Metabolism - Clinical and Experimental

Masthead

2010-02-01

Modification of the acceptance policy for manuscripts

James B. Field — 2009-11-23

The implementation of the Elsevier Editorial System by Metabolism has greatly increased the number of manuscripts submitted to the Journal. In consideration of this increase in quantity of submissions and knowing that we can only publish a certain number of pages per year, the Journal's acceptance policy has been significantly changed. In the past, a priority system was instituted based primarily on the scientific merit of the manuscript. The best priority was 1, and the worst priority was 5. Based on this system, for a manuscript to be accepted, it had to receive an average priority of 3 or better from the reviewers. Thus, many manuscripts were rejected although they were scientifically acceptable, but had a priority score of more than 3. As long as the number of manuscripts submitted to the Journal continues at the present rate, their acceptance will depend upon their scientific merit and a priority of 2 or better. Although this change may be frustrating for some, it will allow Metabolism to publish only the best articles submitted to the Journal; and you, our readers, will benefit from content of only the highest quality. The implementation of the Elsevier Editorial System has also greatly facilitated review of manuscripts by reviewers and reduced the time to obtain a review and the time to make an initial decision. This efficiency has caused a larger backlog of accepted manuscripts; and as such, the time from acceptance of a manuscript until print publication may increase. We anticipate the delay to be temporary and to be mitigated somewhat by having the manuscript available online prior to publication in the Journal's articles in press section. Although many authors will be disappointed by rejection of their manuscript even though they are scientifically acceptable but not of sufficient priority, the overall scientific impact of the Journal should increase.

Serum ferritin is a major determinant of lipid phenotype in familial combined hyperlipidemia and familial hypertriglyceridemia

2009-11-16

Abstract: Familial combined hyperlipidemia (FCH) and familial hypertriglyceridemia (FHTG) share pathogenic mechanisms and a high interaction with components of the metabolic syndrome. The metabolic syndrome associates increased serum ferritin concentration and high cardiovascular risk. The objective was to describe the frequency of iron overload and the relationship between serum ferritin and the phenotype in patients with FCH and FHTG. The study was composed of 211 consecutive unrelated patients aged at least 18 years with primary hypertriglyceridemia, 149 with FCH, and 62 with FHTG. The prevalence of the metabolic syndrome and hyperferritinemia was very high in both hypertriglyceridemic groups (51.7% and 20.1% in FCH and 62.9% and 16.1% in FHTG, respectively), without significant statistical differences between them. Serum ferritin concentration did not show any significant association with the number of metabolic syndrome criteria. Subjects in the highest tertile of ferritin concentration (ferritin >200 μg/L) presented higher concentrations of triglycerides and liver enzymes than subjects in the first tertile of ferritin concentration (ferritin <90 μg/L). The highest positive correlation coefficient for triglycerides was found with ferritin in FCH and in FHTG subjects (R = 0.317 [P < .001] when combined). Ferritin was also the covariate that showed the highest independent association with triglycerides in FCH and FHTG. In contrast, ferritin was not associated with carotid intima-media thickness. In summary, serum ferritin is commonly increased in FCH and in FHTG, it is not related with the presence of metabolic syndrome, and it is highly correlated with liver enzymes.

Increased left ventricular arrhythmogenicity in metabolic syndrome and relationship with myocardial performance, risk factors for atherosclerosis, and low-grade inflammation

2009-09-22

Abstract: Metabolic syndrome (MetS) is a clustering of cardiovascular risk factors recently associated with left ventricular dysfunction. Limited data exist on the association between MetS and ventricular arrhythmogenicity. This study examined differences in ventricular arrhythmogenicity assessed by classic (QT interval) and newer (spatial QRS-T angle [spQRS-Ta]) electrocardiographic markers in subjects with and without MetS. A total of 306 subjects, 153 with and 153 without MetS, matched for sex and age were examined. The spQRS-Ta, which vectorcardiographically quantifies the deviation between the directions of ventricular depolarization and repolarization, was measured using a computer-based electrocardiograph. Left ventricular mass index and myocardial performance were evaluated echocardiographically. The spQRS-Ta was significantly higher in subjects with in comparison with those without MetS. Left ventricular mass index, QT interval, and its dispersion were not different between the 2 groups. Left ventricular myocardial performance was worse in subjects with MetS and was associated with higher values of the spQRS-Ta. Multivariate linear regression analysis demonstrated MetS status as the strongest predictor of ventricular arrhythmogenicity. Addition of the high-sensitivity C-reactive protein in the model increased the explained variance of the spQRS-Ta by 11%. In conclusion, ventricular arrhythmogenicity is present in MetS and is associated with myocardial dysfunction, risk factors for atherosclerosis, and low-grade inflammation. The independent association between the spQRS-Ta and MetS implies that the clustering of the metabolic disturbances has additional prognostic information than its individual components in terms of ventricular arrhythmogenicity and may explain in part the excess cardiovascular risk in subjects with MetS.

