Dietary-challenged mice with Alzheimer-like pathology show increased energy expenditure and reduced adipocyte hypertrophy and steatosis.

Alzheimer's disease (AD) is frequently accompanied by progressing weight loss, correlating with mortality. Counter-intuitively, weight loss in old age might predict AD onset but obesity in midlife increases AD risk. Furthermore, AD is associated with diabetes-like alterations in glucose metabolism. Here, we investigated metabolic features of amyloid precursor protein overexpressing APP23 female mice modeling AD upon long-term challenge with high-sucrose (HSD) or high-fat diet (HFD). Compared to wild type littermates (WT), APP23 females were less prone to mild HSD-induced and considerable HFD-induced glucose tolerance deterioration, despite unaltered glucose tolerance during normal-control diet. Indirect calorimetry revealed increased energy expenditure and hyperactivity in APP23 females. Dietary interventions, especially HFD, had weaker effects on lean and fat mass gain, steatosis and adipocyte hypertrophy of APP23 than WT mice, as shown by 1H-magnetic-resonance-spectroscopy, histological and biochemical analyses. Proteome analysis revealed differentially regulated expression of mitochondrial proteins in APP23 livers and brains. In conclusion, hyperactivity, increased metabolic rate, and global mitochondrial dysfunction potentially add up to the development of AD-related body weight changes in APP23 females, becoming especially evident during diet-induced metabolic challenge. These findings emphasize the importance of translating this metabolic phenotyping into human research to decode the metabolic component in AD pathogenesis.

Energy Expenditure in Free-Living Japanese People with Obesity and Type 2 Diabetes, Measured Using the Doubly-Labeled Water Method.

We determined the total energy expenditure (TEE) of healthy overweight or obese people, and those with impaired glucose tolerance and/or impaired fasting glycemia (IGT/IFG), or type 2 diabetes (T2DM) using the doubly-labeled water method. As a second purpose, we compared the measured TEE with the target energy intake recommended in the treatment guidelines for diabetes. The participants were normal glucose tolerance (NGT), and IGT/IFG (n=11) and T2DM (n=9) patients, who were 50-59 y and had a body mass index >25 kg/m2. The median TEE/body mass (BM) values were 32.6, 33.3, and 34.4 kcal/kg BM and the TEE/target BM values (target BM: BM at a BMI of 22 kg/m2) were 43.7, 50.2, and 46.5 kcal/kg target BM for each group, respectively, and did not differ significantly among them. Obese Japanese participants with T2DM in this study had lower TEE/BM than previously studied in non-obese participants with T2DM. In IGT/IFG or T2DM patients, if 30 kcal/kg target BM was used as the energy coefficient, on the basis of the treatment guidelines, the difference between TEE and the target energy intake would be -1,174±552 kcal (-38±11%). When 35 kcal/kg target BM was used as the energy coefficient, the difference between TEE and the target energy intake would be -877±542 kcal (-27±13%). Thus, the energy coefficients used to estimate target energy intake during lifestyle modification in obese/overweight patients with T2DM are considered to be quite low during the first step of diet therapy.

Maternal high-fat diet sex-specifically alters placental morphology and transcriptome in rats: Assessment by next-generation sequencing.

INTRODUCTION: Maternal nutrition is an extremely important health issue. We evaluated the impact of maternal high fat diet (HFD) on pregnancy outcomes, elucidated how the rat placenta and fetus respond to diet manipulation based on fetal sex, and identified candidate genes and pathways. METHODS: Rats were fed a normal or HFD diet for 10 weeks before conception and during gestation. The placenta was collected on gestational day 21 and sexed. Placental histology was analyzed and placental candidate genes and pathways were identified using whole-genome RNA next-generation sequencing. RESULTS: Pup weights in both sexes from HFD dams were reduced. The weight of the placenta from the HFD group was also decreased in both sexes, but changes in placental layer distributions were only significant for female fetuses. Maternal HFD altered the placental transcriptome in a sex-specific manner. Activation of the placental renin-angiotensin system (RAS) by maternal HFD was associated with fetal growth restriction in both fetal sexes. CONCLUSIONS: The placenta reacts to maternal HFD by altering the placental layer distribution and gene expression in a sex-specific manner. The male placenta in late gestation is thought to exhibit greater plasticity relative to the female placenta; however, fetuses of both sexes exhibited similar growth restriction. Our data reveal an association between the placental RAS and HFD-induced fetal growth restriction.

