Dr Ralph Manders


Lecturer in Exercise Physiology
+44 (0)1483 688668
29 PG 00
9am - 6pm

Biography

Areas of specialism

Exercise physiology; Glycemic control; Muscle metabolism; Nutrition; Sport science

University roles and responsibilities

  • Admissions Tutor for BSc (Hons) Sport and Exercise Science
  • Programme Leader for BSc (Hons) Sport and Exercise Science
  • Radiation Protection Supervisor FHMS

Research

Research interests

Research projects

Supervision

Postgraduate research supervision

Postgraduate research supervision

My teaching

My publications

Highlights

Rees Jordan L., Chang Courtney R., François Monique E., Marcotte-Chénard Alexis, Fontvieille Adeline, Klaprat Nika D., Dyck Rebecca A., Funk Deanna R., Snydmiller Gary, Bastell Kent, Godkin Florence E., Dubé Marie-Christine, Riesco Eléonor, McGavock Jon M., Yardley Jane E., Sigal Ronald J., Gibala Martin J., Weisnagel S. John, Prado Carla M., Jung Mary, Manders Ralph, Lee Terry, Singer Joel, Boulé Normand G., Little Jonathan P. (2019) Minimal effect of walking before dinner on glycemic responses in type 2 diabetes: outcomes from the multi-site E-PAraDiGM study, Acta Diabetologica 56 (7) pp. 755-765 Springer Verlag

DOI: 10.1007/s00592-019-01358-x

Darling A. L., Manders R. J. F., Sahni S., Zhu K., Hewitt C. E., Prince R. L., Millward D. J., Lanham-New S. A. (2019) Dietary protein and bone health across the life-course: an updated systematic review and meta-analysis over 40 years, Osteoporosis International 30 (4) pp. 741-761 Springer London

DOI: 10.1007/s00198-019-04933-8

Faithfull Sara, Turner Lauren, Poole Karen, Joy Mark, Manders Ralph, Weprin Jennifer, Winters-Stone Kerri, Saxton John (2019) Prehabilitation for adults diagnosed with cancer: A systematic review of long-term physical function, nutrition and patient-reported outcomes, European Journal of Cancer Care e13023 pp. 1-22 Wiley