Sex hormone–binding globulin and lipid profile in pubertal children

2009-09-18

Abstract: Men and women have different lipid profiles throughout life, related to changes in sex hormones; and this has been associated with sex-related differences in the prevalence of coronary heart disease. The influence of sex hormone changes during puberty on the lipid profile has been reported, but levels of sex hormone–binding globulin (SHBG) (the specific plasma binding protein of sex hormones) have not been evaluated even though its regulatory role might be crucial. The aim of this study was to analyze the relationship between sex hormones and SHBG and changes in plasma lipid levels during puberty. Our population-based sample included 370 healthy schoolchildren (175 male and 195 female), ranging from 12 to 15 years old. High-density lipoprotein cholesterol (HDL-C) levels were significantly lower in 15-year–olds than in younger boys, and apolipoprotein (apo) A-I levels steeply decreased across the studied age groups. Parallel to these changes, testosterone levels increased whereas SHBG decreased as age increases in boys. In girls, no significant differences were observed in these variables among the age groups. Testosterone and SHBG were highly correlated with anthropometric variables. Sex hormone–binding globulin was negatively associated with triglycerides (TG) in both sexes, remaining statistically significant after further adjustment for age and body mass index (BMI) in girls. Sex hormone–binding globulin was the only predictive variable for HDL-C and TG in multiple linear regression analysis, after adjustment by BMI, in both sexes, accounting for 10% of the variance of HDL-C in boys and for around 5% of the variance of TG in both sexes. In boys, testosterone and SHBG remained significantly correlated to apo A-I levels, even after adjusting for age and BMI, and were the most important predictive variables for apo A-I in multiple linear regression analysis. In conclusion, SHBG levels are related to a decrease in HDL-C and apo A-I levels during puberty in boys and to a decrease in TG levels during puberty in both sexes.

Contribution of skeletal muscle mass on sex differences in 2-hour plasma glucose levels after oral glucose load in Thai subjects with normal glucose tolerance

Chatchalit Rattarasarn, Rattana Leelawattana, Supamai Soonthornpun — 2009-09-18

Abstract: Women have higher 2-hour plasma glucose levels after oral glucose challenge than men. The smaller skeletal muscle mass in women may contribute to the higher postload glucose levels. The objective of this study was to test the hypothesis that the different amount of skeletal muscle mass between men and women contributed to sex difference in postload plasma glucose levels in subjects with normal glucose tolerance. Forty-seven Thai subjects with normal glucose tolerance, 23 women and 24 age- and body mass index–matched men, were studied. Body fat, abdominal fat, and appendages lean mass were measured by dual-energy x-ray absorptiometry. Skeletal muscle insulin sensitivity was determined by euglycemic-hyperinsulinemic clamp. First-phase insulin secretion and hepatic insulin sensitivity were determined from oral glucose tolerance data. β-Cell function was estimated from the homeostasis model assessment of %B by the homeostasis model assessment 2 model. Correlation and linear regression analysis were performed to identify factors contributing to variances of postload 2-hour plasma glucose levels. This study showed that women had significantly higher 2-hour plasma glucose levels and smaller skeletal muscle mass than men. Measures of insulin secretion and insulin sensitivity were not different between men and women. Male sex (r = −0.360, P = .013) and appendages lean mass (r = −0.411, P = .004) were negatively correlated with 2-hour plasma glucose, whereas log 2-hour insulin (r = 0.571, P < .0001), total body fat (r = 0.348, P = .016), and log abdominal fat (r = 0.298, P = .042) were positively correlated with 2-hour plasma glucose. The correlation of 2-hour plasma glucose and sex disappeared after adjustment for appendages lean mass. By multivariate linear regression analysis, log 2-hour insulin (β = 18.9, P < .0001), log 30-minute insulin (β = −36.3, P = .001), appendages lean mass (β = −1.0 × 10−3, P = .018), and hepatic insulin sensitivity index (β = −17.3, P = .041) explained 54.2% of the variance of 2-hour plasma glucose. In conclusion, the higher postload 2-hour plasma glucose levels in women was not sex specific but was in part a result of the smaller skeletal muscle mass. The early insulin secretion, hepatic insulin sensitivity, and skeletal muscle mass were the significant factors negatively predicting 2-hour postload plasma glucose levels in Thai subjects with normal glucose tolerance.

Serum aminotransferase changes with significant weight loss: sex and age effects

2009-09-18

Abstract: In obese subjects, the liver may be differentially affected by significant weight loss depending on as yet unknown factors. We explored clinical factors associated with serum alanine aminotransferase (ALT) changes during significant weight loss in a residential weight loss program. Clinical data from 362 adults who received a comprehensive weight loss intervention (ie, diets, physical fitness, and behavioral modification) in the program were analyzed. Serum ALT was used as a surrogate marker of liver injury. The ALT changes during the program were calculated to create study outcome categories (improvement, no change, or deterioration of ALT during significant weight loss). Variables of demography, lifestyle, and comorbidities at baseline, and total/rate of weight change during the program were explored for associations with the ALT change categories using multiple logistic regression models. Variation by sex was apparent among predictors of ALT deterioration; men with rapid weight loss and women with higher initial body mass index were more likely to experience ALT deterioration, whereas men with prior alcohol consumption were less likely to experience ALT deterioration even after adjusting for baseline ALT (Ps < .03). Variation by age was apparent among predictors of ALT improvement; younger patients with current smoking and older patients with rapid weight loss, diabetes or impaired fasting glucose, or sleep apnea or who followed a reduced-carbohydrate diet were less likely to experience ALT improvement (Ps < .05). A number of clinical factors influence ALT changes during weight loss in sex- and age-specific manners. The patterns that we detected may have pathophysiologic significance beyond the practical implications of our findings in clinical practice related to underlying changes in fat metabolism.

