Metabolism - Clinical and Experimental - Articles in Press

Effect of niacin on preβ-1 high-density lipoprotein levels in diabetes - Corrected Proof

2010-03-19

Abstract: Preβ-1 high-density lipoprotein (HDL) is an acceptor of peripheral free cholesterol and thus a participant in reverse cholesterol transport. Because patients with diabetes may have defects in reverse cholesterol transport, we hypothesized that (1) preβ-1 HDL might be decreased in diabetes and (2) because niacin improves reverse cholesterol transport and may stimulate preβ-1 HDL maturation, niacin would further decrease steady-state levels of preβ-1 HDL in diabetes. Absolute levels of preβ-1 HDL mass were measured using an isotopic dilution-ultrafiltration assay that measures apolipoprotein (apo) A-I after physically isolating preβ-1. Plasma apo A-I concentration and routine lipids were also evaluated in 11 diabetic patients. Diabetic subjects have a nearly 50% reduction of circulating levels of preβ-1 HDL to 36 ± 22 (1 SD) μg/mL compared with our previously published values of 73 ± 44 μg/mL in 136 healthy subjects. After niacin therapy, there was a further 17% reduction of preβ-1 HDL levels to 30 ± 26 μg/mL (P < .026) compared with baseline. The percentage of preβ-1 HDL in diabetic patients, as a percentage of total apo A-I, was about half of the normal value of 6.1% ± 3.6%; after niacin in diabetic patients, the percentage further decreased from 3.3% ± 2.1% to 2.3% ± 1.9% (P < .003). Absolute levels of apo A-I were similar in diabetic patients (1.14 ± 0.29) and healthy subjects (1.24 ± 0.24), and were unchanged by niacin in diabetic patients. We conclude with the novel observations that diabetes is associated with significantly reduced levels of preβ-1 HDL and that, after niacin treatment, a further lowering of preβ-1 HDL levels occur. Several altered mechanisms of RCT in diabetes are consistent with low levels of preβ-1 HDL both before and after niacin treatment.

Dietary glycemic index, glycemic load, and intake of carbohydrate and rice in relation to risk of mortality from stroke and its subtypes in Japanese men and women - Corrected Proof

2010-03-19

Abstract: We assessed the relationship of the dietary glycemic index (GI), glycemic load (GL), and intake of carbohydrate and rice, and risk of mortality from stroke and its subtypes. The cohort consisted of 12 561 men and 15 301 women residing in Takayama, Japan, in 1992. At the baseline, a food frequency questionnaire was administered; and the dietary GI, GL, and intake of carbohydrates and rice were estimated. Deaths from stroke occurring in the cohort were prospectively noted until 1999 with data from the office of the National Vital Statistics. The risk of mortality from stroke was assessed with a Cox proportional hazard model after adjusting for age; body mass index; smoking status; physical activity; history of hypertension; education; and intake of total energy, alcohol, dietary fiber, salt, and total fat. The risk of stroke subtypes was assessed in the age-adjusted model. The hazard ratios of total stroke comparing the highest vs the lowest quartiles of the dietary GI were 0.78 (95% confidence interval [CI], 0.41-1.47) with Ptrend = .50 in men and 2.09 (95% CI, 1.01-4.31) with Ptrend = .10 in women. Among women, the association was also significant with the risk of ischemic stroke (hazard ratio = 2.45; 95% CI, 1.01-5.92; Ptrend = .03); and a significant positive trend was also observed between dietary GL and mortality from hemorrhagic stroke (Ptrend = .05). The current study implies that diets with a high dietary GI increase the risk of mortality from stroke among Japanese women.

Insulin resistance and lower plasma adiponectin increase malignancy risk in nondiabetic continuous ambulatory peritoneal dialysis patients - Corrected Proof

2010-03-19

Abstract: End-stage renal disease patients have a higher risk for developing cancer. Although several causes for this increased risk have been proposed, the risk factors for cancer development in this population have not been elucidated. The aim of this study was to determine whether metabolic derangements, including insulin resistance and altered adipokines, increase the risk of developing malignancies in peritoneal dialysis (PD) patients, who are vulnerable to metabolic disorders because of excessive glucose absorbed from the dialysate. Study subjects comprised 106 nondiabetic PD patients who had been on PD for a minimum of 3 months with no overt malignancy. Baseline anthropometry, fasting glucose, insulin, and adiponectin were measured. The development of malignancy was evaluated during the follow-up period. During the mean follow-up of 47.0 ± 23.7 months, malignancy occurred in 15 patients (14.2%). The most common site of cancer was the kidney (26.7%), followed by thyroid (13.3%) and stomach (13.3%). Baseline insulin levels and homeostasis model assessment of insulin resistance were significantly higher, whereas plasma adiponectin levels were significantly lower, in patients who developed malignancy. Cox proportional hazards analysis revealed that insulin levels, homeostasis model assessment of insulin resistance, and lower adiponectin were independent predictors of malignancy. These findings demonstrate that insulin resistance and lower adiponectin levels could be risk factors for malignancy in nondiabetic PD patients.

The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression - Corrected Proof

2010-03-19

Abstract: Metformin demonstrates anorectic effects in vivo and inhibits neuropeptide Y expression in cultured hypothalamic neurons. Here we investigated the mechanisms implicated in the modulation of feeding by metformin in animals rendered obese by long-term high-fat diet (diet-induced obesity [DIO]) and in animals resistant to obesity (diet resistant [DR]). Male Long-Evans rats were kept on normal chow feeding (controls) or on high-fat diet (DIO, DR) for 6 months. Afterward, rats were treated 14 days with metformin (75 mg/kg) or isotonic sodium chloride solution and killed. Energy efficiency, metabolic parameters, and gene expression were analyzed at the end of the high-fat diet period and after 14 days of metformin treatment. At the end of the high-fat diet period, despite higher leptin levels, DIO rats had higher levels of hypothalamic neuropeptide Y expression than DR or control rats, suggesting a central leptin resistance. In DIO but also in DR rats, metformin treatment induced significant reductions of food intake accompanied by decreases in body weight. Interestingly, the weight loss achieved by metformin was correlated with pretreatment plasma leptin levels. This effect was paralleled by a stimulation of the expression of the leptin receptor gene (ObRb) in the arcuate nucleus. These data identify the hypothalamic ObRb as a gene modulated after metformin treatment and suggest that the anorectic effects of the drug are potentially mediated via an increase in the central sensitivity to leptin. Thus, they provide a rationale for novel therapeutic approaches associating leptin and metformin in the treatment of obesity.

Contribution of APOA5−1131C allele to the increased susceptibility of diabetes mellitus in association with higher triglyceride in Korean women - Corrected Proof

Ki Ho Lee, Oh Yoen Kim, Hyo Hee Lim, Young Jin Lee, Yangsoo Jang, Jong Ho Lee — 2010-03-19

Abstract: Apolipoprotein A5 (APOA5) −1131C allele is associated with higher triglyceride, an independent cardiovascular risk factor and a commonly recognized lipid abnormality in diabetes mellitus (DM). We investigated the association of APOA5 −1131T>C or S19W with DM. Study subjects were all women and categorized into metabolically healthy controls (n = 2033) and DM subjects (n = 304). Association of APOA5 −1131T>C with DM was calculated by odds ratio (OR). Anthropometric parameters, fasting glucose, and lipid profiles were measured. C carriers, particularly those with CC homozygote, had higher triglyceride and lower high-density lipoprotein cholesterol in both healthy controls (P < .001 and P < .001) and DM patients (P = .002 and P = .006) after the adjustment for age, body mass index, menopause, smoking, and drinking. APOA5 −1131C allele was associated with an increased risk of DM (OR, 1.61 [95% confidence interval {CI}, 1.23-2.10]; P < .001) after adjustment for the above confounders. Further adjustment for fasting triglyceride or/and high-density lipoprotein cholesterol attenuated a little bit, but still significantly increased the risk of DM in C carriers (OR2, 1.36 [95% CI, 1.02-1.80]; P = .035 and OR3, 1.36 [95% CI, 1.032-1.79]; P = .029, respectively). Interestingly, C allele carriers in DM patients showed a positive correlation between fasting glucose and triglyceride after the adjustment (r = 0.172, P = .035). On the other hand, this significant correlation was not observed in healthy women. Regarding S19W, minor allele was not found in our study population from prescreening test. In conclusion, APOA5 −1131C allele may contribute to the increased susceptibility of DM in Korean women. In addition, positive correlation between fasting glucose and triglyceride in C carriers of DM patients suggested that C allele in hyperglycemic states may be more susceptible to the risk of cardiovascular disease.

Widespread effects of nicotinic acid on gene expression in insulin-sensitive tissues: implications for unwanted effects of nicotinic acid treatment - Corrected Proof

2010-03-19

Abstract: Nicotinic acid (NA; or niacin) has been used as a hypolipidemic agent for more than 4 decades. However, the mechanisms underlying the effects of NA treatment (wanted and unwanted) are still poorly understood. In the present study, we discovered that NA infusion in rats resulted in dephosphorylation (ie, activation) of the forkhead transcription factor FOXO1 in insulin-sensitive tissues such as skeletal and cardiac muscles, liver, and adipose tissue. These NA effects were opposite to the effects of insulin to increase FOXO1 phosphorylation. To test whether NA alters gene expression in these tissues, rats were infused for 7 hours with NA (30 μmol/h) and/or insulin (5 mU/[kg min]); and gene expression was evaluated using a microarray analysis. Nicotinic acid had widespread effects on gene expression in all of the tissues studied, and the number of genes affected by NA greatly exceeded that of genes affected by insulin. A systematic (or strategic) analysis of the microarray data revealed that there were numerous genes whose expression was regulated inversely by insulin and NA in correlation with FOXO1 phosphorylation, representing potential FOXO1 target genes. We also identified a group of genes whose expression was altered by NA exclusively in adipose tissue, presumably because of stimulation of the NA receptor in this tissue. Finally, there were genes whose expression was altered by both NA and insulin, likely via lowering plasma free fatty acid levels, including lipoprotein lipase and adenosine triphosphate–binding cassette A1, which play a major role in the regulation of circulating lipids. Thus, our data suggest that NA alters gene expression in insulin-sensitive tissues by various mechanisms. Some of the NA-induced changes in gene expression are discussed as potential mechanisms underlying wanted and unwanted effects of NA treatment.