Postpartum assessment of the beta cell function and insulin resistance for Chinese women with previous gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) imparts a high risk of developing postpartum diabetes and is considered to be an early stage of type 2 diabetes mellitus (T2DM). In this study, a 75-g oral glucose tolerance test was performed on 472 women with GDM at 6-8 weeks after delivery. The clinical and metabolic characteristics were compared between the patients with normal glucose tolerance (NGT) and abnormal glucose metabolism (AGM). These data were then compared between pre-diabetic and diabetic patients. A total of 37.7% of the women with GDM continued to have abnormal glucose levels after delivery. Compared with the women who reverted to normal, HOMA-IR was significantly higher in AGM. A multiple stepwise regression analysis revealed that age, the postpartum body mass index (BMI), low density lipoprotein-cholesterol (LDL-C), 2 h glucose load plasma glucose (2 h PG), triglycerides (TG), hemoglobin A1c (HbA1c), 1 h glucose load plasma insulin (INS) level, and 2 h INS level were independent risk factors for the development of insulin resistance after delivery. This study has identified a high prevalence of AGM after GDM. Insulin resistance appears to be the major contributor. Any treatment to reduce the postpartum BMI and lipids level may be beneficial to decrease insulin resistance.

Assessing the predictive accuracy of oral glucose effectiveness index using a calibration model.

PURPOSE: Current reference methods for measuring glucose effectiveness (GE) are the somatostatin pancreatic glucose clamp and minimal model analysis of frequently sampled intravenous glucose tolerance test (FSIVGTT), both of which are laborious and not feasible in large epidemiological studies. Consequently, surrogate indices derived from an oral glucose tolerance test (OGTT) to measure GE (oGE) have been proposed and used in many studies. However, the predictive accuracy of these surrogates has not been formally validated. In this study, we used a calibration model analysis to evaluate the accuracy of surrogate indices to predict GE from the reference FSIVGTT (SgMM). METHODS: Subjects (n = 123, mean age 48 ± 11 years; BMI 35.9 ± 7.3 kg/m2) with varying glucose tolerance (NGT, n = 37; IFG/IGT, n = 78; and T2DM, n = 8) underwent FSIVGTT and OGTT on two separate days. Predictive accuracy was assessed by both root mean squared error (RMSE) of prediction and leave-one-out cross-validation-type RMSE of prediction (CVPE). RESULTS: As expected, insulin sensitivity, SgMM, and oGE were reduced in subjects with T2DM and IFG/IGT when compared with NGT. Simple linear regression analyses revealed a modest but significant relationship between oGE and SgMM (r = 0.25, p < 0.001). However, using calibration model, measured SgMM and predicted SgMM derived from oGE were modestly correlated (r = 0.21, p < 0.05) with the best fit line suggesting poor predictive accuracy. There were no significant differences in CVPE and RMSE among the surrogates, suggesting similar predictive ability. CONCLUSIONS: Although OGTT-derived surrogate indices of GE are convenient and feasible, they have limited ability to robustly predict GE.

Testosterone therapy to prevent type 2 diabetes mellitus in at-risk men (T4DM): Design and implementation of a double-blind randomized controlled trial.

BACKGROUND: Low circulating testosterone is associated with an increased risk of developing type 2 diabetes (T2DM) in overweight men with impaired glucose tolerance (IGT). AIMS: To determine in a multi-centre, double-blinded placebo-controlled randomized trial whether testosterone treatment combined with lifestyle intervention (Weight Watchers) relative to lifestyle intervention alone reduces T2DM incidence and improves glucose tolerance at 2 years. STUDY POPULATION: Overweight or obese men aged 50-74 years with a serum testosterone of ≤14 nmol/L and IGT or newly diagnosed T2DM established by an oral glucose tolerance test (OGTT). SETTING, DRUG AND PROTOCOL: Six Australian capital city-based tertiary care centres. Participants were randomized 1:1 and injected with testosterone undecanoate (1000 mg/4 mL) or vehicle (4 mL castor oil), at baseline, 6 weeks and 3-monthly thereafter. PRIMARY ENDPOINTS: (a) Proportion of participants with 2-hour OGTT ≥11.1 mmol/L at 2 years, and (b) a difference at 2 years ≥0.6 mmol/L in the mean 2-hour OGTT glucose between treatments. SECONDARY ENDPOINTS: Fasting insulin, HbA1c, body composition, maximal handgrip strength; sexual function and lower urinary tract symptoms; serum sex steroids and sex hormone binding globulin; mood and psychosocial function; adherence to lifestyle intervention; and healthcare utilization and costs. SAFETY: Overseen by an Independent Data Safety Monitoring Committee. Haematocrit, lipids and prostate-specific antigen (PSA) are assessed 6-monthly and information relating to haematological, urological and cardiovascular adverse events from each clinic visit. SUB-STUDIES: (a) Changes in bone density and micro-architecture, (b) motivation and behaviour, (c) telomere length, (d) extended treatment up to 4 years, and (e) hypothalamo-pituitary testicular axis recovery at treatment end.

Loss of OcaB Prevents Age-Induced Fat Accretion and Insulin Resistance by Altering B-Lymphocyte Transition and Promoting Energy Expenditure.

The current demographic shift toward an aging population has led to a robust increase in the prevalence of age-associated metabolic disorders. Recent studies have demonstrated that the etiology of obesity-related insulin resistance that develops with aging differs from that induced by high-calorie diets. Whereas the role of adaptive immunity in changes in energy metabolism driven by nutritional challenges has recently gained attention, its impact on aging remains mostly unknown. Here we found that the number of follicular B2 lymphocytes and expression of the B-cell-specific transcriptional coactivator OcaB increase with age in spleen and in intra-abdominal epididymal white adipose tissue (eWAT), concomitantly with higher circulating levels of IgG and impaired glucose homeostasis. Reduction of B-cell maturation and Ig production-especially that of IgG2c-by ablation of OcaB prevented age-induced glucose intolerance and insulin resistance and promoted energy expenditure by stimulating fatty acid utilization in eWAT and brown adipose tissue. Transfer of wild-type bone marrow in OcaB-/- mice replenished the eWAT B2-cell population and IgG levels, which diminished glucose tolerance, insulin sensitivity, and energy expenditure while increasing body weight gain in aged mice. Thus these findings demonstrate that upon aging, modifications in B-cell-driven adaptive immunity contribute to glucose intolerance and fat accretion.

Genetic ablation of phosphatidylcholine transfer protein/StarD2 in ob/ob mice improves glucose tolerance without increasing energy expenditure.

OBJECTIVE: Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is highly expressed in liver and oxidative tissues. PC-TP promotes hepatic glucose production during fasting and aggravates glucose intolerance in high fat fed mice. However, because PC-TP also suppresses thermogenesis in brown adipose tissue (BAT), its direct contribution to obesity-associated diabetes in mice remains unclear. Here we examined the effects of genetic PC-TP ablation on glucose homeostasis in leptin-deficient ob/ob mice, which exhibit both diabetes and altered thermoregulation. ANIMALS/METHODS: Mice lacking both PC-TP and leptin (Pctp-/-;ob/ob) were prepared by crossing Pctp-/- with ob/+ mice. Glucose homeostasis was assessed by standard assays, and energy expenditure was determined by indirect calorimetry using a comprehensive laboratory animal monitoring system, which also recorded physical activity and food intake. Body composition was determined by NMR and hepatic lipids by enzymatic assays. Core body temperature was measured using a rectal thermocouple probe. RESULTS: Pctp-/-;ob/ob mice demonstrated improved glucose homeostasis, as evidenced by markedly improved glucose and pyruvate tolerance tests, without changes in insulin tolerance. However, there were no differences in EE at any ambient temperature. There were also no effects of PC-TP expression on physical activity, food intake or core body temperature. CONCLUSIONS: Improved glucose tolerance in Pctp-/-;ob/ob mice in the absence of increases in energy expenditure or core body temperature indicates a direct pathogenic role for PC-TP in diabetes in leptin deficient mice.

Development and assessment of the disposition index based on the oral glucose tolerance test in subjects with different glycaemic status.