Changes of peripheral α-melanocyte–stimulating hormone in childhood obesity

2009-09-22

Abstract: Relationships of blood circulating melanocortins to childhood obesity are not well established. We evaluated serum α-melanocyte–stimulating hormone (α-MSH) in lean children and different study groups of childhood obesity. We examined serum α-MSH in 52 otherwise healthy children with childhood obesity (Ob; mean age, 11 years; 32 girls/20 boys), 27 normal-weight children of same age, 7 additional obese patients with reduced melanocortin-4 receptor function (MC4Rmut), and 22 patients with craniopharyngioma (CP). Fasting serum α-MSH and leptin were measured by radioimmunoassay. Serum α-MSH was also evaluated 1 hour after 500-kcal liquid meal (CP and Ob) and at the end of 1-year lifestyle intervention in 24 Ob patients. The α-MSH levels were similar in obese vs lean children but significantly lower in CP (P< .001) and significantly higher (P < .05) in MC4Rmut patients compared with Ob. One hour after liquid meal, α-MSH increased in patients with Ob but not with CP. After 1 year, α-MSH levels increased significantly in the successful weight reduction Ob subgroup despite unchanged cortisol levels. The α-MSH changes correlated to weight status changes (r = 0.67, P = .0003) but not to changes of cortisol, insulin, or homeostasis model assessment of insulin resistance index. Persistently low α-MSH levels in CP patients are suspected to be due to pituitary or hypothalamic damage. High peripheral levels in MC4Rmut carriers indicate up-regulation of α-MSH. Changes of weight status are associated with changes of peripheral α-MSH.

Circulating adiponectin concentrations were related to free thyroxine levels in thyroid cancer patients after thyroid hormone withdrawal

Shih-Yi Lin, Shu-Chuan Huang, Wayne Huey-Herng Sheu — 2009-09-18

Abstract: Because it is unclear whether adipose-derived hormones are related to thyroid hormone metabolism, this study evaluated the relationship between adiponectin concentrations and changes in the thyroid hormones in athyreotic patients after thyroid hormone withdrawal. Twenty-eight athyreotic thyroid cancer patients (4 male and 24 female; mean age, 52.2 ± 11.3 years) were analyzed on the final day of levothyroxine treatment and 1 day before serum thyroglobulin and radioiodine scanning examinations after an average of 4 weeks of thyroid hormone withdrawal. Evaluations included analysis of thyroid function test, serum adiponectin, body composition by bioimpedance analysis, and insulin sensitivity index as determined by the homeostasis model assessment of insulin resistance (HOMA-IR). Discontinuation of thyroid hormone treatment resulted in a significant change in thyroid-stimulating hormone (82.1 ± 9.8 vs 1.0 ± 0.4 mL/L, P < .05), free thyroxine (FT4) (5.7 ± 0.4 vs 18.7 ± 2.3 pmol/L, P < .05), and free triiodothyronine levels (1.8 ± 0.2 vs 3.4 ± 0.2 pmol/L, P < .05) as compared with the prewithdrawal values, whereas circulating adiponectin levels (5.7 ± 0.6 vs 5.4 ± 0.6 mg/L), body fat mass (20.3 ± 1.2 vs 19.4 ± 1.2 kg), and insulin sensitivity index (1.8 ± 0.2 vs 2.2 ± 0.3) remained unaltered. A positive correlation between adiponectin and FT4 (r = 0.61, P < .01) independent of age, sex, fat body mass, HOMA-IR, and other potential covariates known to affect thyroid hormone metabolism, such as renal and liver functions, was observed after thyroid hormone withdrawal. In addition, baseline circulating adiponectin levels were correlated with a diminished postwithdrawal reduction of FT4 concentrations after adjusting for baseline FT4 levels and changes in body mass index, fat body mass, and HOMA-IR (r = 0.71, P < .01). In conclusion, adiponectin concentrations were associated with FT4 levels in the athyreotic patients after thyroid hormone withdrawal. The relevant roles of adiponectin in the regulation of thyroid hormone metabolism require further investigation.