Increased apolipoprotein E level and reduced high-density lipoprotein mean particle size associate with low high-density lipoprotein cholesterol and features of metabolic syndrome - Corrected Proof

2010-03-08

Abstract: The metabolic syndrome (MetS) pandemic predisposes patients to low high-density lipoprotein cholesterol (HDL-C). To successfully treat low HDL-C, there is an urgent need for a better understanding of the changes in HDL particles in the low–HDL-C state. Especially, apolipoprotein (apo) E metabolism in HDL particles is an emerging and important issue. Therefore, we determined HDL subspecies, apo E distribution, and the impact of the MetS in subjects with low and high HDL-C. We studied 246 subjects derived from the Finnish Health 2000 Health Examination Survey. The 2 groups included 113 low–HDL-C (≤10th percentile) and 133 high–HDL-C (≥90th percentile) subjects. The low–HDL-C subjects had higher apo E concentration (39.4 ± 19.4 vs 25.6 ± 8.0 μg/mL, P < .001) and smaller HDL mean particle size (9.0 ± 0.2 vs 9.8 ± 0.3 nm, P < .001). The distribution of apo E genetic isoforms could not explain the difference. Apolipoprotein E content of very low-density lipoprotein particles was comparable between the study groups. In the low–HDL-C subjects, apo E level in large HDL particles was lower (P < .001) compared with that in the high–HDL-C subjects. The subjects with MetS had smaller HDL mean particle size and higher serum apo E concentration. Serum apo E concentration associated positively with different MetS markers (waist circumference, triglycerides, and glucose), whereas HDL mean particle size associated with those negatively. Our results highlight that, in the low–HDL-C state, there are changes in the size and composition of HDL particles associating with MetS. Apolipoprotein E, although generally considered antiatherogenic, associates with MetS and low HDL-C. Our results emphasize the need for a better understanding of apo E metabolism in HDL particles.

What have trials of pulsatile intravenous insulin taught us? - Corrected Proof

Larry A. Weinrauch, Ray E. Gleason, John A. D’Elia — 2010-03-08

Dr Leinung expresses concern about a multicenter publication published a decade ago . Recruitment began in 1992, at which time the Diabetes Control and Complications Trial and captopril studies had established that the preferred approach to therapy was multiple insulin injections plus angiotensin-converting enzyme (ACE) inhibitors. Baseline blood pressure and glycohemoglobin A1c in this randomized study were not significantly different between study groups. Control vs pulsatile insulin infusion patients who were not treated with ACE inhibitors (9 of 34 controls, 17 of 37 infusions) had nearly identical slopes of creatinine clearance decline at −5.3 vs −5.2 mL/(min y) (P = .98) at 52 weeks and at −5.9 vs −5.5 mL/(min y) (P = .91) at 78 weeks. Control vs infusion patients treated with ACE inhibitors had slopes of −7.1 vs −0.96 at 52 weeks (P = .11) and −8.86 vs −0.60 at 78 weeks (P = .016). Thus, the infusion group with a lower percentage treated with ACE inhibition still had statistically significantly slower declines in creatinine clearance due to very different results in those treated with ACE inhibitors. As shown in the figure in that publication, there was no difference in the slope of the decline for patients in the original 52-week protocol vs those who elected to stay on for an additional 26 weeks. Dr Leinung refers to this as “dropout.” We see this as electing not to continue after having completed one's agreed commitment.

Comments on a pilot study to test the effect of pulsatile insulin infusion on type 1 diabetes mellitus patients with proteinuria - Corrected Proof

Matthew C. Leinung — 2010-03-08

Outpatient intravenous insulin infusion (OVIT) given weekly in a pulsatile fashion added to a regimen of subcutaneous multiple daily insulin (MDI) injections has been touted by a select number of authors as superior to MDI alone for the treatment of type 1 diabetes mellitus. Weinrauch and colleagues have published apparently supportive data in this journal, and I wish to take exception to one publication in particular.

Relation of metabolic syndrome components to left ventricular mass in Mexican Americans vs non-Hispanic whites - Corrected Proof

2010-03-08

Abstract: Metabolic syndrome (MetS) is associated with increased risk for cardiovascular disease (CVD). Mexican Americans (MA) exhibit increases in CVD risk factors compared with non-Hispanic whites (NHW), but few data exist comparing the relation of MetS to subclinical CVD, for example, left ventricular (LV) mass. Asymptomatic subjects (104 MA and 101 NHW, 52.2% female, aged 48 ± 12 years) were studied by echocardiography (echo) and by blood and urine tests. Metabolic syndrome was defined based on the American Heart Association/National Heart, Lung, and Blood Institute definition. Echo LV mass was compared with the presence or absence of MetS and with the number of MetS components. Multiple linear regression also examined the association of MetS with LV mass adjusted for non-MetS risk factors. Left ventricular mass was lower in MA (145.5 ± 43.9 g) compared with NHW (160.2 ± 49.9 g) (P < .05), although this difference was attenuated after adjusting for MetS and other risk factors. Left ventricular mass was higher in those with vs without MetS in both MA and NHW men and women (P < .05 to P < .01). There was a significant (P < .001) graded increase in echo LV mass with increasing number of MetS components both in MA (108.3 to 153.8 g) and NHW (144.3 to 215.1 g). In multiple regression analysis, male sex and MetS remained independently associated (P < .0001) with LV mass; however, body mass index explained much of this association, indicating the strong association of obesity with LV mass. Mean LV mass in both MA and NHW adults was higher in those with vs without MetS and with increasing number of MetS components, with body mass index the principal component of MetS associated with LV mass. The prognostic significance of LV mass in persons with MetS requires further study.

Cytokines (interferon-γ and tumor necrosis factor–α)-induced nuclear factor–κB activation and chemokine (C-X-C motif) ligand 10 release in Graves disease and ophthalmopathy are modulated by pioglitazone - Corrected Proof

2010-03-08

Abstract: Until now, the following are not known: (1) the mechanisms underlying the induction of chemokine (C-X-C motif) ligand 10 (CXCL10) secretion by cytokines in thyrocytes; (2) if pioglitazone is able, like rosiglitazone, to inhibit the interferon (IFN)-γ–induced chemokine expression in Graves disease (GD) or ophthalmopathy (GO); and (3) the mechanisms underlying the inhibition by thiazolidinediones of the cytokines-induced CXCL10 release in thyrocytes. The aims of this study were (1) to study the mechanisms underlying the induction of CXCL10 secretion by cytokines in GD thyrocytes; (2) to test the effect of pioglitazone on IFNγ-inducible CXCL10 secretion in primary thyrocytes, orbital fibroblasts, and preadipocytes from GD and GO patients; and (3) to evaluate the mechanism of action of thiazolidinediones on nuclear factor (NF)–κB activation. The results of the study (1) demonstrate that IFNγ + TNFα enhanced the DNA binding activity of NF-κB in GD thyrocytes, in association with the release of CXCL10; (2) show that pioglitazone exerts a dose-dependent inhibition on IFNγ + TNFα–induced CXCL10 secretion in thyrocytes, orbital fibroblasts, and preadipocytes, similar to the effect observed with rosiglitazone; and (3) demonstrate that thiazolidinediones (pioglitazone and rosiglitazone) act by reducing the IFNγ + TNFα activation of NF-κB in Graves thyrocytes. To the best of our knowledge, this is the first study showing that cytokines are able to activate NF-κB in Graves thyrocytes and a parallel inhibitory effect of pioglitazone both on CXCL10 chemokine secretion and NF-κB activation. Future studies will be needed to verify if new targeted peroxisome proliferator-activated receptor–γ activators may be able to exert the anti-inflammatory effects without the risk of expanding retrobulbar fat mass.

Increased plasma basic fibroblast growth factor is associated with coronary heart disease in adult type 2 diabetes mellitus - Corrected Proof

2010-03-08

Abstract: Basic fibroblast growth factor (bFGF) is a potent endothelial and smooth muscle cell mitogen that does not normally circulate. Plasma bFGF-like bioactivity was increased in association with persistent microalbuminuria (a risk marker for cardiovascular disease) in adult type 2 diabetes mellitus. In the present study, we tested whether baseline plasma bFGF immunoreactivity (IR) predicts the occurrence of a subset of cardiovascular disease outcomes in adults with advanced type 2 diabetes mellitus from the Veterans Affairs Diabetes Trial (mean: age, 59 years; diabetes duration, 11 years; baseline hemoglobin A1c, 9.5%). Plasma bFGF-IR was determined with a sensitive and specific 2-site enzyme-linked immunoassay in 399 patients at the baseline visit. These results were then evaluated as possible predictors of the occurrence of prespecified cardiovascular or coronary heart disease end points. There was a borderline-significant association (P = .07) between plasma bFGF-IR and the main study cardiovascular disease outcome (myocardial infarction, congestive heart failure, cerebrovascular accident, amputation, cardiovascular death, coronary, cerebrovascular or peripheral revascularization, and inoperable coronary artery disease). Plasma bFGF-IR was significantly associated with the occurrence of coronary heart disease (P = .01). After adjusting for clinical risk factors, bFGF (hazard ratio [HR], 1.013; 95% confidence interval [CI], 1.007-1.019; P < .0001), prior macrovascular event (HR, 3.55; 95% CI, 2.154-5.839; P < .0001), and duration of diabetes (HR, 1.041; 95% CI, 1.012-1.071; P = .0055) were all significantly associated with time to first postrandomization coronary heart disease occurrence. These results suggest that increased plasma bFGF-IR may be a novel risk marker for coronary heart disease occurrence in adult men with advanced type 2 diabetes mellitus.

Adiponectin is associated with abnormal lipid profile and coronary microvascular dysfunction in patients with dilated cardiomyopathy without overt heart failure - Corrected Proof

2010-03-04

Abstract: Reduced plasma adiponectin has been associated with abnormal lipid profile, reduced left ventricle (LV) function, and the extent of coronary atherosclerosis in coronary artery disease. The aim of this study was to assess these relationships in patients with dilated cardiomyopathy (DCM) without overt heart failure. Plasma adiponectin was measured in 55 DCM patients (age, 59 ± 12 years; male, 36; body mass index [BMI], 26.9 ± 0.49 kg/m2; LV ejection fraction, 39.8% ± 1.3%; New York Heart Association class I-II) and in 40 age- and BMI-matched healthy controls. In a subset of 25 patients, myocardial blood flow (MBF) was measured at rest and during intravenous dipyridamole (0.56 mg/kg in 4 minutes) by positron emission tomography and 13N-ammonia as a flow tracer. Adiponectin was 6.6 ± 0.34 μg/mL in controls and 10.9 ± 0.85 μg/mL in DCM patients (P < .001), where it was related inversely with BMI (P = .009) and directly with brain natriuretic peptide (P = .017), high-density lipoprotein (HDL) cholesterol (P = .002), and MBF dipyridamole (P = .020). Adiponectin lesser than median value in patients was associated with higher total to HDL cholesterol ratio (4.8 ± 0.24 vs 3.9 ± 0.18, P = .009) and lower MBF reserve (1.76 ± 0.16 vs 2.43 ± 0.19, P = .01). These results could suggest that down-regulation of the adiponectin levels and reduced HDL cholesterol have a key role in causing impaired coronary function and myocardial perfusion in DCM.

