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Authors: Vivienne Vu and Bas Valentin

Institute: Amsterdam University of Applied sciences Department: Nutrition and Dietetics

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1 Authors: Vivienne Vu Bas Valentin Thesis number: 2018100 University:

Amsterdam University of Applied Sciences

Bachelor:

Nutrition and Dietetics

In authority of:

Dr. P.J.M. Weijs Lector Weight Management

Department of Nutrition & Dietetics University of Applied Sciences Dr Meurerlaan 8, 1067 SM Amsterdam Supervisor: R.G. Memelink External supervisor: A. Tump Mentor: A.M. Verreijen Assessor: A. van der Steen

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Acknowledgements

This thesis was written as a part of the finalisation of our Bachelor degree Nutrition and Dietetics at the Amsterdam University of Applied Sciences. In this thesis we evaluated the effect of an integrated weight-loss program combining dietary counselling and resistance training on weight loss and glycaemic control in obese older adults with type 2 diabetes.

The data we used were from the PROBE study, that was commissioned by Dr. P.J.M. Weijs, Lecturer from the research group Weight Management at the Amsterdam University of Applied Sciences. The study was in collaboration with Nutricia, TNO, Tromp Medical and Vialente-Diëtheek.

We would like to express our gratitude towards the people that helped us during this process and assisted us to write this thesis.

Firstly we would like to thank our supervisor and advisor from the Amsterdam University of Applied Sciences R.G. Memelink. He allowed this thesis to be our own work, but guided us in the right direction whenever he thought we needed it. In addition he provided us with feedback on our writing. Furthermore he provided us with datasets from the PROBE study.

Secondly we would like to acknowledge our mentor from the Amsterdam University of Applied Sciences A.M. Verreijen. We are grateful for her valuable comments and feedback on our thesis. Not only did she guide us through the writing process, she motivated us to reach our full potential. Thirdly we would like to thank A. Tump, our external supervisor from Diëtheek. She provided us with the information regarding dietary counselling during the intervention. She sent us the latest news related to our thesis. She also gave us the opportunity to share our results with dietitians from the work field and expand our network.

Lastly we would like thank our fellow students from the Amsterdam University of Applied Sciences at the Amsterdam Nutritional Assessment Centre, that helped us out when needed and provided a pleasant atmosphere and work setting.

Amsterdam, January 2018

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Contents

Acknowledgements ... 2 Abstract ... 6 Introduction ... 6 Method ... 9

PROBE study design: overview ... 9

Subjects ... 10

Subject recruitment ... 10

The PROBE intervention ... 10

Hypocaloric diet ... 10

Group classes ... 10

Resistance exercise programme ... 11

Brief mentioning of products in original study ... 11

Primary parameters ... 11

Body weight ... 12

HbA1c ... 12

Change in diabetes medication ... 12

Secondary parameters ... 12

Statistical analysis ... 13

Results ... 14

Subjects ... 14

Total body weight ... 14

Glycaemic control ... 15

HbA1c ... 15

Medication use ... 15

Body composition ... 16

Effectiveness PROBE intervention vs standard care ... 17

Total bodyweight ... 17

HbA1c ... 18

Effect of the PROBE-STUDY on physical performance ... 18

Compliance PROBE study ... 16

Dietary intake ... 16

Exercise sessions ... 17

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The main question ... 19

Unexpected findings ... 19

Comparison with standard treatment ... 19

Study limitations ... 19

Comparing PROBE and DIEET data ... 19

FFM ... 20

Compliance ... 20

Avenues for future research... 20

Implication for practitioners... 21

Advise to current practice ... 21

A multidisciplinary approach ... 21

Achieving a multidisciplinary approach ... 21

The value of measuring body composition ... 22

Screening tools ... 22 Limitations ... 23 Avenues ... 23 Steps to take ... 23 Conclusion ... 24 Conclusion statement ... 24 References ... 25 Appendix ... 27

Appendix A: inclusion criteria and exclusion criteria ... 27

Appendix B: guide for determining on rep maximum ... 28

Appendix C: PROBE resistance training ... 29

Appendix D: diabetes medicine influencing HbA1c ... 30

Figures and tables

Figure 1 ………...9 Figure 2………..14 Figure 3………..15 Figure 4………..15 Figure 5………..16 Figure 6………..17 Figure 7………..17 Figure 8………..18 Figure 9………..23 Table 1……….18 Table 2………8 Table 3………8

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Abbreviations

DM2: diabetes type two TBW: total body weight FFM: fat free mass FM: fat mass

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Abstract

Background

In 2040 slightly more than 25% of the Dutch population will be older than 65. Since the prevalence of obesity and diabetes type 2 (DM2) is high among older adults, the need for good treatment of DM2 among older adults is high. The current guideline for dietary treatment for DM2 focuses on losing weight and performing moderate activity. Furthermore weight loss leads to metabolic benefits but is also known for potential muscle mass loss in older patients. Preservation of muscle mass during weight loss might lead to better glycaemic control. So far several studies evaluated the effect of caloric restriction combined with training on weight loss in the obese older subjects with DM2, but to our knowledge only few studies evaluated the effect on glycaemic control.

Aim

The aim of this study is to evaluate the effect of a thirteen week intensive intervention including resistance training and a hypocaloric dietary treatment on body weight and glycaemic control in obese older adults with DM2.

Method

Subjects between the age of 55-85 with obesity and DM2 were included in the data analysis. All participants followed a weight loss program including resistance training (3x per week, for 1 hour) and a hypo-caloric diet (600 kcal below estimated energy needs, including a protein or control supplement). At baseline and after 13 weeks total bodyweight (TBW) (BodPod), fat free mass (FFM) (Dual-Energy X-Ray absorptiometry), HbA1c (mmol/mol) and medicine use were recorded.

Changes in TBW, body composition and glycaemic control over the intervention period were tested using a paired sample t-test. Change in medication use was presented as percentage of subjects with a decrease, increase or no changes. To compare the effectiveness of the intervention to standard care, data of the DIEET study were used which will represent the standard dietetic care in The Netherlands. Differences in changes in TBW were tested with an independent sample t-test. Results

The 13 week intervention was completed by 105 subjects. In total 82 (65.5%) men and 43 (34.4%) women participated, with a mean age of 66. A significant decrease was observed in TBW (p = 0.001). Mean difference in HbA1c is -5.0 ± 7.8 mmol/mol with a significant value p<0.001. 29% of the diabetes medication users lowered their medication during the intervention. Whereas 66.7% had no change and 4.4% increased their medication. The FFM was preserved (change was +0.03 ± 2.01 kg) (p = 0.898). A significant decrease was also observed in fat mass (FM), BMI and waist circumference (p < 0.001). Compared to standard care, the difference in bodyweight was 2.72 ± 3.10 kg for PROBE and -3.58 ± 4.36 kg for DIEET (p = 0.132). The subjects had a 1± mmol/mol greater decrease in HbA1c (p = 0.528) (PROBE had -5 mmol/mol and DIEET -4 mmol/mol loss). The subjects in the PROBE study increased their SPPB score with +0.4 points and 400 m walk time with 9 seconds. The daily energy deficit was lower than the dietary advise from the PROBE study (-419 ± 1099 kcal/day mean

difference between dietary advise and intake week 13). Mean exercise attendance was 82% after the 13 weeks.

