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Cut Down on Carbohydrate Usage in the Diet of Type 2 Diabetes. The Hypo-energetic Study (CutDM-Hypo)

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ClinicalTrials.gov Identifier: NCT03814694
Recruitment Status : Recruiting
First Posted : January 24, 2019
Last Update Posted : January 30, 2019
Sponsor:
Collaborators:
University of Copenhagen
University of Aarhus
The Danish Dairy Research Foundation, Denmark
Arla Foods
Information provided by (Responsible Party):
Mads N Thomsen, Bispebjerg Hospital

Brief Summary:

Scientific evidence for the dietary treatment of type 2 diabetes (T2D) is insufficient, which is why the investigators aim to reform dietary recommendation to the overweight or obese patient with type 2 diabetes. This clinical study will examine the effect of a highly controlled hypo-energetic carbohydrate-reduced high-protein (CRHP) diet intervention under caloric restriction-induced body weight loss as a treatment modality in T2D. The investigators hypothesize that this intervention compared to the conventional diabetes (CD) diet with similar loss in body weight improves metabolic control and cardiovascular risk profile in T2D by:

  • Reducing diurnal and postprandial glycaemia, thereby facilitating a significant reduction in HbA1c
  • Reducing ectopic lipid deposits in liver, muscle and pancreas
  • Improving lipid profile towards a less atherogenic profile
  • Improving metabolic actions of insulin, through increased sensitivity and β-cell function
  • Reducing diurnal blood pressure with no adverse effect on heart rate variability

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Overweight and Obesity Dietary Supplement: CRHP Diet Dietary Supplement: CD Diet Not Applicable

Detailed Description:

The present study will be performed as a 6-week randomized fully controlled feeding study, which will address the effect of the hypo-energetic CRHP diet compared with the hypo-energetic CD diet with the macronutrient composition currently recommended to patients with T2D combined with a caloric restriction-induced 5-7% body weight loss on T2D. The study includes n=80 T2D patients.

Measurements include fasting blood samples every 2 weeks during the 6 weeks of the study. Additionally, larger measurement programs will be undertaken at baseline and after 6 weeks, including MRi/s for liver, pancreas and muscle fat content and visceral and subcutaneous adipose tissue; DXA scans for body composition; oral glucose tolerance tests (OGTT); continuous glucose monitoring (CGM); diurnal blood pressure and holter recording. Questionnaires of health-related quality of life, level of physical activity and satiety by visual analogue scale will be performed at baseline and week 6 as well as fecal and diurnal urine sampling.

To ensure a similar body weight loss between intervention groups as well as participants, aimed at 5-7%, caloric intake during the 6 weeks of the study will be hypo-energetic adjusted for each participant according to estimated daily total energy expenditure (TEE). A calculation requiring sex, age, weight and height will be performed to estimate resting energy expenditure (REE), which multiplied with the participant's physical activity level (PAL) will estimate TEE, and thus with an initial caloric deficit of 5% determine the caloric content in the hypo-energetic diet for each participant. Additionally, participants will be weighed twice a week and caloric content adjusted accordingly to ensure a controlled body weight loss.

It is important to recognize that the CRHP diet and the CD diet principally do not differ in the quality of carbohydrate and protein. Thus, this study is unable to address a potential benefit of changes in quality of carbohydrate; however, both diet interventions exhibit a relatively low glycemic index of maximum 55.

Until week 6 diets will be prepared and distributed from the research kitchen of the Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark, to optimize compliance and adherence to the prescribed diet. Following this period and again after approximately 3 months participants will be invited to group sessions with dietician guidance on how to sustain their body weight loss and continue with their assigned diet. A follow-up visit at week 30 will include a blood sample, a spot urine sample and body weight measurement.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cut Down on Carbohydrate Usage in the Diet of Type 2 Diabetes; Mechanisms of Effective Therapy of Diabetes by Selective Choice of Macronutrients. The Hypo-energetic Study.
Actual Study Start Date : January 29, 2019
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: CRHP Diet
Hypo-energetic carbohydrate-reduced high-protein (CRHP) dietary intervention with a controlled 5-7% loss in body weight.
Dietary Supplement: CRHP Diet
Dietary macronutrient composition of 30 E% from carbohydrate, 30 E% from protein and 40 E% from fat

Active Comparator: CD Diet
Hypo-energetic conventional diabetes (CD) dietary intervention with a controlled 5-7% loss in body weight.
Dietary Supplement: CD Diet
Dietary macronutrient composition of 50 E% from carbohydrate, 17 E% from protein and 33 E% from fat




Primary Outcome Measures :
  1. Change in glycated hemoglobin (HbA1c) during 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    The change in HbA1c will be assessed during 6 weeks of fully provisioned hypo-energetic CRHP diet compared with hypo-energetic CD diet, while achieving concurrent body weight loss of 5-7 percent in both groups. Levels of HbA1c will be measured at baseline, week 2, 4, 5 and 6. HbA1c will be expressed in mmol/mol.