Venous blood gas and metabolite response to low-intensity muscle contractions with external limb compression - Corrected Proof

2010-03-04

Abstract: The effect of low-intensity resistance exercise with external limb compression (100 [EC100] and 160 [EC160] mm Hg) on limb blood flow and venous blood gas-metabolite response was investigated and compared with that of high-intensity resistance exercise (no external compression). Unilateral elbow flexion muscle contractions were performed at 20% (75 repetitions, 4 sets, 30-second rest intervals) and 70% of 1-repetition maximum (1-RM; 3 sets, each set was until failure, 3-minute rest intervals). Precontraction brachial arterial blood flow (Doppler ultrasound) was reduced with EC100 or EC160 (56% and 39% of baseline value, respectively) compared with no external compression (control). At 20% 1-RM, brachial arterial blood flow increased after contractions performed with EC160 (190%), but not with the others. Decreases in venous oxygen partial pressure (PvO2) and venous oxygen saturation (SvO2) were greater during EC100 and EC160 than control (mean [SE]: PvO2, 28 [3] vs 26 [2] vs 33 [2] mm Hg; SvO2, 41% [5%] vs 34% [4%] vs 52% [5%], respectively). Changes in venous pH (pHv), venous carbon dioxide partial pressure (PvCO2), and venous lactate concentration ([L−]v) were greater with EC160 than EC100 and/or control (pHv, 7.19 [0.01] vs 7.25 [0.01] vs 7.27 [0.02]; PvCO2, 72 [3] vs 64 [2] vs 60 [3] mm Hg; [L−]v, 5.4 [0.6] vs 3.7 [0.4] vs 3.0 [0.4] mmol/L, respectively). Seventy percent 1-RM contractions resulted in greater changes in pHv (7.14 [0.02]), PvCO2 (91 [5] mm Hg), and [L−]v (7.0 [0.5] mmol/L) than EC100 and EC160, but PvO2 (30 [4] mm Hg) and SvO2 (40% [3%]) were similar. In conclusion, changes in pHv, PvCO2, and [L−]v, but not in PvO2 and SvO2, are sensitive to changes in relative, “internal” intensity of low-intensity muscle contractions caused by reduced blood flow (EC160) or high-intensity muscle contractions. Given the magnitude of the changes in pHv, PvCO2, and [L−]v, it appears plausible that they may be involved in stimulating the observed increase in muscle activation via group III and IV afferents.

Plasma fetuin-A concentrations in young and older high- and low-active men - Corrected Proof

Nathan T. Jenkins, Jennifer A. McKenzie, James M. Hagberg, Sarah Witkowski — 2010-03-04

Abstract: Fetuin-A is a liver-derived factor that may play a role in insulin resistance and age-related chronic diseases (eg, type 2 diabetes mellitus and cardiovascular [CV] disease). Regular exercise improves CV risk and insulin sensitivity; however, it is unknown whether chronic exercise training is related to circulating levels of fetuin-A. Therefore, this study examined whether plasma fetuin-A levels were related to age and chronic physical activity in men. We hypothesized that chronic physical activity would be related to lower plasma fetuin-A levels in younger and older men. In healthy high-active (HI) and low-active (LO) young (HI, n = 7; LO, n = 8) and older (HI, n = 12, LO, n = 11) men, we determined cardiorespiratory fitness (maximal oxygen uptake), plasma fetuin-A levels, plasma insulin, insulin resistance (homeostasis model assessment of insulin resistance), and the standard risk factors for CV disease. Groups were matched for body mass index. Fetuin-A was significantly higher (∼20%) in both young and older LO men compared with their HI counterparts, and fetuin-A was inversely related to maximal oxygen uptake (r = −0.40, P = .014). Plasma fetuin-A levels showed trends to be significantly correlated with insulin (r = -0.34, P = .052) and homeostasis model assessment of insulin resistance (r = 0.33, P = .058) in the older individuals. In younger participants, fetuin-A was related to blood pressure and cholesterol measures. These results indicate that low levels of fetuin-A are related to cardiorespiratory fitness and a number of conventional CV and metabolic disease risk factors independent of age and body mass index. Therefore, the maintenance of low levels of circulating fetuin-A may be a novel mechanism contributing to enhanced insulin sensitivity with regular physical activity.

The relationship between heat shock protein 72 expression in skeletal muscle and insulin sensitivity is dependent on adiposity - Corrected Proof

2010-03-04

Abstract: Decreased gene expression of heat shock protein 72 (HSP72) in skeletal muscle is associated with insulin resistance in humans. We aimed to determine whether HSP72 protein expression in insulin-sensitive tissues is related to criterion standard measures of adiposity and insulin resistance in a young healthy human population free of hyperglycemia. Healthy participants (N = 17; age, 30 ± 3 years) underwent measurement of body composition (dual-energy x-ray absorptiometry), a maximum aerobic capacity test (V̇o2max), an oral glucose tolerance test, and a hyperinsulinemic-euglycemic clamp (M) to access insulin sensitivity. Skeletal muscle and subcutaneous adipose tissue biopsies were obtained by percutaneous needle biopsy. HSP72 protein expression in skeletal muscle was inversely related to percentage body fat (r = −0.54, P < .05) and remained significant after adjustment for age and sex (P < .05). Insulin sensitivity was also related to HSP72 protein expression in skeletal muscle (r = 0.52, P < .05); however, this relationship disappeared after adjustment for percentage body fat (P = .2). In adipose tissue, HSP72 protein expression was not related to adiposity or insulin sensitivity. Physical activity and aerobic fitness did not show any association with HSP72 protein expression in either tissue studied. A lower expression of HSP72 protein in human skeletal muscle was associated with increased adiposity and decreased insulin sensitivity in healthy individuals. These findings are consistent with rodent data suggesting that HSP72 stimulates fat oxidation with consequent reduction in fat storage and adiposity.

Impact of dietary fat type within the context of altered cholesterol homeostasis on cholesterol and lipoprotein metabolism in the F1B hamster - Corrected Proof

2010-03-03

Abstract: Cholesterol status and dietary fat alter several metabolic pathways reflected in lipoprotein profiles. To assess plasma lipoprotein response and mechanisms by which cholesterol and dietary fat type regulate expression of genes involved in lipoprotein metabolism, we developed an experimental model system using F1B hamsters fed diets (12 weeks) enriched in 10% (wt/wt) coconut, olive, or safflower oil with either high cholesterol (0.1%; cholesterol supplemented) or low cholesterol coupled with cholesterol-lowering drugs 10 days before killing (0.01% cholesterol, 0.15% lovastatin, 2% cholestyramine; cholesterol depleted). Irrespective of dietary fat, cholesterol depletion, relative to supplementation, resulted in lower plasma non–high-density lipoprotein (non-HDL) and HDL cholesterol, and triglyceride concentrations (all Ps < .05). In the liver, these differences were associated with higher sterol regulatory element binding protein–2, low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and 7α-hydroxylase messenger RNA (mRNA) levels; higher scavenger receptor B1 and apolipoprotein A-I mRNA and protein levels; lower apolipoprotein E protein levels; and in intestine, modestly lower sterol transporters adenosine triphosphate–binding cassette (ABC) A1, ABCG5, and ABCG8 mRNA levels. Irrespective of cholesterol status, coconut oil, relative to olive and safflower oils, resulted in higher non-HDL cholesterol and triglyceride concentrations (both Ps < .05) and modestly higher sterol regulatory element binding protein–2 mRNA levels. These data suggest that, in F1B hamsters, differences in plasma lipoprotein profiles in response to cholesterol depletion are associated with changes in the expression of genes involved in cholesterol metabolism, whereas the effect of dietary fat type on gene expression was modest, which limits the usefulness of the experimental animal model.

Influence of G1359A polymorphism of the cannabinoid receptor gene on anthropometric parameters and insulin resistance in women with obesity - Corrected Proof

2010-03-03

Abstract: A silent polymorphism (1359 G/A) of the cannabinoid receptor gene was reported as a common polymorphism in white populations. The aim of our study was to investigate the influence of this polymorphism (G1359A) of cannabinoid receptor gene on obesity, insulin resistance, and adipocytokines in women with obesity. A population of 290 women was analyzed. Indirect calorimetry, tetrapolar electrical bioimpedance, blood pressure measurement, serial assessment of nutritional intake with 3-day written food records, and biochemical analysis were performed. One hundred fifty-nine patients (54.8%) had the genotype G1359G (wild-type group), and 131 (45.2%) patients had G1359A (116 patients, 40.0%) or A1359A (15 patients, 5.2%) (mutant-type group). Triglycerides (122.3 ± 65.9 vs 107.2 ± 44.8 mg/dL, P < .05), insulin (15.8 ± 9.4 vs 13.6 ± 6.9 mUI/L, P < .05), and homeostasis model assessment values (3.85 ± 2.2 vs 3.33 ± 1.9, P < .05) were higher in the wild-type group than the mutant-type group. High-density lipoprotein cholesterol levels (56.8 ± 24.1 vs 58.3 ± 13.9 mg/dL, P < .05) were higher in the mutant-type group than the wild-type group. The novel finding of this study is the association of the mutant-type group G1359A and A1359A with a better cardiovascular profile (triglyceride, high-density lipoprotein cholesterol, insulin, and homeostasis model assessment levels) than the wild-type group.

A comparison of the effects of swimming and walking on body weight, fat distribution, lipids, glucose, and insulin in older women—the Sedentary Women Exercise Adherence Trial 2 - Corrected Proof

Kay L. Cox, Valerie Burke, Lawrence J. Beilin, Ian B. Puddey — 2010-03-03

Abstract: All types of aerobic exercise are assumed to affect cardiovascular risk similarly. There are few studies of swimming, but complex responses to water-based exercise suggest its potential for differential effects. The aim of the study was to compare the effects of swimming and walking on fitness, body weight, lipids, glucose, and insulin in older women. Sedentary women aged 50 to 70 years (N = 116), randomly assigned to swimming or walking plus usual care or a behavioral intervention, completed 3 sessions per week of moderate-intensity exercise, supervised for 6 months then unsupervised for 6 months. After 6 months, 1.6-km walk time decreased in walkers and swimmers, with greater improvement in walkers (1.0 vs 0.6 minute, P = .001). In swimmers, but not walkers, distance swum in 12 minutes increased (78.1 vs −2.2 m, P = .021). Waist and hip circumferences (80.8 vs 83.1 cm and 101.8 vs 102.4 cm; P = .023 and P = .042, respectively) and insulin area under the curve (oral glucose tolerance test) (5128 vs 5623 μU/[L 120 min], P < .05) were lower with swimming. Lipids did not differ between groups. At 12 months, fitness was maintained. Relative to walking, swimming reduced body weight by (1.1 kg, P = .039) and resulted in lower total and low-density lipoprotein cholesterol (0.3 and 0.2 mmol/L; P = .040 and P = .049, respectively). The magnitude of the difference in the reduction of insulin area under the curve between swimming and walking was greater at 12 months; however, the significance was attenuated (4677 vs 5240 μU/[L 120 min], P = .052). Compared with walking, swimming improved body weight, body fat distribution, and insulin in the short term and, in the longer term, body weight and lipid measures. These findings suggest that the type of exercise can influence health benefits.

