Divergent Mechanisms Controlling Hypoxic Sensitivity and Lifespan by the DAF-2/Insulin/IGF-Receptor Pathway

Organisms and their cells vary greatly in their tolerance of low oxygen environments (hypoxia). A delineation of the determinants of hypoxia tolerance is incomplete, despite intense interest for its implications in diseases such as stroke and myocardial infarction. The insulin/IGF-1 receptor (IGFR) signaling pathway controls survival of Caenorhabditis elegans from a variety of stressors including aging, hyperthermia, and hypoxia. daf-2 encodes a C. elegans IGFR homolog whose primary signaling pathway modulates the activity of the FOXO transcription factor DAF-16. DAF-16 regulates the transcription of a large number of genes, some of which have been shown to control aging. To identify genes that selectively regulate hypoxic sensitivity, we compared the whole-organismal transcriptomes of three daf-2 reduction-of-function alleles, all of which are hypoxia resistant, thermotolerant, and long lived, but differ in their rank of severities for these phenotypes. The transcript levels of 172 genes were increased in the most hypoxia resistant daf-2 allele, e1370, relative to the other alleles whereas transcripts from only 10 genes were decreased in abundance. RNAi knockdown of 6 of the 10 genes produced a significant increase in organismal survival after hypoxic exposure as would be expected if down regulation of these genes by the e1370 mutation was responsible for hypoxia resistance. However, RNAi knockdown of these genes did not prolong lifespan. These genes definitively separate the mechanisms of hypoxic sensitivity and lifespan and identify biological strategies to survive hypoxic injury

Cholecystokinin effects on feeding, glucose, and pancreatic hormones in rhesus monkeys

The effects of cholecystokinin on feeding, and on plasma glucose and pancreatic hormone responses to a mixed-meal were determined in lean rhesus monkeys. Following an overnight fast the octapeptide of cholecystokinin (CCK-8) was administered intravenously over a 6 minute period coincident with the initiation of free feeding or an intragastric infusion of a mixed liquid diet. CCK-8 inhibited feeding and delayed the plasma glucose and insulin response to a mixed-meal. The threshold for the feeding effect ranged from 30 to 120 ng/kg/min across monkeys and did not extend beyond 15 minutes of the start of the CCK infusion. The delays in plasma glucose and insulin were not dependent on rate or amount of food entering the stomach. Further, there were no alterations from basal levels in plasma glucose or insulin prior to the onset of CCK-induced feeding inhibition. There was no evidence that CCK-8 stimulated insulin release, nor was the usual close relationship between plasma glucose and insulin levels in response to a mixed-meal changed by CCK-8.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25259/1/0000702.pd

Effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor α/γ agonist on glycemic and lipid parameters in a primate model of the metabolic syndrome

<p>Abstract</p> <p>Background</p> <p>Glycemic control and management of dyslipidemia to reduce cardiovascular risk are major therapeutic goals in individuals with type 2 diabetes mellitus (T2DM). This study was performed to evaluate the effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor α/γ (PPARα/γ) agonist, on both lipid and glycemic parameters in obese, hypertriglyceridemic, insulin-resistant rhesus monkeys.</p> <p>Methods</p> <p>A 135-day efficacy study was performed in six rhesus monkeys. After a 28-day baseline assessment (vehicle only), monkeys received oral aleglitazar 0.03 mg/kg per day for 42 days, followed by a 63-day washout period. Plasma levels of markers of glycemic and lipid regulation were measured at baseline, at the end of the dosing period, and at the end of the washout period.</p> <p>Results</p> <p>Compared with baseline values, aleglitazar 0.03 mg/kg per day reduced triglyceride levels by an average of 89% (328 to 36 mg/dL; P = 0.0035 when normalized for baseline levels) and increased high-density lipoprotein cholesterol levels by 125% (46 to 102 mg/dL; P = 0.0007). Furthermore, aleglitazar reduced low-density lipoprotein cholesterol levels (41%) and increased levels of apolipoprotein A-I (17%) and A-II (17%). Aleglitazar also improved insulin sensitivity by 60% (P = 0.001). Mean body weight was reduced by 5.9% from baseline values with aleglitazar at this dose (P = 0.043).</p> <p>Conclusions</p> <p>Aleglitazar, a dual PPARα/γ agonist, has beneficial effects on both lipid and glucose parameters and may have a therapeutic role in modifying cardiovascular risk factors and improving glycemic control in patients with T2DM.</p

A Thiazolidinedione Improves In Vivo Insulin Action on Skeletal Muscle Glycogen Synthase in Insulin-Resistant Monkeys

Thiazolidinediones (TZD) have been shown to have anti-diabetic effects including the ability to decrease fasting hyperglycemia and hyperinsulinemia, increase insulin-mediated glucose disposal rate (M) and decrease hepatic glucose production, but the mechanisms of action are not well established. To determine whether a TZD (R-102380, Sankyo Company Ltd., Tokyo, Japan) could improve insulin action on skeletal muscle glycogen synthase (GS), the rate-limiting enzyme in glycogen synthesis, 4 insulin-resistant obese monkeys were given I mg/kg/ day R-102380 p.o. for a 6-week period. Skeletal muscle GS activity and glucose 6-phosphate (G6P) content were compared between pre-dosing and dosing periods before and during the maximal insulin-stimulation of a euglycemic hyperinsulinemic clamp

Regulation of food intake in monkeys: Response to caloric dilution

Ability to regulate level of energy intake was studied in adult rhesus monkeys (Macaca mulatta) using calorically diluted diets. Twenty-four hour access to a complete liquid diet was provided via leakproof gravity feeders. The addition of water provided 4 caloric concentrations over the range of 0.5 to 1.35 kcal/ml. Average caloric intake per kg body weight was 84 +/- 0.7 kcal/kg (mean +/- SE). Seven of the eight monkeys maintained a constant caloric intake by adjusting oral intake in response to randomly ordered but sustained changes in caloric density. One monkey ingested a significantly higher caloric load while receiving the highest density diet. Rates of compensation for dilution following each diet change varied widely, occurring over periods of 3 days to 2 weeks. It was concluded that individual monkeys vary significantly in the rat of adjustment to caloric dilution, and thus long term studies must be used in studying controls of feeding in monkeys.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24454/1/0000728.pd

Linking Metabolic QTLs with Network and cis-eQTLs Controlling Biosynthetic Pathways

Phenotypic variation between individuals of a species is often under quantitative genetic control. Genomic analysis of gene expression polymorphisms between individuals is rapidly gaining popularity as a way to query the underlying mechanistic causes of variation between individuals. However, there is little direct evidence of a linkage between global gene expression polymorphisms and phenotypic consequences. In this report, we have mapped quantitative trait loci (QTLs)–controlling glucosinolate content in a population of 403 Arabidopsis Bay × Sha recombinant inbred lines, 211 of which were previously used to identify expression QTLs controlling the transcript levels of biosynthetic genes. In a comparative study, we have directly tested two plant biosynthetic pathways for association between polymorphisms controlling biosynthetic gene transcripts and the resulting metabolites within the Arabidopsis Bay × Sha recombinant inbred line population. In this analysis, all loci controlling expression variation also affected the accumulation of the resulting metabolites. In addition, epistasis was detected more frequently for metabolic traits compared to transcript traits, even when both traits showed similar distributions. An analysis of candidate genes for QTL-controlling networks of transcripts and metabolites suggested that the controlling factors are a mix of enzymes and regulatory factors. This analysis showed that regulatory connections can feedback from metabolism to transcripts. Surprisingly, the most likely major regulator of both transcript level for nearly the entire pathway and aliphatic glucosinolate accumulation is variation in the last enzyme in the biosynthetic pathway, AOP2. This suggests that natural variation in transcripts may significantly impact phenotypic variation, but that natural variation in metabolites or their enzymatic loci can feed back to affect the transcripts

Control of food intake and meal patterns in monkeys

Feeding patterns have been studied in 10 adult male rhesus monkeys (Macaca mulatta) adapted to primate restraint chairs for physiological studies. Using an automated computer-monitored liquid diet feeding system, feeding behavior was studied under 8 hour and 24 hour feeding schedules. Calorie/kg intake was significantly reduced with the 8 hour schedule (pp&gt;0.10). Meal size was negatively correlated with meal frequency across monkeys, but not within monkeys. Although monkeys ingested 78% of their voluntary intake during the light hours, there was no difference in meal size, meal duration, or rate of feeding between light and dark periods. With feeding restricted to 8 hours during the light period, meal size was positively correlated with the length of the interval preceding the meal in 4 of 6 monkeys, and meal size was also positively correlated with length of the postmeal interval in 3 of 6 monkeys. In contrast, 24 hour ad lib fed monkeys showed no relationship between premeal interval and subsequent meal size, but a positive correlation between meal size and postmeal interval in 3 of 4 monkeys. We conclude that feeding schedule or deprivation state may alter the relative roles of "hunger" and "satiety" signals in regulating food intake amounts and patterns.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24222/1/0000481.pd

Nuclear spin driven quantum relaxation in LiY_0.998Ho_0.002F_4

Staircase hysteresis loops of the magnetization of a LiY_0.998Ho_0.002F_4 single crystal are observed at subkelvin temperatures and low field sweep rates. This behavior results from quantum dynamics at avoided level crossings of the energy spectrum of single Ho^{3+} ions in the presence of hyperfine interactions. Enhanced quantum relaxation in constant transverse fields allows the study of the relative magnitude of tunnel splittings. At faster sweep rates, non-equilibrated spin-phonon and spin-spin transitions, mediated by weak dipolar interactions, lead to magnetization oscillations and additional steps.Comment: 5 pages, 5 eps figures, using RevTe

Prolonged duration of early antibiotic therapy in extremely premature infants.

BackgroundProlonged early antibiotics in extremely premature infants may have negative effects. We aimed to assess prevalence and outcomes of provision of prolonged early antibiotics to extremely premature infants in the absence of culture-confirmed infection or NEC.MethodsCohort study of infants from 13 centers born without a major birth defect from 2008-2014 who were 401-1000 grams birth weight, 22-28 weeks gestation, and survived ≥5 days without culture-confirmed infection, NEC, or spontaneous intestinal perforation. We determined the proportion of infants who received prolonged early antibiotics, defined as ≥5 days of antibiotic therapy started at ≤72 h of age, by center and over time. Associations between prolonged early antibiotics and adverse outcomes were assessed using multivariable logistic regression.ResultsA total of 5730 infants were included. The proportion of infants receiving prolonged early antibiotics varied from 30-69% among centers and declined from 49% in 2008 to 35% in 2014. Prolonged early antibiotics was not significantly associated with death (adjusted odds ratio 1.17 [95% CI: 0.99-1.40], p = 0.07) and was not associated with NEC.ConclusionsThe proportion of extremely premature infants receiving prolonged early antibiotics decreased, but significant center variation persists. Prolonged early antibiotics were not significantly associated with increased odds of death or NEC

On the Approach to the Equilibrium and the Equilibrium Properties of a Glass-Forming Model

In this note we apply some theoretical predictions that arise in the mean field framework for a large class of infinite range models to structural glasses and we present a first comparison of these predictions with numerical results.Comment: 22 pages, 15 figure