DOI: 10.1111/ecc.13023

Publications

Kaastra B, Manders RJF, Van Breda E, Kies A, Jeukendrup AE, Keizer HA, Kuipers H, Van Loon LJC (2006) Effects of increasing insulin secretion on acute postexercise blood glucose disposal, Medicine and Science in Sports and Exercise 38 (2) pp. 268-275
Background: Coingestion of protein and/or free amino acids with carbohydrate has been reported to accelerate postexercise muscle glycogen synthesis due to an increase in the insulin response. Purpose: To determine the extent to which the combined ingestion of carbohydrate and a casein protein hydrolysate with or without additional free leucine can increase insulin levels during postexercise recovery in endurance-trained athletes. To determine how this affects whole-body plasma glucose disposal during postexercise recovery. Methods: Fourteen male athletes (age: 24.3 ± 0.8 yr; V?O 2max: 62.9 ± 1.4 mL·kg-1·min -1) were subjected to three randomized crossover trials in which they performed 2 h of exercise (55% Wmax). Thereafter, subjects were studied for 3.5 h during which they ingested carbohydrate (CHO: 0.8 g·kg -1·h-1), carbohydrate and a protein hydrolysate (CHO-PRO: 0.8 and 0.4 g·kg-1·h-1, respectively), or carbohydrate, a protein hydrolysate, and free leucine (CHO-PRO-LEU: 0.8, 0.4, and 0.1 g·kg-1·h-1, respectively) in a double-blind fashion. Continuous infusions with [6,6- 2H2] glucose were applied to quantify plasma glucose appearance (Ra) and disappearance rates (Rd). Results: Plasma insulin responses were 108 ± 17 and 190 ± 33% greater in the CHO-PRO and CHO-PRO-LEU trial, respectively, compared with the CHO-trial (P
Manders RJF, Hansen D, Zorenc AHG, Dendale P, Kloek J, Saris WHM, Van Loon LJC (2014) Protein co-ingestion strongly increases postprandial insulin secretion in type 2 diabetes patients, Journal of Medicinal Food 17 (7) pp. 758-763
The capacity of nutritional protein to induce endogenous insulin secretion has been well established. However, it is not known whether such a response is applicable in a diverse population of type 2 diabetes patients. The aim of the present study was to assess the impact of co-ingesting either intact or hydrolyzed protein with carbohydrate on postprandial plasma insulin and glucose responses in type 2 diabetes patients. Sixty longstanding, male, type 2 diabetes patients participated in a study in which we determined postprandial plasma insulin and glucose responses after ingesting a single bolus of carbohydrate (0.7g/kg: CHO) with or without an intact protein (0.3g/kg: PRO) or its hydrolysate (0.3g/kg: PROh). Results showed that protein co-ingestion strongly increased postprandial insulin release, with the insulin response +99±41 and +110±10% greater in the CHO+PRO and CHO+PROh experiments when compared with the CHO experiment. The insulinotropic properties of protein co-ingestion were evident in nearly all patients, with 58 out of 60 patients responding >10% when compared with the insulin response following carbohydrate ingestion only (CHO). The concomitant plasma glucose responses were 22±32 and 23±36% lower in the CHO+PRO and CHO+PROh experiments, respectively. We conclude that protein co-ingestion represents an effective dietary strategy to strongly augment postprandial insulin release and attenuate the postprandial rise in glucose concentration in type 2 diabetes patients. © 2014 Mary Ann Liebert, Inc.
van Loon LJ, Koopman R, Manders R, van der Weegen W, van Kranenburg GP, Keizer HA (2004) Intramyocellular lipid content in type 2 diabetes patients compared with overweight sedentary men and highly trained endurance athletes., Am J Physiol Endocrinol Metab 287 (3) pp. E558-E565
Recent evidence suggests that intramyocellular lipid (IMCL) accretion is associated with obesity and the development of insulin resistance and/or type 2 diabetes. However, trained endurance athletes are markedly insulin sensitive, despite an elevated mixed muscle lipid content. In an effort to explain this metabolic paradox, we compared muscle fiber type-specific IMCL storage between populations known to have elevated IMCL deposits. Immunofluorescence microscopy was performed on muscle biopsies obtained from eight highly trained endurance athletes, eight type 2 diabetes patients, and eight overweight, sedentary men after an overnight fast. Mixed muscle lipid content was substantially greater in the endurance athletes (4.0 +/- 0.4% area lipid stained) compared with the diabetes patients and the overweight men (2.3 +/- 0.4 and 2.2 +/- 0.5%, respectively). More than 40% of the greater mixed muscle lipid content was attributed to a higher proportion type I muscle fibers (62 +/- 8 vs. 38 +/- 3 and 33 +/- 7%, respectively), which contained 2.8 +/- 0.3-fold more lipid than the type II fibers. The remaining difference was explained by a significantly greater IMCL content in the type I muscle fibers of the trained athletes. Differences in IMCL content between groups or fiber types were accounted for by differences in lipid droplet density, not lipid droplet size. IMCL distribution showed an exponential increase in lipid content from the central region toward the sarcolemma, which was similar between groups and fiber types. In conclusion, IMCL contents can be substantially greater in trained endurance athletes compared with overweight and/or type 2 diabetes patients. Because structural characteristics and intramyocellular distribution of lipid aggregates seem to be similar between groups, we conclude that elevated IMCL deposits are unlikely to be directly responsible for inducing insulin resistance.
Van Loon LJC, Manders RJF, Koopman R, Kaastra B, Stegen JHCH, Gijsen AP, Saris WHM, Keizer HA (2005) Inhibition of adipose tissue lipolysis increases intramuscular lipid use in type 2 diabetic patients, Diabetologia 48 (10) pp. 2097-2107
Aims/hypothesis: In the present study, we investigated the consequences of adipose tissue lipolytic inhibition on skeletal muscle substrate use in type 2 diabetic patients. Materials and methods: We studied ten type 2 diabetic patients under the following conditions: (1) at rest; (2) during 60 min of cycling exercise at 50% of maximal workload capacity and subsequent recovery. Studies were done under normal, fasting conditions (control trial: CON) and following administration of a nicotinic acid analogue (low plasma non-esterified fatty acid trial: LFA). Continuous [U-13C]palmitate and [6,6 - 2H2]glucose infusions were applied to quantify plasma NEFA and glucose oxidation rates, and to estimate intramuscular triacylglycerol (IMTG) and glycogen use. Muscle biopsies were collected before and after exercise to determine net changes in lipid and glycogen content specific to muscle fibre type. Results: Following administration of the nicotinic acid analogue (Acipimox), the plasma NEFA rate of appearance was effectively reduced, resulting in lower NEFA concentrations in the LFA trial (p
Van Dijk JW, Manders RJF, Canfora EE, Van Mechelen W, Hartgens F, Stehouwer CDA, Van Loon LJC (2013) Exercise and 24-h glycemic control: Equal effects for all type 2 diabetes patients?, Medicine and Science in Sports and Exercise 45 (4) pp. 628-635