Fluid compartmental shifts with efficacious pioglitazone therapy in overweight monkeys: implications for peroxisome proliferator-activated receptor–γ agonist use in prediabetes - Corrected Proof

Kylie Kavanagh, Kathleen K. Brown, Mandy L. Berquist, Li Zhang, Janice D. Wagner — 2010-03-03

Abstract: Pioglitazone is prescribed to improve insulin sensitivity in type 2 diabetes mellitus patients and has been discussed as a therapy for metabolic syndrome. Pioglitazone and other thiazolidinediones are associated with fluid retention and edema that may exacerbate existing or developing congestive heart failure, which is often present in these patients. Using a nonhuman primate model, our aims were to evaluate (1) whether fluid shifts were detectable in normoglycemic monkeys, (2) which fluid compartment changed, and (3) whether fluid retention was dose dependent. Seventeen adult male cynomolgus macaques (Macaca fascicularis) were studied in a Latin square design such that all animals received 0, 1, 2, and 5 mg/kg pioglitazone for 6 weeks with 2 weeks of washout between dosing intervals. Doses approximated human exposures achieved with 30, 45, and 60 mg. At the end of each period, animals were weighed and underwent dual-absorption x-ray absorption scanning for body composition measurements. Fluid volumes were quantitated by Evans blue dilution for plasma volume, equilibration of sodium bromide for extracellular water, and deuterated water for total body water. Significant (P < .05) effects were seen with expansion of PV at both the 2- and 5-mg/kg doses, along with reduced plasma sodium at 5 mg/kg; however, surrogate end points used to indicate fluid retention (body weight, hematocrit, total protein, and albumin) did not change significantly. Significant trends toward increases in interstitial fluid and extracellular water with increasing dose were apparent. Pioglitazone effectively improved metabolic status by significantly decreasing fasting glucose and triglycerides and increasing adiponectin. We conclude that thiazolidinedione-related plasma volume expansion occurs in nondiabetic primates and that fluid retention is detectable when compartments are directly measured.

Improved endothelial function with simvastatin but unchanged insulin sensitivity with simvastatin or ezetimibe - Corrected Proof

2010-03-03

Abstract: In addition to their expected effects on lipid profile, lipid-lowering agents may reduce cardiovascular events because of effects on nonclassic risk factors such as insulin resistance and inflammation. Ezetimibe specifically blocks the absorption of dietary and biliary cholesterol as well as plant sterols. Although it is known that an additional reduction of low-density lipoprotein cholesterol (LDL-C) levels can be induced by the combination of ezetimibe with statins, it is not known if this can enhance some pleiotropic effects, which may be useful in slowing the atherosclerotic process. This study assessed the effects of simvastatin and ezetimibe, in monotherapy or in combination, on markers of endothelial function and insulin sensitivity. Fifty prediabetic subjects with normo- or mild-to-moderate hypercholesterolemia were randomly allocated to 2 groups receiving either ezetimibe (10 mg/d) or simvastatin (20 mg/d) for 12 weeks, after which the drugs were combined for both groups for an additional 12-week period. Clinical and laboratory parameters were measured at baseline and after 12 and 24 weeks of therapy. Homeostasis model assessment of insulin resistance index and the area under the curve of insulin were calculated. As expected, both groups receiving drugs in isolation significantly reduced total cholesterol, LDL-C, apolipoprotein B, and triglyceride levels; and additional reductions were found after the combination period (P < .05). After 12 weeks of monotherapy, plasminogen activator inhibitor–1 levels and urinary albumin excretion were lower in the simvastatin than in the ezetimibe group. No change in homeostasis model assessment of insulin resistance index, area under the curve of insulin, and adiponectin levels was observed after either the monotherapies or the combined therapy. However, simvastatin combined with ezetimibe provoked significant reductions in E-selectin and intravascular cellular adhesion molecule–1 levels that were independent of LDL-C changes. Our findings support claims that simvastatin may be beneficial in preserving endothelial function in prediabetic subjects with normo- or mild-to-moderate hypercholesterolemia. Alternatively, a deleterious effect of ezetimibe on the endothelial function is suggested, considering the increase in intravascular cellular adhesion molecule–1 and E-selectin levels. Simvastatin and ezetimibe, in isolation or in combination, do not interfere with insulin sensitivity.

Pulsatile intermittent intravenous insulin therapy for attenuation of retinopathy and nephropathy in type 1 diabetes mellitus - Corrected Proof

2010-03-02

Abstract: Many hormones are secreted in a pulsatile fashion that is more efficient than continuous secretion when tested in vivo. A trial of multiple daily insulin doses with or without the addition of weekly pulsatile insulin infusion therapy was designed to determine if deterioration of renal and retinal function could be blunted. Sixty-five study subjects were evaluated prospectively in 7 centers. Thirty-six patients were randomly allocated to the infusion group and 29 to the standard therapy group. Mean serum creatinine was 1.6 mg/dL in both groups. Subjects were excluded if clearance was less than 30 mL/min. There were no significant differences between the groups with respect to age, duration of diabetes, sex distribution, glycohemoglobin, blood pressure, angiotensin-converting enzyme inhibitor use, proteinuria, or baseline diabetic retinopathy (DR) severity level (all eyes exhibited DR; 8 were deemed technically not amenable to evaluation). Progression of DR was noted in 31.6% of 57 patients (32.3% treated, 30.8% control; P = 1.0) with both eyes evaluable. For patients with 12 or more months of follow-up, 27.9% of 43 patients demonstrated progression of DR (32.0% treated, 22.2% control; P = .57). There were no significant differences between study groups with respect to progression or marked progression, nor was there any influence of duration of follow-up. Progression of DR was noted in 18.8% of 122 eyes that could be adequately evaluated (17.9% of 67 treated, 20% of 55 controls; P = .39). Serum creatinine increased to 1.7 mg/dL in the treatment group and to 1.9 mg/dL in the control group (P = .03). Statistically significant preservation of renal function by pulsatile insulin infusion was not matched by a statistically significant prevention of DR progression compared with standard diabetes care. Inadequate statistical power or duration of the study, or lack of further benefit of pulsatile insulin infusion on the retina in the presence of angiotensin-converting enzyme inhibition may be responsible.

Effects of ghrelin, growth hormone–releasing peptide–6, and growth hormone–releasing hormone on growth hormone, adrenocorticotropic hormone, and cortisol release in type 1 diabetes mellitus - Corrected Proof

2010-03-02

Abstract: In type 1 diabetes mellitus (T1DM), growth hormone (GH) responses to provocative stimuli are normal or exaggerated, whereas the hypothalamic-pituitary-adrenal axis has been less studied. Ghrelin is a GH secretagogue that also increases adrenocorticotropic hormone (ACTH) and cortisol levels, similarly to GH-releasing peptide–6 (GHRP-6). Ghrelin's effects in patients with T1DM have not been evaluated. We therefore studied GH, ACTH, and cortisol responses to ghrelin and GHRP-6 in 9 patients with T1DM and 9 control subjects. The GH-releasing hormone (GHRH)–induced GH release was also evaluated. Mean fasting GH levels (micrograms per liter) were higher in T1DM (3.5 ± 1.2) than in controls (0.6 ± 0.3). In both groups, ghrelin-induced GH release was higher than that after GHRP-6 and GHRH. When analyzing Δ area under the curve (ΔAUC) GH values after ghrelin, GHRP-6, and GHRH, no significant differences were observed in T1DM compared with controls. There was a trend (P = .055) to higher mean basal cortisol values (micrograms per deciliter) in T1DM (11.7 ± 1.5) compared with controls (8.2 ± 0.8). No significant differences were seen in ΔAUC cortisol values in both groups after ghrelin and GHRP-6. Mean fasting ACTH values were similar in T1DM and controls. No differences were seen in ΔAUC ACTH levels in both groups after ghrelin and GHRP-6. In summary, patients with T1DM have normal GH responsiveness to ghrelin, GHRP-6, and GHRH. The ACTH and cortisol release after ghrelin and GHRP-6 is also similar to controls. Our results suggest that chronic hyperglycemia of T1DM does not interfere with GH-, ACTH-, and cortisol-releasing mechanisms stimulated by these peptides.

Oral adsorbent AST-120 ameliorates tubular injury in chronic renal failure patients by reducing proteinuria and oxidative stress generation - Corrected Proof

2010-03-02

Abstract: AST-120 is an oral adsorbent that attenuates the progression of chronic renal failure (CRF) and improves the prognosis of the patients under dialysis. Although tubulointerstitial injury is more important than glomerulopathy in terms of renal prognosis in patients with CRF, effect of AST-120 on tubular injury in CRF patients remains unknown. In this study, we examined whether and how AST-120 treatment could improve tubular damage in nondiabetic CRF patients. Fifty nondiabetic CRF patients were enrolled in the present study and divided into 2 groups: one was the AST-120–treated group (15 men and 10 women) and the other was the age-, sex-, and clinical variables–matched non–AST-120-treated control group. Patients were followed up for 12 months. We investigated the effects of AST-120 on serum levels of interleukin-6 (IL-6), proteinuria, and urinary excretion levels of 8-hydroxydeoxyguanosine (8-OHdG) and L-fatty acid binding protein (L-FABP), markers of oxidative stress and tubular injury, respectively. AST-120 treatment (6 g/d), but not control treatment, for 12 months significantly reduced IL-6, proteinuria, and urinary excretion levels of L-FABP and 8-OHdG, and inhibited the increase in serum creatinine in CRF patients. In univariate analyses, L-FABP levels were correlated with age, proteinuria, 8-OHdG, and IL-6. In multiple stepwise regression analysis, proteinuria and urinary 8-OHdG levels were independently related to L-FABP levels (R2 = 0.605). Our present study demonstrated for the first time that AST-120 improved tubular injury in nondiabetic CRF patients. AST-120 may exert beneficial effects in CRF patients by protecting tubular damage partly via reduction of proteinuria and oxidative stress generation.