Acute altitude-induced hypoxia suppresses plasma glucose and leptin in healthy humans

2009-09-18

Abstract: To examine the effects of acute altitude-induced hypoxia on the hormonal and metabolic response to ingested glucose, 8 young, healthy subjects (5 men and 3 women; age, 26 ± 2 years; body mass index, 23.1 ± 1.0 kg/m2) performed 2 randomized trials in a hypobaric chamber where a 75-g glucose solution was ingested under simulated altitude (ALT, 4300 m) or ambient (AMB, 362 m) conditions. Plasma glucose, insulin, C-peptide, epinephrine, leptin, and lactate concentrations were measured at baseline and 30, 60, 90, and 120 minutes after glucose ingestion during both trials. Compared with AMB, the plasma glucose response to glucose ingestion was reduced during the ALT trial (P = .04). There were no differences in the insulin and C-peptide responses between trials or in insulin sensitivity based on the homeostasis model assessment of insulin resistance. Epinephrine and lactate were both elevated during the ALT trial (P < .05), whereas the plasma leptin response was reduced compared with AMB (P < .05). The data suggest that the plasma glucose response is suppressed at ALT, but this is not due to insulin per se because insulin and C-peptide levels were similar for both trials. Elevated plasma epinephrine and lactate during ALT are indicative of increased glycogenolysis, which may have masked the magnitude of the reduced glucose response. We conclude that, during acute altitude exposure, there is a rapid metabolic response that is accompanied by a shift in the hormonal milieu that appears to favor increased glucose utilization.

Failure of d-psicose absorbed in the small intestine to metabolize into energy and its low large intestinal fermentability in humans

2009-09-18

Abstract: Experiments with rats have produced data on the metabolism and energy value of d-psicose; however, no such data have been obtained in humans. The authors assessed the availability of d-psicose absorbed in the small intestine by measuring carbohydrate energy expenditure (CEE) by indirect calorimetry. They measured the urinary excretion rate by quantifying d-psicose in urine for 48 hours. To examine d-psicose fermentation in the large intestine, the authors measured breath hydrogen gas and fermentability using 35 strains of intestinal bacteria. Six healthy subjects participated in the CEE test, and 14 participated in breath hydrogen gas and urine tests. d-Psicose fermentation subsequent to an 8-week adaptation period was also assessed by measuring hydrogen gas in 8 subjects. d-Psicose absorbed in the small intestine was not metabolized into energy, unlike glucose, because CEE did not increase within 3 hours of d-psicose ingestion (0.35 g/kg body weight [BW]). The accumulated d-psicose urinary excretion rates were around 70% for 0.34, 0.17, and 0.08 g/kg BW of ingested d-psicose. Low d-psicose fermentability was observed in intestinal bacteria and breath hydrogen gas tests, in which fructooligosaccharide (0.34, 0.17, and 0.08 g/kg BW) was used as a positive control because its available energy is known to be 8.4 kJ/g. Based on the results of the plot of breath hydrogen concentration vs calories ingested, the energy value of d-psicose was expected to be less than 1.6 kJ/g. Incremental d-psicose fermentability subsequent to an adaptation period was not observed.

The role of proliferator-activated receptor γ coactivator–1α in the fatty-acid–dependent transcriptional control of interleukin-10 in hepatic cells of rodents

2009-09-22

Abstract: Interleukin-10 (IL-10) is an endogenous factor that restrains hepatic insulin resistance in diet-induced steatosis. Reducing IL-10 expression increases proinflammatory activity in the steatotic liver and worsens insulin resistance. As the transcriptional coactivator proliferator-activated receptor γ coactivator–1α (PGC-1α) plays a central role in dysfunctional hepatocytic activity in diet-induced steatosis, we hypothesized that at least part of the action of PGC-1α could be mediated by reducing the transcription of the IL-10 gene. Here, we used immunoblotting, real-time polymerase chain reaction, immunocytochemistry, and chromatin immunoprecipitation assay to investigate the role of PGC-1α in the control of IL-10 expression in hepatic cells. First, we show that, in the intact steatotic liver, the expressions of IL-10 and PGC-1α are increased. Inhibiting PGC-1α expression by antisense oligonucleotide increases IL-10 expression and reduces the steatotic phenotype. In cultured hepatocytes, the treatment with saturated and unsaturated fatty acids increased IL-10 expression. This was accompanied by increased association of PGC-1α with c-Maf and p50–nuclear factor (NF) κB, 2 transcription factors known to modulate IL-10 expression. In addition, after fatty acid treatment, PGC-1α, c-Maf, and p50-NFκB migrate from the cytosol to the nuclei of hepatocytes and bind to the IL-10 promoter region. Inhibiting NFκB activation with salicylate reduces IL-10 expression and the association of PGC-1α with p50-NFκB. Thus, PGC-1α emerges as a potential transcriptional regulator of the inflammatory phenomenon taking place in the steatotic liver.

Acute exposure to rosiglitazone does not affect glucose transport in intact human skeletal muscle