Conclusion

The effect of an integrated weight loss program combining dietary counselling and resistance training on weight loss and glycaemic control in obese older adults with DM2, leads to a significant decrease in bodyweight with an average of 2.7 kg with preservation of FFM and a decrease in HbA1c of 5 mmol/mol on average per study subject. In 29% of the study subjects diabetes medication has lowered.

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Introduction

The Dutch population is aging, 2016 counts 3.1 million people older than 65 from the Dutch population which means that seventeen percent of the Dutch population is older than 65 (1). The prevalence of obesity and DM2 is the highest among older adults between the age of 55-75. The trend of an increasing rate of obesity and DM2 will be a great problem in the future, with a high prevalence of obesity and DM2 in the elderly (2). The prevalence for older adults with DM2 on average is 17% (1). Moreover the prevalence for older adults (>60 years) with obesity is 18% for males and 20% for females in the Netherlands (3). Ageing and obesity are associated with a higher risk for DM2, cardiovascular disease and other chronic diseases (4).DM2 influences the quality of life, patients generally feel unhealthy and have to control their diet which in some cases feels as a

burden(5). However, the complications associated with DM2 such as hypo- and hyperglycaemia can be reduced greatly through diet and a healthy lifestyle (6).

The current dietary guideline for dietary treatment for DM2 focuses on losing weight and performing moderate activity on a daily basis according to Dutch guidelines for healthy exercising, which is also known as the ‘Dutch Norm for healthy Exercising’ (7). In August 2017 a new exercise guideline was published; the elderly population is advised to do at least 150 minutes of moderate to intensive effort/exercise divided over a few days per week and to perform muscle and bone density enhancing exercises two times a week (8). This new activity advice is not included in the current dietary

diabetes guidelines. Moreover this guideline has no specific dietary advice for older obese diabetics; it advises to eat according the ‘Guidelines for a healthy diet’ (9) and stimulates weight loss. In 2018 will the current dietary guideline be revised (7). The latest guideline from the NDF (Dutch Diabetes Federation), which is now used in the current practice, advices a low-carbohydrate diet or a Mediterranean diet for overweight adults with DM2. A diet with a maximum of 40 EN% (energy percentage) carbohydrate would have a positive effect on HbA1c, insulin levels and glucose

tolerance. However, this guideline did not include nutritional advice in combination with (resistance) exercises to preserve the muscle mass (10).

There are a few explanations why muscle mass preservation is an important factor in a dietary treatment. Weight loss leads to metabolic benefits but is also known for potential muscle mass decrease in elderly patients (11). Common strategies to stimulate weight loss are calorie restriction and increasing physical activity. Strategies to preserve or gain muscle mass are resistance training and diet (which is rich in protein) (12). An evaluation of ten randomized controlled trials from Waters et al. concluded in their study that lifestyle interventions, using a combination of diet and exercise, were successful in achieving a 10% weight loss in 3-12 months. Which also led to positive changes in physical functioning, metabolic outcomes and cardiovascular risks (13). A combination of adequate diet, and/or resistance training has shown to positively influence insulin sensitivity in elderly

subjects. This effect may be due to the preservation of muscle mass and/or weight loss, or the quality of muscle mass (14). There are studies however that suggest that resistance exercises may improve the insulin sensitivity through the reduction of visceral and abdominal subcutaneous adipose tissue of abdominal obesity (15,16). The adipose tissue produces the hormonal peptides: adipokinen, which can have a positive (adiponectin) but also a negative effect on the insulin sensitivity (TNF-alfa). People with high abdominal tissue have lower adiponectin levels and higher TNF-alfa concentration which leads to a decrease of insulin sensitivity (4).

So far several studies have been performed that evaluate the effect of caloric restriction combined with training on weight loss in the obese elderly with DM2, but to our knowledge only a few studies evaluated the effect on glycaemic control. Dunstan et al.(17) showed an improvement in glycaemic and metabolic control, and a reduction of diabetes medication (P=0.004–0.05) compared to the control group. The intervention group received a high intensity progressive resistance training program with a moderate weight loss program (-0.25kg/week) while the control group received a

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8 moderate weight loss program with control training program (flexibility exercises). Andrews et al. (18) showed a great difference in glycaemic control for participants in the diet plus activity group (the intervention group), which were diagnosed with DM2 2 5-8 months previously. Great differences persisted after 12 months of intervention. The difference between the control group, that received the usual diabetes care, and the intervention group in HbA1c after 6 months was -0.33% (-0.51 to +0.14 95%CI) with p=0.009. However the most recent study from Johanson et al. (19) indicated that their intervention did not reach their criterion for equivalence (p = 0.15). Equivalence was tested by using two 1-sided tests and equivalence was declared if 95% CI was changed in the range -0.4% to +0.4%. From baseline to 12 months follow up, the mean difference in HbA1c level was -0.25% ( 95% CI, -0.52% to -0.01%), which did not reach the criteria for equivalence. However the intervention did lead to some benefits on medication use.

Until now the effects of an integrated approach with exercise training and caloric restriction on glycaemic control are unclear.

To make results of this study more practical for dietary practice, we will make a summarized report with suggestions to improve current treatment. Which is directed to the dietitians from dietician practice Diëtheek. This will be included in the recommendation section. Their dietitians performed the dietary consults and gave personal dietary advise to the study subjects. The objective of this study is to evaluate the effect of the intervention (resistance training, individual and groups consults) on TBW and glycaemic control in obese older subjects, 55-85 years, with DM2.

Based on previous studies, our hypothesis is to see a great difference in HbA1c, medication use and TBW. The main research question of our thesis is: What is the effect of an integrated weight-loss program combining dietary counselling and resistance training on weight loss and glycaemic control in obese older adults with DM2?

The sub questions will focus on the effect of the intervention on: FFM, FM, BMI, waist circumference. Furthermore we will evaluate whether the effect on weight loss and HbA1c is different from regular dietary treatment. Other parameters, physical performance and for compliance: calorie intake and exercise attendance will be evaluated too. We will discuss the results of the data from the PROBE-research and the answers of the sub questions that support our PROBE-research question.

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Method

For the evaluation of the PROBE-intervention data of the PROBE study was used. PROBE is an

intervention study in obese older adults with DM2 over a thirteen week period. Participants received an integrative weight loss trial including caloric restriction, resistance training and dietary

counselling. In the original study subjects were randomized in two groups, one group received a protein rich test product (enriched with leucine and vitamin D) and the other group received a control product which was rich in carbohydrates (both products had the same total calories). All participants followed a hypocaloric diet 600 kcal below the subject’s estimated energy needs. The aim of the PROBE study was to evaluate whether a protein rich supplement would positively influence leg muscle mass compared to an isocaloric placebo supplement. However, we evaluated the effect of the complete program (hypocaloric dietary advice, resistance training) for all study subjects, with or without the test product on TBW and glycaemic control, using two primary parameters: TBW in kilograms and HbA1c in mmol/mol.

PROBE study design: overview

Subjects with obesity and DM2 who fulfilled the eligibility criteria were included in the thirteen week weight loss program. All participants visited the study centre three times a week to attend the 1-hour resistance training. In the even weeks of the 13 week program study subjects visited a dietitian individually where they were given personal lifestyle and dietary advice. In the odd weeks of the 13 week program subjects followed 1 hour groups classes where they were educated on healthy diet and lifestyle topics. After 13 weeks the intervention was completed, study subjects went back to their original life’s and healthcare providers. Six months after the end of the 13 week intervention a follow-up measurement was performed only TBW was measured, data regarding glycaemic control were not available. For a more detailed overview of time timeline see Figure 1.

Figure 1. Overview intervention

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Subjects

In total 123 older subjects were included in the PROBE study. The subjects complied with the criteria for obesity and were diagnosed with DM2. Study subjects did not use insulin.

Important inclusion criteria were as listed below. For the full list of inclusion and exclusion criteria see Appendix A.

Inclusion criteria:

1. Age 55-85 years 2. DM2

3. BMI >30 kg/m2 or >27kg/m2 with a waist circumference of more than 88 cm for women and more than 102cm for men

Subject recruitment

PROBE recruited their subjects via dietitians, general practitioner practices, diabetes units of

hospitals or other relevant healthcare providers, and available databases, flyer and poster campaigns in communities or through advertisement on websites, and regional newspapers. Subjects entered the trial in a ‘batch’ mode; five successive cohorts of subjects were enrolled from February 2014 until July 2017.

The PROBE intervention

Hypocaloric diet

The subjects followed a hypocaloric diet, 600 kcal less than their estimated energy needs as estimated by indirect calorimetry using the ventilated hood method (Vmax Encore N29, Viasys Healthcare) and multiplied with their individual physical activity level estimated by a 3-day activity record. [REE X PAL – 600 kcal, total is including the study product]. The diets were conform the national Dutch guidelines for a healthy diet, also known as “Guidelines Healthy Nutrition(10)”. Example diets consisted of 1400 to 1900 kcal with a distribution of carbohydrates over different meals per day, with a variety of meal examples and products. Their instructions were based on the dietary habits of the subjects and if needed instructions were adjusted. Dietary advise was based on the subjects dietary diary (two week days and one weekend day). As mentioned, subjects had biweekly individual meetings with the dietitian, and bi-weekly group classes.

Group classes

All group classes were given by different fourth years Nutrition & Dietetics students from the Amsterdam University of Applied sciences under supervision of a senior dietitian. To support the groups classes, PowerPoint presentations were used. Group classes mainly focussed on information on the treatment of obesity, improving insulin sensitivity and lowering side effects associated with DM2. The five lessons are described in more detail below.

Group class 1: consisted of general information on DM2 and explained hypo- and hyperglycaemia. It

also explained the influence of exercising on blood glucose levels and the time timing of carbohydrate rich meals around training sessions.

Group class 2: visual information on translating national guidelines to the public. General

information on healthy lifestyle, HbA1c and sweeteners.

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Group class 3: included information on alcohol, smoking, stress, cinnamon, the kidneys, vitamin D

and prednisone.

Group class 4: Explaining fables regarding nutrition. Practical advice on reading food labels. The

relation between heredity and DM2was discussed. Visual presentation of low carbohydrate foods.

Group class 5: tips were given to maintain one’s diet. Tips on what to do when you are at a party,

around the holidays, or religious events.

Resistance exercise programme

The exercise programme consisted of three supervised group sessions per week lasting one hour. The subjects performed ten resistance exercises during each session focused on the large muscle groups. In week 1 all exercises were explained to the subjects in this period the subjects had time to become familiar with the ten resistance exercises. The instructor also estimated the subject’s one repetition maximum in this week. An estimation of the subjects one repetition maximum was made based on the weight lifted multiplied by the reconversion factor according to the number of repetitions that were performed with that weight (kg). A trainer did this calculation based on the study subjects doing 4-10 repetitions. In Appendix 2 you can find the guide for determining the subjects one repetition maximum.

In week two (after the familiarisation phase) subjects performed exercises at 60% of their estimated one repetition maximum. Intensity increased to 70% and eventually 80%. Sets increased and varied from 1-3 sets, depending on personal progress. Intensity of 60% meant that subjects did 20

repetitions with 60% of their 1 repetition maximum, 70%=10-15 repetitions, 80% = 8-10 repetitions. Every subject received a personal exercise plan, exercises may vary depending on their personal level and sport related limitations (injuries). However, every subjects did ten exercises targeting the large muscle groups as shown in Appendix C.

In week three subjects began doing a 15 minute High Intensity Interval Training (HIIT) at 70% of their maximum work capacity progressing to 90 and finally 110 percent. HIIT interval trainings were included in the training sessions because they were included in the physiotherapy guideline for older adults. These HIIT trainings took place after a 45 minute resistance training. The interval exercise lasted for 30 seconds and were followed by 60 seconds of active rest. Study subjects could choose between a HIIT training on a stationary bike, cross trainer or treadmill. Most of the subjects chose for the stationary bike as this was valued the most comfortable form of HIIT. In the final two cohorts the study subjects did not have the option to choose, everyone performed their HIIT on the stationary bike. The number of intervals varied from 4-8 depending on personal progress. Each training started with a ten minute warm-up using cardiovascular and flexibility exercises.

Brief mentioning of products in original study

The test and control products were powders which were sealed in sachets. A serving of the test product contained 21 grams of protein, 9 grams of carbohydrates and delivered 150 kcal. The control product contained no protein and 24.5 grams of carbohydrates per serving and is therefore isocaloric to the test products. Study subjects took a serving of the product at breakfast and after a training session, a total of 10 servings per week.

Primary parameters

Primary outcome parameters of this thesis were TBW (kg), HbA1c (mmol/mol) and change in diabetes medication.

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Body weight

TBW was measured to the nearest 0.01 kg using a weighing scale (Life measurements, Inc.) at all dietary consults. Subjects where weighted wearing bathing clothes or underwear in week 1 and 13 and arrived at the study centre after a 12 hour fast.

HbA1c

A venous blood sample (30ml total) was taken at week 1 and 13 to measure HbA1c. Blood samples were securely stored at Nutricia or a designated laboratory for up to 15 years after completion of the PROBE study. Blood samples were stored at minus 80 degrees.

Haemoglobin (Hb) is the colour in red blood cells, Hb transports oxygen. Red blood cells meet glucose in the blood stream, which bonds with haemoglobin. The more glucose in one’s blood, the more glucose there is to bond with haemoglobin. Red blood cells have a life expectancy of approximately two to three months. HbA1c give us a percentage of the amount of haemoglobin which has bonded with glucose, which means it gives us a mean value for glucose control in the last two to three months (20). Because HbA1c gave us a mean value for glycaemic control throughout the intervention we have used it as a primary parameter (13). Other studies evaluating glycaemic control use HbA1c as a primary parameter too.

Change in diabetes medication

To evaluate the effect of the intervention on diabetes medication the dosage of diabetes medication was recorded in week one and thirteen.

Among the 123 study subjects we found the following groups of diabetes medication: 1. A-glucosidases-inhibitors

2. Bigunaides 3. DPP-4-inhbitors 4. SU-derivatives

5. Other medicine, excluding insulin  Forxiga and liraglutide victoza

See Appendix D for a breakdown of the influence of these diabetes medications on HbA1c.