Extended metabolic evaluation of suspected symptomatic hypoglycemia: the prolonged fast and beyond - Corrected Proof

2010-03-02

Abstract: The diagnostic evaluation of spontaneous hypoglycemia in adults is mainly directed at detecting an insulinoma. Its interpretation is troublesome in those patients who develop low venous plasma glucose levels with appropriate hypoinsulinemia during a prolonged supervised fast. In this study, we investigated in this group of patients whether abnormalities in intermediary metabolism (fatty acid oxidation and amino/organic acids) could be detected that might explain the hypoinsulinemic hypoglycemia. Ten patients with otherwise unexplained low venous plasma glucose levels (<3 mmol/L) during prolonged fasting were included in the study. The patients participated in an extended metabolic protocol based on stable isotope techniques after an overnight fast to explore abnormalities in endogenous glucose production and intermediary metabolism. Endogenous glucose production, glucoregulatory hormones, plasma acylcarnitines, gluconeogenic amino acids, and rates of fatty acid and carbohydrate oxidation after 16 and 22 hours of fasting were measured. Although during the prolonged fast all patients had low venous plasma glucose level, there were no hypoglycemic events during the extended metabolic protocol. No abnormalities in endogenous glucose production (compared with reference values obtained in young healthy volunteers), fatty acid oxidation, or amino acid/organic acids were found in this patient group. In a group of patients exhibiting low venous plasma glucose levels during prolonged fasting in whom insulinoma was excluded, we found no signs of metabolic disorders. Therefore, the observation of low plasma glucose values in this subgroup of patients probably does not warrant extensive metabolic evaluation.

Adiponectin, total antioxidant status, and urine albumin excretion in the low-risk “Golden Years” type 1 diabetes mellitus cohort - Corrected Proof

2010-02-26

Abstract: Adiponectin is associated with inflammation and oxidative stress. Levels are reduced in type 2 diabetes mellitus and coronary heart disease. Conversely, levels are elevated in type 1 diabetes mellitus (T1DM) and associated with microalbuminuria and diabetic nephropathy. An explanation may be that elevated adiponectin in T1DM represents a beneficial counterregulatory response to disease. Our aim was to examine adiponectin in relation to urinary albumin excretion and plasma total antioxidant status (TAOS) in subjects with long-standing T1DM. Serum adiponectin and plasma TAOS were measured in 338 samples from the Golden Years cohort. These subjects have T1DM for at least 50 years and are at low risk of complications. Subjects were divided into normoalbuminuria, microalbuminuria, and macroalbuminuria groups. Adiponectin was elevated in women (20.53 ± 5.94 vs 11.8 ± 3.6 mg/L, P < .001); therefore, the samples were sex stratified. Within men, adiponectin was higher in those with macroalbuminuria (normoalbuminuria vs microalbuminuria vs macroalbuminuria: 10.97 ± 3.26 vs 11.55 ± 3.50 vs 23.63 ± 7.07 mg/L, P = .002). In women, no difference was observed (20.48 ± 5.61 vs 20.75 ± 7.04 vs 29.62 ± 7.81 mg/L, respectively; P = .42). Plasma TAOS did not differ by groups. The correlation between adiponectin and TAOS showed a linear increase from normoalbuminuria, microalbuminuria, to macroalbuminuria in men (r = 0.33, P = .001; r = 0.48, P < .001; r = 0.59, P = .04) and women (r = 0.25, P = .01; r = 0.63, P < .001; r = 0.79, P = .08). Adiponectin was higher in women. Within men, levels were significantly higher in the presence of macroalbuminuria. In both sexes, adiponectin and TAOS were correlated, which was most marked with micro-/macroalbuminuria. The increase in adiponectin in the face of an insult may be a compensatory mechanism to reduce oxidative burden.

Genetic variation of the interleukin-1 family and nongenetic factors determining the interleukin-1 receptor antagonist phenotypes - Corrected Proof

2010-02-24

Abstract: The natural anti-inflammatory protein interleukin-1 receptor antagonist (IL-1Ra) inhibits the activity of IL-1 and is associated with vascular injury and metabolic disorders. We analyzed genetic and nongenetic determinants of the IL-1Ra phenotype. Fifteen haplotype-tagging single nucleotide polymorphisms (SNPs) in the IL-1α (IL1A), IL-1β (IL1B), and IL-1 receptor antagonist (IL-1RN) genes were determined in the Health 2000 survey (n = 6771) and European myocardial infarction (MI) survivors (n = 972). Three SNPs were genotyped in the FINRISK97 (FR97) study (n = 7222). We found 3 IL1RN variants that were associated with the IL-1Ra phenotype in the study populations and remained significant after Bonferroni correction with increasing significance in meta-analysis (P values for rs3213448, rs315952, rs315949, respectively: 5.5 x 10−11, 1.5 x 10−11, and 4.0 x 10−14). Minor allele of the rare IL1B variant rs1143642 was associated with decreased IL-1Ra levels in the Health 2000 and FR97 populations, and the association strengthened in the meta-analysis (P = 9.4 x 10−7). The proportion of variance explained by the IL1RN variant was larger in MI survivors (5.0%) than in the unselected population (0.5%). Body mass index was the strongest nongenetic predictor of the IL-1Ra phenotype, explaining 11.8% of the variance in Health 2000, 18.1% in FR97, and 25% in MI survivors. In conclusion, 3 IL1RN SNPs and 1 IL1B variant were determining IL-1Ra phenotype independently of body mass index and other metabolic phenotypes. The proportion of phenotypic variation in IL-1Ra explained by the genetic variants was, however, modest compared with the proportion explained by the body mass index.

Increased bone resorption and impaired bone microarchitecture in short-term and extended high-fat diet–induced obesity - Corrected Proof

2010-02-22

Abstract: Although obesity traditionally has been considered a condition of low risk for osteoporosis, this classic view has recently been questioned. The aim of this study was to assess bone microarchitecture and turnover in a mouse model of high-fat diet–induced obesity. Seven-week-old male C57BL/6J mice (n = 18) were randomized into 3 diet groups. One third (n = 6) received a low-fat diet for 24 weeks, one third was kept on an extended high-fat diet (eHF), and the remaining was switched from low-fat to high-fat chow 3 weeks before sacrifice (sHF). Serum levels of insulin, leptin, adiponectin, osteocalcin, and cross-linked telopeptides of type I collagen (CTX) were measured. In addition, bone microarchitecture was analyzed by micro–computed tomography; and lumbar spine bone density was assessed by dual-energy x-ray absorptiometry. The CTX, body weight, insulin, and leptin were significantly elevated in obese animals (sHF: +48%, +24%, +265%, and +102%; eHF: +43%, +52%, +761%, and +292%). The CTX, body weight, insulin, and leptin showed a negative correlation with bone density and bone volume. Interestingly, short-term high-fat chow caused similar bone loss as extended high-fat feeding. Bone volume was decreased by 12% in sHF and 19% in eHF. Bone mineral density was 25% (sHF) and 27% (eHF) lower when compared with control mice on low-fat diet. As assessed by the structure model index, bone microarchitecture changed from plate- to rod-like appearance upon high-fat challenge. Trabecular and cortical thickness remained unaffected. Short-term and extended high-fat diet–induced obesity caused significant bone loss in male C57BL/6J mice mainly because of resorptive changes in trabecular architecture.

Presence or absence of a known diabetic ketoacidosis precipitant defines distinct syndromes of “A-β+” ketosis-prone diabetes based on long-term β-cell function, human leukocyte antigen class II alleles, and sex predilection - Corrected Proof

2010-02-22

Abstract: Ketosis-prone diabetes (KPD) is heterogeneous. Longitudinal follow-up revealed that patients with “A-β+” KPD (absent autoantibodies and preserved β-cell function) segregated into 2 subgroups with distinct evolution of β-cell function and glycemic control. Generalized linear analysis demonstrated that the variable that most significantly differentiated them was presence of a clinically evident precipitating event for the index diabetic ketoacidosis (DKA). Hence, we performed a comprehensive analysis of A-β+ KPD patients presenting with “provoked” compared with “unprovoked” DKA. Clinical, biochemical, and β-cell functional characteristics were compared between provoked and unprovoked A-β+ KPD patients followed prospectively for 1 to 8 years. Human leukocyte antigen class II allele frequencies were compared between these 2 groups and population controls. Unprovoked A-β+ KPD patients (n = 83) had greater body mass index, male preponderance, higher frequency of women with oligo-/anovulation, more frequent African American ethnicity, and less frequent family history of diabetes than provoked A-β+ KPD patients (n = 64). The provoked group had higher frequencies of the human leukocyte antigen class II type 1 diabetes mellitus susceptibility alleles DQB1*0302 (than the unprovoked group or population controls) and DRB1*04 (than the unprovoked group), whereas the unprovoked group had a higher frequency of the protective allele DQB1*0602. β-Cell secretory reserve and glycemic control improved progressively in the unprovoked group but declined in the provoked group. The differences persisted in comparisons restricted to patients with new-onset diabetes. “Unprovoked” A-β+ KPD is a distinct syndrome characterized by reversible β-cell dysfunction with male predominance and increased frequency of DQB1*0602, whereas “provoked” A-β+ KPD is characterized by progressive loss of β-cell reserve and increased frequency of DQB1*0302 and DRB1*04. Unprovoked DKA predicts long-term β-cell functional reserve, insulin independence, and glycemic control in KPD.

Plasma interleukin-1β concentrations are closely associated with fasting blood glucose levels in healthy and preclinical middle-aged nonoverweight and overweight Japanese men - Corrected Proof

2010-02-22

Abstract: Plasma interleukin (IL)-1β and IL-6 are markers that predict the risk of inflammation in diabetes. In the current study, we examined the relationship between fasting glucose and plasma inflammatory cytokines (IL-1β and IL-6) concentrations in healthy and preclinical middle-aged Japanese men (mean ± SD, 58.7 ± 7.8 years old) divided according to body mass index (<25 kg/m2, nonoverweight group; ≥25 kg/m2, overweight group). We conducted a cross-sectional study of 413 healthy and preclinical men aged 40 to 69 years who participated in health checkups in Japan. We measured their clinical parameters, lifestyle factors, and plasma IL-1β and IL-6 concentrations. Participants were classified according to their fasting blood glucose levels, and we compared their plasma cytokine levels. Plasma IL-1β and IL-6 levels in nonoverweight subjects were positively and strongly associated with fasting blood glucose and hemoglobin A1c; in contrast, these cytokines were strongly associated with homeostasis model assessment of insulin resistance and fasting glucose in overweight subjects. Significant positive associations between plasma IL-1β and glucose concentrations were observed within the groups classified according to glucose concentrations, after adjustment for age and body mass index. The results of our current study show that plasma IL-1β levels are strongly associated with fasting blood glucose concentrations in healthy and preclinical nonoverweight and overweight Japanese men.