Purpose: We assessed the effect of a single bout of moderate-intensity exercise on subsequent 24-h glycemic control in 60 type 2 diabetes patients. Moreover, we examined whether individual responses to exercise were related to subjects' baseline characteristics, including age, body mass index, diabetes duration, exercise performance, medication, and HbA1c content. Methods: Sixty type 2 diabetes patients (insulin-treated, n = 23) participated in a randomized crossover experiment. Patients were studied on two occasions for 3 d under strict dietary standardization but otherwise free-living conditions. Parameters of glycemic control (means [95% confidence interval]) were assessed by continuous glucose monitoring over the 24-h period after a single bout of moderate-intensity endurance-type exercise or no exercise at all (control). Results: Type 2 diabetes patients experienced hyperglycemia (blood glucose > 10 mmol·L-1) for as much as 8:16 h:min (6:44 to 9:48 h:min) per day. The prevalence of hyperglycemia was reduced by 31% to 5:38 h:min (3:17 to 7:00 h:min) over the 24-h period after the exercise bout (P
Manders RJF, Van Dijk JWM, Van Loon LJC (2010) Low-intensity exercise reduces the prevalence of hyperglycemia in type 2 diabetes, Medicine and Science in Sports and Exercise 42 (2) pp. 219-225
Introduction: Glycemic instability is a severely underestimated problem in type 2 diabetes treatment. Therapeutic targets should aim to reduce postprandial blood glucose excursions. Exercise prescription can effectively improve glucose homeostasis and reduce the risk of cardiovascular complications. Aim: To assess the impact of a single, isoenergetic bout of low-(LI) and high-intensity (HI) exercise on the prevalence of hyperglycemia throughout the subsequent 24-h postexercise period in longstanding type 2 diabetes patients. Methods: Nine sedentary, male type 2 diabetes patients (age = 57 ± 2 yr, body mass index = 29.0 ± 1.0 kg"m, Wmax = 2.2 ± 0.2 W"kg body weight) were selected to participate in a randomized crossover study. Subjects performed an isoenergetic bout of endurance-type exercise for 60 min at 35% Wmax (LI) or 30 min at 70% Wmax (HI) or no exercise at all (NE). Thereafter, glycemic control was assessed during the subsequent 24-h postexercise period by contnuous glucose monitoring under strict dietary standardization but otherwise free-living conditions. Results: Average 24-h glucose concentrations were reduced after the LI exercise bout (7.8 ± 0.9 mmol"L) when compared with the control experiment (9.4 ± 0.8 mmol"L; P
The loss of muscle mass and strength with aging (i.e., sarcopenia) has a negative effect on functional independence and overall quality of life. One main contributing factor to sarcopenia is the reduced ability to increase skeletal muscle protein synthesis in response to habitual feeding, possibly due to a reduction in postprandial insulin release and an increase in insulin resistance. Branched-chain amino acids (BCAA), primarily leucine, increases the activation of pathways involved in muscle protein synthesis through insulin-dependent and independent mechanisms, which may help counteract the -anabolic resistance{norm of matrix} to feeding in older adults. Leucine exhibits strong insulinotropic characteristics, which may increase amino acid availability for muscle protein synthesis, reduce muscle protein breakdown, and enhance glucose disposal to help maintain blood glucose homeostasis. © 2012 by the authors; licensee MDPI, Basel, Switzerland.
Manders RJF, Praet SFE, Vikstrom MH, Saris WHM, van Loon LJC (2009) Protein hydrolysate co-ingestion does not modulate 24 h glycemic control in long-standing type 2 diabetes patients, EUROPEAN JOURNAL OF CLINICAL NUTRITION 63 (1) pp. 121-126 NATURE PUBLISHING GROUP
Manders RJ, Koopman R, Beelen M, Gijsen AP, Wodzig WK, Saris WH, Van Loon LJ (2008) The muscle protein synthetic response to carbohydrate and protein ingestion is not impaired in men with longstanding type 2 diabetes, Journal of Nutrition 138 (6) pp. 1079-1085
Protein ingestion stimulates muscle protein synthesis and improves net muscle protein balance. Insulin resistance has been suggested to result in a reduced muscle protein synthetic response to food intake. As such, we hypothesized that type 2 diabetes patients have a impaired muscle protein synthetic response to food ingestion. To test this hypothesis, 10 male type 2 diabetes patients using their normal oral glucose-lowering medication (68 ± 2 y) and 10 matched, normoglycemic men (65 ± 2 y) were randomly assigned to 2 crossover treatments in which whole body and muscle protein synthesis were measured following the consumption of either carbohydrate (CHO) or carbohydrate with a protein hydrolysate (CHO+PRO). Primed, continuous infusions with L-[ring-13C6]phenylalanine and L-[ring-2H2]tyrosine were applied and blood and muscle samples were collected to assess whole-body protein balance and mixed muscle protein fractional synthetic rate over a 6-h period. Whole-body phenylalanine and tyrosine flux were higher after the CHO+PRO treatment compared with the CHO treatment in the diabetes and control group (P
Koopman R, Manders RJF, Zorenc AHG, Hul GBJ, Kuipers H, Keizer HA, van Loon LJC (2005) A single session of resistance exercise enhances insulin sensitivity for at least 24 h in healthy men, European Journal of Applied Physiology 94 (1-2) pp. 180-187
The aim of the present study was to determine whether a single session of resistance exercise improves whole-body insulin sensitivity in healthy men for up to 24 h. Twelve male subjects (23±1 years) were studied over a period of 4 days during which they consumed a standardized diet, providing 0.16±0.01 MJ·kg-1·day-1 containing 15±0.1 energy% (En%) protein, 29±0.1 En% fat and 55±0.3 En% carbohydrate. Insulin sensitivity was determined 24 h before and 24 h after a single resistance exercise session (8 sets of 10 repetitions at 75% of 1 repetition maximum for two leg exercise tasks) using an intravenous insulin tolerance test. Insulin sensitivity index was calculated by the decline in arterial blood glucose concentration following intravenous administration of a single bolus of human insulin (0.075 IU·kg-1 fat free mass). Basal glucose and insulin concentrations were not changed up to 24h after the resistance exercise. However, a substantial 13±5% improvement in whole-body insulin sensitivity was observed, 24 h after the resistance exercise (P
Manders RJF, Pennings B, Beckers CPG, Aipassa TI, Van Loon LJC (2009) Prevalence of daily hyperglycemia in obese type 2 diabetic men compared with that in lean and obese normoglycemic men: Effect of consumption of a sucrose-containing beverage, American Journal of Clinical Nutrition 90 (3) pp. 511-518
