Clinical trial NCT03814694: Cut Down on Carbohydrate Usage in the Diet of Type 2 Diabetes. The Hypo-energetic Study
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes Mellitus, Type 2
Overweight and Obesity
Keywords: Weight Loss
Diet, Carbohydrate-Restricted
Diet, High-Protein
Insulin Resistance
Non-alcoholic Fatty Liver Disease
Metabolic Syndrome
Lead sponsor: Bispebjerg Hospital
Sponsor class: OTHER
Collaborators: name: University of Copenhagen
name: University of Aarhus
name: The Danish Dairy Research Foundation, Denmark
name: Arla Foods
First posted: 2019-01-24
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Eligibility criteria: Inclusion Criteria:

* Type 2 diabetes with HbA1c between 48 mmol/mol and 97 mmol/mol with or without metformin and dipeptidyl peptidase-4 (DPP-4) inhibitors
* Overweight or obesity with BMI ≥ 25 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

Primary outcomes:
measure: Change in glycated hemoglobin (HbA1c) during 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
Secondary outcomes:
measure: Change in hepatic fat content after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in fasting plasma triglycerides during 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
Other outcomes:
measure: 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.
timeFrame: 6 weeks
measure: Change in lean body mass (LBM) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in fat mass (FM) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in diurnal blood pressure (DBP) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in heart rate variability (HRV) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in diurnal glycemia after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in glycemic variability after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in insulin sensitivity after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in beta-cell function after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: 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.
timeFrame: 6 weeks
measure: Change in lipid profile after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in glucose after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in insulin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in C-peptide after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in non-esterified fatty acids (NEFA) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in triglycerides after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in glucagon after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in glucagon-like-peptide-1 (GLP-1) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in glucose-dependent insulinotropic polypeptide (GIP) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in peptide YY (PYY) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in ghrelin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in cholecystokinin (CCK) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in gastrin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in growth hormone (GH) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in insulin-like growth factor-1 (IGF-1) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: 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.
timeFrame: 6 weeks
measure: Change in leptin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in adiponectin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in tumor necrosis factor alpha (TNF-alpha) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in interleukin-6 (IL-6) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in high-sensitive C-reactive protein (hsCRP) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: 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.
timeFrame: 6 weeks
measure: Change in urinary excretion of urea and glucose after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in urinary oxidative DNA and RNA modifications after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in subjective satiety after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
measure: Change in health-related quality of life (HRQoL) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
timeFrame: 6 weeks
Locations:
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital
state: Copenhagen NV
Study officials:
affiliation: Dept. of Endocrinology, Copenhagen University Hospital Bispebjerg
name: Steen B Haugaard, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jensen NJ, Wodschow HZ, Skytte MJ, Samkani A, Astrup A, Frystyk J, Hartmann B, Holst JJ, Larsen TM, Madsbad S, Magkos F, Miskowiak KW, Haugaard SB, Krarup T, Rungby J, Thomsen MN. Weight-loss induced by carbohydrate restriction does not negatively affect health-related quality of life and cognition in people with type 2 diabetes: A randomised controlled trial. Clin Nutr. 2022 Jul;41(7):1605-1612. doi: 10.1016/j.clnu.2022.05.005. Epub 2022 May 18.
citation: Thomsen MN, Skytte MJ, Samkani A, Carl MH, Weber P, Astrup A, Chabanova E, Fenger M, Frystyk J, Hartmann B, Holst JJ, Larsen TM, Madsbad S, Magkos F, Thomsen HS, Haugaard SB, Krarup T. Dietary carbohydrate restriction augments weight loss-induced improvements in glycaemic control and liver fat in individuals with type 2 diabetes: a randomised controlled trial. Diabetologia. 2022 Mar;65(3):506-517. doi: 10.1007/s00125-021-05628-8. Epub 2022 Jan 7.