Scientific evidence for the dietary treatment of type 2 diabetes (T2D) is insufficient. The study group hypothesizes that a lower carbohydrate content in the diabetic diet than the recommended 55 energy percentage (E%) will decrease the postprandial glucose excursion. This will reduce postprandial insulin concentration, which together with lower glucose concentration leads to less fat accumulation in the liver and muscle tissue, resulting in an improved insulin sensitivity which together with a reduced glucose load improves the glucose metabolism. This clinical study will examine in subjects with type 2 diabetes the effect of highly controlled dietary low carbohydrate intervention on metabolic pathways with respect to insulin action, pancreatic islet function, lipid metabolism, ectopic fat accumulation, incretin hormones, low grade inflammation in plasma and adipose tissue, novel measures of fatty acid metabolism, and heart rate variability, respectively. The studies exhibit the potential to reform dietary recommendation aiming to prevent and ameliorate type 2 diabetes.

The study will be performed as a randomized 12 weeks controlled, cross-over trial, which will address the effects on T2D of an isoenergetic low carbohydrate diet (carbohydrate 30 E%, protein 30 E%, fat 40 E%) compared to an isoenergetic control diet (carbohydrate 50 E%, protein 17 E%, fat 33 E%) currently recommended to individuals with T2D. The study is extended with 24 weeks on an isoenergetic low carbohydrate diet to examine the prolonged effect of the experimental diet on T2D and its pathophysiology. To test the hypothesis that the isoenergetic control diet is detrimental to glucose metabolism after only a short transition to this diet, the participants are reinforced to eat that diet during 6 weeks after the 24 weeks on low carbohydrate/high protein diet.

The study includes n=30 subjects with T2D. All study participants will be provided all meals for both the low carbohydrate diet and the control diet for free in the first part of the study, i.e. week 0 to 12, and these food items 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 prescriped diet. During the isoenergetic diet study weight stability is reinforced to facilitate interpretation of the diet effect. All diets will be isoenergetic in accordance with the participant's estimated daily total energy expenditure (TEE). A dual energy X-ray absorptiometry (DXA) scan will be undertaken to determine body composition for each participant in order to estimate daily resting energy expenditure (REE). To estimate TEE, physical activity level expressed as PAL = TEE / REE, will be estimated. If a participant develops weight loss or weight gain at three consecutive measurements and/or lose or gain > 1kg of weight compared to baseline, the amount of energy in the diet wil be adjusted accordingly to enforce weight stability throughout the full duration of the study.

Measurements includes glycated hemoglobin (HbA1c) and fasting glucose, insulin, C-peptide and non-esterified fatty acids (NEFA) every 2 weeks during the first 12 weeks of the study and every 4 weeks from week 12.

At baseline, week 6, 12, 36 and 42, respectively larger measurement programs will be undertaken including insulin modified frequently sampled intravenous glucose tests (IM-FSIGT) and meal tests by use of Minimal Modelling, magnetic resonance imaging (MRi) for fat content in liver, abdomen and muscle, adipose tissue biopsies, continous glucose monitoring for 48-hours including diurnal blood pressure and Holter recording.

A standard meal will be provided for dinner a day prior to the measurement programs at week 0, 36 and 42. At weeks 6 and 12 the participants will intake their assigned meals. Participants will be informed to refrain from any strenuous physical activity and alcohol intake two days prior to and during the measurement program days.

Inclusion Criteria:

• Written informed consent signed before any study-specific procedure
• Type 2 diabetes with glycated hemoglobin (HbA1c) between 48 mmol/mol and 97 mmol/mol with or without oral antidiabetic medicine
• Age > 18 years, men and women
• 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
• Systemic corticosteriod 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
• 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
• Blood donation < 1 month prior to the study and during the study

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