Liquiritigenin pharmacokinetics in a rat model of diabetes mellitus induced by streptozotocin: greater formation of glucuronides in the liver, especially M2, due to increased hepatic uridine 5′-diphosphoglucuronic acid level - Corrected Proof

Hee E. Kang, Se I. Sohn, Seung R. Baek, Jee W. Lee, Myung G. Lee — 2010-02-22

Abstract: Liquiritigenin (LQ) is a candidate for the treatment of inflammatory liver disease. Many studies have confirmed that hepatic disease and diabetes mellitus are closely associated. Thus, the pharmacokinetic changes of LQ and its 2 glucuronides, M1 and M2, in a rat model of diabetes mellitus induced by streptozotocin (DMIS rats) were evaluated. Liquiritigenin was administered intravenously (20 mg/kg) or orally (50 mg/kg) in DMIS and control rats. Changes in in vitro activity and in vivo uridine 5′-diphosphoglucuronic acid level in the liver and intestine of DMIS rats compared with controls were also studied. After intravenous administration of LQ in DMIS rats, no significant changes in the pharmacokinetic parameters of LQ were observed. However, the AUCM2/AUCLQ ratio was significantly greater (by 53.0%) than that of controls. After oral administration of LQ, the AUC of LQ and metabolite ratios of M1 and M2 were comparable to controls. The increase in the formation of glucuronides of LQ, especially M2, after intravenous administration of LQ was due to the increased in vivo hepatic uridine 5′-diphosphoglucuronic acid level in DMIS rats as a result of alteration in carbohydrate metabolism in diabetes. The comparable pharmacokinetics of LQ, M1, and M2 after oral administration of LQ were mainly due to the comparable intestinal metabolism of LQ between the control and DMIS rats.

Dissociated effects of glucose-dependent insulinotropic polypeptide vs glucagon-like peptide–1 on β-cell secretion and insulin clearance in mice - Corrected Proof

Giovanni Pacini, Karl Thomaseth, Bo Ahrén — 2010-02-15

Abstract: Glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) potently augment insulin response to glucose. It is less known what their effects are insulin clearance, which also contributes to peripheral hyperinsulinemia observed after administration of incretins together with glucose. The aims of this study were the quantification of C-peptide secretion and the evaluation of insulin clearance after administration of GIP with glucose. This allows the assessment of GIP's effects on hyperinsulinemia. In addition, GIP's effects were compared with those of GLP-1. Anesthetized female NMRI mice were injected intravenously with glucose alone (1 g/kg, n = 35) or glucose together with GIP (50 μg/kg, n = 12). Samples were taken through the following 50 minutes, and C-peptide and insulin concentrations were used to reconstruct C-peptide secretion rate and insulin clearance. In a previous study, GLP-1 (10 μg/kg) was used in 12 mice; and we used those GLP-1 results to compare GIP effects with those of GLP-1. C-peptide secretion rate peaked at 1 minute after glucose injection, and the immediate part of the insulin-releasing process was markedly augmented by both incretin hormones (1-minute suprabasal increment secretory rate was 20 ± 2 pmol/min for GIP and 28 ± 2 pmol/min for GLP-1, vs only 9 ± 1 pmol/min for glucose alone; P < .001). Until 10 minutes after administration, C-peptide secretion remained higher with incretins (P < .0001), whereas starting from 20 minutes, the 3 patterns were undistinguishable (P > .2). Insulin clearance, previously shown to be abridged by 46% with GLP-1, was reduced only by a nonsignificant (P = .27) 21% with GIP. This study thus shows that the 2 incretins markedly augment glucose-stimulated insulin secretion in mice by a preferential action on the immediate response to glucose of insulin secretion. However, the action of GIP is less effective than that of GLP-1. Insulin clearance with GIP is not significantly reduced. We conclude that GIP is less potent than GLP-1 in inducing glucose-stimulated hyperinsulinemia in the mouse.

Does long-term metformin treatment increase cardiac lipoprotein lipase? - Corrected Proof

David Hauton — 2010-02-15

Abstract: Acute activation of adenosine monophosphate–activated protein kinase (AMPK) or jumps in cardiac work increased cardiac endothelial lipoprotein lipase (LPL), yet it is unclear whether chronic AMPK activation maintains this elevated LPL. To activate AMPK chronically, metformin at low (300 mg/kg/d) and high dose (600 mg/kg/d) was administered in drinking water for 14 days. Control, metformin-treated, and 5-amino-imidazole-4-carboxamide riboside (AICAR)–treated (0.5 mmol/L) ex vivo hearts were perfused to investigate uptake of triacylglycerol and cardiac LPL activity. For perfused rat hearts, increased uptake of labeled Intralipid and β-oxidation of Intralipid–fatty acid were noted for both AICAR (P < .05) and high-dose metformin (P < .01). Intralipid incorporation into tissue lipids was decreased by AICAR (P < .05) and increased after high-dose metformin (P < .05), the increase manifest as enhanced triacylglycerol deposition (P < .05). Low-dose metformin did not alter lipid uptake or tissue deposition. Both high-dose metformin and AICAR decreased cardiac acetyl–coenzyme A carboxylase activity (P < .01). Heparin-releasable LPL was increased after treatment with AICAR (P < .05) and high-dose metformin (P < .01). Low-dose metformin did not alter cardiac LPL. High-dose metformin doubled immunoreactive AMPK and phospho-AMPK protein (P < .001) and increased phosphorylation of p38–mitogen-activated protein kinase (P < .05). After heparin pretreatment, the rate of recruitment of LPL to the cardiac endothelium was increased by AICAR (P < .05) but not by high-dose metformin. These data suggest that AMPK activation increased cardiac endothelial LPL, yet acute and chronic activation of AMPK may yield increased LPL through differing mechanisms.

Effects of diabetes family history and exercise training on the expression of adiponectin and leptin and their receptors - Corrected Proof

2010-02-15

Abstract: Daughters of diabetes patients have lower insulin sensitivity than women with no diabetes family history, but increase insulin sensitivity to a greater extent with exercise training. This study aimed to determine whether differences in circulating concentrations of adiponectin and leptin, and adipose tissue expression of their genes and receptors played a role. Women offspring of patients with type 2 diabetes mellitus (n = 34; age, 35.6 ± 7.0 years; body mass index, 28.1 ± 5.1 kg/m2) and matched controls with no diabetes family history (n = 36; age, 33.6 ± 6.1 years; body mass index, 27.3 ± 4.7 kg/m2) participated. Blood and abdominal subcutaneous adipose tissue samples were obtained at baseline and after a controlled 7-week endurance-type exercise intervention (sessions were performed at 65%-80% of maximum heart rate). At baseline, no significant differences were observed between groups in circulating leptin or adiponectin concentrations, or expression of their genes or receptors. In response to exercise, plasma leptin decreased more in offspring than controls (−32.2% vs −7.3%, P = .005 for interaction); and the long isoform of the leptin receptor messenger RNA (mRNA) increased significantly only in the offspring (+39.4%, P = .026 vs +7.7%, P = .892). Leptin mRNA decreased similarly in both groups (−24.7% vs −25.0%, P < .05 for both). Furthermore, changes in plasma leptin (r = −0.432, P < .001) and leptin mRNA (r = −0.298, P = .019) correlated significantly with changes in insulin sensitivity. Plasma adiponectin decreased similarly in both groups (−12.1% vs −15.2%, P < .01 for both), but no significant changes were observed in adiponectin-related gene expression. This work shows that exercise training has differing effects on leptin-related variables between women with and without a diabetes family history and suggests that these molecular differences may contribute to the differential effects of exercise training on insulin sensitivity between these 2 groups.

Effects of adrenaline on whole-body glucose metabolism and insulin-mediated regulation of glycogen synthase and PKB phosphorylation in human skeletal muscle - Corrected Proof

Jørgen Jensen, Toralph Ruge, Yu-Chiang Lai, Maria K. Svensson, Jan W. Eriksson — 2010-02-15

Abstract: In the present study, we investigated the effect of adrenaline on insulin-mediated regulation of glucose and fat metabolism with focus on regulation of skeletal muscle PKB, GSK-3, and glycogen synthase (GS) phosphorylation. Ten healthy subjects (5 men and 5 women) received a 240-minute intravenous infusion of adrenaline (0.05 μg/[kg min]) or saline; after 120 minutes, a hyperinsulinemic-euglycemic clamp was added. Adrenaline infusion increased blood glucose concentration by approximately 50%, but the hyperinsulinemic clamp normalized blood glucose within 30 minutes. Glucose infusion rate during the last hour was approximately 60% lower during adrenaline infusion compared with saline (4.3 ± 0.5 vs 11.2 ± 0.6 mg/kg lean body mass per minute). Insulin increased PKB Ser473, PKB Thr308, and GSK-3β Ser9 phosphorylation in skeletal muscles; coinfusion of adrenaline did not influence insulin-stimulated PKB and GSK-3 phosphorylation. Adrenaline alone did not influence phosphorylation of PKB and GSK-3β. Insulin increased GS fractional activity and decreased GS Ser641 and Ser645,649,653,657 phosphorylation. In the presence of adrenaline, insulin did neither activate GS nor dephosphorylate GS Ser641. Surprisingly, GS Ser7 phosphorylation was not influenced by adrenaline. Adrenaline increased plasma lactate concentration; and muscle glycogen content was reduced in skeletal muscle the day after adrenaline infusion, supporting that insulin does not stimulate glycogen synthesis in skeletal muscles when adrenaline is present. In conclusion, adrenaline did not influence basal or insulin-stimulated PKB and GSK-3β phosphorylation in muscles, but completely blocked insulin-mediated GS activation and Ser641 dephosphorylation. Still, insulin normalized adrenaline-mediated hyperglycemia.