Secondary parameters

Secondary parameters of this thesis were FFM (DXA-scan), FM (DXA-scan), BMI (Body Mass IndRobeex (kg/m2), waist circumference, SPPB and 400m walk.

FFM, FM were measured by dual-energy x-ray absorptiometry (DXA; Discovery A, Hologic), using a whole body scan. For this assessment subjects had to wear underwear or bathing clothes. These measurements took place at week 1 and 13. Body height was measured using a wall mounted Stadiometer (Seca). BMI was measured by Nutricia (kg/m2). Waist circumference was measured to the nearest 0.1 cm using measuring tape at week 1 and 13. The Short Physical Performance Battery is a set of measures that combines the results of the gait speed, chair stand, and balance test, giving a total score (0-12 points). A score of higher than 9 is a no risk score. A score of 4-9 increases the risk of new physical limitations. A score below 4, means that subjects already experience physical

limitations and are advised to seek help from professionals (21). It has been used as a predictive tool for disability and can monitor the function of older people. SPPB test has been performed in week 1 and 13. For the 400-m walk test subjects were instructed to walk 400m as fast as possible, the number of seconds needed to complete the 400 meter walk was recorded, this test has been performed in week 1 and 13.

Parameters were used for interpreting and evaluating the effect of individual dietary advice and group classes in healthy lifestyle plus resistance training and a hypocaloric diet on body composition and physical functioning. The parameter may also help us explain the effect on glycaemic control; as mentioned in the introduction is an increase in muscle mass associated with a higher insulin

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13 sensitivity. Resistance training may also positively increase FFM and therefore improve physical functioning, as sarcopenia is common in older adults and negatively influences physical vulnerability.

Comparison with regular treatment

To compare PROBE data with regular treatment, data from the DIEET study has been used. The DIEET study is an observational study which evaluated the effectiveness of current dietary treatment in dietary disease, including DM2. Patients older than 18, who have not had any dietary advise yet were included in the study. Patients with a food allergy were excluded from the study. All study subjects were given standard dietary treatment by a ‘first line’ dietitian. After 9 months dietitians evaluated the effect of the dietary treatment (22). TBW (kg) data and HbA1c (mmol/mol) data were used from the DIEET datasets. 77 subjects for bodyweight were included in the dataset and 25 subjects for HbA1c were included in the dataset.

Compliance

To evaluate whether study subjects adhered to their dietary and training instructions, dietary instructions from week 1 and dietary intake from week 13 were evaluated. Then an evaluation was done regarding how many percentage of subjects attended resistance training sessions.

Statistical analysis

To evaluate the effects of the intervention on body weight, glycaemic control paired sample t-tests have been used. TBW in kilograms of week 1 and 13 were used to evaluate the effect of the intervention on TBW. Then TBW from week 13 and 37 were evaluated which gives insight in study subjects maintaining their TBW after the intervention. For HbA1c (mmol/mol) data was used from week 1 and 13 to evaluate the effects of the intervention on glycaemic control.

Subjects were divided into three groups to evaluate the effect of the intervention on diabetes medication. The percentage of subjects who’s medication use lowered, was unchanged or increased were presented in a graph. Using data from week 1 and week 13 and then describing whether the total medication had lowered, was unchanged or had increased at week 13. A compound less of metformin, say 1g at week 1 and then 0,5g at week 13 is described as a decrease. SPPB was tested using a paired sample t-test to find any significant difference in physical functioning, using data from week 1 and 13. The 400-m walk test was tested using a paired sample t-test using data from week 1 and 13.

We compared PROBE data with DIEET data on two parameters: TBW (kg) and HbA1c (mmol/mol), using an independent sample t-test.

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Results

Subjects

In total 105 subjects were included in the total data analysis for the PROBE study. Figure 2 presents the participant flow during this study from the screening to 13 weeks of the intervention. In total 220 subjects were recruited and screened, 95 subjects were excluded from the intervention because they didn’t meet the inclusion criteria. 125 subjects had a baseline visit and were enrolled in the PROBE Study and were randomized in either the control group with a placebo supplement or intervention group with a protein supplement. In total 82(65.5%) men and 43 (34.4%) women participated, the mean age (± SD) 66 ± 6.1, mean BMI at baseline was 33 ± 4.4 kg/m².

Figure 2. A flowchart of PROBE-subjects

Total body weight

Overall TBW loss was -2.7 ± 3.2kg; p<0.001. Eight participants had no BodPod test, because of technical problems on the visit day, so they were excluded from the TBW analysis. Four participants had missing values for the parameters FM and FFM due body parts being partially outside the DXA scan area. They were also excluded from the data analysis.

220 participants screened

125 subjects included and randomized

95 subjects did not comply with eligibility criteria and were excluded

105 subjects completed the 13 week intervention and had both the baseline and 13-week visit

20 subjects dropped out due personal circumstances (n=6), because of the use of

SU-derivatives (n=4), or due to a time conflicting schedule (n=2) or didn’t got permission to participate from their physician

(n=6). There were also participants that dropped for unknown reasons (n=2)

96 subject were included in the analysis of TBW

101 subjects were included in the body composition analysis (FM and FFM) 100 subjects were included in the HbA1c

analysis

89 subjects were included in the diabetes medication analysis

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Glycaemic control

HbA1c

In total 100 subjects were included in the data analysis for HbA1c. Some participants (n=5) didn’t have results on baseline or week 13 because they were unable to attend the visit for unknown reasons. The mean HbA1c at baseline was 51.41 ± 9.84 mmol/mol and at week 13 that was 46.55 ± 6.849 mmol/mol.

The mean difference was 4.861mmol/mol with a significant value p<0.001. Figure 3 shows the individual changes in HbA1c over the 13 week intervention.

Figure 3. Individual changes in HbA1c over 13 weeks per mmol/mol

Medication use

We evaluated the change in dosage of medication in 3 groups: subjects of which the medication use stayed the same during the intervention, subjects that had a lower medication use or subjects with a higher medication use at week 13 compared to baseline. Figure 4 displays the percentage of each of these three groups.

In total 90 subjects were included in the medication analysis, since all these subjects reported their diabetes medication use. 61 subjects used only one kind of diabetes medication and 29 subjects used two or more. To determine whether the change in medication use for these subjects was positive (for health) direction, the study physician was asked to evaluate the subjects in one of the three categories.

The change in medication use in percentage is shown in Figure 5. 29% of the subjects had a decrease in total medication use, the increase was 5%, and subjects that remain in medication use is 67%.

Figure 4. Change in diabetes medication in percentage over the 13-week PROBE intervention. -40 -30 -20 -10 0 10 20 H b A 1c ( mmo l/mo l) Study subjects

Change in HbA1c

28,9% 66,7% 4,4% 0,0% 10,0% 20,0% 30,0% 40,0% 50,0% 60,0% 70,0% 80,0%

Decrease No change Increase

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Body composition

Body composition changes over the 13 week intervention are shown in Table 1.

The FFM was preserved during this period of weight loss: the change in FFM was a non-significant 0.03 kg change (p=0.898). Mean loss in body mass index (BMI) was -0.9 kg/m2; p<0.001, mean loss in FM was -2.6kg; p<0.001 and mean loss in waist circumference was -3.7cm; p<0.001. Figure 5 shows the changes in FM and FFM per subject

Table 1. Changes in body composition and waist circumference of the 13 week weight loss intervention¹

₁ all the values are mean ± SD

Figure 5. Individual changes in FM and FFM.