Secondary Outcome Measures :
  1. Change in hepatic fat content after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Hepatic fat content will be assessed by magnetic resonance spectroscopy (MRs) at baseline and week 6.

  2. Change in fasting plasma triglycerides during 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Levels of triglycerides will be measured from fasting at baseline, week 2, 4, 5 and 6. Triglycerides will be expressed in mmol/L.


Other Outcome Measures:
  1. Change in fat content subcutaneously, viscerally and ectopically in pancreas and skeletal muscle after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Subcutaneous, visceral and ectopic fat in pancreas and skeletal muscle will be assessed by magnetic resonance imaging/spectroscopy (MRi/s) at baseline and week 6.

  2. Change in lean body mass (LBM) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    LBM will be assessed by dual-energy X-ray absorptiometry (DXA) at baseline and week 6. Changes will be expressed in kilograms (kg).

  3. Change in fat mass (FM) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    FM will be assessed by dual-energy X-ray absorptiometry (DXA) at baseline and week 6. Changes will be expressed in kilograms (kg).

  4. Change in diurnal blood pressure (DBP) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    DBP will be assessed over 24 hours by a blood pressure monitor (Ontrak 90227 from Spacelabs Healthcare) at baseline and week 6. DBP will be expressed in mmHg.

  5. Change in heart rate variability (HRV) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    HRV will be assessed by 48-hour Holter-monitoring (Faros 360 from Bittium) at baseline and week 6.

  6. Change in diurnal glycemia after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Glycemia will be assessed using 7-day continuous glucose monitoring (CGM) (FreeStyle Libre Pro from Abbott) at baseline and week 6.

  7. Change in glycemic variability after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Glycemic variability will be assessed using 7-day continuous glucose monitoring (CGM) (FreeStyle Libre Pro from Abbott) at baseline and week 6.

  8. Change in insulin sensitivity after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Insulin sensitivity will be assessed based on a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6 and expressed by the Matsuda Index.

  9. Change in beta-cell function after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Beta-cell function will be assessed based on a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6 and expressed by the Insulinogenic Index and Disposition Index.

  10. Change in Homeostasis Model Assessment (HOMA) of insulin resistance and beta-cell function after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    HOMA will be performed at baseline and week 6 and expressed by HOMA-IR and HOMA-beta.

  11. Change in lipid profile after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Lipid profile, including lipoproteins will be assessed from fasting at baseline and week 6.

  12. Change in glucose after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Glucose will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Glucose will be expressed in mmol/L.

  13. Change in insulin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Insulin will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Insulin will be expressed in pmol/L.

  14. Change in C-peptide after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    C-peptide will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. C-peptide will be expressed in pmol/L.

  15. Change in non-esterified fatty acids (NEFA) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    NEFA metabolism will be assessed using the minimal model technique based on an oral glucose tolerance test (OGTT) at baseline and week 6. NEFA will be expressed in micromol/L.

  16. Change in triglycerides after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Triglycerides will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Triglycerides will be expressed in mmol/L.

  17. Change in glucagon after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Glucagon will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Glucagon will be expressed in pmol/L.

  18. Change in glucagon-like-peptide-1 (GLP-1) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    GLP-1 will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. GLP-1 will be expressed in pmol/L.

  19. Change in glucose-dependent insulinotropic polypeptide (GIP) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    GIP will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. GIP will be expressed in pmol/L.

  20. Change in peptide YY (PYY) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    PYY will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. PYY will be expressed in pmol/L.

  21. Change in ghrelin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Ghrelin will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Ghrelin will be expressed in pmol/L.

  22. Change in cholecystokinin (CCK) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    CCK will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. CCK will be expressed in pmol/L.

  23. Change in gastrin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Gastrin will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Gastrin will be expressed in pmol/L.

  24. Change in growth hormone (GH) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    GH will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. GH will be expressed in ng/mL.

  25. Change in insulin-like growth factor-1 (IGF-1) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    IGF-1 will be measured from fasting at baseline and week 6. IGF-1 will be expressed in ng/mL.

  26. Change in insulin-like growth factor-binding protein 1 (IGFBP-1) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    IGFBP-1 will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. IGFBP-1 will be expressed in ng/mL.

