Whey or Casein - Liver Fat Reduction and Metabolic Improvement by Fast vs. Slow Proteins

Study Overview
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Brief Summary
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High-protein diets have been recently demonstrated to effectively reduce insulin resistance, derangements of the lipid profile and liver fat content in subjects with moderately and severely impaired glucose metabolism and non-alcoholic fatty liver disease (LeguAN, LEMBAS, DiNA-P, DiNA-D). The effects can be attributed to prolonged insulin secretion and improved second meal effect, higher energy expenditure by urea synthesis, suppression of glucagon or other mechanisms. Up to now, it is unclear, if proteins with slower or faster digestibility lead to differential results in these study designs. The proposed study will elucidate this question. The Investigators hypothesize, that slowly-digestible proteins induce a prolonged insulin plateau supporting the second-meal effect. The investigators also assume, that these dietary proteins lead to a markedly stronger short-term secretion of glucagon followed by desensitisation of this hormone release. Fast-digestible proteins, on the other hand, will presumably induce a smaller second-meal effect and do not inhibit a second rise of glucagon in a consecutive meal. The investigators intend to study the effects of a 3-weeks high-protein diet in subjects with NAFLD (40 subjects without T2DM, 40 subjects with T2DM) on insulin resistance (mixed-meal tolerance tests; MMTT), second meal effect (second, consecutive MMTT on the same day) and liver fat content (MR spectroscopy) as well body-fat distribution (MR tomography). The investigators expect different results for slow protein (casein) and fast protein (whey), thus comparing both protein species. The two major clinical visits before and after the intervention period will also include fasting blood sampling for later analysis, full anthropometric assessment and a set of behavioral tests, investigating postprandial decision making processes. All clinical assessments will be conducted in Charité (Lead: A.F.H. Pfeiffer). Psychobehavioral tests (Prof. Park), assessment of body fat distribution including liver fat (Dr. Machann) and measurements of amino acid levels throughout the meal tests (Prof. Rohn) are secondary work packages.

Detailed Description
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High-protein diets have been recently demonstrated to effectively reduce insulin resistance, derangements of the lipid profile and liver fat content in subjects with moderately and severely impaired glucose metabolism and non-alcoholic fatty liver disease (LeguAN, LEMBAS, DiNA-P, DiNA-D). The effects can be attributed to prolonged insulin secretion and improved second meal effect, higher energy expenditure by urea synthesis, suppression of glucagon or other mechanisms. Up to now, it is unclear, if proteins with slower or faster digestibility lead to differential results in these study designs. The proposed study will elucidate this question. The investigators hypothesize, that slowly-digestible proteins induce a prolonged insulin plateau supporting the second-meal effect. They also assume, that these dietary proteins lead to a markedly stronger short-term secretion of glucagon followed by desensitisation of this hormone release. Fast-digestible proteins, on the other hand, will presumably induce a smaller second-meal effect and do not inhibit a second rise of glucagon in a consecutive meal. The investigators intend to examine the effects of a 3-weeks high-protein diet in subjects with NAFLD (40 subjects without T2DM, 40 subjects with T2DM) on insulin resistance (mixed-meal tolerance tests; MMTT), second meal effect (second, consecutive MMTT on the same day) and liver fat content (MR spectroscopy) as well body-fat distribution (MR tomography). The investigators expect different results for slow protein (casein) and fast protein (whey), thus comparing both protein species. The two major clinical visits before and after the intervention period will also include fasting blood sampling for later analysis, full anthropometric assessment and a set of behavioral tests, investigating postprandial decision making processes. In order to identify the suitable dosage for protein loads in the 3-weeks intervention trial, the study follows a dose-finding assessment in 40 subjects (20 subjects with Metabolic Syndrome and T2DM; 20 subjects with Metabolic Syndrome without T2DM), which undergo six separate investigation days. On each day of the dose-finding assessment pre-trial one of the following dosages is used in a single oral protein tolerance test (5 g, 20 g and 30 g of whey or casein each). Subjects with NAFLD from this pre-study are eligible for the main trial. Additional test will assess whether mixes of whey and casein in variable proportions induce different hormonal profiles of glucagon and insulin. All clinical assessments will be conducted in the Dept. Endocrinology, Diabetes and Nutrition, Charité, Campus Benjamin Franklin (Lead: DIfE, A.F.H. Pfeiffer). Psychobehavioral tests (Prof. Park), assessment of body fat distribution including liver fat (Dr. Machann) and measurements of amino acid levels throughout the meal tests (Prof. Rohn) are secondary work packages.

