, Volume 62, Issue 11, pp 2066–2078 | Cite as

A carbohydrate-reduced high-protein diet improves HbA1c and liver fat content in weight stable participants with type 2 diabetes: a randomised controlled trial

  • Mads J. SkytteEmail author
  • Amirsalar Samkani
  • Amy D. Petersen
  • Mads N. Thomsen
  • Arne Astrup
  • Elizaveta Chabanova
  • Jan Frystyk
  • Jens J. Holst
  • Henrik S. Thomsen
  • Sten Madsbad
  • Thomas M. Larsen
  • Steen B. Haugaard
  • Thure Krarup



Dietary recommendations for treating type 2 diabetes are unclear but a trend towards recommending a diet reduced in carbohydrate content is acknowledged. We compared a carbohydrate-reduced high-protein (CRHP) diet with an iso-energetic conventional diabetes (CD) diet to elucidate the effects on glycaemic control and selected cardiovascular risk markers during 6 weeks of full food provision of each diet.


The primary outcome of the study was change in HbA1c. Secondary outcomes reported in the present paper include glycaemic variables, ectopic fat content and 24 h blood pressure. Eligibility criteria were: men and women with type 2 diabetes, HbA1c 48–97 mmol/mol (6.5–11%), age >18 years, haemoglobin >6/>7 mmol/l (women/men) and eGFR >30 ml min−1 (1.73 m)−2. Participants were randomised by drawing blinded ballots to 6 + 6 weeks of an iso-energetic CRHP vs CD diet in an open label, crossover design aiming at body weight stability. The CRHP/CD diets contained carbohydrate 30/50 energy per cent (E%), protein 30/17E% and fat 40/33E%, respectively. Participants underwent a meal test at the end of each diet period and glycaemic variables, lipid profiles, 24 h blood pressure and ectopic fat including liver and pancreatic fat content were assessed at baseline and at the end of each diet period. Data were collected at Copenhagen University Hospital, Bispebjerg and Copenhagen University Hospital, Herlev.


Twenty-eight participants completed the study. Fourteen participants carried out 6 weeks of the CRHP intervention followed by 6 weeks of the CD intervention, and 14 participants received the dietary interventions in the reverse order. Compared with a CD diet, a CRHP diet reduced the primary outcome of HbA1c (mean ± SEM: −6.2 ± 0.8 mmol/mol (−0.6 ± 0.1%) vs −0.75 ± 1.0 mmol/mol (−0.1 ± 0.1%); p < 0.001). Nine (out of 37) pre-specified secondary outcomes are reported in the present paper, of which five were significantly different between the diets, (p < 0.05); compared with a CD diet, a CRHP diet reduced the secondary outcomes (mean ± SEM or medians [interquartile range]) of fasting plasma glucose (−0.71 ± 0.20 mmol/l vs 0.03 ± 0.23 mmol/l; p < 0.05), postprandial plasma glucose AUC (9.58 ± 0.29 mmol/l × 240 min vs 11.89 ± 0.43 mmol/l × 240 min; p < 0.001) and net AUC (1.25 ± 0.20 mmol/l × 240 min vs 3.10 ± 0.25 mmol/l × 240 min; p < 0.001), hepatic fat content (−2.4% [−7.8% to −1.0%] vs 0.2% [−2.3% to 0.9%]; p < 0.01) and pancreatic fat content (−1.7% [−3.5% to 0.6%] vs 0.5% [−1.0% to 2.0%]; p < 0.05). Changes in other secondary outcomes, i.e. 24 h blood pressure and muscle-, visceral- or subcutaneous adipose tissue, did not differ between diets.


A moderate macronutrient shift by substituting carbohydrates with protein and fat for 6 weeks reduced HbA1c and hepatic fat content in weight stable individuals with type 2 diabetes.

Trial registration NCT02764021.


The study was funded by grants from Arla Food for Health; the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen; the Department of Clinical Medicine, Aarhus University; the Department of Nutrition, Exercise and Sports, University of Copenhagen; and Copenhagen University Hospital, Bispebjerg.