Background: Hyperglycemia forms a direct and independent risk factor for the development of cardiovascular comorbidities in type 2 diabetes. Consumption of sucrose-sweetened soft drinks might further increase the prevalence of hyperglycemic episodes. Objective: The objective was to assess glycemic control in type 2 diabetic subjects and healthy lean and obese control subjects under strict dietary standardization but otherwise free-living conditions, with and without the consumption of soft drinks. Design: Obese type 2 diabetic men (n = 11) and lean (n = 10) and obese (n = 10) normoglycemic male control subjects participated in a randomized crossover study. The subjects were provided with a standardized diet in 2 periods, during which they consumed 250 mL water with or without (control) sucrose (37.5 g) 2 h after breakfast and lunch. Blood glucose concentrations were assessed by continuous glucose monitoring. Results: In the type 2 diabetic subjects, the mean 24-h glucose concentrations were significantly elevated (9.1 ± 0.6 mmol/L), and hyperglycemia (glucose .10 mmol/L) was evident over 33 ± 8% (8 ± 2 h) of a 24-h period (P
Weseler AR, Geraets L, Moonen HJ, Manders RJ, van Loon LJ, Pennings HJ, Wouters EF, Bast A, Hageman GJ (2009) Poly (ADP-ribose) polymerase-1-inhibiting flavonoids attenuate cytokine release in blood from male patients with chronic obstructive pulmonary disease or type 2 diabetes., J Nutr 139 (5) pp. 952-957
Recently, we identified several flavonoids as inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 in vitro and in vivo. PARP-1 is recognized as coactivator of nuclear factor-kappaB and plays a role in the pathophysiology of diseases with low-grade systemic inflammation, such as chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D). In this study, we assessed the antiinflammatory effects of flavonoids with varying PARP-1-inhibiting effects in whole blood from male patients with COPD or T2D and healthy men. A total of 10 COPD, 10 T2D patients, and 10 healthy volunteers matched for age and BMI were recruited. Blood from each participant was exposed to 1 microg/L lipopolysaccharide (LPS) over 16 h with or without preincubation with 10 micromol/L of flavone, fisetin, morin, or tricetin. Concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, -8, and -10 were measured in the supernatant. Preincubation with fisetin and tricetin strongly attenuated LPS-induced increases in concentrations of TNFalpha in blood from COPD patients [mean (+/- SEM): -41 +/- 4% (fisetin) and -31 +/- 4% (tricetin); P
Praet SF, Manders RJ, Lieverse AG, Kuipers H, Stehouwer CD, Keizer HA, Van Loon LJ (2006) Influence of acute exercise on hyperglycemia in insulin-treated type 2 diabetes, Medicine and Science in Sports and Exercise 38 (12) pp. 2037-2044
Introduction: The impact of exercise on blood glucose homeostasis has not been assessed in long-standing type 2 diabetes patients receiving exogenous insulin treatment. Purpose: To study the effects of an acute bout of exercise on the subsequent 24-h blood glucose excursions under free-living conditions in insulin-treated type 2 diabetes patients. Methods: Eleven male type 2 diabetes patients (59 ± 2 yr) performed an acute bout of exercise. One day before the exercise bout, a continuous glucose monitoring system (GlucoDay®, A. Menarini Diagnostics) was inserted subcutaneously in the periumbilical region. The glucose sensor continuously measured glucose concentrations in the dialysate during a 48-h period. Results: The prevalence of hyperglycemic glucose excursions was reduced by 39% during a 24-h period (equivalent to 3 h) after an acute bout of exercise (P
Manders RJF, van Dijk J-WM, Hartgens F, van Loon LJC (2009) A single bout of low-intensity exercise strongly reduces the prevalence of hyperglycaemia throughout the day in type 2 diabetes patients, DIABETOLOGIA 52 pp. S271-S272 SPRINGER
Little JP, Jung ME, Wright AE, Wright W, Manders RJF (2014) Effects of high-intensity interval exercise versus continuous moderate-intensity exercise on postprandial glycemic control assessed by continuous glucose monitoring in obese adults, Applied Physiology, Nutrition and Metabolism 39 (7) pp. 835-841
The purpose of this study was to examine the impact of acute high-intensity interval training (HIIT) compared with continuous moderate-intensity (CMI) exercise on postprandial hyperglycemia in overweight or obese adults. Ten inactive, overweight or obese adults (41 ± 11 yrs, BMI = 36 ± 7 kg/m2) performed an acute bout of HIIT (10 × 1 min at approximately 90% peak heart rate (HRpeak) with 1-min recovery periods) or matched work CMI (30 min at approximately 65% HRpeak) in a randomized, counterbalanced fashion. Exercise was performed 2 h after breakfast, and glucose control was assessed by continuous glucose monitoring under standardized dietary conditions over 24 h. Postprandial glucose (PPG) responses to lunch, dinner, and the following day's breakfast were analyzed and compared with a no-exercise control day. Exercise did not affect the PPG responses to lunch, but performing both HIIT and CMI in the morning significantly reduced the PPG incremental area under the curve (AUC) following dinner when compared with control (HIIT = 110 ± 35, CMI = 125 ± 34, control = 162 ± 46 mmol/L × 2 h, p 0.05 for all). We conclude that a single session of HIIT has greater and more lasting effects on reducing incremental PPG when compared with CMI. © 2014 Published by NRC Research Press.
Chalil S, Deldicque L, Jaspers RT, Manders RJ, Klein-Nulend J, Bakker AD (2014) Increased Endoplasmic Reticulum Stress in Mouse Osteocytes with Aging Alters Cox-2 Response to Mechanical Stimuli, Calcified Tissue International
Aging reduces bone mass as well as the anabolic response of bone to mechanical stimuli, resulting in osteopenia. Endoplasmic reticulum (ER) stress impairs the response of myogenic cells to anabolic stimuli, and is involved in sarcopenia, but whether ER stress also contributes to osteopenia is unknown. Therefore, we tested whether ER stress exists in bones of aged mice, and whether this impairs the osteocyte response to mechanical stimulation. Primary osteocytes were obtained from long bones of adult (8 months) and old (24?26 months) mice, treated with or without the pharmacological ER stress inducer tunicamycin, and either or not subjected to mechanical loading by pulsating fluid flow (PFF). The osteocyte response to PFF was assessed by measuring cyclooxygenase-2 (Cox-2) mRNA levels and nitric oxide (NO) production. mRNA levels of ER stress markers were higher in old versus adult osteocytes (+40 % for activating transcription factor-4, +120 % for C/EBP homologous protein, and +120 % for spliced X-box binding protein-1, p
van Dijk JW, Manders RJF, Hartgens F, Stehouwer CD, Praet SFE, van Loon LJC (2011) Postprandial hyperglycemia is highly prevalent throughout the day in type 2 diabetes patients, Diabetes Research and Clinical Practice 93 (1) pp. 31-37