Insulin secretion and insulin sensitivity indexes are related by hyperbolic functions, allowing the calculation of the disposition index (DI) as the product of the acute insulin response (AIR) and the insulin sensitivity index (Si) from intravenous glucose tolerance test (IVGTT). Our objective was to develop an oral-DI based on the oral glucose tolerance test (OGTT) and to assess its association with glucose tolerance status. This research is structured in three studies. Study 1: OGTT were performed in 833 non-diabetic Chilean women (18-60 years) without family history of diabetes mellitus. Study 2: an independent group of n = 57 non-diabetic (18-46 years) without family history of diabetes mellitus carried out an OGTT and an abbreviated IVGTT. Study 3: a sample of 1674 Chilean adults (18-60 years) with different glycaemic status performed an OGTT. An adequate statistical fit for a rectangular hyperbola was found between the area under the curve of insulin-to-glucose ratio (AUCI/G-R) and the Matsuda ISI-COMP index (study 1). The oral-DI derived as AUCI/G-R × ISI-COMP was previously termed insulin-secretion-sensitivity index-2 (ISSI-2). ISSI-2 significantly correlated with DI from IVGTT (rho = 0.34; p = 0.009) (study 2). ISSI-2 shows important differences across groups of subjects with different glycaemic status (study 3). We have confirmed that ISSI-2 replicates the mathematical properties of DI, showing significant correlations with DI from the abbreviated MM-IVGTT. These results indicate that ISSI-2 constitutes a surrogate measure of insulin secretion relative to insulin sensitivity and emphasizes the pivotal role of impaired insulin secretion in the development of glucose homeostasis dysregulation.

Assessment of selected carbohydrate parameters in children exposed to gestational diabetes in utero.

OBJECTIVES: The study was undertaken to assess the selected carbohydrate parameters in children exposed to gestational diabetes in utero. METHODS: 50 children exposed to gestational diabetes were compared with 46 control subjects. Anthropometric parameters of a newborn were obtained from the medical records. In all participants height, body mass, waist and hip circumferences were measured; BMI, WHR and WHtR were calculated. Values of fasting glucose, insulin, C-peptide and HbA1c were measured and HOMA2-IR, HOMA2-S, HOMA2-B were calculated. In obese children (BMI ≥95th percentile) OGTT was performed. RESULTS: The prevalence of overweight/obesity in the study group was 38%, in the control group 41% (p=0.19). Higher fasting glucose level (p=0.02) and HbA1c (p=0.00004) were found in the study group comparing to the control. In children exposed to GDM in utero a positive correlation of fasting insulin and WHR (Rs=0.31, p=0.028) as well as significantly lower HOMA2-B (p=0.03) were observed. In the study group higher HOMA2-IR (p=0.0002) and HOMA2-B (p=0.0000039) and also lower HOMA2-S (p=0.0002) were observed among participants with overweight/obesity comparing to children with normal body weight. In the study group a correlation of HOMA2-IR and SD of the birth weight was found (Rs=0.28, p=0.049). CONCLUSIONS: Children exposed to gestational diabetes in utero, in spite of similar prevalence of overweight/obesity comparing to their non-exposed peers, could have higher risk of glucose intolerance and diabetes mellitus in future. Towards observed decreased insulin sensitivity and compensatory increase in insulin secretion, prevention of overweight and obesity in this group seems to be essential.

Physical activity energy expenditure vs cardiorespiratory fitness level in impaired glucose metabolism.

AIM/HYPOTHESIS: Little is known about the relative roles of physical activity energy expenditure (PAEE) and cardiorespiratory fitness (CRF) as determinants of glucose regulation. The aim of this study was to examine the associations of PAEE and CRF with markers of glucose metabolism, and to test the hypothesis that CRF modifies the association between PAEE and glucose metabolism. METHODS: We analysed cross-sectional data from 755 adults from the Danish ADDITION-PRO study. On the basis of OGTT results, participants without known diabetes were classified as having normal glucose tolerance, isolated impaired fasting glycaemia (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG + IGT or screen-detected diabetes mellitus. Markers of insulin sensitivity and beta cell function were determined. PAEE was measured using a combined heart rate and movement sensor. CRF (maximal oxygen uptake) was estimated using a submaximal 8 min step test. The associations were examined by linear regression analysis. Results were adjusted for relevant confounders. RESULTS: PAEE and CRF were reduced in individuals with i-IGT, combined IFG + IGT and screen-detected diabetes mellitus, but were not significantly different in individuals with i-IFG compared with those with normal glucose tolerance. When adjusting CRF for PAEE and vice versa, PAEE and CRF were both associated with lower fasting and 2 h insulin and higher peripheral insulin sensitivity. CRF was additionally associated with lower fasting and 2 h glucose and higher insulin sensitivity and beta cell function. There was no interaction between CRF and PAEE for any markers of glucose metabolism. CONCLUSIONS/INTERPRETATION: Only CRF, not PAEE, appears to be independently associated with plasma glucose levels and beta cell function, suggesting that CRF may be particularly important for glycaemic control.