Carbohydrate restriction Cardiovascular disease Dietary intervention Ectopic fat deposition Glycaemic control Metabolism Non-alcoholic fatty liver disease Nutritional therapy Type 2 diabetes mellitus Weight stability 



Conventional diabetes


Carbohydrate-reduced high-protein


Cardiovascular disease


Energy per cent


Mixed meal test


Non-alcoholic fatty liver disease


Subcutaneous adipose tissue


Total energy expenditure


Visceral adipose tissue



The authors sincerely thank the study participants for their efforts in making this study possible. Further, we thank the kitchen personnel at the Department of Nutrition, Exercise and Sports, University of Copenhagen. Preliminary results from the present study were presented by MJS and AS as poster presentations at the 77th Scientific Session of the ADA, 2017, and at the 54th Annual Meeting of the EASD, 2018.

Contribution statement

MJS and AS conducted the study, acquired and analysed the data, and drafted the manuscript. ADP and MNT contributed to acquisition of data. EC produced and analysed magnetic resonance data and contributed to drafting of the manuscript. AA, JF, JJH, HST, SM and TML contributed to the conception and the design of the study and contributed to the production and the interpretation of data. In addition, TML supervised the food production and distribution. SBH and TK conceived and designed the study, obtained funding, supervised the study and contributed to interpretation of data. TK is the guarantor of the manuscript. All authors critically reviewed the manuscript and approved the version to be published.


The study was funded by grants from: Arla Food for Health; the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen; the Department of Clinical Medicine, Aarhus University; the Department of Nutrition, Exercise and Sports, University of Copenhagen; and Copenhagen University Hospital, Bispebjerg. Dietary ingredients were partly provided by Arla Foods, JAN Import A/S, Royal Greenland and Danish Crown. The study sponsors, Arla Food for Health, Arla Foods, JAN Import A/S, Royal Greenland and Danish Crown, were informed, but not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. Co-authors from the University of Copenhagen and Aarhus University were involved in the study, as detailed in the contribution statement.

Duality of interest

AA is a member of advisory boards/consultant for: BioCare Copenhagen, Denmark; the Dutch Beer Institute, the Netherlands; Gelesis, USA; Groupe Éthique et Santé, France; McCain Foods Limited, USA; Navamedic, Denmark; Novo Nordisk, Denmark; Pfizer, USA; Saniona, Denmark; Weight Watchers, USA; and is a recipient of travel grants and honoraria as speaker for a wide range of Danish and international concerns. AA is co-owner and a member of the board of the consultancy company Dentacom ApS, Denmark; co-founder and co-owner of UCPH spin-outs Mobile Fitness A/S, Flaxslim ApS and Personalized Weight Management Research Consortium ApS ( AA is co-inventor of a number of patents owned by UCPH, in accordance with Danish law. AA is co-author of a number of diet and cookery books, including books on personalised diet. AA is not an advocate or activist for specific diets, and is not strongly committed to any specific diet, e.g. veganism, Atkins diet, gluten-free diet, high-animal protein diet or dietary supplements. TML is an advisor for ‘Sense’ diet programme. None of the other authors have conflicts of interest to declare.

Supplementary material

125_2019_4956_MOESM1_ESM.pdf (116 kb)
ESM (PDF 115 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Mads J. Skytte
    • 1
    Email author
  • Amirsalar Samkani
    • 1
  • Amy D. Petersen
    • 1
  • Mads N. Thomsen
    • 1
  • Arne Astrup
    • 2
  • Elizaveta Chabanova
    • 3
  • Jan Frystyk
    • 4
  • Jens J. Holst
    • 5
  • Henrik S. Thomsen
    • 3
  • Sten Madsbad
    • 6
  • Thomas M. Larsen
    • 2
  • Steen B. Haugaard
    • 1
    • 7
  • Thure Krarup
    • 1
  1. 1.Department of EndocrinologyCopenhagen University Hospital BispebjergCopenhagenDenmark
  2. 2.Department of Nutrition, Exercise and SportsUniversity of CopenhagenCopenhagenDenmark
  3. 3.Department of RadiologyCopenhagen University Hospital HerlevCopenhagenDenmark
  4. 4.Department of Clinical MedicineAarhus UniversityAarhusDenmark
  5. 5.Novo Nordisk Foundation Center for Basic Metabolic ResearchUniversity of CopenhagenCopenhagenDenmark
  6. 6.Department of EndocrinologyCopenhagen University Hospital Amager HvidovreCopenhagenDenmark
  7. 7.Department of Internal MedicineCopenhagen University Hospital Amager HvidovreCopenhagenDenmark

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