Aim: Although postprandial hyperglycemia is recognized as an important target in type 2 diabetes treatment, information on the prevalence of postprandial hyperglycemia throughout the day is limited. Therefore, we assessed the prevalence of hyperglycemia throughout the day in type 2 diabetes patients and healthy controls under standardized dietary, but otherwise free-living conditions. Methods: 60 male type 2 diabetes patients (HbA 1c 7.5±0.1% [58±1mmol/mol]) and 24 age- and BMI-matched normal glucose tolerant controls were recruited to participate in a comparative study of daily glycemic control. During a 3-day experimental period, blood glucose concentrations throughout the day were assessed by continuous glucose monitoring. Results: Type 2 diabetes patients experienced hyperglycemia (glucose concentrations >10mmol/L) 38±4% of the day. Even diabetes patients with an HbA 1c level below 7.0% (53mmol/mol) experienced hyperglycemia for as much as 24±5% throughout the day. Hyperglycemia was negligible in the control group (3±1%). Conclusion: Hyperglycemia is highly prevalent throughout the day in type 2 diabetes patients, even in those patients with a HbA 1c level well below 7.0% (53mmol/mol). Standard medical care with prescription of oral blood glucose lowering medication does not provide ample protection against postprandial hyperglycemia. © 2011 Elsevier Ireland Ltd.
Koopman R, Verdijk L, Manders RJF, Gijsen AP, Gorselink M, Pijpers E, Wagenmakers AJM, Van Loon LJC (2006) Co-ingestion of protein and leucine stimulates muscle protein synthesis rates to the same extent in young and elderly lean men, American Journal of Clinical Nutrition 84 (3) pp. 623-632
Background: The progressive loss of skeletal muscle mass with aging is attributed to a disruption in the regulation of skeletal muscle protein turnover. Objective: We investigated the effects on whole-body protein balance and mixed-muscle protein synthesis rates of the ingestion of carbohydrate with or without protein and free leucine after simulated activities of daily living. Design: Eight elderly (75 ± 1 y) and 8 young (20 ± 1 y) lean men were randomly assigned to 2 crossover experiments in which they consumed either carbohydrate (CHO) or carbohydrate plus protein and free leucine (CHO+Pro+Leu) after performing 30 min of standardized activities of daily living. Primed, continuous infusions with L-[ring-13C6]phenylalanine and L-[ring-2H2]tyrosine were applied, and blood and muscle samples were collected to assess whole-body protein turnover and the protein fractional synthetic rate in the vastus lateralis muscle over a 6-h period. Results: Whole-body phenylalanine and tyrosine flux were significantly higher in the young than in the elderly men (P
Chalil S, Pierre N, Bakker A, Manders R, Pletsers A, Francaux M, Klein-Nulend J, Jaspers R, Deldicque L (2015) Aging related ER stress is not responsible for anabolic resistance in mouse skeletal muscle., Biochemical and Biophysical Research Communications 468 (4) pp. 702-707
Hansen D, Dendale P, Beelen M, Jonkers R, Manders R, Corluy L, Mullens A, Meeusen R, van Loon L (2008) Low intensity exercise is as effective as high intensity exercise to improve glycemic control in obese type 2 diabetes, ACTA CARDIOLOGICA 63 (1) pp. 94-94 ACTA CARDIOLOGICA
Praet SFE, Manders RJF, Meex RCR, Lieverse AG, Stehouwer CDA, Kuipers H, Keizer HA, Van Loon LJC (2006) Glycaemic instability is an underestimated problem in Type II diabetes, Clinical Science 111 (2) pp. 119-126
The aim of the present study was to assess the level of glycaemic control by the measurement of 24 h blood glucose profiles and standard blood analyses under identical nutritional and physical activity conditions in patients with Type II diabetes and healthy normoglycaemic controls. A total of 11 male patients with Type II diabetes and 11 healthy matched controls participated in a 24 h CGMS (continuous subcutaneous glucose-monitoring system) assessment trial under strictly standardized dietary and physical activity conditions. In addition, fasting plasma glucose, insulin and HbA1c (glycated haemoglobin) concentrations were measured, and an OGTT (oral glucose tolerance test) was performed to calculate indices of whole-body insulin sensitivity, oral glucose tolerance and/or glycaemic control. In the healthy control group, hyperglycaemia (blood glucose concentration > 10 mmol/l) was hardly present (2 ± 1% or 0.4 + 0.2/24 h). However, in the patients with Type II diabetes, hyperglycaemia was experienced for as much as 55 + 7% of the time (13 ± 2 h over 24 h) while using the same standardized diet. Breakfast-related hyperglycaemia contributed most (46 ± 7%; P
Hansen D, Dendale P, Jonkers RAM, Beelen M, Manders RJF, Corluy L, Mullens A, Berger J, Meeusen R, van Loon LJC (2009) Continuous low- to moderate-intensity exercise training is as effective as moderate- to high-intensity exercise training at lowering blood HbA(1c) in obese type 2 diabetes patients, DIABETOLOGIA 52 (9) pp. 1789-1797 SPRINGER
Chalil S, Jaspers RT, Manders RJ, Klein-Nulend J, Bakker AD, Deldicque L (2014) Increased Endoplasmic Reticulum Stress in Mouse Osteocytes with Aging Alters Cox-2 Response to Mechanical Stimuli, Calcified Tissue International 96 (2) pp. 123-128
© 2014, Springer Science+Business Media New York.Aging reduces bone mass as well as the anabolic response of bone to mechanical stimuli, resulting in osteopenia. Endoplasmic reticulum (ER) stress impairs the response of myogenic cells to anabolic stimuli, and is involved in sarcopenia, but whether ER stress also contributes to osteopenia is unknown. Therefore, we tested whether ER stress exists in bones of aged mice, and whether this impairs the osteocyte response to mechanical stimulation. Primary osteocytes were obtained from long bones of adult (8 months) and old (24?26 months) mice, treated with or without the pharmacological ER stress inducer tunicamycin, and either or not subjected to mechanical loading by pulsating fluid flow (PFF). The osteocyte response to PFF was assessed by measuring cyclooxygenase-2 (Cox-2) mRNA levels and nitric oxide (NO) production. mRNA levels of ER stress markers were higher in old versus adult osteocytes (+40 % for activating transcription factor-4, +120 % for C/EBP homologous protein, and +120 % for spliced X-box binding protein-1, p 
Koopman R, Wagenmakers AJM, Manders RJF, Zorenc AHG, Senden JMG, Gorselink M, Keizer HA, Van Loon LJC (2005) Combined ingestion of protein and free leucine with carbohydrate increases postexercise muscle protein synthesis in vivo in male subjects, American Journal of Physiology - Endocrinology and Metabolism 288 (4 51-4)
The present study was designed to determine postexercise muscle protein synthesis and whole body protein balance following the combined ingestion of carbohydrate with or without protein and/or free leucine. Eight male subjects were randomly assigned to three trials in which they consumed drinks containing either carbohydrate (CHO), carbohydrate and protein (CHO+PRO), or carbohydrate, protein, and free leucine (CHO+PRO+Leu) following 45 min of resistance exercise. A primed, continuous infusion of L-[ring-13C6] phenylalanine was applied, with blood samples and muscle biopsies collected to assess fractional synthetic rate (FSR) in the vastus lateralis muscle as well as whole body protein turnover during 6 h of postexercise recovery. Plasma insulin response was higher in the CHO+PRO+Leu compared with the CHO and CHO+PRO trials (+240 ± 19% and +77 ± 11%, respectively, P
