Reduction in Glycated Hemoglobin and Daily Insulin Dose Alongside Circadian Clock Upregulation in Patients With Type 2 Diabetes Consuming a Three-Meal Diet: A Randomized Clinical Trial Diabetes Care 2019;42:2171–2180 | https://doi.org/10.2337/dc19-1142 OBJECTIVE In type 2 diabetes, insulin resistance and progressive b-cell failure require treatment with high insulin doses, leading to weight gain. Our aim was to study whether a three-meal diet (3Mdiet) with a carbohydrate-rich breakfast may upregulate clock gene expression and, as a result, allow dose reduction of insulin, leading to weight loss and better glycemic control compared with an isocaloric six-meal diet (6Mdiet). RESEARCH DESIGN AND METHODS Twenty-eight volunteers with diabetes (BMI 32.4 6 5.2 kg/m 2 and HbA 1c 8.1 6 1.1% [64.5 6 11.9 mmol/mol]) were randomly assigned to 3Mdiet or 6Mdiet. Body weight, glycemic control, continuous glucose monitoring (CGM), appetite, and clock gene expression were assessed at baseline, after 2 weeks, and after 12 weeks. RESULTS 3Mdiet, but not 6Mdiet, led to a significant weight loss (25.4 6 0.9 kg) (P < 0.01) and decreased HbA 1c (212 mmol/mol [21.2%]) (P < 0.0001) after 12 weeks. Fasting glucose and daily and nocturnal glucose levels were significantly lower on the 3Mdiet. CGM showed a significant decrease in the time spent in hyperglycemia only on the 3Mdiet. Total daily insulin dose was significantly reduced by 26 6 7 units only on the 3Mdiet. There was a significant decrease in the hunger and cravings only in the 3Mdiet group. Clock genes exhibited oscillation, increased expression, and higher amplitude on the 3Mdiet compared with the 6Mdiet. CONCLUSIONS A 3Mdiet, in contrast to an isocaloric 6Mdiet, leads to weight loss and significant reduction in HbA 1c , appetite, and overall glycemia, with a decrease in daily insulin. Upregulation of clock genes seen in this diet intervention could contribute to the improved glucose metabolism. Diet intervention is a pivotal component of the medical management of diabetes (1). Treatment of insulin-resistant patients with type 2 diabetes with progressive b-cell failure usually starts with a diet intervention consisting of five or six small meals per day, with calories and carbohydrates uniformly distributed throughout the day (2–4) 1 Diabetes Unit, Wolfson Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Holon, Israel 2 Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agri- culture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel 3 Diabetes Unit, Department of Internal Medicine, Hadassah Hebrew University Hospital, The He- brew University of Jerusalem, Jerusalem, Israel 4 Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden 5 Department of Molecular Genetics, Faculty of Biochemistry, Weizmann Institute of Science, Rehovot, Israel Corresponding authors: Oren Froy, oren.froy@ mail.huji.ac.il, and Daniela Jakubowicz, daniela. jak@gmail.com Received 6 June 2019 and accepted 26 August 2019 Clinical trial reg. no. NCT02709915, clinicaltrials .gov This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/ doi:10.2337/dc19-1142/-/DC1. D.J., Z.L., and S.T. contributed equally to this work. © 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More infor- mation is available at http://www.diabetesjournals .org/content/license. Daniela Jakubowicz, 1 Zohar Landau, 1 Shani Tsameret, 2 Julio Wainstein, 1 Itamar Raz, 3 Bo Ahren, 4 Nava Chapnik, 2 Maayan Barnea, 5 Tali Ganz, 1 Miriam Menaged, 1 Naomi Mor, 1 Yosefa Bar-Dayan, 1 and Oren Froy 2 Diabetes Care Volume 42, December 2019 2171 CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL Downloaded from http://diabetesjournals.org/care/article-pdf/42/12/2171/528804/dc191142.pdf by guest on 19 June 2022