Paulina Skrobuk, Heidi Kuoppamaa, Anne Hiukka, Heikki A. Koistinen — 2009-09-18

Abstract: Thiazolidinediones (TZDs) such as rosiglitazone are widely used as antidiabetic drugs. Animal studies suggest that TZDs may have direct metabolic actions in skeletal muscle. Here, we examined if acute exposure to rosiglitazone stimulates glucose transport rate and affects proximal insulin signaling in isolated skeletal muscle strips from nondiabetic men. Open muscle biopsies were obtained from musculus vastus lateralis from 15 nondiabetic men (50 ± 3 years old, 26.9 ± 1.1 kg/m2). Skeletal muscle strips were isolated and exposed to rosiglitazone (1 or 10 μmol/L), 5-aminoimidazole-4-carboxamide 1-β-d-ribonucleoside (1 mmol/L), insulin (120 nmol/L), or a combination of insulin (120 nmol/L) and rosiglitazone (10 μmol/L) in vitro for 1 hour. Glucose transport was analyzed by accumulation of intracellular 3-O-methyl [3H] glucose; phosphorylation of Akt-Ser473 and Akt-Thr308 and phosphorylation of acetyl coenzyme A carboxylase β were determined using phosphospecific antibodies. 5-Aminoimidazole-4-carboxamide 1-β-d-ribonucleoside and insulin increased glucose transport rate 1.5-fold (P < .05) and 1.7-fold (P < .01) in isolated muscle strips, respectively. Exposure to rosiglitazone transiently increased phosphorylation of acetyl coenzyme A carboxylase β, with a maximum effect at 15 minutes and return to baseline at 60 minutes. However, rosiglitazone did not affect basal or insulin-stimulated glucose transport rate, or phosphorylation of Akt-Ser473 or Akt-Thr308 in isolated muscle strips. In conclusion, acute exposure to rosiglitazone does not affect glucose transport in human skeletal muscle.

Postprandial effects of a lipid-rich meal in the rat are modulated by the degree of unsaturation of 18C fatty acids

Patrick Even, François Mariotti, Dominique Hermier — 2009-09-24

Abstract: The fatty acid composition of high-fat diets is known to influence the magnitude of postprandial events that increase the risk of metabolic syndrome. These variations in magnitude may be directly ascribed to differences in the channeling of lipids toward oxidation or storage. A study was designed to compare the effects of 4 dietary fats on postprandial energy expenditure and on some risk factors of the metabolic syndrome. To avoid usual confounding factors due to simultaneous variations in chain length and double-bounds number of fatty acids, dietary fats were chosen to provide mainly 18-carbon fatty acids with 0 (stearic acid [SA]), 1 (oleic acid [OA]), 2 (linoleic acid [LA]), or 3 (α-linolenic acid [ALA]) double bounds. They were given as single high-fat test meals to 4 different groups of male rats. The resting metabolic rate and the lipid and carbohydrate oxidation were measured from oxygen consumption and carbon dioxide production using indirect calorimetry 2 hours before and 6.5 hours after the test meal. Plasma glucose, triglyceride, and chylomicron concentrations were determined at 0, 1.5, and 4 hours after the test meal. Postprandial concentration of glucose and triglyceride did not vary with the nature of the test meals, whereas that of chylomicrons was the highest after the LA test meal and the lowest after the SA test meal. Postprandial increase in resting metabolic rate was the highest after the LA and OA test meals, and the lowest after the SA and ALA test meals. Compared with the 3 other diets, the ALA test meal enhanced lipid oxidation and decreased glucose oxidation during the early postprandial period (0.25-3.25 hours). This suggests that stearic acid may not induce all the adverse effects classically described for other saturated fatty acids and that α-linolenic acid may beneficially influence energy partitioning, especially during the early postprandial state.

Insulin resistance and inflammation may have an additional role in the link between cystatin C and cardiovascular disease in type 2 diabetes mellitus patients

2009-09-18

Abstract: Recent studies suggest that serum cystatin C level is not only a sensitive marker for renal dysfunction but also a predictive marker for cardiovascular disease (CVD). However, the mechanism of this connection is not fully understood. We aimed to determine whether insulin resistance or various biomarkers of cardiovascular risk have a role in the link between cystatin C and CVD in type 2 diabetes mellitus patients. Anthropometric measurements and biochemical studies including inflammatory biomarkers were performed in 478 patients with type 2 diabetes mellitus. The degree of insulin resistance was assessed by homeostasis model assessment (HOMA-IR) and indicators of metabolic syndrome. Estimated glomerular filtration rate (eGFR) was derived from the Modification of Diet in Renal Disease study equation. After adjusting for age, sex, body mass index, and eGFR, the cystatin C level increased significantly in proportion to the number of metabolic syndrome components present (1.08 ± 0.06, 1.19 ± 0.04, 1.20 ± 0.04, 1.23 ± 0.04, and 1.37 ± 0.06 mg/L; P < .0001); and HOMA-IR increased significantly in proportion to cystatin C quartiles (1.16 ± 0.15, 1.40 ± 0.13, 1.49 ± 0.13, and 2.00 ± 0.17; P < .0001) (means ± SE). Albumin-creatinine ratio, fibrinogen, uric acid, homocysteine, high-sensitivity C-reactive protein, and lipoprotein(a) all showed significant correlations with cystatin C that were generally higher than those with eGFR. Cystatin C level was independently associated with HOMA-IR (β = 0.0380, P = .0082), albumin-creatinine ratio (β = 0.0004, P < .0001), uric acid (β = 0.0666, P < .0001), and homocysteine (β = 0.0087, P = .0004). In conclusion, cystatin C level was significantly associated with insulin resistance and biomarkers reflecting inflammation independent of renal function. These components may have a role in addition to that of eGFR in explaining the link between cystatin C and CVD in type 2 diabetes mellitus patients.

Superoxide production by mitochondria of insulin-sensitive tissues: mechanistic differences and effect of early diabetes

Judy A. Herlein, Brian D. Fink, William I. Sivitz — 2009-09-18

Abstract: Obesity and mild hyperglycemia are characteristic of early or “prediabetes.” The associated increase in fatty acid flux is posited to enhance substrate delivery to mitochondria, leading to enhanced superoxide production that results in mitochondrial dysfunction and progressive worsening of the hyperglycemic state. We quantified superoxide production by gastrocnemius muscle, heart, and liver mitochondria in a rodent model that mimics the pathophysiology of prediabetes by administering low-dose streptozotocin to rats fed high fat (HF). Superoxide was rigorously determined indirectly as H2O2 largely released from the matrix and by electron paramagnetic resonance spectroscopy that directly detects superoxide released externally. Both HF and low-dose streptozotocin mildly increased glycemia (P < .05 by 2-way analysis of variance). Matrix and external superoxide production by gastrocnemius mitochondria respiring on the complex II substrate succinate and matrix superoxide production by liver mitochondria respiring on the complex I substrates glutamate plus malate were significantly reduced by HF feeding but not affected by mild hyperglycemia. Superoxide production was not significantly altered by either treatment in heart mitochondria fueled by either complex I or II substrates. The functional status of the mitochondria was assayed as simultaneous respiration and membrane potential that were not affected by HF or mild hyperglycemia. Comparison of substrate and inhibitor effects on superoxide release implied marked differences in the redox mechanisms regulating mitochondrial superoxide production from liver mitochondria compared with muscle and heart. In summary, superoxide production from mitochondria of different insulin-sensitive tissues differs mechanistically. However, in any case, excess superoxide production as an intrinsic property of mitochondria of insulin-sensitive tissues does not result from conditions mimicking the pathophysiology of pre- or early diabetes.

Glutamate permeability at the blood-brain barrier in insulinopenic and insulin-resistant rats

2009-09-30

Abstract: The influence of diabetes on brain glutamate (GLU) uptake was studied in insulinopenic (streptozotocin [STZ]) and insulin-resistant (diet-induced obesity [DIO]) rat models of diabetes. In the STZ study, adult male Sprague-Dawley rats were treated with STZ (65 mg/kg intravenously) or vehicle and studied 3 weeks later. The STZ rats had elevated plasma levels of glucose, ketone bodies, and branched-chain amino acids; brain uptake of GLU was very low in both STZ and control rats, examined under conditions of normal and greatly elevated (by intravenous infusion) plasma GLU concentrations. In the DIO study, rats ingested a palatable, high-energy diet for 2 weeks and were then divided into weight tertiles: rats in the heaviest tertile were designated DIO; rats in the lightest tertile, diet-resistant (DR); and rats in the intermediate tertile, controls. The DIO and DR rats continued to consume the high-energy diet for 4 more weeks, whereas the control rats were switched to standard rat chow. All rats were studied at 6 weeks (subgroups were examined under conditions of normal or elevated plasma GLU concentrations). The DIO rats ate more food and were heavier than the DR or control rats and had higher plasma leptin levels and insulin-glucose ratios. In all diet groups, the blood-brain barrier showed very low GLU penetration and was unaffected by plasma GLU concentration. Brain GLU uptake also did not differ among the diet groups. Together, the results indicate that the blood-brain barrier remains intact to the penetration of GLU in 2 models of diabetes under the conditions examined.

Lipid oxidation in overweight men after exercise and food intake

2009-10-01

Abstract: Fat oxidation (FO) is optimized during low- to moderate-intensity exercise in lean and obese subjects, whereas high-intensity exercise induces preferential FO during the recovery period. After food intake during the postexercise period, it is unknown if FO differs according to the intensity exercise in overweight subjects. Fat oxidation was thus evaluated in overweight men after low- and high-intensity exercise during the recovery period before and after food intake as well as during a control session. Ten healthy, sedentary, overweight men (age, 27.9 ± 5.6 years; body mass index, 27.8 ± 1.3 kg m−2; maximal oxygen consumption, 37 ± 3.9 mL min−1 kg−1) exercised on a cycloergometer (energy expenditure = 300 kcal) at 35% (E35) or 70% (E70) maximal oxygen consumption or rested (Cont). The subjects were fed 30 minutes after the exercise with 300 kcal (1256 kJ) more energy in the exercise sessions than in the Cont session. Respiratory quotient and FO were calculated by indirect calorimetry. Blood samples were analyzed to measure plasma glycerol, nonesterified fatty acid, glucose, and insulin. During exercise, mean respiratory quotient was lower (P < .05) and FO was higher (P < .01) in the E35 than in the E70 session (FO [in mg min−1]: E35 = 290 ± 12, E70 = 256 ± 38, and Cont = 131 ± 7). Conversely, FO was higher in the E70 than in both the E35 session and the Cont session during the immediate recovery as well as during the postprandial recovery period (P = .005 for all; FO from the end of the exercise to the end of the session [in grams]: E70 = 45.7 ± 8.9, E35 = 38.2 ± 6.8, and Cont = 36.0 ± 4.3). Blood parameters did not differ between the 3 sessions but changed according to the absorption of the nutrients. In overweight subjects, high-intensity exercise increased FO during the postexercise period even after food intake compared with the low-intensity exercise and the control session.

