Timothy J. Fairchild

Traveling the Vitamin B12 Pathway: Oral Delivery of Protein and Peptide Drugs

Oral routes of administration for therapeutic peptides and proteins face two major barriers: proteolytic degradation in the stomach and an inadequate absorption mechanism for polypeptides within the intestinal lumen. As a result, peptide-based therapeutics are administered by injection, a painful process associated with lower patient compliance. The development of a means of overcoming these two major obstacles and enabling the successful delivery of peptide therapeutics by the oral route of administration has therefore been the target of extensive scientific endeavor. This Minireview focuses on oral peptide/protein delivery by the dietary uptake pathway for vitamin B(12). Recent progress in this field includes the delivery of erythropoietin, granulocyte-colony-stimulating factor, luteinizing-hormone-releasing hormone, and insulin.

High-intensity intermittent exercise attenuates ad-libitum energy intake

Objective:To examine the acute effects of high-intensity intermittent exercise (HIIE) on energy intake, perceptions of appetite and appetite-related hormones in sedentary, overweight men.Design:Seventeen overweight men (body mass index: 27.7±1.6 kg m−2; body mass: 89.8±10.1 kg; body fat: 30.0±4.3%; VO2peak: 39.2±4.8 ml kg−1 min−1) completed four 30-min experimental conditions using a randomised counterbalanced design. CON: resting control, MC: continuous moderate-intensity exercise (60% VO2peak), HI: high-intensity intermittent exercise (alternating 60 s at 100% VO2peak and 240 s at 50% VO2peak), VHI: very-high-intensity intermittent exercise (alternating 15 s at 170% VO2peak and 60 s at 32% VO2peak). Participants consumed a standard caloric meal following exercise/CON and an ad-libitum meal 70 min later. Capillary blood was sampled and perceived appetite assessed at regular time intervals throughout the session. Free-living energy intake and physical activity levels for the experimental day and the day after were also assessed.Results:Ad-libitum energy intake was lower after HI and VHI compared with CON (P=0.038 and P=0.004, respectively), and VHI was also lower than MC (P=0.028). Free-living energy intake in the subsequent 38 h remained less after VHI compared with CON and MC (P⩽0.050). These observations were associated with lower active ghrelin (P⩽0.050), higher blood lactate (P⩽0.014) and higher blood glucose (P⩽0.020) after VHI compared with all other trials. Despite higher heart rate and ratings of perceived exertion (RPE) during HI and VHI compared with MC (P⩽0.004), ratings of physical activity enjoyment were similar between all the exercise trials (P=0.593). No differences were found in perceived appetite between trials.Conclusions:High-intensity intermittent exercise suppresses subsequent ad-libitum energy intake in overweight inactive men. This format of exercise was found to be well tolerated in an overweight population.

Glycogen synthesis in muscle fibers during active recovery from intense exercise

PURPOSE There is evidence that active recovery impairs glycogen repletion in skeletal muscles of fasted individuals. Our main goal was to examine the impact of active recovery on the glycogen stores of the different muscle fiber types. METHODS Eight endurance-trained individuals cycled for 2.5 min at 130% [OV0312]O(2peak) followed by a 30-s all-out cycling sprint. After exercise, the participants were subjected to either a passive recovery or an active recovery protocol that consisted of pedalling for 45 min at 40% [OV0312]O(2peak). RESULTS During active recovery, blood lactate and pH returned more rapidly toward preexercise levels than during passive recovery. In contrast, average muscle glycogen content remained at stable levels during active recovery (209 +/- 32 and 202 +/- 30 mmol.kg-1 at 0 and 45 min of recovery, respectively) but increased significantly in response to passive recovery (from 185 +/- 27 to 283 +/- 42 mmol.kg-1). The pattern of change in periodic acid-Schiff staining intensity across muscle fibers suggests that the impact of active recovery on average muscle glycogen content is different from that observed at the levels of the individual muscle fibers, with active recovery having no effect on glycogen resynthesis in Type II muscle fibers but causing glycogen breakdown in Type I muscle fibers. Although active recovery was also associated with higher plasma catecholamines and lower insulin levels, such an unfavorable hormonal environment had no effect on glycogen resynthesis in Type II muscle fibers. CONCLUSION Active recovery in comparison to passive recovery does not affect glycogen resynthesis in Type II muscle fibers despite being associated with an unfavorable hormonal environment but results in a marked glycogen mobilization in Type I muscle fibers.