Compliance PROBE study

Dietary intake

Figure 6 shows the adherence to the dietary advise per subject (n =95). The mean daily dietary energy intake was 1960 ± 995 kcal/day. This is including -600 kcal according to the dietary advise. The mean dietary intake after the 13-week intervention was 1546 ± 418 kcal/day. The mean difference in kcal/day between the dietary advise and week 13 was -419 ±1099 kcal/day. Which indicates that the daily intake was lower than the dietary advise from the PROBE study.

N Baseline Week 13 Difference P-value

FFM (kg) DXA 101 63.3 ± 10.9 63.3 ± 10.7 +0.03 ± 2.0 P=0.898 FM (kg) DXA 101 33.9 ± 9.3 31.3 ± 8.7 -2.6 ± 2.3 p<0.001 BMI kg/m2 96 33 ± 4.5 32 ± 4.3 -0.899 ± 1.0 p<0.001 Waist circumference (cm) 93 114.4 ± 10 110.8 ± 10.1 -3.7 ± 3.6 p<0.001 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 Ki logra m Study subjects

Body composition

FM FFM

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Figure 6. The calorie-intake per subject after the intervention compared to the dietary advise from the PROBE-study.

Exercise sessions

The mean adherence to the exercise protocol in percentage is 82 ± 13% (n=104). There were 39 training sessions during the 13 week intervention, mean attendance was 37 session. One subject reported to attend more sessions (45 sessions). Figure 7 shows the attendance per subject in percentage

Figure 7. Attendance exercise protocol per subject.

Effectiveness PROBE intervention vs standard care

Total bodyweight

PROBE study had 96 subjects and the DIEET study had 77 subjects for the data analysis in TBW. Mean loss in TBW in the PROBE study was -2,72 ± 3,10 kg and in the DIEET study that was -3.58 ± 4.36kg with a p-value: p = 0,132 therefore not statistically significant. Figure 8 shows the mean changes between the two studies over time. DIEET only had two test results compared to the PROBE study, which had also included the results from the six months follow-up. The follow-up had mean increase of +0,576kg ± 3,60 with a p-value; p = 0,202 which indicates not statistically significant.

0 50 100 150 p erce n ta ge at ten d an cy Study subjects

Attendance excersise session

intervention attendence attendance training in% 0 500 1000 1500 2000 2500 3000 3500 4000 En ergy (Kcal/d ay ) Study subjects

Dietary intake

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18 Figure 8. Mean loss in TBW PROBE and DIEET²

² TBW in the PROBE study is evaluated after 6 months and the DIEET study is evaluated after 9 months

HbA1c

In the HbA1c analysis, 100 subjects from PROBE were compared with 25 subjects from DIEET.

Changes over the regular treatment after 9 months are compared with the changes over de 13-week PROBE intervention. Mean loss in PROBE study was -5 ± 7.8 mmol/mol and in the DIEET study was -4 ± 10.4 mmol/mol with a p-value of 0.528 which indicates no statistically significant difference. The mean differences are shown in Table 2.

Table 2. Comparing the effects of the PROBE study and DIEET STUDY on HbA1c.

PROBE study DIEET study

n Baseline mean ± Week 13 mean ± Mean differenc e N Baseline mean ± 9 months mean ± Mean difference P-value HbA1c (mmol/mol) 100 51 ± 9.8 47±6.9 4.9 ± 7.8 25 52 ± 15.7 49 ± 9.5 -3.68 ± 10.4 p=0.528

Effect of the PROBE-STUDY on physical performance

Table 3 shows an overview of the functional effects on the subjects after the PROBE-study. The mean difference in SPPB was 0.4 points with p <0.001. A significant change in walking speed was observed, subjects were on average 9 seconds faster than in week 1.

Table 3. The effect of the PROBE-study on physical functions.

N Mean score week 1 Mean score SPPB week 13 Mean difference p- value SPPB (points) 103 11 ± 1.4 11 ± 1.2 +0.4 ± 1 p < 0.001 400m walk (time in sec) 98 282 ± 50 273 ± 52 -9 ± 27 p < 0.001 86 88 90 92 94 96 98

baseline week 13 6/9 months

Ki

logra

m

Change in total bodyweight

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19

Discussion

The main question

In the present study in overweight and obese older adults with DM2 we observed a significant effect in lowering total TBW and HbA1c during a thirteen week intensive lifestyle intervention. We also observed a decrease in use of diabetes medication in 29% of the subjects. Although the loss of TBW in the PROBE subjects was modest, FFM was preserved during weight loss.

Unexpected findings

Waters et al. already showed that most weight loss trials in obese older adults are associated with a decrease of FFM (13).

The results show that PROBE subjects preserved FFM, while the general expectation is that when people lose a kilogram of total TBW 25% of it is FFM and 75% of it is FM (23). A meta-analysis from 2014 concluded that the Quarter FFM rule is at best an approximation as the proportion of weight loss, including lean tissue varies over time and is determined by multiple factors including: energy intake, diet composition, sex, baseline adiposity, in- or activity, metabolic state and hormonal response (24).

However, Verreijen et al. showed in a randomized controlled trial evaluating the effect of high protein diet and/or resistance exercise on the preservation of FFM during weight loss in overweight and obese older adults, that a combined intervention of resistance exercise and a high protein diet can significantly increase FFM compared to the control treatment(25).

Comparison with standard treatment

We compared the results of the PROBE intervention with standard care (DIEET study). After

comparing the two studies our main finding was that an intensive lifestyle was non-equivalent with standard care. We found a modest non-significant difference in HbA1c reduction favouring the PROBE-study group. However, in the DIEET study group the loss of total TBW was greater (1kg). The difference in weight loss could be explained by the PROBE subjects maintaining FFM and the DIEET group decreasing a higher amount of TBW, including a higher amount of FFM according to the Quarter FFM rule.

A similar randomized controlled study from 2014 found that their intervention was non equivalent to standard care too (19). This randomized controlled trial in which they evaluated the effect of an intensive lifestyle intervention on glycaemic control in patients with DM2, found a reduction of glucose lowering medication in 73.5% of the study subjects after a 12 month follow up. In our study we found a far more modest percentage of study subjects whose medication lowered (29%). Differences in results may be explained by the methods of both interventions. In this recently published intervention subjects mainly did aerobic training sessions of 30-60 minutes, 5-6 times a week, 2-3 of these sessions were combined with resistance training. In the PROBE intervention there was a maximum of three training session which were al 1 hour resistance trainings followed by an 15 minute HIIT. Another reason which could have caused the outcomes is the approach to dietary treatment. PROBE focused on a 600 calorie restriction and a diet of minimum 1400 and maximum 1900 calories. The recently published article’s dietary advice was given to achieve a BMI lower than 25kg/m2(19)

Study limitations

Comparing PROBE and DIEET data

The first problem which occurred was in PROBE inclusion criteria. In the DIEET study we missed data for waist circumference, so we could not evaluate whether study subjects would still fit the PROBE

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20 inclusion criteria when their BMI was between 27kg/m2 and 30kg/m2. If we would exclude these

study subjects we were left with 40 subjects from the DIEET study to compare. From the DIEET study we could compare 25 study subjects for HbA1c whom fulfilled two measurements, and were confirm the PROBE inclusion criteria: diagnosed with DM2, obese, older than 55, and did not use insulin. For the PROBE study we were able to include data for 100 study subjects for evaluating HbA1c. This problem did not occur when we compared the effect of both interventions on TBW, both groups had the about the same amount of participants. Another limitation in this comparison is the difference in timeline. We evaluated two measurements for both groups. For PROBE we used data from baseline and after the intervention at thirteen weeks. For the DIEET data we used baseline data and data after nine months of the intervention. In this case subjects from the DIEET study had three times more time to let their treatment work in to them, they had six months extra to either gain or lose weight, improve or worsen glycaemic control. So was the average weight loss in the DIEET subjects 3.5kg and did their HbA1c drop with 4.0mmol/mol.