Novel CYP17A1 mutation in a Japanese patient with combined 17α-hydroxylase/17,20-lyase deficiency

Noriyuki Katsumata, Eishin Ogawa, Ikuma Fujiwara, Kaori Fujikura — 2009-09-30

Abstract: Combined 17α-hydroxylase/17,20-lyase deficiency is caused by a defect of P450c17 that catalyzes both 17α-hydroxylase and 17,20-lyase reactions in adrenal glands and gonads. In the present study, we analyzed the CYP17A1 gene in a Japanese girl with 17α-hydroxylase/17,20-lyase deficiency. The patient was referred to us for clitoromegaly at the age of 3 years. The karyotype was 46,XY. The patient was diagnosed as having 17α-hydroxylase/17,20-lyase deficiency based on the clinical and laboratory findings. Analysis of the CYP17A1 gene revealed a compound heterozygous mutation. One mutation was a deletion of codon 53 or 54 encoding Phe (TTC) in exon 1 (ΔF54) on a maternal allele, which has been previously shown to partially abolish both 17α-hydroxylase and 17,20-lyase activities. The other was a novel missense mutation resulting in a substitution of Asn (AAC) for His (CAC) at codon 373 in exon 6 (H373N) on a paternal allele. Functional expression study demonstrated that the H373N mutation almost completely eliminates enzymatic activity. Previous studies have demonstrated that replacement of histidine by leucine at position 373 causes complete loss of both 17α-hydroxylase and 17,20-lyase activities with a defect in heme binding due to a global alteration of P450c17 structure, indicating the importance of H373 for P450c17 structure and function. Together, these results indicate that the patient is a compound heterozygote for the ΔF54 and H383N mutations and that these mutations inactivate both 17α-hydroxylase and 17,20-lyase activities and give rise to clinically manifest combined 17α-hydroxylase/17,20-lyase deficiency.

Insulin resistance is associated with increased renal resistive index independent of other factors in newly diagnosed type 2 diabetes mellitus and hypertensive patients

Baris Afsar, Rengin Elsurer, Siren Sezer, Fatma Nurhan Ozdemir — 2009-09-30

Abstract: Renal resistive index (RRI) is increased in subjects with diabetes. We analyzed whether insulin resistance is independently related with RRI. Medical history, physical examination, laboratory analysis, Doppler ultrasonography, and 24-hour urinary albumin excretion were analyzed. The threshold for an increased RRI was at least 0.70, which has been previously shown to be discriminatory of increased RRI level. Eighty newly diagnosed essential hypertensive and type 2 diabetes mellitus patients were included. Sixty-one patients had low RRI (<0.70). When compared with low-RRI patients, those with high RRI were older and had higher pulse pressure, serum creatinine, and homeostasis model assessment (HOMA) index. The HOMA index and RRI were positively correlated (r = +0.371, P = .001). In multivariate logistic regression analysis, age (odds ratio [OR] = 1.164, 95% confidence interval [CI] = 1.040-1.303, P = .008), pulse pressure (OR = 1.188, 95% CI = 1.020-1.384, P = .027), and HOMA index (OR = 1.422, 95% CI = 1.085-1.862, P = .011) were independently associated with high RRI. Increased insulin resistance is independently related with increased RRI.

Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression

2009-10-05

Abstract: Our previous work demonstrated that berberine (BBR) increases insulin receptor (InsR) expression and improves glucose utility both in vitro and in animal models. Here, we study the InsR–up-regulating and glucose-lowering activities of BBR in humans. Our results showed that BBR increased InsR messenger RNA and protein expression in a variety of human cell lines, including CEM, HCT-116, SW1990, HT1080, 293T, and hepatitis B virus–transfected human liver cells. Accordingly, insulin-stimulated phosphorylations of InsR β-subunit and Akt were increased after BBR treatment in cultured cells. In the clinical study, BBR significantly lowered fasting blood glucose (FBG), hemoglobin A1c, triglyceride, and insulin levels in patients with type 2 diabetes mellitus (T2DM). The FBG- and hemoglobin A1c–lowering efficacies of BBR were similar to those of metformin and rosiglitazone. In the BBR-treated patients, the percentages of peripheral blood lymphocytes that express InsR were significantly elevated after therapy. Berberine also lowered FBG effectively in chronic hepatitis B and hepatitis C patients with T2DM or impaired fasting glucose. Liver function was improved greatly in these patients by showing reduction of liver enzymes. Our results confirmed the activity of BBR on InsR in humans and its relationship with the glucose-lowering effect. Together with our previous report, we strongly suggest BBR as an ideal medicine for T2DM with a mechanism different from metformin and rosiglitazone.