Vitamin B12 in drug delivery: breaking through the barriers to a B12 bioconjugate pharmaceutical

Importance of the field: Vitamin B12 (B12) is a rare and vital micronutrient for which mammals have developed a complex and highly efficient dietary uptake system. This uptake pathway consists of a series of proteins and receptors, and has been utilized to deliver several bioactive and/or imaging molecules from 99mTc to insulin. Areas covered in this review: The current field of B12-based drug delivery is reviewed, including recent highlights surrounding the very pathway itself. What the reader will gain: Despite over 30 years of work, no B12-based drug delivery conjugate has reached the market-place, hampered by issues such as limited uptake capacity, gastrointestinal degradation of the conjugate or high background uptake by healthy tissues. Variability in dose response among individuals, especially across ageing populations and slow oral uptake (several hours), has also slowed development and interest. Take home message: This review is intended to stress again the great potential, as yet not fully realized, for B12-based therapeutics, tumor imaging and oral drug delivery. This review discusses recent reports that demonstrate that the issues noted above can be overcome and need not be seen as negating the great potential of B12 in the drug delivery field.

Vitamin B12 as a carrier for the oral delivery of insulin.

The noninvasive delivery of insulin continues to be a major goal for the treatment of diabetes mellitus. Oral-enteric administration would make insulin delivery easier and more effective, as higher patient compliance and improved glycemic control are likely; yet the oral-enteric pathway has been unfeasible owing to insulins susceptibility to proteolytic degradation and inefficient enteric uptake. Herein we show that a noninvasive oral delivery route for insulin is possible through the vitamin B12 uptake pathway. In diabetic rat models, insulin-B12 conjugates can significantly lower blood glucose levels when administered orally.

Rapid carbohydrate loading after a short bout of near maximal-intensity exercise

PURPOSE One limitation shared by all published carbohydrate-loading regimens is that 2-6 d are required for the attainment of supranormal muscle glycogen levels. Because high rates of glycogen resynthesis are reported during recovery from exercise of near-maximal intensity and that these rates could in theory allow muscle to attain supranormal glycogen levels in less than 24 h, the purpose of this study was to examine whether a combination of a short bout of high-intensity exercise with 1 d of a high-carbohydrate intake offers the basis for an improved carbohydrate-loading regimen. METHODS Seven endurance-trained athletes cycled for 150 s at 130% VO2peak followed by 30 s of all-out cycling. During the following 24 h, each subject was asked to ingest 12 g.kg-1 of lean body mass (the equivalent of 10.3 g.kg-1 body mass) of high-carbohydrate foods with a high glycemic index. RESULTS Muscle glycogen increased from preloading levels (+/- SE) of 109.1 +/- 8.2 to 198.2 +/- 13.1 mmol.kg-1 wet weight within only 24 h, these levels being comparable to or higher than those reported by others over a 2- to 6-d regimen. Densitometric analysis of muscle sections stained with periodic acid-Schiff not only corroborated these findings but also indicated that after 24 h of high-carbohydrate intake, glycogen stores reached similar levels in Type I, IIa, and IIb muscle fibers. CONCLUSION This study shows that a combination of a short-term bout of high-intensity exercise followed by a high-carbohydrate intake enables athletes to attain supranormal muscle glycogen levels within only 24 h.

Energy intake and appetite-related hormones following acute aerobic and resistance exercise

Previous research has shown that resistance and aerobic exercise have differing effects on perceived hunger and circulating levels of appetite-related hormones. However, the effect of resistance and aerobic exercise on actual energy intake has never been compared. This study investigated the effect of an acute bout of resistance exercise, compared with aerobic exercise, on subsequent energy intake and appetite-regulating hormones. Ten active men completed 3 trials in a counterbalanced design: 45 min of resistance exercise (RES; free and machine weights), aerobic exercise (AER; running), or a resting control trial (CON). Following exercise or CON, participants had access to a buffet-style array of breakfast foods and drinks to consume ad libitum. Plasma concentrations of a range of appetite-regulating hormones were measured throughout each trial. Despite significantly higher energy expenditure with AER compared with RES (p < 0.05), there was no difference in total energy intake from the postexercise meal between trials (p = 0.779). Pancreatic polypeptide was significantly higher prior to the meal after both RES and AER compared with CON. In contrast, active ghrelin was lower following RES compared with both CON and AER (p ≤ 0.05), while insulin was higher following RES compared with CON (p = 0.013). In summary, the differential response of appetite-regulating hormones to AER and RES does not appear to influence energy intake in the postexercise meal. However, given the greater energy expenditure associated with AER compared with RES, AER modes of exercise may be preferable for achieving short-term negative energy balance.

