Effects of Ordered Eating on Various Postprandial Measures

Postprandial glucose (PPG) is an indicator of acute and chronic overall health, and aberrations in glucose, insulin, and other postprandial (PP) markers are common in obesity and cardiometabolic disorders. Chronically elevated glucose can lead to a number of health problems such as type 2 diabetes mellitus. Additionally, PPG responses can impact substrate utilization responses to exercise, which may have implications for both healthy and diseased populations. One potentially simple lifestyle modification to alter PPG and related markers is to change the order in which foods are consumed within meals. The purpose of this dissertation was to further explore the impact of ordered eating on a variety of PP measures and its possible effects on exercise responses in an acute setting. Study 1 was a systematic review of existing literature to assess the effect of ordered eating on a variety of PP measures including glucose, insulin, C-peptide, hunger, and satiety. Study 2 was a randomized crossover laboratory-based experiment that examined the effects of ordered eating on PPG, substrate utilization, hunger, satiety, and other variables surrounding an exercise bout. For Study 1, three databases were searched, reference lists of identified reports were searched, and an author of several studies was consulted to verify that relevant literature was included. The review included acute interventions that administered isocaloric meals of the same foods but with foods eaten in different orders. Participants for Study 2 were recreationally active, generally healthy adults aged 18 to 60 years old and had fasting blood glucose measured as well as resting gaseous exchange before being given a standard meal consisting of chicken, broccoli, and rice, which was ordered in a rice first (RF) condition on one day and a rice last (RL) condition on a different day. Following the meal, participants rested for 60 minutes prior to beginning a 30-minute exercise bout at 70% of maximum heart rate. Throughout rest and exercise, participants rated hunger, appetite, satiety, and fullness and had gaseous exchange and blood glucose measured regularly. The main statistical analysis for study 2 was a two-way ANOVA with time and condition as within-subject factors to compare the RL and RF conditions. Results, in brief, showed that there was a significant effect of meal order throughout the literature, on PPG and PP insulin—consuming carbohydrate-dense foods last in meal sequence leads to lower glucose and insulin excursions on average. Glucagon like peptide-1 area under the curve was also generally higher when carbohydrate was consumed at the end of a meal. Still, evidence around incretin, gut hormone responses, and perceptual measures was generally of low or very low quality, leaving gaps for further research. Within the lab study, the impact on PPG was successfully replicated, and there was also an effect of meal sequence on substrate utilization—a RF sequence led to higher utilization of carbohydrate both at rest and during exercise. In sum, this dissertation demonstrates that the relatively novel approach of altering the meal sequence may have significant implications relating to blood glucose and substrate utilization

Pearls of Elschnig

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Lexical Derivation of the PINT Taxonomy of Goals: Prominence, Inclusiveness, Negativity Prevention, and Tradition

What do people want? Few questions are more fundamental to psychological science than this. Yet, existing taxonomies disagree on both the number and content of goals. We thus adopted a lexical approach and investigated the structure of goal-relevant words from the natural English lexicon. Through an intensive rating process, 1,060 goal-relevant English words were first located. In Studies 1-2, two relatively large and diverse samples (total n = 1,026) rated their commitment to approaching or avoiding these goals. Principal component analyses yielded 4 replicable components: Prominence, Inclusiveness, Negativity prevention, and Tradition (the PINT Taxonomy). Study 3-7 (total n = 1,396) supported the 4-factor structure of an abbreviated scale and found systematic differences in their relationships with past goal-content measures, the Big 5 traits, affect, and need satisfaction. This investigation thus provides a data-driven taxonomy of higher-order goal-content and opens up a wide variety of fascinating lines for future research

New Constraints on the Lyman Continuum Escape Fraction at z~1.3

We examine deep far-ultraviolet (1600 Angstrom) imaging of the Hubble Deep Field-North (HDFN) and the Hubble Ultra Deep Field (HUDF) to search for leaking Lyman continuum radiation from starburst galaxies at z~1.3. There are 21 (primarily sub-L*) galaxies with spectroscopic redshifts between 1.1<z<1.5 and none are detected in the far-UV. We fit stellar population templates to the galaxies' optical/near-infrared SEDs to determine the starburst age and level of dust attenuation, giving an accurate estimate of the intrinsic Lyman continuum ratio, f_1500/f_700, and allowing a conversion from f_700 limits to relative escape fractions. We show that previous high-redshift studies may have underestimated the amplitude of the Lyman Break, and thus the relative escape fraction, by a factor of ~2. Once the starburst age and intergalactic HI absorption are accounted for, 18 galaxies in our sample have limits to the relative escape fraction, f_esc,rel < 1.0 with some limits as low as f_esc,rel < 0.10 and a stacked limit of f_esc,rel < 0.08. This demonstrates, for the first time, that most sub-L* galaxies at high redshift do not have large escape fractions. When combined with a similar study of more luminous galaxies at the same redshift we show that, if all star-forming galaxies at z~1 have similar relative escape fractions, the value must be less than 0.14 (3 sigma). We also show that less than 20% (3 sigma) of star-forming galaxies at z~1 have relative escape fractions near unity. These limits contrast with the large escape fractions found at z~3 and suggest that the average escape fraction has decreased between z~3 and z~1. (Abridged)Comment: Accepted for publication in ApJ. aastex format. 39 pages, 11 figure

Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism

OBJECTIVE: The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). We evaluated whether MPC inhibitors (MPCi) might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH. METHODS: Circulating BCAA concentrations were measured in people with NASH and type 2 diabetes, who participated in a recent randomized, placebo-controlled Phase IIB clinical trial to test the efficacy and safety of the MPCi MSDC-0602K (EMMINENCE; NCT02784444). In this 52-week trial, patients were randomly assigned to placebo (n = 94) or 250 mg MSDC-0602K (n = 101). Human hepatoma cell lines and mouse primary hepatocytes were used to test the direct effects of various MPCi on BCAA catabolism in vitro. Lastly, we investigated how hepatocyte-specific deletion of MPC2 affects BCAA metabolism in the liver of obese mice and MSDC-0602K treatment of Zucker diabetic fatty (ZDF) rats. RESULTS: In patients with NASH, MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes, had decreased plasma concentrations of BCAAs compared to baseline while placebo had no effect. The rate-limiting enzyme in BCAA catabolism is the mitochondrial branched chain ketoacid dehydrogenase (BCKDH), which is deactivated by phosphorylation. In multiple human hepatoma cell lines, MPCi markedly reduced BCKDH phosphorylation and stimulated branched chain keto acid catabolism; an effect that required the BCKDH phosphatase PPM1K. Mechanistically, the effects of MPCi were linked to activation of the energy sensing AMP-dependent protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) kinase signaling cascades in vitro. BCKDH phosphorylation was reduced in liver of obese, hepatocyte-specific MPC2 knockout (LS-Mpc2-/-) mice compared to wild-type controls concomitant with activation of mTOR signaling in vivo. Finally, while MSDC-0602K treatment improved glucose homeostasis and increased the concentrations of some BCAA metabolites in ZDF rats, it did not lower plasma BCAA concentrations. CONCLUSIONS: These data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation by activating the mTOR axis. However, the effects of MPCi on glucose homeostasis may be separable from its effects on BCAA concentrations

Type Ia Supernova Rate Measurements To Redshift 2.5 From CANDELS: Searching For Prompt Explosions In The Early Universe

dThe Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS) was a multi-cycle treasury program on the Hubble Space Telescope (HST) that surveyed a total area of -0.25 deg2 with -900 HST orbits spread across five fields over three years. Within these survey images we discovered 65 supernovae (SNe) of all types, out to z 2.5. We classify -24 of these as Type Ia SNe (SNe Ia) based on host galaxy redshifts and SN photometry (supplemented by grism spectroscopy of six SNe). Here we present a measurement of the volumetric SN Ia rate as a function of redshift, reaching for the first time beyond z =- 2 and putting new constraints on SN Ia progenitor models. Our highest redshift bin includes detections of SNe that exploded when the universe was only -3 Gyr old and near the peak of the cosmic star formation history. This gives the CANDELS high redshift sample unique leverage for evaluating the fraction of SNe Ia that explode promptly after formation ( 40 Myr. However, mild tension is apparent between ground-based low-z surveys and space-based high-z surveys. In both CANDELS and the sister HST program CLASH (Cluster Lensing And Supernova Survey with Hubble), we find a low rate of SNe Ia at z > 1. This could be a hint that prompt progenitors are in fact relatively rare, accounting for only 20% of all SN Ia explosions-though further analysis and larger samples will be needed to examine that suggestion. Key words: infrared: general - supernovae:Astronom

A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus

The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses

Usage Patterns of Stop Smoking Medications in Australia, Canada, the United Kingdom, and the United States: Findings from the 2006–2008 International Tobacco Control (ITC) Four Country Survey

Varenicline is a new prescription stop smoking medication (SSM) that has been available in the United States since August 1, 2006, in the United Kingdom and other European Union countries since December 5, 2006, in Canada since April 12, 2007, and in Australia since January 1, 2008. There are few population-based studies that have examined use rates of varenicline and other stop smoking medications. We report data from the ITC Four Country survey conducted with smokers in the US, UK, Canada, and Australia who reported an attempt to quit smoking in past year in the 2006 survey (n = 4,022 participants), 2007 (n = 3,790 participants), and 2008 surveys (n = 2,735 participants) Respondents reported use of various stop smoking medications to quit smoking at each survey wave, along with demographic and smoker characteristics. The self-reported use of any stop smoking medication has increased significantly over the 3 year period in all 4 countries, with the sharpest increase occurring in the United States. Varenicline has become the second most used stop smoking medication, behind NRT, in all 4 countries since being introduced. Between 2006 and 2008, varenicline use rates increased from 0.4% to 21.7% in the US, 0.0% to 14.8% in Canada, 0.0% to 14.5% in Australia, and 0.0% to 4.4% in the UK. In contrast, use of NRT and bupropion remained constant in each country. Males and non-whites were significantly less likely to report using any SSM, while more educated smokers were significantly more likely to use any SSM, including varenicline. Our findings suggest that the introduction of varenicline led to an increase in the number of smokers who used evidence-based treatment during their quit attempts, rather than simply gaining market share at the expense of other medications. From a public health perspective, messages regarding increased success rates among medication users and the relative safety of stop smoking medications should be disseminated widely so as to reach all smokers of all socioeconomic classifications equally

Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids

Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation o