Ischemic Preconditioning Attenuates Rating of Perceived Exertion But Does Not Improve Maximal Oxygen Consumption or Maximal Power Output.

ABSTRACT: ter Beek, F, Jokumsen, PS, Sloth, BN, Thomas Stevenson, AJ, and Larsen, RG. Ischemic preconditioning attenuates rating of perceived exertion but does not improve maximal oxygen consumption or maximal power output. J Strength Cond Res 36(9): 2479-2485, 2022-Brief consecutive periods of limb ischemia and reperfusion, known as ischemic preconditioning (IPC), have been reported to increase maximal power output (MPO) during cycling. However, the underlying mechanisms are unclear. Therefore, the purpose of the study was to investigate the effects of IPC on MPO, maximal oxygen consumption (V̇ o2 max), muscle oxygenation, and rating of perceived exertion (RPE) during an incremental cycling test. Fourteen healthy young men participated in this double-blinded, randomized crossover study, involving IPC (250 mm Hg; four 5-minute cycles of ischemia) and sham (20 mm Hg) treatment followed by an incremental cycling test to exhaustion. During the cycling test, V̇ o2 , RPE, heart rate (HR), blood lactate (BL), and muscle oxygenation and deoxygenation (near-infrared spectroscopy) were measured. MPO, V̇ o2 max, HRmax, and muscle deoxygenation did not change with IPC (all p -values > 0.13). Furthermore, IPC had no significant effect on V̇ o2 , HR, or muscle oxygenation during the incremental cycling test (all p -values > 0.18). However, IPC attenuated RPE during cycling at 210 W (IPC: median 17.0 [interquartile range 15.3-19.0]; sham: 17.5 [17.0-19.0]; p = 0.007) and 245 W (IPC: 18.0 [17.0-18.8]; sham: 19.0 [18.0-19.8]; p = 0.011). A single session of IPC did not improve MPO, V̇ o2 max, or measures of oxygen consumption during the cycling test. However, IPC lowered RPE at 210 and 245 W, suggesting that IPC may attenuate the perception of effort at higher submaximal exercise intensities.

Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib.

Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS]). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. A clinical trial with 6 APDS patients was conducted as a 12-week, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We observed normalization of circulating transitional and naive B cells, reduction in PD-1+CD4+ and senescent CD57+CD4- T cells, and decreases in elevated serum immunoglobulin M and inflammatory markers including interferon γ, tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), respectively. Thus, leniolisib was well tolerated and improved laboratory and clinical parameters in APDS, supporting the specific inhibition of PI3Kδ as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kδ pathway. This trial was registered at www.clinicaltrials.gov as #NCT02435173.

A low glycemic index diet does not affect postprandial energy metabolism but decreases postprandial insulinemia and increases fullness ratings in healthy women.

At present, it is difficult to determine whether glycemic index (GI) is an important tool in the prevention of lifestyle diseases, and long-term studies investigating GI with diets matched in macronutrient composition, fiber content, energy content, and energy density are still scarce. We investigated the effects of 2 high-carbohydrate (55%) diets with low GI (LGI; 79) or high GI (HGI; 103) on postprandial blood profile, subjective appetite sensations, energy expenditure (EE), substrate oxidation rates, and ad libitum energy intake (EI) from a corresponding test meal (LGI or HGI) after consuming the diets ad libitum for 10 wk. Two groups of a total of 29 healthy, overweight women (age: 30.5 ± 6.6 y; BMI: 27.6 ± 1.5 kg/m(2)) participated in the 10-wk intervention and a subsequent 4-h meal test. The breakfast test meals differed in GI but were equal in total energy, macronutrient composition, fiber content, and energy density. The LGI meal resulted in lower plasma glucose, serum insulin, and plasma glucagon-like peptide (GLP)-1 and higher plasma glucose-dependent insulinotropic polypeptide concentrations than the HGI meal (P ≤ 0.05). Ratings of fullness were slightly higher and the desire to eat something fatty was lower after the test meal in the LGI group (P < 0.05). Postprandial plasma GLP-2, plasma glucagon, serum leptin, plasma ghrelin, EE, substrate oxidation rates, and ad libitum EI at lunch did not differ between groups. In conclusion, postprandial glycemia, insulinemia, and subjective appetite ratings after a test meal were better after 10-wk ad libitum intake of a LGI compared to a HGI diet. EE and substrate oxidation rates were, however, not affected. These findings give some support to recommendations to consume a LGI diet.

Long-term safety and tolerability of bimagrumab (BYM338) in sporadic inclusion body myositis.

OBJECTIVE: To assess the long-term safety and tolerability and to monitor benefits of extended use of bimagrumab in individuals with sporadic inclusion body myositis (sIBM) who completed a single-dose core study. METHODS: In this multicenter, open-label extension study, 10 adults received bimagrumab 10 mg/kg IV every 4 weeks up to 2 years (104 weeks). Safety (primary endpoint) was assessed by recording adverse events (AEs). Clinical benefits were assessed by changes from baseline in thigh muscle volume (TMV), lean body mass (LBM), 6-minute walk distance (6MWD), handgrip, and quadriceps strength. RESULTS: Participants had a mean age of 70.1 (SD 10.4) years. All participants (n = 10) discontinued the treatment due to early termination of the study (n = 7) or AEs (n = 3; myocardial infarction, esophageal carcinoma, and dementia, none of which were treatment related). The most common AEs were muscle spasms and falls (both 9 of 10, 90%), followed by diarrhea (6 of 10, 60%) and acne and skin eruption (both 5 of 10, 50%). At weeks 8 and 16, mean TMV increased from baseline by 4.1% (SD 4.3%) and 4.5% (SD 6.3%). Mean LBM increased from baseline and was sustained at 6.9% (SD 3.9%) at week 76. Means of 6MWD showed a progressive decline from baseline to week 76, during which there was a modest numerical increase in handgrip strength and no significant changes in quadriceps strength. CONCLUSIONS: Long-term treatment up to 2 years with bimagrumab had a good safety profile and was well tolerated in individuals with sIBM. An increase in muscle mass was noted on a group level; however, there was no evidence of clinical improvement. CLINICALTRIALSGOV IDENTIFIER: NCT02250443. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with sIBM, long-term bimagrumab treatment was safe and well tolerated and did not lead to functional improvement.

The effect of a high-MUFA, low-glycaemic index diet and a low-fat diet on appetite and glucose metabolism during a 6-month weight maintenance period.

We aimed to test the effects of three different weight maintenance diets on appetite, glucose and fat metabolism following an initial low-energy diet (LED) induced body weight loss. Following an 8-week LED and a 2-3-week refeeding period, 131 subjects were randomized to three diets for 6 months: MUFA, moderate-fat (35-45 energy percentage (E%) fat), high in MUFA with low glycaemic index; LF, low fat (20-30 E% fat) or CTR, control (35 E% fat). A meal test study was performed in a subgroup, before and after the 6-month dietary intervention, with forty-two subjects completing both meal tests. No difference in body weight, energy intake or appetite ratings were observed between diets. Both the LF and MUFA diets compared to CTR diet reduced postprandial glycaemia and insulinaemia and lowered fasting insulin from month 0 to month 6. Following the 8-week LED period lower levels of the appetite regulating peptides, pancreatic polypeptide, peptide YY, glucagon-like peptide-1 and glucagon-like peptide-2, along with increased appetite scores were seen in comparison to measurements performed after the 6-month dietary intervention. In conclusion, the two competing diets, MUFA and LF, were equally good with respect to glucose metabolism, whereas the CTR diet resembling the typical Western diet, high in SFA, sugar and high glycaemic carbohydrates, indicated associations to lowering of insulin sensitivity. Lower levels of appetite regulatory peptides along with increased appetite scores following an 8-week LED and 2-3-week refeeding period, suggest that strategies for physiological appetite control following a LED period are needed, in order to prevent weight regain.

A low-glycemic-index diet reduces plasma plasminogen activator inhibitor-1 activity, but not tissue inhibitor of proteinases-1 or plasminogen activator inhibitor-1 protein, in overweight women.

BACKGROUND: The development of obesity has been suggested to involve plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of proteinases-1 (TIMP-1). Plasma PAI-1 is elevated in obesity. A low-glycemic-index (LGI) diet may have a beneficial effect on obesity through a decrease in plasma PAI-1, but whether it affects plasma TIMP-1 in healthy humans has not been studied. OBJECTIVE: We investigated whether a 10-wk intake of an LGI or a high-glycemic-index (HGI), high-carbohydrate, low-fat, ad libitum diet is associated with decreases in plasma PAI-1 and TIMP-1 concentrations in overweight women. DESIGN: Forty-four overweight women [body mass index (BMI; in kg/m2): 27.5+/-0.23] were randomly assigned to consume an HGI or an LGI diet for 10 wk. A subgroup of 29 women was assigned to participate in an additional 4-h meal test on the last day of the 10-wk intervention. RESULTS: PAI-1 activity decreased after 10 wk of the LGI diet and was significantly different between groups. Changes in PAI-1 antigen followed the same trend, but no significant difference was observed between groups. No difference in plasma TIMP-1 concentrations was observed between groups. PAI-1 and TIMP-1 concentrations after the 4-h meal test were not significantly different between groups. CONCLUSION: An LGI diet reduces fasting plasma PAI-1 activity and therefore may be useful for diminishing the adverse cardiovascular effects of obesity. This trial was registered at clinicaltrials.gov as NCT00324090.

Measuring the glycemic index of foods: interlaboratory study.

BACKGROUND: Many laboratories offer glycemic index (GI) services. OBJECTIVE: We assessed the performance of the method used to measure GI. DESIGN: The GI of cheese-puffs and fruit-leather (centrally provided) was measured in 28 laboratories (n=311 subjects) by using the FAO/WHO method. The laboratories reported the results of their calculations and sent the raw data for recalculation centrally. RESULTS: Values for the incremental area under the curve (AUC) reported by 54% of the laboratories differed from central calculations. Because of this and other differences in data analysis, 19% of reported food GI values differed by >5 units from those calculated centrally. GI values in individual subjects were unrelated to age, sex, ethnicity, body mass index, or AUC but were negatively related to within-individual variation (P=0.033) expressed as the CV of the AUC for repeated reference food tests (refCV). The between-laboratory GI values (mean+/-SD) for cheese-puffs and fruit-leather were 74.3+/-10.5 and 33.2+/-7.2, respectively. The mean laboratory GI was related to refCV (P=0.003) and the type of restrictions on alcohol consumption before the test (P=0.006, r2=0.509 for model). The within-laboratory SD of GI was related to refCV (P<0.001), the glucose analysis method (P=0.010), whether glucose measures were duplicated (P=0.008), and restrictions on dinner the night before (P=0.013, r2=0.810 for model). CONCLUSIONS: The between-laboratory SD of the GI values is approximately 9. Standardized data analysis and low within-subject variation (refCV<30%) are required for accuracy. The results suggest that common misconceptions exist about which factors do and do not need to be controlled to improve precision. Controlled studies and cost-benefit analyses are needed to optimize GI methodology. The trial was registered at clinicaltrials.gov as NCT00260858.

Glycemic and insulinemic responses as determinants of appetite in humans.

BACKGROUND: The importance of the postprandial glycemic and insulinemic responses for appetite and energy intake (EI) is controversial. OBJECTIVE: The aim of the study was to test the hypothesis that postprandial appetite sensations and subsequent EI are determined by postprandial glycemic and insulinemic responses after the intake of a range of breakfast meals. DESIGN: The study was a randomized, crossover meal test including 28 healthy young men, each of whom tested 10 of 14 breakfast meals. Each meal contained 50 g carbohydrate with various glycemic index and energy and macronutrient contents. Blood samples were taken, and appetite sensations were measured 3 h after the meals. Subsequently, EI at lunch (EI(lunch)) was recorded. RESULTS: The glycemic response was unrelated to appetite sensations, whereas the insulinemic response was positively associated with postprandial fullness (R2 = 0.33, P < 0.05). In contrast, the insulinemic response was unrelated to the subsequent EI(lunch), whereas the glycemic response was positively associated with EI(lunch) (R2 = 0.33, P < 0.05). Although no significant difference in EI(lunch) was observed between different breakfast conditions, a low breakfast EI was associated with a high EI(lunch) (R2 = 0.60, P < 0.001). CONCLUSIONS: The current study does not support the contention that the postprandial glycemic response has an important effect on short-term appetite sensations, but a low-glycemic index meal may reduce subsequent EI. In contrast, postprandial insulin seems to affect short-term appetite sensations.

No difference in body weight decrease between a low-glycemic-index and a high-glycemic-index diet but reduced LDL cholesterol after 10-wk ad libitum intake of the low-glycemic-index diet.