Glycogen resynthesis in the absence of food ingestion during recovery from moderate or high intensity physical activity: novel insights from rat and human studies

The finding that during recovery from high intensity exercise, rats have the capacity to replenish their muscle glycogen stores even in the absence of food intake has provided us with an experimental model of choice to explore further this process. Our objective here is to share those questions arising from research carried out by others and ourselves on rats and humans that are likely to be of interest to comparative biochemists/physiologists. On the basis of our findings and those of others, it is proposed that across vertebrate species: (1). the capacity of muscles to replenish their glycogen stores from endogenous carbon sources is dependent on the type of physical activity and animal species; (2). lactate and amino acids are the major endogenous carbon sources mobilized for the resynthesis of muscle glycogen during recovery from exercise, their relative contributions depending on the duration of recovery and type of exercise; (3). the relative contributions of lactate glyconeogenesis and hepatic/renal gluconeogenesis to muscle glycogen synthesis is species- and muscle fiber-dependent; and (4). glycogen synthase and phosphorylase play an important role in the control of the rate of glycogen synthesis post-exercise, with the role of glucose transport being species-dependent.

The Use of Mixed-Method, Part-Body Pre-Cooling Procedures for Team-Sport Athletes Training in the Heat

Duffield, R, Steinbacher, G, and Fairchild, TJ. The use of mixed-method, part-body pre-cooling procedures for team-sport athletes training in the heat. J Strength Cond Res 23(9): 2524-2532, 2009-The current study investigated the effects of a pre-cooling intervention on physiological and performance responses to team-sport training in the heat. Seven male lacrosse players performed a familiarization session and 2 randomized, counterbalanced sessions consisting of a 30-minute intermittent-sprint conditioning session. Prior to the sessions, players performed a 20-minute mixed-method, part-body cooling intervention (consisting of cooling vests, cold towels to the neck, and ice packs to the quadriceps) or no cooling intervention. Performance was determined from collection of 1 Hz global positioning system (GPS) data and analyzed for distance and speed. Prior to, during, and following the sessions, core temperature, heart rate, rating of perceived exertion (RPE), and thermal sensation scale (TSS) were measured; additionally, a venous blood sample was collected before and after each session for measurement of interleukin-6 (IL-6), insulin-like growth factor (IGF-1) and insulin-like growth factor-binding protein3 (IGF-BP3). Results indicated that a greater distance was covered during the pre-cooling condition (3.35 ± 0.20 vs. 3.11 ± 0.13 km; p = 0.05). Further, most of this improvement was evident from a greater distance covered during moderate intensities of 7 to 14 km/h (2.28 ± 0.18 vs. 2.00 ± 0.24 km; p = 0.05). Peak speeds and very-high-intensity efforts (20 km/h ±) were not different between conditions (p > 0.05). The increase in core temperature was blunted following cooling, with a lower core temperature throughout the cooling session (38.8 ± 0.3 vs. 39.3 ± 0.4°C; p < 0.05). However, there were no differences in heart rate, RPE, TSS, IL-6, IGF-1, or IGF-BP3 between conditions (p > 0.05). Accordingly, the use of a mixed-method, part-body cooling intervention prior to an intermittent-sprint training session in the heat can assist in reducing thermoregulatory load and improve aspects of training performance for team sports.

Oral Delivery of the Appetite Suppressing Peptide hPYY(3–36) through the Vitamin B12 Uptake Pathway

hPYY(3-36) injections have shown positive effects on appetite regulations, sparking increased interest in hPYY(3-36) research. Of great interest is oral delivery of hPYY(3-36) that can achieve clinically relevant weight-loss outcomes in what would be a highly patient compliant route. Successful oral delivery of other peptides utilizing the vitamin B12 pathway has been shown but below clinically relevant levels. Herein, we present clinically relevant in vivo oral delivery of B12-hPYY(3-36) conjugates.