FFM

Results regarding maintaining FFM may be due to the origin of the study where study subjects received a protein enriched supplement with vitamin D and leucine or an iso-caloric control product with no protein and carbohydrates instead. The preservation of FFM may be increased among the study subjects who were given the test product. Results on HbA1c and total TBW may be different too between the two groups. We cannot correct for this as we were provided with blinded data.

Compliance

Study subjects were advised on average to consume 1964 calories, this is including the 600 kcal restriction. The average intake of the PROBE subjects was estimated 1545 kcal, which would mean that PROBE subjects had around 1000 kcal restriction. Therefor we expect that either study subjects underreported their dietary intake. Or students working on the PROBE study were not consequent processing dietary data, as multiple students per year filled in data and may have followed different instructions regarding processing dietary data.

Avenues for future research

Firstly, measuring insulin sensitivity from baseline and on the end of an intervention may explain the effect resistance training on insulin sensitivity and show a correlation between FFM and insulin sensitivity.

Secondly, revealing the population’s data according protein intake may show a correlation between protein intake and preservation of FFM, as protein may have an extra beneficial effect next to resistance training. In order; preservation of FFM may increase muscle mass, which would positively affect muscle strength and then physical functioning.

Thirdly, it would be interesting to take physical functioning in account as muscle loss negatively influences physical vulnerability. Therefor future studies would also benefit from measuring strength progress. The PROBE subjects did improve their walking speed with an average of nine seconds, their total SPPB score remained eleven, improvement of their walking speed may be due to their loss of TBW, and maintaining FFM. Future studies may find similar effects of resistance training and dietary counselling on physical performance.

Lastly, a randomized controlled trial from 2011 found that dietary support soon after the diagnosis of DM2 is beneficial. This dietary input consisting (6・5 h additional time across the 12 months of the study, consisting of 2h with a dietitian and 4・5 h with a nurse) improved glycaemic control, weight loss and reduced need for drug treatment compared with usual care in England. In this intensive design with an increased frequency of dietary consults we did not find significant effects on TBW and

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21 glycaemic control. Further research is needed to evaluate whether an increased frequency of dietary treatment is beneficial for patients (18).

Implication for practitioners

After evaluating the PROBE data we found that standard care and the PROBE intervention do not significantly differ, but that the PROBE intervention does preserve FFM. With data from this study dietitians now have some extra information about the benefit of resistance exercise for obese older adults with DM2. Current national guidelines explain that resistance training enhances bone and muscle density, now we know it may also preserve FFM during weight loss.

For older individuals the preservation of FFM has great value, as it improves there physical

independency, function and lowers their physical vulnerability (23). As the study subjects maintained their FFM, all of the lost weight was FM. There are studies that suggest that resistance exercises may improve the insulin sensitivity through the reduction of visceral and abdominal subcutaneous adipose tissue of abdominal obesity (15,16). Even though the weight loss was greater in standard care we found a greater decrease in HbA1c (1 mmol/mol). This may have been caused by maintaining FFM, reducing subcutaneous adipose tissue of abdominal obesity, resistance training or a

combination of these three factors (15,16).

In the current dietary treatment based on the DIEET data a dietitian sees their patient/client once every six weeks. Consisting of an intake and follow up consults. NIVEL care registrations from 2016 show that dietitians on average had 3.1 consults taking up 2.1 hours of treatment time (direct and indirect) (26). In the PROBE interventions dietitians had a total of six individual consults and five group consults leading to a total treatment time of 180 minutes per study subject. In total three hours, which are fully declarable in the Netherlands. Meaning that dietitians performing this dietary treatment can work more cost efficient as they can see more patients/clients in less time. Over a period of six week a dietitian would see the patient/client six times instead of two times. But they could also vary the structure their consults. Like sharing global information about products in group consults and evaluate or discuss personal goals and achievements in personal consults. Seeing a dietitian more often would also make a dietitian more approachable and may keep a client/patient more motivated to accomplish dietary treatment goals. At the moment 34% of clients achieve their dietary treatment goals (26). This may increase when a dietitians sees their patient/client more often.

Advise to current practice

A multidisciplinary approach

To perform the PROBE intervention in dietary practices certain steps have to be taken, as some limitations occur: dietitians lack the knowledge to properly advise clients regarding resistance training. So a multi-disciplinary approach between a physiotherapist or personal trainer and a dietitian is needed. In the Netherlands it is hard to find this multi-disciplinary teams outside secondary healthcare institutions such as hospitals and nursing-homes.

Achieving a multidisciplinary approach

General practitioners (GP) are the first professional clients go to and they are the ones to refer clients to physiotherapists and dietitians. There is a scientific association of general practitioners in the Netherlands (NHG) which aims to promote a scientifically sound treatment among GP. By translating science into GP practice, the NHG contributes the professionalization of their profession. In-service training is one of the core activities of NHG, the quality of NHG schooling lies in translating broad scientific knowledge and experience into independent and up-to-date-in-service training (21,27 ). Dietitians are the professional in translating dietary advice to the public, so dietitians may play a role in translating and promoting innovative treatments to GPs, in example at NHG. Another way to

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22 inform GPs about this multidisciplinary approach is via congresses and columns in professional magazines.

The value of measuring body composition

It is important to show a client’s body composition as TBW loss may be less significant than a client would expect. Clients may preserve or gain FFM while losing a small amount TBW. Maintaining FFM may be a great motivation for clients to comply with their dietary and training instructions. But also explaining physiological processes such as; resistance training may positively influence muscle strength and stimulate the preservation of FFM, then it may increase muscle mass. Resistance

training may also improve HbA1c through the reduction of subcutaneous adipose tissue of abdominal obesity.

Screening tools

Table 4 shows an example of differences in screening tools to measure body composition, including; possible advantages and disadvantages of the screening tools. A dietitian in primary healthcare may find a screening tool which is valuable to their practice using Table 4 below.

Table 4. Comparison of screening tools to measure body composition (28).

Advantage Disadvantage

Weighting scale - Not invasive

- Price vary from cheap to expensive.

- Is not always precise, results may be different between weighting scales. Hand help dymometer JAMAR(29) - Invasive: No - Price low: around €300- 600 - Screening tool for

sarcopenia

- Screens overall muscle strength

- Doesn’t measure FM or FFM, it only indicates the muscle strength Bioelectral impendance analyser Tanita - Invasive: No - Prices start at €1.500 - Relatively valid in measuring FM and FFM

- External factors may affect results

- Does not include measuring the upper body except the arms

Bioelectral

impendance analyser BODY STAT 500

- Invasive: slightly more than the Tanita - Prices start at €1.600

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- Relatively valid in measuring FM and FFM, includes whole body.

- External factors may affect results

- Location with a bed is needed.

- The price doesn’t include the electrodes.

DXA - Measures FM and FFM

very precisely. - Validity is very high - Invasive: average

- External factors may affect results.

- Price is very high, not affordable for dietitians in primary healthcare.

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23

Limitations

Dietitians and physiotherapists would need a location to give their dietary group consults and resistance training. Physiotherapists are not in basic health care packages, while consults with a dietitian are declarable up to 3 hours.

Avenues

It is a challenge for both disciplines to fulfil this treatment and keep it cost efficient for themselves and clients. A way to make this multidisciplinary approach more cost efficient is by sharing costs with/ in a multidisciplinary team. Another way is by promoting this multidisciplinary approach at healthcare providers and convincing them this treatment may be more cost efficient for clients and health care providers as patients lower their diabetes medication needs. Lifestyle changes are becoming more prominent in the Dutch culture and governments are promoting a healthy lifestyle, perhaps submissions can be given to health care providers who are willing to compensate this dietary treatment.

Steps to take

In the figure below (Figure 9) you can find a summary of steps to intake to imply the PROBE intervention in your practice.

1. Inform local general practitioners about the intervention you wish to offer an innovative dietary treatment to obese older adults with DM2. Inform the general practitioner this a multi-disciplinary method to preserve FFM in this group while improving HbA1c and in 29% of the cases diabetes medication is lowered.

2. Get in touch with physiotherapists and personal trainers to be able to safely advise clients to perform resistance exercises three times a week. Physiotherapists also benefit from this approach as resistance training is associated with improving glycaemic control (15, 16).

3. Find a location which can support group classes. Universities (of Applied Sciences) may want to offer class rooms. Locations may also be found in local gyms, as they start offering special memberships targeting older clients. Physiotherapists with their own practice may want to offer a location too.

4. Consider purchasing a screening tool which allows you evaluate FFM and FM. Physiotherapists, personal trainers and GYMS would also benefit from this. As TBW loss may not always be as significant as expected, but clients may on the other hand lose more FM than they would think or maintain FFM. Screening tools that can be considered are the Hand Held Dynamometers (for example the JAMAR) and the Bio-electrical impedance analyzer, Body stat 500 or Tanita. Purchasing is in example available through: premed.nl, Euromedix.nl, Tanita.nl. More information about screening tools in dietary practise: Database praktijk tools at the NVD (Dutch Dietitian Association) website.

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24

Conclusion

In conclusion, the effect of an integrated weight loss program combining dietary counselling and resistance training on weight loss and glycaemic control in obese older adults with DMII, leads to a significant decrease in TBW with an average of 2.7 kg and preservation of FFM and it leads to an average decrease in HbA1c of 5mmol/mol. In 29% of the study subjects diabetes medication has lowered.

Conclusion statement

This thesis has shown that an integrated weight loss program combining dietary counselling and resistance training can significantly affect TBW and glycaemic control in obese older adults with DM2. This intervention even ensures the preservation of FFM in obese older adults with DM2. Decreasing FM and resistance training are both associated with increasing insulin sensitivity (4, 15,16). Therefore we recommend the current practice to imply resistance training three times per week in their dietary treatment.

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25

References

1. Centraal Bureau van Statistiek (CBS). Vergrijzing Nederland. 16-12-2016. https://www.cbs.nl/nl-nl/dossier/dossier-vergrijzing

2. Eurostat. News Release. Obesity in Europe. PDF. October 2016.

http://ec.europa.eu/eurostat/documents/2995521/7700898/3-20102016-BP-EN.pdf/c26b037b-d5f3-4c05-89c1-00bf0b98d646

3. Centraal bureau voor de statistiek. Stateline. Lengte en gewicht van personen, ondergewicht en overgewicht. 2016.

http://statline.cbs.nl/Statweb/publication/?DM=SLNL&PA=81565ned&D1=0-4&D2=1-2&D3=9-12&D4=0&D5=20,35&HDR=T&STB=G1,G2,G3,G4&VW=T

4. Heine R, Stehouwer C. Diabetes mellitus. In: van der Meer J., Stehouwer C. Interne geneeskunde. Houten: Bohn Stafleu van Loghum; 2007. p. 729-751

5. Mathus-Vliegen EM; Obesity Management Task Force of the European Association for the Study of Obesity. Prevalence, pathophysiology, health consequences and treatment options of obesity in the elderly: a guideline. Obes Facts. 2012;5(3):460-83. doi: 10.1159/000341193. Epub 2012 Jun 30. Review. Erratum in: Obes Facts. 2016;9(1):40.

6. World Health Organisation. Redefining the Diabetes treatment. PDF 2,54MB. Full text. 2000. http://www.who.int/nutrition/publications/obesity/09577082_1_1/en

7. Dieet behandelrichtlijnen. Diabetes. Den Haag: 2013 Uitgevers.

8. Voedingscentrum. Nederlandse Norm Gezond Bewegen. Ouderen. 2017. http://www.voedingscentrum.nl/encyclopedie/bewegen.aspx

9. Gezondheidsraad. Richtlijnen Goede Voeding. 2015.

10. Nederlandse Diabetes Federatie. Voedingsrichtlijnen diabetes. 2015.

http://www.zorgstandaarddiabetes.nl/wp-content/uploads/2015/06/DEF-NDF-Voedingsrichtlijn-Diabetes-2015-versie-1.3.pdf

11. Houston DK, Nicklas BJ, Zizza CA. Weighty concerns: the growing prevalence of obesity among older adults. J Am Diet Assoc 2009;109:1886–95.

12. Heymsfield SB, Thomas D, Nguyen AM, Peng JZ, Martin C, Shen W, Strauss B, Bosy-Westphal A, Muller MJ. Voluntary weight loss: systematic review of early phase body composition changes. Obes Rev. 2011 May;12(5):e348-61

13. Waters DL, Ward AL, Villareal DT. Weight loss in obese adults 65years and older: a review of the controversy. Exp Gerontol. 2013 Oct;48(10):1054-61

14. Flemming Dela, Michael Kjaer. Resistance training, insulin sensitivity, and muscle function in the elderly. Essay in biochemistry. November 27, 2006.

15. Venables MC, Jeukendrup. AE. Endurance training and obesity: effect on substrate metabolism and insuline sensetivity. Med Sci Sports Exerc. 2008 Marc; 40(3): 495-502 16. Arciero PJ, Baur D, Connelly S, Ormsbee MJ. Timed-daily ingestion of whey protein and

exercise training reduces visceral adipose tissue mass and improves insulin resistance: the PRISE study. J Appl Physiol (1985). 2014 Jul1;117(1):1-10. doi:

10.1152/japplphysiol.00152.2014. Epub 2014 May 15.