BACKGROUND: The role of glycemic index (GI) in appetite and body-weight regulation is still not clear. OBJECTIVE: The objective of the study was to investigate the long-term effects of a low-fat, high-carbohydrate diet with either low glycemic index (LGI) or high glycemic index (HGI) on ad libitum energy intake, body weight, and composition, as well as on risk factors for type 2 diabetes and ischemic heart disease in overweight healthy subjects. DESIGN: The study was a 10-wk parallel, randomized, intervention trial with 2 matched groups. The LGI or HGI test foods, given as replacements for the subjects' usual carbohydrate-rich foods, were equal in total energy, energy density, dietary fiber, and macronutrient composition. Subjects were 45 (LGI diet: n = 23; HGI diet: n = 22) healthy overweight [body mass index (in kg/m(2)): 27.6 +/- 0.2] women aged 20-40 y. RESULTS: Energy intake, mean (+/- SEM) body weight (LGI diet: -1.9 +/- 0.5 kg; HGI diet: -1.3 +/- 0.3 kg), and fat mass (LGI diet: -1.0 +/- 0.4 kg; HGI diet: -0.4 +/- 0.3 kg) decreased over time, but the differences between groups were not significant. No significant differences were observed between groups in fasting serum insulin, homeostasis model assessment for relative insulin resistance, homeostasis model assessment for beta cell function, triacylglycerol, nonesterified fatty acids, or HDL cholesterol. However, a 10% decrease in LDL cholesterol (P < 0.05) and a tendency to a larger decrease in total cholesterol (P = 0.06) were observed with consumption of the LGI diet as compared with the HGI diet. CONCLUSIONS: This study does not support the contention that low-fat LGI diets are more beneficial than HGI diets with regard to appetite or body-weight regulation as evaluated over 10 wk. However, it confirms previous findings of a beneficial effect of LGI diets on risk factors for ischemic heart disease.

Effect of subcutaneous injections of PYY1-36 and PYY3-36 on appetite, ad libitum energy intake, and plasma free fatty acid concentration in obese males.

Intraveneous (i.v.) PYY(3-36) infusions have been reported to reduce energy intake (EI) in humans, whereas few studies exist on effects of PYY(1-36). The aim of the present study was to examine effects of subcutaneous (sc) injections of PYY(1-36) and PYY(3-36) on appetite, ad libitum EI, plasma concentrations of PYY and free fatty acids (FFA) in obese males. Twenty-four males (BMI 27-40 kg/m(2)) were randomly assigned to two groups receiving sc injections of either PYY(1-36) or PYY(3-36) in a blinded, placebo-controlled, dose-escalating, cross-over study. Subjects were studied 5 days in succession, with escalating doses of PYY(1-36) [saline, 50, 100, 150, and 200 pmol PYY(1-36)/kg lean body mass (LBM)], or PYY(3-36) (saline, 25, 50, 75, and 100 pmol PYY(3-36)/kg LBM), respectively. PYY injections resulted in dose-dependent increases in plasma PYY levels but no effect on EI in either the PYY(1-36) or the PYY(3-36) group. However, increasing doses of PYY(3-36), but not PYY(1-36), resulted in increased ratings of satiety and decreased ratings of hunger, thirst, and prospective food consumption. Although not dose dependently, significant elevation of plasma FFA was seen after injection of PYY(3-36), but not PYY(1-36). Although sc administration of PYY was well tolerated, it remains to be determined whether high-dose PYY(3-36) is sufficient in reducing EI in long-term trials, and if so, whether the reduction in EI occurs without nausea. PYY(1-36) is unlikely to be important in regulating energy intake. The PYY(3-36) administrations caused a non-dose-dependent mobilization of FFA, likely through a direct effect.

Effects of PYY1-36 and PYY3-36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects.

Peptide YY (PYY)(3-36) has been shown to produce dramatic reductions in energy intake (EI), but no human data exist regarding energy expenditure (EE), glucose and fat metabolism. Nothing is known regarding PYY1-36. To compare effects of PYY(1-36) and PYY(3-36) on appetite, EI, EE, insulin, glucose and free fatty acids (FFA) concentrations, 12 lean and 12 obese males participated in a blinded, randomized, crossover study with 90-min infusions of saline, 0.8 pmol x kg(-1) x min(-1) PYY(1-36) and PYY(3-36). Only four participants completed PYY(3-36) infusions because of nausea. Subsequently, six lean and eight obese participants completed 0.2 pmol x kg(-1) x min(-1) PYY(3-36) and 1.6 pmol x kg(-1) x min(-1) PYY(1-36) infusions. PYY(3-36) [corrected] produced [corrected] lower ratings of well-being and [corrected] increases in heart rate, [corrected] FFA, and [corrected] postprandial [corrected] insulin concentrations. Furthermore, high-dose [corrected] PYY(3-36) (0.8 [corrected] pmol x kg(-1) x min(-1)) produced decreased [corrected] EI and increased postprandial [corrected] glucose concentrations and tendency to reduced EE [corrected]