Dietary carbohydrate restriction augments weight loss-induced improvements in glycaemic control and liver fat in individuals with type 2 diabetes: a randomised controlled trial

Mads N Thomsen, Mads J Skytte, Amirsalar Samkani, Martin H Carl, Philip Weber, Arne Astrup, Elizaveta Chabanova, Mogens Fenger, Jan Frystyk, Bolette Hartmann, Jens J Holst, Thomas M Larsen, Sten Madsbad, Faidon Magkos, Henrik S Thomsen, Steen B Haugaard, Thure Krarup, Mads N Thomsen, Mads J Skytte, Amirsalar Samkani, Martin H Carl, Philip Weber, Arne Astrup, Elizaveta Chabanova, Mogens Fenger, Jan Frystyk, Bolette Hartmann, Jens J Holst, Thomas M Larsen, Sten Madsbad, Faidon Magkos, Henrik S Thomsen, Steen B Haugaard, Thure Krarup

Abstract

Aims/hypothesis: Lifestyle modification and weight loss are cornerstones of type 2 diabetes management. However, carbohydrate restriction may have weight-independent beneficial effects on glycaemic control. This has been difficult to demonstrate because low-carbohydrate diets readily decrease body weight. We hypothesised that carbohydrate restriction enhances the beneficial metabolic effects of weight loss in type 2 diabetes.

Methods: This open-label, parallel RCT included adults with type 2 diabetes, HbA1c 48-97 mmol/mol (6.5-11%), BMI >25 kg/m2, eGFR >30 ml min-1 [1.73 m]-2 and glucose-lowering therapy restricted to metformin or dipeptidyl peptidase-4 inhibitors. Participants were randomised by a third party and assigned to 6 weeks of energy restriction (all foods were provided) aiming at ~6% weight loss with either a carbohydrate-reduced high-protein diet (CRHP, percentage of total energy intake [E%]: CH30/P30/F40) or a conventional diabetes diet (CD, E%: CH50/P17/F33). Fasting blood samples, continuous glucose monitoring and magnetic resonance spectroscopy were used to assess glycaemic control, lipid metabolism and intrahepatic fat. Change in HbA1c was the primary outcome; changes in circulating and intrahepatic triacylglycerol were secondary outcomes. Data were collected at Copenhagen University Hospital (Bispebjerg and Herlev).

Results: Seventy-two adults (CD 36, CRHP 36, all white, 38 male sex) with type 2 diabetes (mean duration 8 years, mean HbA1c 57 mmol/mol [7.4%]) and mean BMI of 33 kg/m2 were enrolled, of which 67 (CD 33, CRHP 34) completed the study. Body weight decreased by 5.8 kg (5.9%) in both groups after 6 weeks. Compared with the CD diet, the CRHP diet further reduced HbA1c (mean [95% CI] -1.9 [-3.5, -0.3] mmol/mol [-0.18 (-0.32, -0.03)%], p = 0.018) and diurnal mean glucose (mean [95% CI] -0.8 [-1.2, -0.4] mmol/l, p < 0.001), stabilised glucose excursions by reducing glucose CV (mean [95% CI] -4.1 [-5.9, -2.2]%, p < 0.001), and augmented the reductions in fasting triacylglycerol concentration (by mean [95% CI] -18 [-29, -6]%, p < 0.01) and liver fat content (by mean [95% CI] -26 [-45, 0]%, p = 0.051). However, pancreatic fat content was decreased to a lesser extent by the CRHP than the CD diet (mean [95% CI] 33 [7, 65]%, p = 0.010). Fasting glucose, insulin, HOMA2-IR and cholesterol concentrations (total, LDL and HDL) were reduced significantly and similarly by both diets.

Conclusions/interpretation: Moderate carbohydrate restriction for 6 weeks modestly improved glycaemic control, and decreased circulating and intrahepatic triacylglycerol levels beyond the effects of weight loss itself compared with a CD diet in individuals with type 2 diabetes. Concurrent differences in protein and fat intakes, and the quality of dietary macronutrients, may have contributed to these results and should be explored in future studies.

