Interrelationships between carbohydrate, fat and protein metabolism

This thesis is primarily concerned with the relationship of energy metabolism to protein metabolism. The field of enquiry was subsequently extended to the metabolism of liver phospholipids and ribonucleic acid, since both of these display certain metabolic features in common with liver protein. The influence of energy intake on protein metabolism in the rat was explored in a study of nitrogen-balance and the protein content of the liver. Rats were fed diets, either adequate in protein content or free from protein, in combination with various levels of energy intake provided by carbohydrate or fat. At the adequate level of protein intake, nitrogen-balance and the protein content of the liver were affected in a strictly linear fashion by variations in energy supply, whereas on the protein-free diet energy intake appeared to have no considerable effect on these. A study was made of the bodily distribution of the changes in nitrogen balance produced by varying the energy content of the diet containing protein. As an extension of these experiments, measurements were made, under the same nutritional conditions, of the rate of incorporation of an isotopically labelled amino acid (glycine-2-14G) into the mixed proteins of the liver. In the post-absorptive state, the rate of glycine incorporation was essentially the same, at any given plane of energy intake, for animals previously fed the protein-containing and protein-free diets. At each level of protein intake, however, the influence of the energy content of the preceding diet was apparent, the effect being considerably more marked when the preceding diet contained protein. This difference in the response of protein metabolism to energy Intake at the two protein levels accounts for the fact that energy intake affected the amount of protein in the liver on one diet, but not on the other. On feeding protein, the pattern of protein metabolism was completely changed. The influx of amino, acids into the liver promoted a rapid increase in the rate of Incorporation of labelled glycine, independent of both the protein and energy content of the previous diet. These observations suggest that synthesis of liver protein proceeds in intermittent bursts, following the ingestion of protein, while the effect of energy Intake on the rate of protein synthesis is a prolonged one exerted between meals on the so-called "endogenous" metabolism of protein. The picture obtained in studying phospholipid metabolism in the liver showed some resemblance to that of liver protein. Only when the diet did the synthesis of phospholid in the liver increase in response to increments in response to increments in energy intake. It is suggested that the feeding of a protein-free diet so reduces the concentration of some precursor or essential component in phospholipid formation that it becomes the limiting factor in the rate of synthesis. Choline was eliminated as the missing factor. No such factor restricts the response of ribonucleic acid metabolism to changes in the energy level of the protein-free diet; the rate of synthesis of ribonucleic acid, as measured by combined quantitative and isotopic studies (32P and glycine-2A4C), appears to be determined, by the energy content of the diet, rather than by its protein content, a fact of particular interest in view of the alleged relationship between ribonucleic acid and protein synthesis. The stimulating effect of an increased energy intake on ribonucleic acid synthesis has been shown to result from the improvement in energy balance rather than from direct involvement in energy balance rather than from direct involvement of ribonucleic acid in energy metabolism. Vitamin B12 was eliminated as a dietary factor affecting the synthesis of ribonucleic acid under the conditions of these experiments. As an hypothesis consistent with these observations on the metabolism of protein, phospholipids and ribonucleic acid in the liver, the availability of energy may be pictured as the factor governing their rates of synthesis. Provided no other component of the synthetic mechanism limits the response to a change in available energy, an improvement in energy balance is associated with an augmented rate of synthesis, It would, however, seem that the increased protein synthesis following the ingestion of protein is independent of energy intake. The findings of these experiments are discussed in the light of current views on the biosynthesis of proteins

Efficacy and Safety Outcomes with Diroximel Fumarate After Switching from Prior Therapies or Continuing on DRF: Results from the Phase 3 EVOLVE-MS-1 Study.

INTRODUCTION: Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF has a safety/efficacy profile similar to DMF but with improved gastrointestinal (GI) tolerability and low (\u3c 1%) treatment discontinuation due to GI adverse events (AEs). Efficacy and safety outcomes in patients who switched to DRF from other disease-modifying therapies (DMTs) have not been evaluated. METHODS: EVOLVE-MS-1 is an ongoing, 2-year, open-label, phase 3 study of DRF in adults with relapsing-remitting MS. Patients either entered as newly enrolled to DRF trials, or from the 5-week, randomized, head-to-head, phase 3 EVOLVE-MS-2 study of DRF and DMF. This analysis evaluated safety and GI tolerability in patients continuing on DRF (DRF-rollover) or switching from DMF (DMF-rollover) following EVOLVE-MS-2. Safety and efficacy were evaluated in a subset of newly enrolled patients who had received prior glatiramer acetate (GA; GA/DRF) or interferons (IFN; IFN/DRF) as their most recent DMT, prior to switching to DRF in EVOLVE-MS-1. RESULTS: As of September 1, 2020, 1057 patients were enrolled in EVOLVE-MS-1, including 166, 182, 239, and 225 patients in the GA/DRF, IFN/DRF, DRF-rollover, and DMF-rollover groups, respectively. Treatment discontinuation due to GI AEs was \u3c 1% in all groups. GA/DRF and IFN/DRF patients experienced improvements from baseline in clinical and radiological efficacy outcomes, including significantly reduced annualized relapse rates. Rollover patients had low rates of new or recurrent GI AEs (DRF-rollover, 26.8%/4.2%; DMF-rollover, 27.1%/4.9%). CONCLUSION: After 2 years of DRF exposure, patients with prior GA, IFN, or fumarate treatment had safety outcomes consistent with previous fumarate studies. Efficacy in patients with prior GA or IFN treatment was consistent with previous fumarate studies. The data suggest that transition to DRF from GA, IFN, or DMF is a reasonable treatment strategy, with low rates of discontinuation due to GI AEs. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02634307). INFOGRAPHIC