Effect of 2 weeks of sprint interval training on health-related outcomes in sedentary overweight/obese men - Corrected Proof

Laura J. Whyte, Jason M.R. Gill, Andrew J. Cathcart — 2010-02-15

Abstract: The aim of this study was to investigate the effects of very high intensity sprint interval training (SIT) on metabolic and vascular risk factors in overweight/obese sedentary men. Ten men (age, 32.1 ± 8.7 years; body mass index, 31.0 ± 3.7 kg m−2) participated. After baseline metabolic, anthropometric, and fitness measurements, participants completed a 2-week SIT intervention, comprising 6 sessions of 4 to 6 repeats of 30-second Wingate anaerobic sprints on an electromagnetically braked cycle ergometer, with 4.5-minute recovery between each repetition. Metabolic, anthropometric, and fitness assessments were repeated post-intervention. Both maximal oxygen uptake (2.98 ± 0.15 vs 3.23 ± 0.14 L min−1, P = .013) and mean Wingate power (579 ± 24 vs 600 ± 19 W, P = .040) significantly increased after 2 weeks of SIT. Insulin sensitivity index (5.35 ± 0.72 vs 4.34 ± 0.72, P = .027) and resting fat oxidation rate in the fasted state (0.13 ± 0.01 vs 0.11 ± 0.01 g min−1, P = .019) were significantly higher and systolic blood pressure (121 ± 3 vs 127 ± 3 mm Hg, P = .020) and resting carbohydrate oxidation in the fasted state (0.03 ± 0.01 vs 0.08 ± 0.02 g min−1, P = .037) were significantly lower 24 hours post-intervention compared with baseline, but these changes were no longer significant 72 hours post-intervention. Significant decreases in waist (98.9 ± 3.1 vs 101.3 ± 2.7 cm, P = .004) and hip (109.8 ± 2.2 vs 110.9 ± 2.2 cm, P = .017) circumferences compared with baseline were also observed after the intervention. Thus, 2 weeks of SIT substantially improved a number of metabolic and vascular risk factors in overweight/obese sedentary men, highlighting the potential for this to provide an alternative exercise model for the improvement of vascular and metabolic health in this population.

Demonstration of increased toll-like receptor 2 and toll-like receptor 4 expression in monocytes of type 1 diabetes mellitus patients with microvascular complications - Corrected Proof

Sridevi Devaraj, Ishwarlal Jialal, Jung-Mi Yun, Andrew Bremer — 2010-02-15

Abstract: Type 1 diabetes mellitus (T1DM) is associated with increased microvascular complications and is a proinflammatory state. The toll-like receptors (TLRs) are pattern recognition receptors on monocytes and important in atherosclerosis. We have shown increased TLR2 and TLR4 expression on monocytes of T1DM compared with controls. In this report, we tested the surface expression of TLR2 and TLR4 on monocytes of T1DM patients with microvascular complications (T1DM-MV) compared with those without (T1DM) and healthy controls. The study was performed at the University of California Davis. Healthy controls (n = 31), T1DM patients (n = 31), and T1DM-MV patients (n = 34) were included. The TLR2 and TLR4 surface expression was significantly increased in T1DM-MV monocytes compared with T1DM and controls (P < .01). In addition, nuclear factor κB activity and interleukin-1β release were significantly increased in monocytes from T1DM-MV compared with T1DM (P < .005). Thus, we make the novel observation that TLR2 and TLR4 expression and signaling are increased in T1DM-MV compared with T1DM and may contribute to the accentuated proinflammatory state and complications of T1DM.

Assessment of non–insulin-mediated glucose uptake: association with body fat and glycemic status - Corrected Proof

Reiner Jumpertz, Marie S. Thearle, Joy C. Bunt, Jonathan Krakoff — 2010-02-15

Abstract: In the fasting state, approximately 83% of glucose uptake occurs via non–insulin-mediated mechanisms. A widely accepted static rate for NIMGU is 1.62 mg kg−1·min−1. To investigate the variability of NIMGU, we examined differences by glucose tolerance, sex, age, race (American Indian/African American/Caucasian), and adiposity in 616 volunteers (including individuals with normal glucose regulation [NGR] and impaired glucose regulation [IGR] and diabetes mellitus [DM]) using data from euglycemic-hyperinsulinemic clamp experiments. NIMGU was determined by plotting basal glucose output and insulin action against fasting and steady-state clamp insulin. The intercept with the y-axis after extrapolation was interpreted as NIMGU at zero insulin. Body composition was determined by dual-energy x-ray absorptiometry; and glucose regulation, by a 75-g oral glucose tolerance test. Energy expenditure was measured by indirect calorimetry in a metabolic chamber. In individuals with NGR (n = 385), NIMGU was 1.63 mg kgestimated metabolic body size (fat free mass + 17.7 kg)−1 min−1 (95% confidence interval, 1.59-1.66). NIMGU increased with IGR and DM (IGR: n = 189, 1.67 [1.62-1.72]; DM: n = 42, 2.39 [2.29-2.49]; P < .0001 across groups). NIMGU did not differ by sex (P = .13), age (P = .22), or race (P = .06); however, NIMGU was associated with percentage body fat (r2 = 0.04, P < .0001). Furthermore, NIMGU was positively associated with 24-hour and sleep energy expenditure (r2 = 0.002, P = .03; r2 = 0.01, P < .01). Extrapolated NIMGU in individuals with NGR is remarkably consistent with previously published data. Our results indicate that NIMGU is associated with adiposity. NIMGU increases with declining glucose tolerance perhaps to preserve glucose uptake during increased insulin resistance.

Insulin resistance and metabolic syndrome in patients with nonfunctioning adrenal incidentalomas: a cause-effect relationship? - Corrected Proof

2010-02-15

Abstract: The objective of the study was to assess insulin resistance (IR) and metabolic syndrome (MS) in patients with nonfunctioning adrenal incidentalomas (NFAIs). Among a total cohort of 46 patients with adrenal incidentalomas, we studied 29 patients with NFAIs (mean age, 54 ± 9 years; body mass index, 29 ± 3 kg/m2) and 37 age-, sex-, and body mass index–matched healthy controls. Besides the endocrine workup, IR was evaluated using fasting glucose and insulin concentrations, homeostasis model assessment of IR, and quantitative insulin sensitivity check index. In a subgroup of patients undergoing an oral glucose tolerance test, Matsuda index and total area under the curve for glucose and insulin were also evaluated. Total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, and other biochemical parameters were measured with standard techniques. Body composition was determined with dual-energy x-ray absorptiometry. Patients with NFAIs exhibited higher fasting glucose, insulin, and homeostasis model assessment of IR values; decreased quantitative insulin sensitivity check index and Matsuda index; and an increased—although not statistically significant—area under the curve for glucose and insulin compared with controls (P < .05). In addition, they exhibited higher systolic and diastolic blood pressure, triglycerides, and γ-glutamyltransferase and lower high-density lipoprotein cholesterol levels compared with controls (P < .05). Patients with NFAIs were all obese with a central type of fat accumulation and increased appendicular lean mass. Indices of IR showed a positive correlation with indices of MS (P < .05), but no correlation with markers of hormonal activity. Nonfunctioning adrenal incidentalomas are characterized by IR, hypertension, dyslipidemia, and fatty liver disease, all of them being components of MS. Thus, patients with NFAIs should be screened for MS during their initial workup to identify those at cardiometabolic risk and implement the appropriate interventions.

Influence of macronutrient intake and anthropometric characteristics on plasma insulin after eccentric exercise - Corrected Proof

Mary P. Miles, Chris M. Depner, Rochelle D. Kirwan, Sara J. Frederickson — 2010-02-15

Abstract: To increase understanding of the interaction between macronutrients and insulin resistance (IR), this study sought to determine the influence of macronutrient intake and anthropometric differences on IR and inflammation responses to eccentric resistance exercise. Men and women (n = 12, 19-36 years old) participated in a crossover study and completed 6 sets of 10 unilateral maximal eccentric contractions of the elbow flexors and extensors followed by controlled diet conditions for the first 8 hours postexercise of carbohydrate/fat/protein proportions of either 75%/15%/10% (CHO) or 6%/70%/24% (FAT/PRO). Fasting glucose, insulin, homeostatic model assessment (HOMA) variables, and interleukin (IL)-1β were measured preexercise and 23 hours postexercise (additional measures of glucose and insulin 1 hour after meals consumed 0.5, 3, and 7 hours postexercise). Insulin increased more (P < .01) in the CHO compared with the FAT/PRO condition at 1.5, 4, and 8 hours postexercise. Insulin, HOMA-IR, and HOMA-β-cell function increased 23 hours postexercise in both conditions, whereas IL-1β increased 23 hours postexercise only in the CHO condition. Magnitude of change (Δ) for these variables associated positively with body mass index (BMI) and waist to hip ratio (WHR) in the CHO and inversely in the FAT/PRO condition; that is, r = 0.53 (P = .10) and r = −0.82 (P < .01) for BMI vs Δ insulin in CHO and FAT/PRO conditions, respectively. The Δ IL-1β associated with BMI (r = 0.62, P < .05) and WHR (r = 0.84, P < .01) in the CHO condition. The CHO enhanced IR and inflammation as BMI and WHR increased, whereas fat and protein enhanced IR as BMI and WHR decreased. Thus, BMI and WHR may need to be taken into account in the development of nutritional strategies to prevent IR.

Beneficial effects of IH-901 on glucose and lipid metabolisms via activating adenosine monophosphate–activated protein kinase and phosphatidylinositol-3 kinase pathways - Corrected Proof

Hai-Dan Yuan, Sung Jip Kim, Sung-Hyun Chung — 2010-02-12

Abstract: IH-901 is an intestinal metabolite of ginsenosides found in Panax ginseng. In the present study, effects of IH-901 on glucose and lipid metabolisms were examined using C2C12 myotubes and C57BL/ksJ db/db mice. A significant increase in phosphorylated adenosine monophosphate–activated protein kinase was observed when differentiated C2C12 myotubes were treated with IH-901. Glucose transporter 4 protein expressions were also up-regulated when muscle cells were treated with of IH-901 up to 60 minutes, resulting in stimulation of glucose uptake by 25% as compared with untreated cells. In addition, phosphatidylinositol-3 kinase and Akt protein expressions were increased when C2C12 myotubes were exposed to IH-901 for up to 3 hours; and these effects including glucose uptake were attenuated by pretreatment with LY294002, a selective phosphatidylinositol-3 kinase inhibitor. In animal study, IH-901 at 25 mg/kg lowered the plasma glucose, triglyceride, cholesterol, and nonesterified fatty acid levels by 20.7%, 41.6%, 20.2%, and 24.6%, respectively, compared with control mice. In the meantime, plasma insulin levels were significantly increased by 2.2 and 3.4 times in 10 and 25 mg/kg–treated mice, respectively, compared with control mice, in parallel with the histologic observation showing a preserved architecture of the pancreatic islet. Protein and gene expression patterns for adenosine monophosphate–activated protein kinase, sterol regulatory element binding protein–1a, and glucose transporter 4 in the liver and skeletal muscles were similar to those in cell studies. In summary, IH-901 might be a promising therapeutic agent improving altered glucose and lipid metabolisms revealed in type 2 diabetes mellitus patients.