Trial registration: ClinicalTrials.gov NCT03814694.

Funding: The study was funded by Arla Foods amba, The Danish Dairy Research Foundation, and Copenhagen University Hospital Bispebjerg Frederiksberg.

Keywords: Carbohydrate restriction; Dietary intervention; Dyslipidaemia; Glycaemic control; Low-energy diet; Non-alcoholic fatty liver disease; Nutritional therapy; Obesity; Type 2 diabetes mellitus; Weight loss.

© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Figures

Fig. 1
Fig. 1
Participant flow diagram. The median (25th, 75th percentile) time from randomisation to initiation of dietary intervention upon which participants were unblinded was 22 (18, 30) days for the CRHP diet and 22 (19, 31) days for the CD diet
Fig. 2
Fig. 2
Fasting measures of body weight (p = 0.83) (a), HbA1c (p = 0.018) (b), plasma glucose (p = 0.64) (c), serum insulin (p = 0.92) (d) and serum triacylglycerol (TAG) (p < 0.01) (e) during 6 weeks of a CRHP (n = 34) or CD (n = 33) diet. Data are presented as mean with SEM error bars, including back-transformed data in (c–e) following log-transformation. Changes from baseline to week 6 were evaluated between diets, and p values for these differences are included

References

    1. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383(9922):1068–1083. doi: 10.1016/S0140-6736(13)62154-6.
    1. Lean MEJ, Leslie WS, Barnes AC, et al. Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. Lancet Diabetes Endocrinol. 2019;7(5):344–355. doi: 10.1016/S2213-8587(19)30068-3.
    1. Franz MJ, Boucher JL, Rutten-Ramos S, VanWormer JJ. Lifestyle weight-loss intervention outcomes in overweight and obese adults with type 2 diabetes: a systematic review and meta-analysis of randomized clinical trials. J Acad Nutr Diet. 2015;115(9):1447–1463. doi: 10.1016/j.jand.2015.02.031.
    1. Heller SR, Group AC A summary of the ADVANCE trial. Diabetes Care. 2009;32(Suppl 2):S357–S361. doi: 10.2337/dc09-S339.
    1. Baum A, Scarpa J, Bruzelius E, Tamler R, Basu S, Faghmous J. Targeting weight loss interventions to reduce cardiovascular complications of type 2 diabetes: a machine learning-based post-hoc analysis of heterogeneous treatment effects in the Look AHEAD trial. Lancet Diabetes Endocrinol. 2017;5(10):808–815. doi: 10.1016/S2213-8587(17)30176-6.
    1. American Diabetes Association 5. Facilitating behavior change and well-being to improve health outcomes: standards of medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S48–S65. doi: 10.2337/dc20-S005.
    1. Mann JI, De Leeuw I, Hermansen K, et al. Evidence-based nutritional approaches to the treatment and prevention of diabetes mellitus. Nutr Metab Cardiovasc Dis. 2004;14(6):373–394. doi: 10.1016/s0939-4753(04)80028-0.
    1. Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019;42(5):731–754. doi: 10.2337/dci19-0014.
    1. Huntriss R, Campbell M, Bedwell C. The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. Eur J Clin Nutr. 2018;72(3):311–325. doi: 10.1038/s41430-017-0019-4.
    1. Skytte MJ, Samkani A, Petersen AD, et al. A carbohydrate-reduced high-protein diet improves HbA1c and liver fat content in weight stable participants with type 2 diabetes: a randomised controlled trial. Diabetologia. 2019;62(11):2066–2078. doi: 10.1007/s00125-019-4956-4.
    1. Mardinoglu A, Wu H, Bjornson E, et al. An integrated understanding of the rapid metabolic benefits of a carbohydrate-restricted diet on hepatic steatosis in humans. Cell Metab. 2018;27(3):559–571. doi: 10.1016/j.cmet.2018.01.005.
    1. Look ARG, Wing RR, Bolin P, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145–154. doi: 10.1056/NEJMoa1212914.