Caracterización del metabolismo óseo mineral en pacientes con enfermedad renal crónica en hemodiálisis en el Servicio de Salud Metropolitano Sur, Santiago de Chile / Bone mineral metabolism in patients with chronic kidney disease on dialysis in Southern Metropolitan Santiago

Background: Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is a condition of dialysis patients associated with both morbidity and mortality. Management is based on clinical guidelines with goals that are hard to comply with. Aim: To describe and compare biochemical variables associated with this disorder in two different time periods. Material and Methods: Revision of medical records of 814 patients (49% females) dialyzed during 2009 and 1018 patients (48% females), dialyzed during 2012 in Southern Metropolitan Santiago. Information about serum calcium, phosphorus, parathyroid hormone (PTH) and albumin was retrieved. Results: Median PTH values in 2009 and 2012 were 222.5 and 353.5 pg/ml respectively (p < 0.05). The figures for serum calcium corrected by albumin were 9.0 and 8.5 mg/dl respectively (p < 0.05). The figures for phosphorus were 4.7 and 5.0 mg/dl respectively (p < 0.05). The Calcium x Phosphorus product was 41.4 and 42.5 mg²/dl² (p < 0.05). Of note, the proportion patients with serum calcium below recommended levels (< 8.4 mg/dl) increased from 16% to 40% from 2009 to 2012. The proportion of patients with biochemical variables within recommended ranges was lower in 2012 than in 2009. Conclusions: There was a low proportion of patients with bone metabolism parameters within ranges recommended by clinical guidelines. These parameters were worst in 2012.

The regulation of glucose metabolism: implications and considerations for the assessment of glucose homeostasis in rodents.

The incidence of insulin resistance and type 2 diabetes (T2D) is increasing at alarming rates. In the quest to understand the underlying causes of and to identify novel therapeutic targets to treat T2D, scientists have become increasingly reliant on the use of rodent models. Here, we provide a discussion on the regulation of rodent glucose metabolism, highlighting key differences and similarities that exist between rodents and humans. In addition, some of the issues and considerations associated with assessing glucose homeostasis and insulin action are outlined. We also discuss the role of the liver vs. skeletal muscle in regulating whole body glucose metabolism in rodents, emphasizing the importance of defective hepatic glucose metabolism in the development of impaired glucose tolerance, insulin resistance, and T2D.

Assessment of small C-fiber status for screening of oxidative stress in patients at risk of diabetes.

Oxidized LDL (oxLDL), anti-oxLDL antibody (anti-oxLDL) and paraoxonase (PON1) are increasingly being reported to be associated with diabetic atherosclerosis. Oxidative stress could affect also small C-fibers innervating the sweat glands even in prediabetes. Hence it could be hypothesized that sweat dysfunction may be a predictor of oxidative stress status for early detection of diabetes. Ezscan, a new device, has recently been developed to measure the sweat function. Therefore, this study was aimed to determine the relevance of this Ezscan method to identify impairment in oxidative stress parameters. Plasma levels of oxLDL and anti-oxLDL were measured by enzyme immunoassay and ELISA respectively. Small C-fiber status was assessed by measurement of hand and foot sweat function with the help of Ezscan device and subsequent calculation of a risk score. Out of 82 subjects recruited in this study, 38 had impaired glucose tolerance and 6 had newly diagnosed diabetes mellitus. Ezscan risk score was significantly (p=0.004) correlated with oxLDL/anti-oxLDL ratio (0.32). Area under the curve (AUC) of receiver operating characteristics (ROC) analysis for detection of oxLDL/anti-oxLDL ratio (>0.12) was 0.76. For an Ezscan risk score of 50%, the sensitivity and specificity were 68% and 71% respectively. After adjustment for age and BMI, PON1 activity showed significant difference among the 3 risk groups defined by Ezscan risk score. Based on these results it may be concluded that Ezscan could be a useful screening tool in daily practice to assess alterations in oxidative stress parameters in individuals at risk of developing diabetes.

Assessment of insulin action on carbohydrate metabolism: physiological and non-physiological methods.

Carbohydrate metabolism in humans is regulated by insulin secretion from pancreatic ß-cells and glucose disposal by insulin-sensitive tissues. Insulin facilitates glucose utilization in peripheral tissues and suppresses hepatic glucose production. Any defects in insulin action predispose an individual to glucose intolerance and Type 2 diabetes mellitus. Early detection of defects in insulin action could provide opportunities to prevent or delay progression of the disease state. There are different approaches to assess insulin action. Initial methods, such as peripheral insulin concentration and simple indices, have several limitations. Subsequently, researchers developed methodologies using intravenous glucose infusion to determine glucose fluxes. However, these methodologies are limited by being non-physiological. Newer, innovative techniques that have been developed are more sophisticated and physiological. By modelling glucose kinetics using isotope dilution techniques, several robust parameters can be obtained that are physiologically relevant and sound. This brief review summarizes most of the non-physiological and physiological methodologies used to measure the variables of insulin action.

The effect of increased ambulatory activity on markers of chronic low-grade inflammation: evidence from the PREPARE programme randomized controlled trial.

AIMS: To investigate whether an exercise intervention programme, with or without pedometer use, is effective at reducing chronic low-grade inflammation in those with impaired glucose tolerance. METHODS: Using baseline and 12-month data from the Pre-diabetes Risk Education and Physical Activity Recommendation and Encouragement (PREPARE) programme randomized controlled trial, we investigated whether the pedometer or the standard version of the PREPARE programme is associated with reduced chronic low-grade inflammation. Outcomes included interleukin-6, C-reactive protein, fasting and 2 h post-challenge glucose values and objectively measured ambulatory activity. RESULTS: Seventy-four participants (31% female; mean age, 65 years; body mass index, 29.3 ± 4.8 kg/m(2) ) were included, of which 26 were in the control group and 24 were in each intervention group. At 12 months there was an increase in ambulatory activity of 1351 and 1849 steps/day in the standard and pedometer group, respectively, compared with control conditions; however, there was no significant change in markers of chronic low-grade inflammation. Across the pooled study sample, change in ambulatory activity was significantly correlated with change in interleukin-6 (r = -0.32, P = 0.01) after adjustment for group, age, sex, ethnicity, aspirin and statin medication, baseline body mass index and change in body mass index. Change in interleukin-6 was also significantly correlated with change in 2 h glucose after adjustment for the same variables (r = 0.26, P = 0.03). CONCLUSIONS: This study failed to show reductions in markers of chronic low-grade inflammation following an intervention that promoted modest increases in ambulatory activity; however, across the study sample, increased ambulatory activity was associated with reduced interleukin-6, independent of obesity.

Adipose tissue-specific inhibition of hypoxia-inducible factor 1{alpha} induces obesity and glucose intolerance by impeding energy expenditure in mice.

Hypoxia in adipose tissue has been postulated as a possible contributor to obesity-related chronic inflammation, insulin resistance, and metabolic dysfunction. HIF1α (hypoxia-inducible factor 1α), a master signal mediator of hypoxia response, is elevated in obese adipose tissue. However, the role of HIF1α in obesity-related pathologies remains to be determined. Here we show that transgenic mice with adipose tissue-selective expression of a dominant negative version of HIF1α developed more severe obesity and were more susceptible to high fat diet-induced glucose intolerance and insulin resistance compared with their wild type littermates. Obesity in the transgenic mice was attributed to impaired energy expenditure and reduced thermogenesis. Histological examination of interscapular brown adipose tissue (BAT) in the transgenic mice demonstrated a markedly increased size of lipid droplets and decreased mitochondrial density in adipocytes, a phenotype similar to that in white adipose tissue. These changes in BAT of the transgenic mice were accompanied by decreased mitochondrial biogenesis and reduced expression of key thermogenic genes. In the transgenic mice, angiogenesis in BAT was decreased but was little affected in white adipose tissue. These findings support an indispensable role of HIF1α in maintaining the thermogenic functions of BAT, possibly through promoting angiogenesis and mitochondrial biogenesis in this tissue.