17. Dunstan DW, Daly RM, Owen N, Jolley D, De Courten M, Shaw J, Zimmet P. High intensity resistance training in older patients with type II diabetes. Diabetes Care. 2002 Oct; 25(10) 18. Andrews RC, Cooper AR, Montgomery AA, Norcross AJ, Peters TJ, Sharp DJ, Jackson N,

Fitzsimons K, Bright J, Coulman K, England CY, Gorton J, McLenaghan A, Paxton E, Polet A, Thompson C, Dayan CM. Diet or diet plus physical activity versus usual care in patients with newly diagnosed type 2 diabetes: the Early ACTID randomised controlled trial. Lancet. 2011 Jul 9;378(9786):129-39. doi:10.1016/S0140-6736(11)60442-X. Epub 2011 Jun 24.

19. Johansen MY, MacDonald CS, Hansen KB, Karstoft K, Christensen R, Pedersen M,Hansen LS, Zacho M, Wedell-Neergaard AS, Nielsen ST, Iepsen UW, Langberg H, Vaag AA, Pedersen BK,

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26 Ried-Larsen M. Effect of an Intensive Lifestyle Intervention on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA. 2017 Aug 15;318(7):637-646. doi: 10.1001/jama.2017.10169.

20. Internisten. De nieuwe eenheid van de HbA1c- waarde. 2010. PDF. P1-4. www.nieuwediabeteswaarde.nl

21. Nederlandse huisartsen genootschap. Organisatie en beleid. https://www.nhg.org/organisatie

22. Kenniscentrum Beweging, sport en voeding. DIEET: Diëtetiek Effectief en

Toekomstbestendig. Hogeschool van Amsterdam. 2017. http://www.hva.nl/kc-bsv/gedeelde-

content/projecten/projecten-gewichtsmanagement/dietetiek-effectief-en-toekomstbestendig-dieet-project.html

23. Bauer JM, Sieber CC. Sarcopenia and frailty: a clinician’s controversial point of view. Exp Gerontol 2008; 43: 674-678

24. Heymsfield SB, Gonzalez MC, Shen W, Redman L, Thomas D. Weight loss composition is one-fourth fat-free mass: a critical review and critique of this widely cited rule. Obes Rev. 2014 Apr;15(4):310-21. doi: 10.1111/obr.12143. Epub. 2014 Jan 22.

25. Verreijen AM, Engberink MF, Memelink RG, van der Plas SE, Visser M, Weijs PJ. Effect of a high protein diet and/or resistance exercise on the preservation of fat free mass during weight loss in overweight and obese older adults: a randomized controlled trial. Nutr J. 2017 Feb 6;16(1):10. doi:10.1186/s12937-017-0229-6. PubMed PMID: 28166780;

26. NIVEL Zorgregistraties. Zorg door de diëtist. jaarcijfers 2016 en trendcijfers 2012 ‐ 2016. PDF. https://www.nivel.nl/sites/default/files/bestanden/2016_jaarrapport_dietetiek.pdf

27. Nederlandse huisartsen genootschap. Scholing. https://www.nhg.org/scholing 28. Heerkens YF, Visser WK, Tiebie J, Runia S. Informatorium voor Voeding en Diëtetiek:

Meetinstrumenten voor de diëtetiek. Houten: Bohn Stafleu van Loghum; 2014. Hfd 3. 29. Guerra RS, Amaral TF. Comparison of hand dynamometers in elderly people. J Nutr Health

Aging. 2009 Dec;13(10):907-12. PubMed PMID: 19924352.

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27

Appendix

Appendix A: inclusion criteria and exclusion criteria

PROBE handed the following inclusion criteria:

1. Age 55-85 years

2. Ambulant type 2 diabetes patient (to be verified by used medication for diabetes). In the event no medication is used. HbA1c should be equal or higher than 43mmol/l

3. –BMI >30 kg/m2 or

- >27kg/m2 with a waist circumference of more than 88 cm. for woman and more than 101 cm. for men

4. Willingness that the general practitioner of the patient will be notified 5. Patients that use SU-derivatives:

A. Agreement from patient that his/her diabetes medication may be adapted

B. Agreement from the treating physician to possible adjustments of SU-derivative dose at the start and during the patients study

6. Written conform consent

7. Willingness and ability to comply with the protocol

8. Ability to comply with the exercise protocol as assessed by a sports physician PROBE handed the following exclusion criteria

1. Specific medical history: instable Angina Pectoris, cardiac infarcts and/or cardiac surgery within 3 months prior to baseline. Any malignant disease during the last five years except for adequately treated prostate cancer without evidence of metastases, localized bladder cancer and other relevant medical history that could affect the study outcome as judged by the study physician

2. Any gastrointestinal disease that interferes with bowel function and nutritional intake (e.g. constipation or diarrhoea secondary to neuropathy, diarrhoea due to chronic inflammatory bowel disease, gastroparesis (partial) gastrectomy or any other procedure for stomach volume reduction including gastric banding).

3. Wearing electric implant(s) and/or pacemaker

4. Renal disease (GFR <60mL/min clearance based on MDRD formula)

5. Hepatic disease (liver enzymes ALAT, ASAT, GGT or ALP greater than 3 times of upper limit normal values)

6. Use within 2 weeks prior to baseline and/or expected use during study of: - Corticosteroids

- Antibiotics for systematic use 7. Use of insulin

8. Change in dose within three months prior to baseline of: - Antidepressants

- Neuroleptics

- Lipid lowering medication

9. Specific dietary and/or lifestyle factors present within three months prior to baseline: - Involuntary weight loss of at least 5%

- Use of protein containing or amino acid containing nutritional supplements 10. Known allergy to cow’s milk and milk products or the ingredients of the study products 11. Known galactosaemia

12. Known lactose intolerance

13. More than 22ug (880 IU) Vitamin D intake from non-food sources (such as supplements and prescribed medication)

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28 14. More than 500mg of daily calcium intake from non-food sources (such as supplements and

prescribed medication)

15. Current alcohol or drug abuse in opinion of the investigator

16. Investigators uncertainty about the willingness or ability of the subject to comply with the protocol requirements

17. Participation in any other study involving investigational or marketed products concomitantly or within four weeks prior to baseline

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29

Appendix C: PROBE resistance training program

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30

Appendix D: diabetes medicine influencing HbA1c

A-glucosidases-inhibitors slow the breakdown of complex carbohydrates to glucose. Which slows

down the glucose absorption and lowers the postprandial glucose values. The sugars will be digested in a later part of the intestine. A lowering of HbA1c of 0,5% can be expected when using this

medicine (18).

Metformin slows down the glucose production in the liver and increases glucose absorption in

skeletal muscle due to a higher sensitivity for insulin. A lowering of HbA1c of 1,5-2,0% can be expected when using this medicine (18).

DPP-4-Inhibitors are enzymes that break down incretin hormones into inactive products, such as

glucagon-like-peptide-1 and glucose-dependant-insulinotropic polypeptide. Inhibition of DPP-4 increases the concentration of active incretin hormones. After a sugar rich meal the concentration of these hormones increase, which increase the release of insulin from the beta cell in the pancreas. GLP-1 does also reduce the secretion of glucagon from the alpha cells in the pancreas when glucose levels are normal or elevated. Lower glucagon concentrations in the blood, in combination with higher insulin concentrations lead to a reduced glucose production which decreases blood glucose levels. A lowering of HbA1c with 0,3-0,4% can be expected when using this medicine (18).

SU-derivatives stimulate the secretion of insulin by increasing the sensitivity of the beta cell in the

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