    1. Mifflin MD, St Jeor ST, Hill LA, Scott BJ, Daugherty SA, Koh YO. A new predictive equation for resting energy expenditure in healthy individuals. Am J Clin Nutr. 1990;51(2):241–247. doi: 10.1093/ajcn/51.2.241.
    1. Hall KD. What is the required energy deficit per unit weight loss? Int J Obes. 2008;32(3):573–576. doi: 10.1038/sj.ijo.0803720.
    1. Craig CL, Marshall AL, Sjostrom M, et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc. 2003;35(8):1381–1395. doi: 10.1249/01.MSS.0000078924.61453.FB.
    1. Carlsson ER, Fenger M, Henriksen T, et al. Reduction of oxidative stress on DNA and RNA in obese patients after roux-en-Y gastric bypass surgery-an observational cohort study of changes in urinary markers. PLoS One. 2020;15(12):e0243918. doi: 10.1371/journal.pone.0243918.
    1. Chabanova E, Fonvig CE, Bojsoe C, Holm JC, Thomsen HS. (1)H MRS assessment of hepatic fat content: comparison between Normal- and excess-weight children and adolescents. Acad Radiol. 2017;24(8):982–987. doi: 10.1016/j.acra.2017.02.010.
    1. Fonvig CE, Bille DS, Chabanova E, Nielsen TR, Thomsen HS, Holm JC. Muscle fat content and abdominal adipose tissue distribution investigated by magnetic resonance spectroscopy and imaging in obese children and youths. Pediatr Rep. 2012;4(1):e11. doi: 10.4081/pr.2012.e11.
    1. Battelino T, Danne T, Bergenstal RM, et al. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. Diabetes Care. 2019;42(8):1593–1603. doi: 10.2337/dci19-0028.
    1. Bingham SA. Urine nitrogen as a biomarker for the validation of dietary protein intake. J Nutr. 2003;133 Suppl 3(3):921S–924S. doi: 10.1093/jn/133.3.921S.
    1. American Diabetes Association 6. Glycemic targets: standards of medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S66–S76. doi: 10.2337/dc20-S006.
    1. Qian F, Korat AA, Malik V, Hu FB. Metabolic effects of monounsaturated fatty acid-enriched diets compared with carbohydrate or polyunsaturated fatty acid-enriched diets in patients with type 2 diabetes: a systematic review and Meta-analysis of randomized controlled trials. Diabetes Care. 2016;39(8):1448–1457. doi: 10.2337/dc16-0513.
    1. Nuttall FQ, Almokayyad RM, Gannon MC. Comparison of a carbohydrate-free diet vs. fasting on plasma glucose, insulin and glucagon in type 2 diabetes. Metabolism. 2015;64(2):253–262. doi: 10.1016/j.metabol.2014.10.004.
    1. Samkani A, Skytte MJ, Kandel D, et al. A carbohydrate-reduced high-protein diet acutely decreases postprandial and diurnal glucose excursions in type 2 diabetes patients. Br J Nutr. 2018;119(8):910–917. doi: 10.1017/S0007114518000521.
    1. Cavalot F, Petrelli A, Traversa M, et al. Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the san Luigi Gonzaga diabetes study. J Clin Endocrinol Metab. 2006;91(3):813–819. doi: 10.1210/jc.2005-1005.
    1. Thomsen MN, Skytte MJ, Astrup A, et al. The clinical effects of a carbohydrate-reduced high-protein diet on glycaemic variability in metformin-treated patients with type 2 diabetes mellitus: a randomised controlled study. Clin Nutr ESPEN. 2020;39:46–52. doi: 10.1016/j.clnesp.2020.07.002.
    1. Tay J, Thompson CH, Luscombe-Marsh ND, et al. Effects of an energy-restricted low-carbohydrate, high unsaturated fat/low saturated fat diet versus a high-carbohydrate, low-fat diet in type 2 diabetes: a 2-year randomized clinical trial. Diabetes Obes Metab. 2018;20(4):858–871. doi: 10.1111/dom.13164.
    1. Kotronen A, Juurinen L, Hakkarainen A, et al. Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care. 2008;31(1):165–169. doi: 10.2337/dc07-1463.
    1. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343–1351. doi: 10.1172/JCI23621.
    1. Schwarz JM, Linfoot P, Dare D, Aghajanian K. Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets. Am J Clin Nutr. 2003;77(1):43–50. doi: 10.1093/ajcn/77.1.43.
    1. Bozzetto L, Prinster A, Annuzzi G, et al. Liver fat is reduced by an isoenergetic MUFA diet in a controlled randomized study in type 2 diabetic patients. Diabetes Care. 2012;35(7):1429–1435. doi: 10.2337/dc12-0033.
    1. Sandby K, Geiker NRW, Dalamaga M, Gronbaek H, Magkos F. Efficacy of dietary manipulations for depleting intrahepatic triglyceride content: implications for the Management of non-alcoholic Fatty Liver Disease. Curr Obes Rep. 2021;10(2):125–133. doi: 10.1007/s13679-021-00430-4.
    1. Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Patterson BW, Klein S. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology. 2009;136(5):1552–1560. doi: 10.1053/j.gastro.2009.01.048.
    1. Haufe S, Engeli S, Kast P, et al. Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects. Hepatology. 2011;53(5):1504–1514. doi: 10.1002/hep.24242.
    1. Inaishi J, Saisho Y. Beta-cell mass in obesity and type 2 diabetes, and its relation to pancreas fat: a Mini-review. Nutrients. 2020;12(12):3846. doi: 10.3390/nu12123846.
    1. Al-Mrabeh A, Hollingsworth KG, Shaw JAM, et al. 2-year remission of type 2 diabetes and pancreas morphology: a post-hoc analysis of the DiRECT open-label, cluster-randomised trial. Lancet Diabetes Endocrinol. 2020;8(12):939–948. doi: 10.1016/S2213-8587(20)30303-X.
    1. Kirkpatrick CF, Bolick JP, Kris-Etherton PM, et al. Review of current evidence and clinical recommendations on the effects of low-carbohydrate and very-low-carbohydrate (including ketogenic) diets for the management of body weight and other cardiometabolic risk factors: a scientific statement from the National Lipid Association Nutrition and lifestyle task force. J Clin Lipidol. 2019;13(5):689–711. doi: 10.1016/j.jacl.2019.08.003.
    1. Nezu U, Kamiyama H, Kondo Y, Sakuma M, Morimoto T, Ueda S. Effect of low-protein diet on kidney function in diabetic nephropathy: meta-analysis of randomised controlled trials. BMJ Open. 2013;3(5):e002934. doi: 10.1136/bmjopen-2013-002934.
    1. Goldenberg JZ, Day A, Brinkworth GD, et al. Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission: systematic review and meta-analysis of published and unpublished randomized trial data. BMJ. 2021;372:m4743. doi: 10.1136/bmj.m4743.
    1. Gannon MC, Hoover H, Nuttall FQ. Further decrease in glycated hemoglobin following ingestion of a LoBAG30 diet for 10 weeks compared to 5 weeks in people with untreated type 2 diabetes. Nutr Metab (Lond) 2010;7:64. doi: 10.1186/1743-7075-7-64.
    1. Silva FM, Kramer CK, de Almeida JC, Steemburgo T, Gross JL, Azevedo MJ. Fiber intake and glycemic control in patients with type 2 diabetes mellitus: a systematic review with meta-analysis of randomized controlled trials. Nutr Rev. 2013;71(12):790–801. doi: 10.1111/nure.12076.
    1. Schwingshackl L, Strasser B, Hoffmann G. Effects of monounsaturated fatty acids on glycaemic control in patients with abnormal glucose metabolism: a systematic review and meta-analysis. Ann Nutr Metab. 2011;58(4):290–296. doi: 10.1159/000331214.
    1. Alzahrani AH, Skytte MJ, Samkani A et al (2021) Body weight and metabolic risk factors in patients with type 2 diabetes on a self-selected high-protein low-carbohydrate diet. Eur J Nutr 60(8):4473–4482. 10.1007/s00394-021-02605-0

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner