by indirect calorimetry (mREE), along with fat mass (FM) and fat-free mass (FFM) by bioelectrical impedance analysis. Eleven established equations were used to predict REE (pREE), with 9 equations basing on the anthropometric parameters body weight and height and 2 equations including body composition parameters (FM, FFM). All equations provided pREE values that significantly correlated with mREE (r > 0.66, P < .001), although 8 equations systematically underestimated mREE (P < .05). Of note, even the best equation was not able to accurately predict mREE with a deviation of less than ±10% in more than 70% of the tested women. Furthermore, equations using body composition data were not superior in predicting REE as compared with equations exclusively including anthropometric variables. Multiple linear regression analyses revealed 2 new equations—one including body weight and age and another including FM, FFM, and age—that explained 56.9% and 57.2%, respectively, of variance in mREE. However, when these 2 new equations were applied to an independent sample of 33 obese women, they also provided an accurate prediction (±10%) of mREE in only 56.7% and 60.6%, respectively, of the women. Data show that an accurate prediction of REE is not feasible using established equations in obese women. Equations that include body composition parameters as assessed by bioelectrical impedance analysis do not increase the accuracy of prediction. Based on our results, we conclude that calculating REE by standard prediction equations does not represent a reliable alternative to indirect calorimetry for the assessment of REE in obese women.

l-Carnitine l-tartrate supplementation favorably affects biochemical markers of recovery from physical exertion in middle-aged men and women - Corrected Proof

2010-01-04

Abstract: The purpose of this study was to examine the effects of Carnipure tartrate (Lonza, Allendale, NJ) supplementation (total dose of 2 g/d of l-carnitine) on markers of performance and recovery from physical exertion in middle-aged men and women. Normally active and healthy men (n = 9, 45.4 ± 5.3 years old) and women (n = 9, 51.9 ± 5.0 years old) volunteered to participate in the investigation. Double-blind, placebo, balanced treatment presentation and crossover design were used with 3 weeks and 3 days of supplementation followed by a 1-week washout period before the other counterbalanced treatment was initiated. After 3 weeks of each supplementation protocol, each participant then performed an acute resistance exercise challenge of 4 sets of 15 repetitions of squat/leg press at 50% 1-repetition maximum and continued supplementation over the recovery period that was evaluated. Blood samples were obtained at preexercise and at 0, 15, 30, and 120 minutes postexercise during the acute resistance exercise challenge and during 4 recovery days as well. Two grams of l-carnitine supplementation had positive effects and significantly (P ≤ .05) attenuated biochemical markers of purine metabolism (ie, hypoxanthine, xanthine oxidase), free radical formation (malondialdehyde), muscle tissue disruption (myoglobin, creatine kinase), and muscle soreness after physical exertion. However, markers of physical performance (ie, strength, power, get up and go) were not affected by supplementation. These findings support our previous findings of l-carnitine in younger people that such supplementation can reduce chemical damage to tissues after exercise and optimize the processes of muscle tissue repair and remodeling.