Koopman R, Manders RJF, Jonkers RAM, Hul GBJ, Kuipers H, van Loon LJC (2006) Intramyocellular lipid and glycogen content are reduced following resistance exercise in untrained healthy males, European Journal of Applied Physiology 96 (5) pp. 525-534
Resistance exercise has recently been shown to improve whole-body insulin sensitivity in healthy males. Whether this is accompanied by an exercise-induced decline in skeletal muscle glycogen and/or lipid content remains to be established. In the present study, we determined fibre-type-specific changes in skeletal muscle substrate content following a single resistance exercise session. After an overnight fast, eight untrained healthy lean males participated in a
Manders RJF, Wagenmakers AJM, Koopman R, Zorenc AHG, Menheere PPCA, Schaper NC, Saris WHM, Van Loon LJC (2005) Co-ingestion of a protein hydrolysate and amino acid mixture with carbohydrate improves plasma glucose disposal in patients with type 2 diabetes, American Journal of Clinical Nutrition 82 (1) pp. 76-83
Background: Although insulin secretion after carbohydrate ingestion is severely impaired in patients with type 2 diabetes, amino acid and protein co-ingestion can substantially increase plasma insulin responses. Objective: We investigated insulin responses and the subsequent plasma glucose disposal rates after the ingestion of carbohydrate alone (CHO) or with a protein hydrolysate and amino acid mixture (CHO+PRO) in patients with a long-term diagnosis of type 2 diabetes. Design: Ten type 2 diabetic patients [mean (±SEM) age: 62 ± 2 y; body mass index (kg/m2): 27 ± 1] and 9 healthy control subjects (age: 58 ± 1 y; body mass index: 27 ± 1) participated in 2 trials in which the plasma insulin response was measured after the ingestion of 0.7 g carbohydrate · kg-1 · h -1 with or without 0.35 g · kg-1 · h -1 of a mixture that contained a protein hydrolysate, leucine, and phenylalanine. Continuous infusions with [6,6-2H2]glucose were then given to investigate plasma glucose disposal. Results: Plasma insulin responses were higher by 299 ± 64% and 132 ± 63% in the CHO+PRO trial than in the CHO trial in the diabetic patients and the matched control subjects, respectively (P
Hansen D, Dendale P, Beelen M, Jonkers RAM, Manders R, Corluy L, Mullens A, Berger J, Meeusen R, van Loon LJC (2008) Low Intensity Exercise Is Equally Effective As High Intensity Exercise Training To Improve Glycemic Control In Obese Type 2 Diabetes Patients, MEDICINE AND SCIENCE IN SPORTS AND EXERCISE 40 (5) pp. S42-S42 LIPPINCOTT WILLIAMS & WILKINS
Manders RJ, Koopman R, Sluijsmans WE, Van Den Berg R, Verbeek K, Saris WH, Wagenmakers AJ, Van Loon LJ (2006) Co-ingestion of a protein hydrolysate with or without additional leucine effectively reduces postprandial blood glucose excursions in type 2 diabetic men, Journal of Nutrition 136 (5) pp. 1294-1299
This study examined postprandial plasma insulin and glucose responses after co-ingestion of an insulinotropic protein (Pro) hydrolysate with and without additional free leucine with a single bolus of carbohydrate (Cho). Male patients with long-standing Type 2 diabetes (n = 10) and healthy controls (n = 10) participated in 3 trials in which plasma glucose, insulin, and amino acid responses were determined after the ingestion of beverages of different composition (Cho: 0.7 g/kg carbohydrate, Cho+Pro: 0.7 g/kg carbohydrate with 0.3 g/kg protein hydrolysate, or Cho+Pro+Leu: 0.7 g/kg carbohydrate, 0.3 g/kg protein hydrolysate and 0.1 g/kg free leucine). Plasma insulin responses [expressed as area under the curve (AUC)] were 141 and 204% greater in patients with Type 2 diabetes and 66 and 221% greater in the controls in the Cho+Pro and Cho+Pro+Leu trials, respectively, compared with those in the Cho trial (P
van Dijk J-W, Manders RJF, Tummers K, Bonomi AG, Stehouwer CDA, Hartgens F, van Loon LJC (2012) Both resistance- and endurance-type exercise reduce the prevalence of hyperglycaemia in individuals with impaired glucose tolerance and in insulin-treated and non-insulin-treated type 2 diabetic patients, DIABETOLOGIA 55 (5) pp. 1273-1282 SPRINGER
Manders RJF, Praet SFE, Meex RCR, Koopman R, De Roos AL, Wagenmakers AJM, Saris WHM, Van Loon LJC (2006) Protein hydrolysate/leucine co-ingestion reduces the prevalence of hyperglycemia in type 2 diabetic patients, Diabetes Care 29 (12) pp. 2721-2722
Punyadeera C, Zorenc AH, Koopman R, McAinch AJ, Smit E, Manders R, Keizer HA, Cameron-Smith D, van Loon LJ (2005) The effects of exercise and adipose tissue lipolysis on plasma adiponectin concentration and adiponectin receptor expression in human skeletal muscle., Eur J Endocrinol 152 (3) pp. 427-436
OBJECTIVE: It has been suggested that adiponectin regulates plasma free fatty acid (FFA) clearance by stimulating FFA uptake and/or oxidation in muscle. We aimed to determine changes in plasma adiponectin concentration and adiponectin receptor 1 and 2 mRNA expression in skeletal muscle during and after prolonged exercise under normal, fasting conditions (high FFA trial; HFA) and following pharmacological inhibition of adipose tissue lipolysis (low FFA trial; LFA). Furthermore, we aimed to detect and locate adiponectin in skeletal muscle tissue. METHODS: Ten subjects performed two exercise trials (120 min at 50% VO(2max)). Indirect calorimetry was used to determine total fat oxidation rate. Plasma samples were collected at rest, during exercise and during post-exercise recovery to determine adiponectin, FFA and glycerol concentrations. Muscle biopsies were taken to determine adiponectin protein and adiponectin receptor 1 and 2 mRNA expression and to localise intramyocellular adiponectin. RESULTS: Basal plasma adiponectin concentrations averaged 6.57+/-0.7 and 6.63+/-0.8 mg/l in the HFA and LFA trials respectively, and did not change significantly during or after exercise. In the LFA trial, plasma FFA concentrations and total fat oxidation rates were substantially reduced. However, plasma adiponectin and muscle adiponectin receptor 1 and 2 mRNA expression did not differ between trials. Immunohistochemical staining of muscle cross-sections showed the presence of adiponectin in the sarcolemma of individual muscle fibres and within the interfibrillar arterioles. CONCLUSION: Plasma adiponectin concentrations and adiponectin receptor 1 and 2 mRNA expression in muscle are not acutely regulated by changes in adipose tissue lipolysis and/or plasma FFA concentrations. Adiponectin is abundantly expressed in muscle, and, for the first time, it has been shown to be present in/on the sarcolemma of individual muscle fibres.
Lemanska Agnieszka, Poole Karen, Aning Jonathan J., Griffin Bruce A., Manders Ralph, Saxton John M., Wainwright Joe, Faithfull Sara (2019) The Siconolfi step test: a valid and reliable assessment of cardiopulmonary fitness in older men with prostate cancer,European Review of Aging and Physical Activity 16 (1) pp. 1-10 BMC

Background

Assessing fitness and promoting regular physical activity can improve health outcomes and early recovery in prostate cancer. This is however, underutilised in clinical practice. The cardiopulmonary exercise test (CPET) is increasingly being used pre-treatment to measure aerobic capacity and peak oxygen consumption (VO2peak - a gold standard in cardiopulmonary fitness assessment). However, CPET requires expensive equipment and may not always be appropriate. The Siconolfi step test (SST) is simpler and cheaper, and could provide an alternative.

The aim of this study was to evaluate the validity and reliability of SST for predicting cardiopulmonary fitness in men with prostate cancer. Men were recruited to this two-centre study (Surrey and Newcastle, United Kingdom) after treatment for locally advanced prostate cancer. They had one or more of three risk factors: elevated blood pressure, overweight (BMI Ã 25), or androgen deprivation therapy (ADT). Cardiopulmonary fitness was measured using SST and cycle ergometry CPET, at two visits three months apart. The validity of SST was assessed by comparing it to CPET. The VO2peak predicted from SST was compared to the VO2peak directly measured with CPET. The reliability of SST was assessed by comparing repeated measures. Bland-Altman analysis was used to derive limits of agreement in validity and reliability analysis.

Results

Sixty-six men provided data for both SST and CPET. These data were used for validity analysis. 56 men provided SST data on both visits. These data were used for reliability analysis. SST provided valid prediction of the cardiopulmonary fitness in men à 60 years old. The average difference between CPET and SST was 0.64 ml/kg/min with non-significant positive bias towards CPET (P = 0.217). Bland-Altman 95% limits of agreement of SST with CPET were ± 7.62 ml/kg/min. SST was reliable across the whole age range. Predicted VO2peak was on average 0.53 ml/kg/min higher at Visit 2 than at Visit 1 (P = 0.181). Bland-Altman 95% limits of agreement between repeated SST measures were ± 5.84 ml/kg/min.

Conclusions

SST provides a valid and reliable alternative to CPET for the assessment of cardiopulmonary fitness in older men with prostate cancer. Caution is advised when assessing men 60 years old or younger because the VO2peak predicted with SST was significantly lower than that measured with CPET.

Faithfull Sara, Turner Lauren, Poole Karen, Joy Mark, Manders Ralph, Weprin Jennifer, Winters-Stone Kerri, Saxton John (2019) Prehabilitation for adults diagnosed with cancer: A systematic review of long-term physical function, nutrition and patient-reported outcomes,European Journal of Cancer Care e13023 pp. 1-22 Wiley

Objective

Prehabilitation is increasingly being used to mitigate treatment?related complications and enhance recovery. An individual's state of health at diagnosis, including obesity, physical fitness and comorbidities, are influencing factors for the occurrence of adverse effects. This review explores whether prehabilitation works in improving health outcomes at or beyond the initial 30 days post?treatment and considers the utility of prehabilitation before cancer treatment.

Methods

A database search was conducted for articles published with prehabilitation as a pre?cancer treatment intervention between 2009 and 2017. Studies with no 30 days post?treatment data were excluded. Outcomes post?prehabilitation were extracted for physical function, nutrition and patient?reported outcomes.

Results

Sixteen randomised controlled trials with a combined 2017 participants and six observational studies with 289 participants were included. Prehabilitation interventions provided multi?modality components including exercise, nutrition and psychoeducational aspects. Prehabilitation improved gait, cardiopulmonary function, urinary continence, lung function and mood 30 days post?treatment but was not consistent across studies.

Conclusion

When combined with rehabilitation, greater benefits were seen in 30?day gait and physical functioning compared to prehabilitation alone. Large?scale randomised studies are required to translate what is already known from feasibility studies to improve overall health and increase long?term cancer patient outcomes.

Darling A. L., Manders R. J. F., Sahni S., Zhu K., Hewitt C. E., Prince R. L., Millward D. J., Lanham-New S. A. (2019) Dietary protein and bone health across the life-course: an updated systematic review and meta-analysis over 40 years,Osteoporosis International 30 (4) pp. 741-761 Springer London
We undertook a systematic review and meta-analysis of published papers assessing dietary protein and bone health. We found little benefit of increasing protein intake for bone health in healthy adults but no indication of any detrimental effect, at least within the protein intakes of the populations studied. This systematic review and meta-analysis analysed the relationship between dietary protein and bone health across the life-course. The PubMed database was searched for all relevant human studies from the 1st January 1976 to 22nd January 2016, including all bone outcomes except calcium metabolism. The searches identified 127 papers for inclusion, including 74 correlational studies, 23 fracture or osteoporosis risk studies and 30 supplementation trials. Protein intake accounted for 0?4% of areal BMC and areal BMD variance in adults and 0?14% of areal BMC variance in children and adolescents. However, when confounder adjusted (5 studies) adult lumbar spine and femoral neck BMD associations were not statistically significant. There was no association between protein intake and relative risk (RR) of osteoporotic fractures for total (RR(random) = 0.94; 0.72 to 1.23, I2 = 32%), animal (RR (random) = 0.98; 0.76 to 1.27, I2 = 46%) or vegetable protein (RR (fixed) = 0.97 (0.89 to 1.09, I2 = 15%). In total protein supplementation studies, pooled effect sizes were not statistically significant for LSBMD (total n = 255, MD(fixed) = 0.04 g/cm2 (0.00 to 0.08, P = 0.07), I2 = 0%) or FNBMD (total n = 435, MD(random) = 0.01 g/cm2 (?0.03 to 0.05, P = 0.59), I2 = 68%). There appears to be little benefit of increasing protein intake for bone health in healthy adults but there is also clearly no indication of any detrimental effect, at least within the protein intakes of the populations studied (around 0.8?1.3 g/Kg/day). More studies are urgently required on the association between protein intake and bone health in children and adolescents.
Lemanska Agnieszka, Poole Karen, Griffin Bruce A., Manders Ralph, Saxton John M, Turner Lauren, Wainwright Joe, Faithfull Sara (2019) Community pharmacy lifestyle intervention to increase physical activity and improve cardiovascular health of men with prostate cancer: a phase II feasibility study,BMJ Open 9 (6) e025114 BMJ Publishing group

Objectives:

To assess the feasibility and acceptability of a community pharmacy lifestyle intervention to improve physical activity and cardiovascular health of men with prostate cancer. To refine the intervention.

Design:

Phase II feasibility study of a complex intervention.

Setting:

Nine community pharmacies in the UK.

Intervention:

Community pharmacy teams were trained to deliver a health assessment including fitness, strength and anthropometric measures. A computer algorithm generated a personalised lifestyle prescription for a homebased programme accompanied by supporting resources. The health assessment was repeated 12 weeks later and support phone calls were provided at weeks 1 and 6.

Participants:

116 men who completed treatment for prostate cancer.

Outcome measures:

The feasibility and acceptability of the intervention and the delivery model were assessed by evaluating study processes (rate of participant recruitment, consent, retention and adverse events), by analysing delivery data and semi-structured interviews with participants and by focus groups with pharmacy teams. Physical activity (measured with accelerometry at baseline, 3 and 6 months) and patient reported outcomes (activation, dietary intake and quality of life) were evaluated. Change in physical activity was used to inform the sample size calculations for a future trial.

Results:

Out of 403 invited men, 172 (43%) responded and 116 (29%) participated. Of these, 99 (85%) completed the intervention and 88 (76%) completed the 6-month follow-up (attrition 24%). Certain components of the intervention were feasible and acceptable (eg, community pharmacy delivery), while others were more challenging (eg, fitness assessment) and will be refined for future studies. By 3 months, moderate to vigorous physical activity increased on average by 34 min (95% CI 6 to 62, p=0.018), but this was not sustained over 6 months.

Conclusions:

The community pharmacy intervention was feasible and acceptable. Results are encouraging and warrant a definitive trial to assess the effectiveness of the refined intervention.

Rees Jordan L., Chang Courtney R., François Monique E., Marcotte-Chénard Alexis, Fontvieille Adeline, Klaprat Nika D., Dyck Rebecca A., Funk Deanna R., Snydmiller Gary, Bastell Kent, Godkin Florence E., Dubé Marie-Christine, Riesco Eléonor, McGavock Jon M., Yardley Jane E., Sigal Ronald J., Gibala Martin J., Weisnagel S. John, Prado Carla M., Jung Mary, Manders Ralph, Lee Terry, Singer Joel, Boulé Normand G., Little Jonathan P. (2019) Minimal effect of walking before dinner on glycemic responses in type 2 diabetes: outcomes from the multi-site E-PAraDiGM study,Acta Diabetologica 56 (7) pp. 755-765 Springer Verlag

Aim

To examine the effect of walking before dinner on 24-h glycemic control in individuals with type 2 diabetes using the standardized multi-site Exercise-Physical Activity and Diabetes Glucose Monitoring (E-PAraDiGM) Protocol.

Methods

Eighty participants were studied under two conditions (exercise vs. non-exercise control) separated by 72 h in a randomized crossover design. Each condition lasted 2 days during which standardized meals were provided. Exercise consisted of 50 min of treadmill walking at 5.0 km/h before the evening meal, while control involved 50 min of sitting. The primary outcome measure was mean glucose during the 24-h period following exercise (or sitting) measured by continuous glucose monitoring.

Results

Of the 80 participants who were initially randomized, 73 completed both exercise and control. Sixty-three participants [29 males, 34 females; age = 64 ± 8 years, body mass index = 30.5 ± 6.5 kg/m2 and HbA1c = 51 ± 8 mmol/mol (6.8 ± 0.7%), mean ± SD] complied with the standardized diets and had complete continuous glucose monitoring data. Exercise did not affect mean 24-h glucose compared to control (0.03 mmol/L; 95% CI ? 0.17, 0.22, P = 0.778) but individual differences between conditions ranged from ? 2.8 to +1.8 mmol/L. Exercise did not affect fasting glucose, postprandial glucose or glucose variability. Glucose concentrations measured by continuous glucose monitoring were reduced during the 50 min of walking in exercise compared to sitting in control (? 1.56 mmol/L; 95% CI ? 2.18, ? 0.95, p  0.001).

Conclusion

Contrary to previous acute exercise studies, 50 min of walking before dinner in the E-PAraDiGM protocol did not affect 24-h glucose profiles. However, highly heterogeneous responses to exercise were observed.

Vitamin D deficiency (Â25nmol/L) and insufficiency (Â50nmol/L) has become an increasingly popular topic. Current research focusses upon the potential ergogenic effects of vitamin D (vitD) in sporting performance; however, the relationship between vitD (dietary intake and nutritional status) and bone health within a University athlete cohort remains under-investigated. Therefore, the aims of this Thesis were to (1) examine vitD status longitudinally across the University competitive seasons and; (2) examine the implications that vitD deficiency/ insufficiency may have upon physical performance parameters or bone health.

In the first study, fifty-seven competitive University level- athletes from varied sports were observed from autumn to spring. Radial bone mineral density (BMD) and physical performance parameters were investigated; for the analysis of vitD and parathyroid hormone, blood samples were collected. Within the cohort 7% presented with deficiency during the autumn; increasing to 44% during spring. However, this did not have a significant effect upon physical performance and bone health despite an average status of 31.5±16.4 nmol/L in spring.

In the second study, 34 University athletes and sixteen sedentary students were recruited and followed from spring to summer. Whole body, hip and tibial scans were conducted to determine BMD and bone mineral content (BMC). Physical performance parameters including jump height, aerobic fitness, muscular strength and blood biochemistry were also collected. During the summer term, 26% of the cohort were vitD insufficient. Moreover, an insufficient vitD status was associated with a lowered jump height (p=0.015) but not aerobic fitness (p=0.07). There was also a significant positive relationship between vitD status, femoral neck BMC (r=0.685; pÂ0.02) and BMD (r=0.679; pÂ0.02). Our results show that BMD was higher in weight bearing athletes. The final study found that racket sport athletes had a significantly superior bone profile in their dominant arm when contrasted to controls.

Overall, these findings suggest that an insufficient vitD status was associated with lower indices of muscular power and aerobic fitness in University students. Therefore, being vitD replete may not only play an important role in musculoskeletal health but could also be a key determining factor in athletic performance.

Additional publications