No difference between high-fructose and high-glucose diets on liver triacylglycerol or biochemistry in healthy overweight men.

BACKGROUND & AIMS: Diets high in fructose have been proposed to contribute to nonalcoholic fatty liver disease. We compared the effects of high-fructose and matched glucose intake on hepatic triacylglycerol (TAG) concentration and other liver parameters. DESIGN: In a double-blind study, we randomly assigned 32 healthy but centrally overweight men to groups that received either a high-fructose or high-glucose diet (25% energy). These diets were provided during an initial isocaloric period of 2 weeks, followed by a 6-week washout period, and then again during a hypercaloric 2-week period. The primary outcome measure was hepatic level of TAG, with additional assessments of TAG levels in serum and soleus muscle, hepatic levels of adenosine triphosphate, and systemic and hepatic insulin resistance. RESULTS: During the isocaloric period of the study, both groups had stable body weights and concentrations of TAG in liver, serum, and soleus muscle. The high-fructose diet produced an increase of 22 ± 52 µmol/L in the serum level of uric acid, whereas the high-glucose diet led to a reduction of 23 ± 25 µmol/L (P < .01). The high-fructose diet also produced an increase of 0.8 ± 0.9 in the homeostasis model assessment of insulin resistance, whereas the high-glucose diet produced an increase of only 0.1 ± 0.7 (P = .03). During the hypercaloric period, participants in the high-fructose and high-glucose groups had similar increases in weight (1.0 ± 1.4 vs 0.6 ± 1.0 kg; P = .29) and absolute concentration of TAG in liver (1.70% ± 2.6% vs 2.05% ± 2.9%; P = .73) and serum (0.36 ± 0.75 vs 0.33 ± 0.38 mmol/L; P = .91), and similar results in biochemical assays of liver function. Body weight changes were associated with changes in liver biochemistry and concentration of TAGs. CONCLUSIONS: In the isocaloric period, overweight men who were on a high-fructose or a high-glucose diet did not develop any significant changes in hepatic concentration of TAGs or serum levels of liver enzymes. However, in the hypercaloric period, both high-fructose and high-glucose diets produced significant increases in these parameters without any significant difference between the 2 groups. This indicates an energy-mediated, rather than a specific macronutrient-mediated, effect. Clinical trials.gov no: NCT01050140.

Identification of LY3522348: A Highly Selective and Orally Efficacious Ketohexokinase Inhibitor.

The identification of clinical candidate LY3522348 (compound 23) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). Optimization began with highly efficient (S)-2-(2-methylazetidin-1-yl)-6-(1H-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile (3). Efforts focused on developing absorption, distribution, metabolism, potency, and in vitro safety profiles to support oral QD dosing in patients. Structure-based design leveraged vectors for substitution of the pyrazole ring, which provided an opportunity to interact with several different proximal amino acid residues in the protein. LY3522348 displayed a robust pharmacodynamic response in a mouse model of fructose metabolism and was advanced into clinical trials.

The Influence of Rotations on Match Running Performance in Female Australian Football Midfielders.

PURPOSE: With female Australian football (AF) gaining popularity, understanding match demands is becoming increasingly important. The aim of this study was to compare running performances of rotated and whole-quarter state-level female AF players during match quarters. METHODS: Twenty-two state-level female AF midfielders wore Global Positioning System units during 14 games to evaluate activity profiles. The Yo-Yo Intermittent Recovery Test Level 1 (Yo-Yo IR1) was used as a measure of high-intensity running ability. Data were categorized into whole quarter, rotation bout 1, and rotation bout 2 before being further divided into quartiles. Players were separated into high- or low-Yo-Yo IR1 groups using a median split based on their Yo-Yo IR1 performance. Short (4-6 min), moderate (6-12 min), and long (12-18 min) on-field bout activity profiles were compared with whole-quarter players. RESULTS: High Yo-Yo IR1 performance allowed players to cover greater relative distances (ES = 0.57-0.88) and high-speed distances (ES = 0.57-0.86) during rotations. No differences were reported between Yo-Yo IR1 groups when players were required to play whole quarters (ES ≤ 0.26, likelihood ≤64%). Players who were on field for short to moderate durations exhibited greater activity profiles than whole-quarter players. CONCLUSIONS: Superior high-speed running ability results in a greater activity profile than for players who possess lower high-speed running ability. The findings also highlight the importance of short to moderate (4-12 min) rotation periods and may be used to increase high-intensity running performance within quarters in female AF players.