Our objective is to identify genes that influence the development of any phenotypes of type 2 diabetes (T2D) or kidney disease in obese animals. We use the reproductively isolated UC Davis fatty Zucker strain rat model in which the defective chromosome 4 leptin receptor (LeprfaSte/faSte) results in fatty obesity. We previously produced a congenic strain with the distal half of chromosome 1 from the Brown Norway strain (BN) on a Zucker (ZUC) background (BN.ZUC-D1Rat183-D1Rat90). Previously published studies in males showed that the BN congenic donor region protects from some phenotypes of renal dysfunction and T2D. We now expand our studies to include females and expand phenotyping to gene expression. We performed diabetes and kidney disease phenotyping in chow-fed females of the BN.ZUC-D1Rat183-D1Rat90 congenic strain to determine the specific characteristics of the UC Davis model. Fatty LeprfaSte/faSte animals of both BN and ZUC genotype in the congenic donor region had prediabetic levels of fasting blood glucose and blood glucose 2 hours after a glucose tolerance test. We observed significant congenic strain chromosome 1 genotype effects of the BN donor region in fatty females that resulted in decreased food intake, urine volume, glucose area under the curve during glucose tolerance test, plasma triglyceride levels, and urine glucose excretion per day. In fatty females, there were significant congenic strain BN genotype effects on non-fasted plasma urea nitrogen, triglyceride, and creatinine. Congenic region genotype effects were observed by quantitative PCR of mRNA from the kidney for six genes, all located in the chromosome 1 BN donor region, with potential effects on T2D or kidney function. The results are consistent with the hypothesis that the BN genotype chromosome 1 congenic region influences traits of both type 2 diabetes and kidney function in fatty UC Davis ZUC females and that there are many positional candidate genes.

Determining fluctuations in focus properties is essential for many experiments at Self-Amplified-Spontaneous-Emission (SASE) based Free-Electron-Lasers (FELs), in particular for imaging single non-crystalline biological particles. We report on a diffractive imaging technique to fully characterize highly focused, single-shot pulses using an iterative phase retrieval algorithm, and benchmark it against an existing Hartmann wavefront sensor. The results, both theoretical and experimental, demonstrate the effectiveness of this technique to provide a comprehensive and convenient shot-to-shot measurement of focused-pulse wave fields and source-point positional variations without the need for manipulative optics between the focus and the detector.

No reports of serum parathyroid hormone (PTH) concentrations are available for Alaska Native populations. Design: Cross‐sectional study. Methods: PTH, serum 25(OH)D, dietary calcium and demographic variables were collected from 496 Alaska Natives of Western Alaska (43% males) ages 14‐92y residing in Southwestern Alaska. Results: Estimated calcium intake was 470 ± 341 and 376 ± 245 mg/d among men and women, respectively. Median PTH concentration (pmol/L) was 6.96 (2.4‐37.2), and 6.0 (2.4‐24.2) among men and 7.7 (2.6‐37.2) among women. In MLR models, predictors of PTH were 25(OH)D (P=0.02) and BMI (P=0.04) among men, and BMI (P<0.01), 25(OH)D (P=0.01) and an age x BMI interaction (P=0.02) among women.ConclusionBroadly low calcium intake was likely related to elevated PTH levels, but resulted in a weak calcium and PTH relationship. PTH concentrations were apparently moderated by 25(OH)D.

We previously reported that a congenic rat with Brown Norway (BN) alleles on chromosome 1 reduces renal disease of 15-week old fatty Zucker rats (ZUC). Development of renal disease in fatty BN congenic and fatty ZUC rats from 9 through 28 weeks is now examined. Analysis of urine metabolites by (1)H nuclear magnetic resonance (NMR) spectroscopy revealed a significantly increased urinary loss of glucose, myo-inositol, urea, creatine, and valine in ZUC. Food intake was lower in the BN congenic rats at weeks 9-24, but they weighed significantly more at 28 weeks compared with the ZUC group. Fasting glucose was significantly higher in ZUC than congenic and adiponectin levels were significantly lower in ZUC, but there was no significant genotype effect on Insulin levels. Glucose tolerance tests exhibited no significant differences between ZUC and congenic when values were normalized to basal glucose levels. Quantitative PCR on livers revealed evidence for higher gluconeogenesis in congenics than ZUC at 9 weeks. Plasma urea nitrogen and creatinine were more than 2-fold higher in 28-week ZUC. Twelve urine protein markers of glomerular, proximal and distal tubule disease were assayed at three ages. Several proteins that indicate glomerular and proximal tubular disease increased with age in both congenic and ZUC. Epidermal growth factor (EGF) level, a marker whose levels decrease with distal tubule disease, was significantly higher in congenics. Quantitative histology of 28 week old animals revealed the most significant genotype effect was for tubular dilation and intratubular protein. The congenic donor region is protective of kidney disease, and effects on Type 2 diabetes are likely limited to fasting glucose and adiponectin. The loss of urea together with a small increase of food intake in ZUC support the hypothesis that nitrogen balance is altered in ZUC from an early age.

OBJECTIVES:American Indians and Alaska Natives (ANs) report among the lowest levels of physical activity in the USA, but there is very little systematic research examining the determinants of physical activity patterns in these populations. This study investigated the relationships between enculturation (or cultural traditionality), psychosocial stress, and physical activity in a community-based sample of Yup'ik women and men living in rural AN communities. Associations between these variables and several metabolic risk factors were also examined. DESIGN:A sample of 488 Yup'ik participants (284 women and 204 men) from six villages in the Yukon-Kuskokwim Delta region completed a wellness survey and an array of physiological assessments [e.g., body mass index (BMI), blood pressure]. A subset of 179 participants also completed a 3-day pedometer assessment of physical activity. RESULTS:Multivariate linear regression models indicated that participants who were more enculturated (i.e., living more of a traditional lifestyle) and who experienced lower levels of psychosocial stress were significantly more physically active. In turn, both lower levels of psychosocial stress and higher levels of physical activity were associated with lower BMI, lower percent body fat, and lower waist circumference. CONCLUSIONS:Findings underscore the importance of gaining a culturally specific understanding of physical activity patterns in indigenous groups in order to inform effective health promotion strategies.

Background: Low serum vitamin D is associated with higher latitude, age, body fat percentage and low intake of fatty fish. Little documentation of vitamin D concentrations is available for Alaska Native populations. Objective: This study was undertaken to investigate serum 25-hydroxyvitamin D (25(OH)D) concentrations of the Yup'ik people of southwestern Alaska in relation to demographic and lifestyle variables, particularly with the use of locally harvested (local) foods. Design: Cross-sectional study. Methods: We estimated 25(OH)D, dietary vitamin D and calcium, percent of energy from local foods and demographic variables in 497 Yup'ik people (43% males) aged 14–92 residing in southwestern Alaska. Sampling was approximately equally divided between synthesizing and non-synthesizing seasons, although the preponderance of samples were drawn during months of increasing daylight. Results: Mean vitamin D intake was 15.1±20.2 µg/d, while local foods accounted for 22.9±17.1% of energy intake. The leading sources of vitamin D were local fish (90.1%) followed by market foods. Mean 25(OH)D concentration was 95.6±40.7 nmol/L. Participants in the upper 50th percentile of 25(OH)D concentration tended to be older, male, of lower body mass index, sampled during the synthesizing season, and among the upper 50th percentile of local food use. Conclusions: A shift away from locally harvested foods will likely increase the risk for serum 25(OH)D insufficiency in this population.

Objective: To evaluate the efficacy of an herbal blend.Design and Methods: A randomized, double-blind, clinical trial in 60 subjects with body mass index (BMI) between 30 and 40 kg/m(2). Participants were randomized into two groups receiving either 400 mg herbal capsules or 400 mg placebo capsules twice daily. The herbal blend comprises of extracts from Sphaeranthus indicus and Garcinia mangostana. Participants received a standard diet (2,000 kcal per day) and walked 30 min 5 days per week.Results: After 8 weeks, significant net reductions in body weight (3.74 kg; P < 0.0001), BMI (1.61 kg/m(2); P < 0.0001), and waist circumference (5.44 cm; P < 0.05) were observed in the herbal group compared with placebo. Additionally, a significant increase in serum adiponectin concentration was found in the herbal group versus placebo (P = 0.001). Adverse events were mild and were equally distributed between the two groups. In vitro studies in the 3T3-L1 adipocyte cell line showed that the herbal extract markedly downregulated the expression of peroxisome proliferator-activated receptor gamma, adipocyte-differentiation related protein, and cluster of differentiation 36 but increased adiponectin expression. The herbal extract also reduced the expression and the recruitment of perilipin onto the membrane of lipid droplets.Conclusion: Supplementation with the herbal blend resulted in a greater degree of weight loss than placebo over 8 weeks.

BACKGROUND:Over 50% of adults currently use dietary supplements (DS) but manufacturers do not have to prove the safety or efficacy of a DS before it is marketed. Therefore, consumers may be exposed to inaccurate DS information, may lack confidence in choosing appropriate DS and may seek advice for usage. The objective of this study was to examine trends in usage, attitudes, and sources of information regarding DS according to geographic location, demographic group, and lifestyle choices.METHODS:Eligible individuals completed a 10-item researcher-developed survey tool to determine DS use, sources of DS information, and DS-related knowledge and attitudes over the previous year. Healthy participants (637 individuals aged 21-75 years) from two population-based cohorts that had been recruited for lipoprotein assessment studies at Tufts University in Boston, Massachusetts and University of California at Davis. Outcome measures included participants' use, beliefs regarding essentiality of DS, confidence in choosing appropriate DS, and sources of information on DS. Univariate and multivariate logistic regression were utilized to examine differences in survey responses between groups.RESULTS:Of the total population 72.7% reported taking dietary supplements in the previous year. Those living on the West Coast (80.3%) had greater use than those living on the East Coast (60.7%). Those on the East Coast were more likely to believe DS were essential to health (48.7%) and to feel confident in choosing DS that were appropriate for them (51.0%). Overall, physicians were the most frequent source of DS information for more than 50% of participants on both coasts.CONCLUSION:Because DS usage is widespread, health care providers and nutrition educators must encourage patients to discuss their DS use and be equipped to provide information conducive to safe, efficacious consumption. Tailoring interventions for healthcare providers, media sources, industry, and the public may allow for dissemination of up-to-date information regarding DS.

BACKGROUND:The recommendation to restrict dietary sodium for management of hypertensive cardiovascular disease assumes that sodium intake exceeds physiologic need, that it can be significantly reduced, and that the reduction can be maintained over time. In contrast, neuroscientists have identified neural circuits in vertebrate animals that regulate sodium appetite within a narrow physiologic range. This study further validates our previous report that sodium intake, consistent with the neuroscience, tracks within a narrow range, consistent over time and across cultures.METHODS:Peer-reviewed publications reporting 24-hour urinary sodium excretion (UNaV) in a defined population that were not included in our 2009 publication were identified from the medical literature. These datasets were combined with those in our previous report of worldwide dietary sodium consumption.RESULTS:The new data included 129 surveys, representing 50,060 participants. The mean value and range of 24-hour UNaV in each of these datasets were within 1 SD of our previous estimate. The combined mean and normal range of sodium intake of the 129 datasets were nearly identical to that we previously reported (mean = 158.3±22.5 vs. 162.4±22.4 mmol/d). Merging the previous and new datasets (n = 190) yielded sodium consumption of 159.4±22.3 mmol/d (range = 114-210 mmol/d; 2,622-4,830mg/d).CONCLUSIONS:Human sodium intake, as defined by 24-hour UNaV, is characterized by a narrow range that is remarkably reproducible over at least 5 decades and across 45 countries. As documented here, this range is determined by physiologic needs rather than environmental factors. Future guidelines should be based on this biologically determined range.

ObjectiveTo assess primary sources of information about dietary supplements (DS) and to determine if the sources differ between geographic regions.MethodsQuestionnaires and verification of supplement labels were used to assess DS use and sources of information for 646 healthy male and female subjects aged 21–75 who had been recruited for lipoprotein assessment studies at Tufts University and UC Davis. A chi‐square test with an alpha of 0.05 was used.ResultsDS were taken by 65.2% of participants (M 49.5%; F 50.5%). In contrast to earlier studies that showed physicians were infrequent sources of DS information, this study found the most common source of DS advice for all respondents was physicians (52.4%). Other sources of information differed significantly depending on geographic location. Those in the east were more likely to ask health food retailers or pharmacists (p<0.001). Those in the west were more likely to rely on family (p=0.002) and friends (p=0.021) and magazines/journals/news and the internet (p<0.001).ConclusionWhen DS use is discussed with health care providers more informed use and fewer possible drug‐DS interactions may occur. Physicians may benefit from increased education about DS since they will be accountable for accurate information regarding DS use. (Research support: Bastyr University)

Linkage mapping in a backcross of {Brown Norway [BN/Crl (BN)] × ZUC- LeprfaSte(ZUC)} × ZUC identified a male-specific quantitative trait locus (QTL) for urinary albumin excretion (UAE) on rat chromosome 1. A homozygous ZUC.BN-( D1Rat42- D1Rat90)/Ste congenic was produced containing BN donor alleles from 135 to 276 Mb from chromosome 1 on the ZUC background. We observed threefold higher urinary albumin-to-creatinine ratios (ACR) in 15-wk-old Zucker background strain males than in same sex and age congenic animals when both strains are also homozygous for the ZUC leptin receptor fatty mutation ( LeprfaSte) ( P < 0.0001). We then linkage mapped within the donor region without confounded effects from other chromosomes. Phenotypes were collected in 248 F2 male rats in a population made by crossing parents heterozygous for both the BN donor region and ZUC LeprfaSte. Significant interactions were observed between the Lepr genotype and chromosome 1 QTL for six renal traits: urine volume, UAE at 10 and 15 wk, ACR, right kidney weight, and plasma urea nitrogen. A few traits, such as UAE and ACR, exhibit a second peak at the distal end of the chromosome. Hydronephrosis exhibited one or two QTLs contingent on adjustment for body weight. The results now demonstrate at least two sets of coincident traits with different correlations to kidney function.

Background: Epidemiological data shows low dietary magnesium(Mg) may be related to incidence and progression of asthma. Objective To determine if long term(6.5 month) treatment with oral Mg would improve asthma control and increase serum measures of Mg status in men and women with mild-to-moderate asthma. Subjects: 55 males and females aged 21 to 55 years with mild to moderate asthma according to the 2002 National Heart, Lung, and Blood Institute(NHLBI) and Asthma Education and Prevention Program(NAEPP) guidelines and who used only beta-agonists or inhaled corticosteroids(ICS) as asthma medications were enrolled. Design: Subjects were randomly assigned to consume 340 mg(170 mg twice a day) of Mg or a placebo for 6.5 months. Measurements: Multiple measures of Mg status including serum, erythrocyte, urine, dietary, ionized and IV Mg were measured. Objective: markers of asthma control were: methacholine challenge test(MCCT) and pulmonary function test(PFT) results. Subjective validated questionnaires on asthma quality of life(AQLQ) and control(ACQ) were completed by participants. Markers of inflammation, including c-reactive protein(CRP) and exhaled nitric oxide(eNO) were determined. Results: The concentration of methacholine required to cause a 20% drop in forced expiratory volume in in minute(FEV1) increased significantly from baseline to month 6 within the Mg group. Peak expiratory flow rate(PEFR) showed a 5.8% predicted improvement over time(P = 0.03) in those consuming the Mg. There was significant improvement in AQLQ mean score units(P < 0.01) and in overall ACQ score only in the Mg group(P = 0.05) after 6.5 months of supplementation. Despite these improvements, there were no significant changes in any of the markers of Mg status. Conclusion: Adults who received oral Mg supplements showed improvement in objective measures of bronchial reactivity to methacholine and PEFR and in subjective measures of asthma control and quality of life.

We have previously shown that 90% of outbred obese Zucker Lepr(fa/fa) rats die prematurely of renal disease. Thus, renal disease in obese Zucker Lepr(fa/fa) rats may be caused by the LEPR mutation on chromosome 5, by the obesity, or it may be influenced by Zucker susceptibility alleles of genes on other chromosomes. We have searched for susceptibility genes on other chromosomes using urinary albumin excretion (UAE) as an early indicator of altered renal function in a backcross of (Brown Norway × inbred Zucker) F1 × inbred Zucker, which we name the BZZ cross. We killed 237 BZZ backcross animals at 15 wk of age. All included animals were homozygous for the fatty mutation of LEPR and were obese. Urinary creatinine measurements were used to calculate the albumin-to-creatinine ratio (ACR). We identified direct effect quantitative trait loci (QTLs) for UAE and ACR on chromosome 1 (LOD scores = 3.6 and 2.86, respectively) in males, and chromosome 4 (LOD score = 2.9) in females. Significant QTLs were identified for left kidney weight for females on chromosomes 3 and 12. We also demonstrated that kidneys from 15 wk old obese inbred Zucker rats already show evidence of kidney pathology: tubular dilation, proteinaceous fluid accumulation, evidence for inflammation, and mild mesangial and tubular membrane basement membrane thickening. Both lean Zucker rats and the Brown Norway rats showed no evidence for these changes. Thus, by removing the influence of the Lepr(fa/fa) mutation from analysis we have identified UAE QTLs unlinked to LEPR.

Evidence indicates that rural youth are more likely than their urban counterparts to participate in risky behaviors, many of which translate into a higher burden of cardiovascular disease (CVD). Alaska Native youth may be at particularly high risk. Our objective was to evaluate the clustering of health and behavioral risk factors for CVD in 315 Alaska Native youth and young adults (ages 14‐25 years) who participated in the Center for Alaska Native Health Research Study. The prevalence of health risk factors (overweight, hypertension and high HDL, low glucose, and high triglyceride concentration) was estimated using age and gender appropriate criteria. Behavioral risk factors (diet and smoking) were assessed using computer assisted 24‐hour recalls and standardized questionnaires. Clustering of risk factors was common. Approximately 75% of the sample had 0‐1 health risk factors; the remaining 25% had 2‐3 risk factors. The most prevalent risk factors were overweight (40.3%), low HDLs (26.3%) and high triglycerides (21.3%). More than 30% reported smoking regularly. Added sugars and saturated fat contributed substantially to energy intake (19% and 11%, respectively). The risk of CVD increases with each additional risk factor. To promote healthy aging among Alaska Native youth the development of ecologically appropriate CVD prevention programs is essential.NIH (P20 RR16430)

Macrophages (MΦ) infiltrate white adipose tissue (WAT) with increasing adiposity and are primarily localized to necrotic adipocytes. Mechanisms underlying WAT MΦ recruitment, tissue migration/retention, and function in obese animals is unclear. Integrins are cell adhesion proteins critical for leukocyte extravasation, migration, and phagocytosis. CD11d encodes the α‐subunit of the integrin αDβ2 and is expressed predominantly on monocytes/MΦ; however, its role in systemic and WAT inflammation is poorly understood. We have demonstrated for the first time that CD11d expression in retroperitoneal (RP) WAT is increased dramatically (by >200 fold) in obese female Zucker rats (n=7) compared to lean controls (n=9), further confirmed in a polygenic obese SD male rat model (~70 fold). To assess whether this upregulation in WAT is the result of obesity‐induced inflammation or generalized inflammation outside the context of obesity, we measured CD11d expression in RP WAT of non‐obese mice administered lipopolysaccharide (LPS) at 0.5 mg/kg (5 day; n=5) vs. vehicle‐treated controls. CD11d expression was increased by LPS treatment, but the fold increase (~3.6 fold) was far less than observed in obesity. Our results are consistent with the hypothesis that CD11d plays a critical role in WAT MΦ migration, tissue retention, and or phagocytosis of cellular debris and lipid from necrotic adipocytes in obesity.Grant Funding SourceWestern Human Nutrition Research Center