Dipeptidyl peptidase IV in the hypothalamus and hippocampus of monosodium glutamate obese and food-deprived rats - Corrected Proof

2010-02-12

Abstract: Proline-specific dipeptidyl peptidases are emerging as a protease family with important roles in the regulation of signaling by peptide hormones related to energy balance. The treatment of neonatal rats with monosodium glutamate (MSG) is known to produce a selective damage on the arcuate nucleus with development of obesity. This study investigates the relationship among dipeptidyl peptidase IV (DPPIV) hydrolyzing activity, CD26 protein, fasting, and MSG model of obesity in 2 areas of the central nervous system. Dipeptidyl peptidase IV and CD26 were, respectively, evaluated by fluorometry, and enzyme-linked immunosorbent assay and reverse transcriptase polymerase chain reaction in soluble (SF) and membrane-bound (MF) fractions from the hypothalamus and hippocampus of MSG-treated and normal rats, submitted or not to food deprivation (FD). Dipeptidyl peptidase IV in both areas was distinguished kinetically as insensitive (DI) and sensitive (DS) to diprotin A. Compared with the controls, MSG and/or FD decreased the activity of DPPIV-DI in the SF and MF from the hypothalamus, as well as the activity of DPPIV-DS in the SF from the hypothalamus and in the MF from the hippocampus. Monosodium glutamate and/or FD increased the activity of DPPIV-DI in the MF from the hippocampus. The monoclonal protein expression of membrane CD26 by enzyme-linked immunosorbent assay decreased in the hypothalamus and increased in the hippocampus of MSG and/or FD relative to the controls. The existence of DPPIV-like activity with different sensitivities to diprotin A and the identity of insensitive with CD26 were demonstrated for the first time in the central nervous system. Data also demonstrated the involvement of DPPIV-DI/CD26 hydrolyzing activity in the energy balance probably through the regulation of neuropeptide Y and β-endorphin levels in the hypothalamus and hippocampus.

Regression of preestablished cholesterol gallstones by dietary garlic and onion in experimental mice - Corrected Proof

Satyakumar Vidyashankar, Kari Sambaiah, Krishnapura Srinivasan — 2010-02-12

Abstract: We have recently reported the health beneficial potential of dietary garlic and onion in reducing the incidence and severity of cholesterol gallstone (CGS) during its experimental induction in mice. In the current study, the efficacy of dietary garlic and onion in regressing preestablished CGS was investigated in experimental mice. After inducing CGS in mice with a lithogenic diet for 10 weeks, they were maintained on basal diets containing 0.6% dehydrated garlic or 2% dehydrated onion for a further 10 weeks. Dietary garlic and onion, either raw or heat processed, regressed preformed CGS in mice up to 53% to 59%, whereas the regression in the basal control diet group was only 10%. The antilithogenic potency of garlic was decreased by its heat processing, but not in the case of onion. Biliary cholesterol was significantly decreased in garlic- and onion-fed animals. Biliary cholesterol saturation index and hydrophobicity index were significantly lowered by dietary garlic and onion. Serum and liver cholesterol levels were decreased by feeding these spices during post-CGS induction period. Hepatic hydroxymethylglutaryl–coenzyme A reductase activity was increased after feeding garlic and onion, whereas activities of the cholesterol-degrading enzymes cholesterol-7α-hydroxylase and sterol-27-hydroxylase were increased in spice-fed groups. These results indicate that feeding garlic and onion effectively accelerates the regression of preformed CGS by promoting cholesterol desaturation in bile. This observation is significant in the context of evolving dietary intervention strategy to address regression of existing CGS and stopping the possible recurrence.

Glycosylphosphatidylinositol-specific phospholipase D improves glucose tolerance - Corrected Proof

2010-02-12

Abstract: Insulin regulation of energy metabolism is complex and involves numerous signaling cascades. Insulin has been suggested to stimulate a phospholipase that cleaves glycosylphosphatidylinositols resulting in the generation of an inositol glycan that serves as an insulin mediator. To determine if glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) may play a role in glucose metabolism, we examined the effect of overexpressing GPI-PLD using adenovirus-mediated gene transfer in C57BL/6 mice. Overexpressing GPI-PLD was associated with a decrease in fasting glucose as well as an improvement in glucose tolerance as determined by an intraperitoneal glucose tolerance test. This effect to improve glucose tolerance does not result from an increase in insulin sensitivity, as overexpressing GPI-PLD does not alter the response to insulin. In contrast, the insulin response during the glucose tolerance test in GPI-PLD–overexpressing mice was increased. Overexpressing GPI-PLD in an insulinoma cell line enhanced glucose-stimulated insulin secretion, suggesting that enhanced insulin secretion in vivo may have contributed to the improved glucose tolerance.

Addition of metformin to exogenous glucagon-like peptide–1 results in increased serum glucagon-like peptide–1 concentrations and greater glucose lowering in type 2 diabetes mellitus - Corrected Proof

Joy Cuthbertson, Steven Patterson, Finbarr P. O'Harte, Patrick M. Bell — 2010-02-12

Abstract: Glucagon-like peptide–1 (GLP-1) is an incretin hormone that lowers blood glucose after meals in type 2 diabetes mellitus. The therapeutic potential of GLP-1 in diabetes is limited by rapid inactivation by the enzyme dipeptidylpeptidase-4 (DPP-4). Metformin has been reported to inhibit DPP-4. Here we investigated the acute effects of metformin and GLP-1 alone or in combination on plasma DPP-4 activity, active GLP-1 concentrations, and glucose lowering in type 2 diabetes mellitus. Ten subjects with type 2 diabetes mellitus (8 male and 2 female; age, 68.7 ± 2.6 years [mean ± SEM]; body mass index, 29.6 ± 1.7 kg/m2; hemoglobin A1c, 7.0% ± 0.1%) received 1 of 3 combinations after an overnight fast in a randomized crossover design: metformin 1 g orally plus subcutaneous injection saline (Metformin), GLP-1 (1.5 nmol/kg body weight subcutaneously) plus placebo tablet (GLP-1), or metformin 1 g plus GLP-1(Metformin + GLP-1). At 15 minutes, glucose was raised to 15 mmol/L by rapid intravenous infusion of glucose; and responses were assessed over the next 3 hours. This stimulus does not activate the enteroinsular axis and secretion of endogenous GLP-1, enabling the effect of exogenously administered GLP-1 to be examined. Mean area under curve (AUC) 0-180 minutes plasma glucose responses were lowest after Metformin + GLP-1 (mean ± SEM, 1629 ± 90 mmol/[L min]) compared with GLP-1 (1885 ± 86 mmol/[L min], P < .002) and Metformin (2045 ± 115 mmol/[L min], P < .001). Mean AUC serum insulin responses were similar after either Metformin + GLP-1 (5426 ± 498 mU/[L min]) or GLP-1 (5655 ± 854 mU/[L min]) treatment, and both were higher than Metformin (3521 ± 410 mU/[L min]; P < .001 and P < .05, respectively). Mean AUC for plasma DPP-4 activity was lower after Metformin + GLP-1 (1505 ± 2 μmol/[mL min], P < .001) and Metformin (1508 ± 2 μmol/[mL min], P < .002) compared with GLP-1 (1587 ± 3 μmol/[mL min]). Mean AUC measures for plasma active GLP-1 concentrations were higher after Metformin + GLP-1 (820 × 104 ± 51 × 104 pmol/[L min]) compared with GLP-1 (484 × 104 ± 31 × 104 pmol/[L min], P < .001) and Metformin (419 × 104 ± 34 × 104 pmol/[L min], P < .001), respectively. In patients with type 2 diabetes mellitus, metformin inhibits DPP-4 activity and thus increases active GLP-1 concentrations after subcutaneous injection. In combination with GLP-1, metformin significantly lowers plasma glucose concentrations in type 2 diabetes mellitus subjects compared with GLP-1 alone, whereas insulin responses were similar. Metformin enhances serum concentrations of injected active GLP-1(7-36)amide, and the combination results in added glucose-lowering potency.

The effect of genetic variability on the correlation between blood glucose and glycated hemoglobin levels - Corrected Proof

2010-02-12

Abstract: The disturbing results of recent clinical trials aimed to control cardiovascular risk of diabetes by aggressive control of blood glucose prompted us to analyze the effect of genetic variability of 2 polymorphic enzymes abundant in red blood cells on the correlation between blood glucose and glycated hemoglobin (Hb). Two hundred eighty subjects with type 2 diabetes mellitus were studied. Adenylate kinase locus 1 (AK1) and acid phosphatase locus 1 were determined. Correlation between blood glucose and glycated Hb was determined for phenotypes of the 2 systems. The correlation between blood glucose and glycated Hb is higher in carriers of AK1*2 allele than in subjects with AK11 phenotype. The highest coefficient is observed in acid phosphatase locus 1 phenotypes with the highest enzymatic activity; and the lowest, in phenotypes with the lowest activity. Effects of sex, blood glucose level, age, age at onset, and duration of disease have been also considered. Our data are in agreement with recent observation in healthy subjects suggesting a role of genetic factors on glycated Hb level. If glycation of structural and functional protein is dependent not only on blood glucose level but also on genetic factors, these factors could have an important role in the susceptibility and clinical course of diabetes.

Changes in α-glucosidase activities along the jejunal-ileal axis of normal rats by the α-glucosidase inhibitor miglitol - Corrected Proof

Kazuki Mochizuki, Emiko Hanai, Kazuhito Suruga, Sachi Kuranuki, Toshinao Goda — 2010-02-12

Abstract: Miglitol, an α-glucosidase inhibitor that inhibits postprandial hyperglycemia by delaying carbohydrate digestion and absorption along the jejunal-ileal axis, has recently been approved for use in patients with type 2 diabetes mellitus. Miglitol treatment may lead to increased α-glucosidase activities toward the ileum because carbohydrate flow toward the ileum increases. However, it is not yet known if miglitol treatment alters the α-glucosidase activities along the jejunal-ileal axis. In this study, we examined the effects of miglitol supplementation for 3 or 7 days on α-glucosidase activities along the jejunal-ileal axis of Wistar rats. Supplementation with miglitol for 3 or 7 days in rats increased tissue weights of the lower jejunum and ileum, but did not alter tissue weights of the upper jejunum and cecum or the contents of the cecum. Furthermore, supplementation with miglitol for 7 days reduced the activities of isomaltase and maltase in the upper jejunum and increased the activities of sucrase, isomaltase, and maltase in the lower jejunum and ileum. These results suggest that the delay in carbohydrate digestion and absorption along the jejunal-ileal axis by miglitol supplementation in rats is associated with increased α-glucosidase activities toward the ileum.

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.