Official Title
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Molke Oder Casein - Leberfettreduktion Und Stoffwechselverbesserung Durch Schnelle vs. Langsame Proteine (Whey or Casein - Liver Fat Reduction and Metabolic Improvement by Fast vs. Slow Proteins)

Conditions
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Type2 Diabetes, NAFLD

Intervention / Treatment
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* Dietary Supplement: protein supplement
* Dietary Supplement: placebo supplement


Participation Criteria
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Eligibility Criteria
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Subcohort 1 (n=40): Inclusion Criteria: healthy with NAFLD 18-79 years Exclusion Criteria: severe endocrine, gastrointestinal, metabolic, cardiovascular, pulmonary, inflammatory or psychiatric disorder active or recent relevant cancer Subcohort 2 (n=40): Inclusion Criteria: T2DM with NAFLD 18-79 years Exclusion Criteria: severe endocrine, gastrointestinal, metabolic, cardiovascular, pulmonary, inflammatory or psychiatric disorder active or recent relevant cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: parallel-designed randomised controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Whey protein supplement, 2x 30g/day<br>Three weeks, twice daily supplementation with 30 g of whey protein (=60 g / day) | Dietary Supplement: protein supplement<br>* protein supplement, twice daily, 2 x 30 g of protein, 3 weeks of intervention; blinded to patients and personnel<br>|
| Active Comparator: Casein supplement, 2x 30g/day<br>Three weeks, twice daily supplementation with 30 g of casein (=60 g / day) | Dietary Supplement: protein supplement<br>* protein supplement, twice daily, 2 x 30 g of protein, 3 weeks of intervention; blinded to patients and personnel<br>|
| Active Comparator: pea protein supplement, 2x 30g/day<br>Three weeks, twice daily supplementation with 30 g of pea protein (=60 g / day) | Dietary Supplement: protein supplement<br>* protein supplement, twice daily, 2 x 30 g of protein, 3 weeks of intervention; blinded to patients and personnel<br>|
| Placebo Comparator: placebo arm<br>Three weeks, twice daily supplementation with 30 g of placebo (=60 g / day) | Dietary Supplement: placebo supplement<br>* Placebo supplement, twice daily, 2 x 30 g of placebo, 3 weeks of intervention; blinded to patients and personnel<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver fat change after three weeks | absolute liver fat reduction after three weeks (MR spectroscopy) | 3 weeks | 
| change of 2-hours glucose levels in mixed meal test | change of 2-hours glucose levels in mixed meal test | 3 weeks | 
| change of glucagon concentration pg/ml (ELISA) in mixed-meal test | change of glucagon concentration (pg/ml) in mixed-meal test | 3 weeks | 
| change of insulin concentration (mIU/ml) in mixed-meal test | change of insulin concentration (mIU/ml) in mixed-meal test calculated as (disposition index) | 3 weeks | 
| change of dynamic insulin sensitivity in mixed-meal test | change of dynamic insulin sensitivity in mixed-meal test (Matsuda) | 3 weeks | 
| change of fasting insulin sensitivity in mixed-meal test | change of fasting insulin sensitivity in mixed-meal test (HOMA-IR) | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change of insulin secretion in consecutive mixed-meal test after an initial breakfast MMT | change of insulin secretion in consecutive mixed-meal test after an initial breakfast MMT | 3 weeks | 
| change of urea concentration in serum(mmol/l) | change of urea concentration in Serum (mmol/l) | 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAFLD, type 2 diabetes, casein, second meal effect, whey protein