  27. Change in leptin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Leptin will be measured from fasting at baseline and week 6. Leptin will be expressed in ng/mL.

  28. Change in adiponectin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Adiponectin will be measured from fasting at baseline and week 6. Adiponectin will be expressed in microg/mL.

  29. Change in tumor necrosis factor alpha (TNF-alpha) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    TNF-alpha will be measured from fasting at baseline and week 6 and expressed in pg/mL.

  30. Change in interleukin-6 (IL-6) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    IL-6 will be measured from fasting at baseline and week 6 and expressed in pg/mL.

  31. Change in high-sensitive C-reactive protein (hsCRP) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    hsCRP will be measured from fasting at baseline and week 6 and expressed in mg/L.

  32. Change in renal function assessed from eGFR and diurnal excretion of albumin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    eGFR and diurnal excretion of albumin will be assessed at baseline and week 6.

  33. Change in urinary excretion of urea and glucose after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Urinary excretion of urea and glucose will be assessed at baseline and week 6.

  34. Change in urinary oxidative DNA and RNA modifications after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Urinary oxidative DNA and RNA modifications will be assessed at baseline and week 6.

  35. Change in subjective satiety after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    Subjective satiety will be assessed by a self-reported visual analog scale (VAS) questionnaire with four questions regarding experienced satiety (range 0-100 mm) integrated into one composite satiety score at baseline and week 6.

  36. Change in health-related quality of life (HRQoL) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet. [ Time Frame: 6 weeks ]
    HRQoL will be assessed using a self-reported 36-item Short-Form (SF-36) health survey with 36 questions regarding different domains of HRQoL (each scoring from 0-100 points) at baseline and week 6. HRQoL will be reported as composite scores; a physical and mental component summary (PCS/MCS) score.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 diabetes with HbA1c between 55 mmol/mol and 97 mmol/mol with or without metformin and dipeptidyl peptidase-4 (DPP-4) inhibitors
  • Overweight or obesity with BMI ≥ 27 kg/m2 and desired weight loss
  • Non-smokers for > 1 year
  • Willingness to abstain from alcohol for 6 weeks
  • Hemoglobin > 7 mmol/L for men and > 6 mmol/L for women
  • Estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2

Exclusion Criteria:

  • Critical illness as evaluated by the principal investigator
  • Systemic corticosteroid treatment, e.g. prednisolone
  • Reported or journalized severe food allergy or intolerance
  • Reported or journalized severe gut disease e.g. Crohn's disease, Coeliac disease etc.
  • Reported or journalized alcohol dependence syndrome
  • Injectable diabetes medication, including insulin and GLP-1 analogues
  • Sulfonylureas (SUs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, unless discontinuation is possible, in which case a 2-month wash-out is mandatory
  • Repeated fasting plasma glucose > 13.3 mmol/L
  • Urine albumin / creatinine ratio > 300 mg/g
  • Lactation, pregnancy or planning of pregnancy during the study
  • Inability, physically or mentally, to comply with the procedures required by the study protocol, as evaluated by the principal investigator
  • Presently participating in other clinical trials

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03814694


Contacts
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Contact: Mads N Thomsen, MD +45 25724299 mads.norvin.thomsen@regionh.dk
Contact: Steen B Haugaard, Professor +45 53555066 steen.bendix.haugaard.01@regionh.dk

Locations
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Denmark
Bispebjerg Hospital Recruiting
Copenhagen, Copenhagen NV, Denmark, 2400
Contact: Mads N Thomsen, MD         
Sponsors and Collaborators
Bispebjerg Hospital
University of Copenhagen
University of Aarhus
The Danish Dairy Research Foundation, Denmark
Arla Foods
Investigators
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Principal Investigator: Steen B Haugaard, Professor Dept. of Endocrinology, Copenhagen University Hospital Bispebjerg

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Responsible Party: Mads N Thomsen, Principal Investigator, Bispebjerg Hospital
ClinicalTrials.gov Identifier: NCT03814694     History of Changes
Other Study ID Numbers: CUTDM-HYPO
First Posted: January 24, 2019    Key Record Dates
Last Update Posted: January 30, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Individual participant data (IPD) may be shared by request to the corresponding author in accordance with the Danish Data Protection Agency.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mads N Thomsen, Bispebjerg Hospital:
Weight Loss
Diet, Carbohydrate-Restricted
Diet, High-Protein
Insulin Resistance
Non-alcoholic Fatty Liver Disease
Metabolic Syndrome

Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Overweight
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Body Weight
Signs and Symptoms
Nutrients
Growth Substances
Physiological Effects of Drugs