Increased oxidative stress levels and normal antioxidant enzyme activity in circulating mononuclear cells from patients of familial hypercholesterolemia

2009-10-05

Abstract: Familial hypercholesterolemia (FH) is a clinical condition with high risk for developing atherosclerosis. Increased oxidative stress (OS) and FH have been related to atherosclerosis, but no data are available on levels of OS and antioxidant enzyme activity in circulating mononuclear cells (CMCs) from FH patients. Circulating mononuclear cells are important mediators in atherosclerosis development, and chronically increased blood OS present in FH can induce modification in CMC activity. The objective of the study was to analyze the OS levels in CMCs from FH patients and controls. We have selected 30 nonrelated FH index patients and 30 normoglycemic and normocholesterolemic controls matched by age, sex, body mass index, abdominal circumference, and homeostasis model assessment index. Production of free radicals was analyzed by measurement of xanthine oxidase activity in plasma, reduced and oxidized glutathione (GSH and GSSG, respectively), and malonyldialdehyde in levels CMCs. Antioxidant status was analyzed by measuring antioxidant enzyme activity as superoxide dismutase, catalase, and glutathione peroxidase. We have found that FH patients showed significantly higher xanthine oxidase and malonyldialdehyde enzyme activities, as well as increased GSSG and lower GSH values resulting in a higher GSSG/GSH ratio. These data indicate a higher free radical production in plasma and increased OS levels in CMCs from patients than from controls. No significant differences were found in superoxide dismutase, catalase, and glutathione peroxidase activities between both groups. These data show an important alteration of OS regulation in FH and the absence of antioxidant response in CMCs mediated by some of the major antioxidant enzymes.

Should triglycerides and the triglycerides to high-density lipoprotein cholesterol ratio be used as surrogates for insulin resistance?

2009-10-01

Abstract: The aims of the present study were to examine whether triglycerides (TG) and the triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) could predict insulin resistance in healthy African Americans and whites. This cross-sectional study included 99 African American and 50 white men and women between 18 and 45 years of age with body mass indexes between 18.5 and 38.0 kg/m2. Anthropometric measures were obtained; and overnight fasting blood was collected for TG, HDL-C, glucose, and insulin. Insulin resistance was defined by fasting insulin concentration of at least 13.13 μU/mL and homeostasis model assessment of insulin resistance (HOMA-IR) of at least 2.5. Receiver operating characteristic curves were used to analyze the data. African Americans and whites had comparable demographic and anthropometric measures. Fasting insulin was higher in African Americans (12.4 ± 7.8 μU/mL) than whites (10.2 ± 7.5 μU/mL), but HOMA-IR did not differ significantly (African Americans, 2.9 ± 2.0; whites, 2.4 ± 1.9). Triglycerides and TG/HDL-C were significantly lower in African Americans (TG, 68.2 ± 43.3 mg/dL; TG/HDL-C, 1.8 ± 2.1) compared with whites (TG, 105.4 ± 55.2 mg/dL; TG/HDL-C, 2.8 ± 1.8). Area under the receiver operating characteristic curves revealed that both TG and TG/HDL-C were acceptable markers of insulin resistance, as defined by fasting insulin concentration, in whites, 0.770 and 0.765, respectively, but poor predictors in African Americans, 0.633 and 0.651, respectively. Similarly, TG and TG/HDL-C were acceptable in predicting insulin resistance, as measured by HOMA-IR, in whites, 0.763 and 0.770, respectively, but poor in predicting HOMA-IR in African Americans, with areas of 0.625 and 0.639, respectively. In conclusion, the relationship between TG and TG/HDL-C with insulin resistance differs by ethnicity; and using TG and TG/HDL-C to predict insulin resistance in African Americans would not be appropriate.

2010-02-01

Editorial Board

2010-02-01

Notes to Contributors

2010-02-01

Metabolism - Clinical and Experimental

Masthead

Modification of the acceptance policy for manuscripts

Serum ferritin is a major determinant of lipid phenotype in familial combined hyperlipidemia and familial hypertriglyceridemia

Increased left ventricular arrhythmogenicity in metabolic syndrome and relationship with myocardial performance, risk factors for atherosclerosis, and low-grade inflammation

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Contribution of skeletal muscle mass on sex differences in 2-hour plasma glucose levels after oral glucose load in Thai subjects with normal glucose tolerance

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Acute exposure to rosiglitazone does not affect glucose transport in intact human skeletal muscle

Postprandial effects of a lipid-rich meal in the rat are modulated by the degree of unsaturation of 18C fatty acids

Insulin resistance and inflammation may have an additional role in the link between cystatin C and cardiovascular disease in type 2 diabetes mellitus patients

Superoxide production by mitochondria of insulin-sensitive tissues: mechanistic differences and effect of early diabetes

Glutamate permeability at the blood-brain barrier in insulinopenic and insulin-resistant rats

Lipid oxidation in overweight men after exercise and food intake

Novel CYP17A1 mutation in a Japanese patient with combined 17α-hydroxylase/17,20-lyase deficiency

Insulin resistance is associated with increased renal resistive index independent of other factors in newly diagnosed type 2 diabetes mellitus and hypertensive patients

Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression

Increased oxidative stress levels and normal antioxidant enzyme activity in circulating mononuclear cells from patients of familial hypercholesterolemia

Should triglycerides and the triglycerides to high-density lipoprotein cholesterol ratio be used as surrogates for insulin resistance?

Table of contents

Editorial Board

Notes to Contributors