Ethnic difference in inter-East Asian subjects with normal glucose tolerance and impaired glucose regulation: a systematic review and meta-analysis focusing on fasting serum insulin.

AIMS: To investigate ethnic difference by focusing on fasting serum insulin (FSI) in inter-East Asian subjects with normal glucose tolerance (NGT) and impaired glucose regulation (IGR). METHODS: Data sources included MEDLINE and EMBASE between 2001 and 2007. We conducted a search for articles containing mean or geometric mean values of FSI in East Asian subjects with NGT, IGR, or type 2 diabetes (T2DM). The Monte Carlo method was used for simulation of the mean and standard deviation of individual measures in each ethnic group; calculation of the median ratio and 95% confidence interval of individual measures between ethnic groups. RESULTS: Twenty-two articles fully met our pre-determined criteria and were included in the meta-analysis. Results of the meta-analysis revealed that FSI level is significantly lower in Japanese subjects with NGT, IGR, or T2DM than in Korean and Chinese subjects. CONCLUSIONS: Ethnic difference in FSI level between East Asians was observed in not only T2DM patients but also subjects with NGT or IGR. The lower FSI level in Japanese subjects was accompanied by lower triglyceride level. These results suggest that ethnic difference in dietary habit was one of the most influential factors for the ethnic difference in FSI.

Brain glucagon-like peptide 1 signaling controls the onset of high-fat diet-induced insulin resistance and reduces energy expenditure.

Glucagon-like peptide-1 (GLP-1) is a peptide released by the intestine and the brain. We previously demonstrated that brain GLP-1 increases glucose-dependent hyperinsulinemia and insulin resistance. These two features are major characteristics of the onset of type 2 diabetes. Therefore, we investigated whether blocking brain GLP-1 signaling would prevent high-fat diet (HFD)-induced diabetes in the mouse. Our data show that a 1-month chronic blockage of brain GLP-1 signaling by exendin-9 (Ex9), totally prevented hyperinsulinemia and insulin resistance in HFD mice. Furthermore, food intake was dramatically increased, but body weight gain was unchanged, showing that brain GLP-1 controlled energy expenditure. Thermogenesis, glucose utilization, oxygen consumption, carbon dioxide production, muscle glycolytic respiratory index, UCP2 expression in muscle, and basal ambulatory activity were all increased by the exendin-9 treatment. Thus, we have demonstrated that in response to a HFD, brain GLP-1 signaling induces hyperinsulinemia and insulin resistance and decreases energy expenditure by reducing metabolic thermogenesis and ambulatory activity.

Insulin resistance as a risk factor for carotid atherosclerosis: a comparison of the Homeostasis Model Assessment and the short insulin tolerance test.

BACKGROUND AND PURPOSE: The independent contribution of insulin resistance to atherosclerosis is still under debate. We compared associations of 2 different indices of insulin resistance, the Homeostasis Model Assessment (HOMA) index and kITT from a short insulin tolerance test with carotid atherosclerosis. METHODS: A total of 1771 middle-aged white patients were investigated. Intima media thickness (IMT) and extent of carotid atherosclerosis were quantified by ultrasound. HOMA was calculated and an insulin tolerance test was performed. RESULTS: HOMA and kITT were significant predictors for average carotid IMT (P<0.001). After adjustment for age and the components of the metabolic syndrome, HOMA still remained an independent predictor for IMT(avg) (P=0.02), whereas kITT failed to do so. HOMA and kITT were also predictive (P=0.004 and P=0.024) for carotid plaques and extent of carotid atherosclerosis (P<0.001). After adjustment for age and the components of the metabolic syndrome, neither HOMA nor kITT were independently predictive any more. CONCLUSIONS: Our results provide evidence that HOMA rather than kITT is associated with carotid atherosclerosis and that the association is largely explained by the clustered expression of the components of the metabolic syndrome.