title: Meal sequence and glucose excursion, gastric emptying and incretin secretion in type 2 diabetes: a randomised, controlled crossover, exploratory trial.
abstract: OBJECTIVE
  Investigation of dietary therapy for diabetes has focused on meal size and composition; examination of the effects of meal sequence on postprandial glucose management is limited. The effects of fish or meat before rice on postprandial glucose excursion, gastric emptying and incretin secretions were investigated.
  
  
  METHODS
  The experiment was a single centre, randomised controlled crossover, exploratory trial conducted in an outpatient ward of a private hospital in Osaka, Japan. Patients with type 2 diabetes (n = 12) and healthy volunteers (n = 10), with age 30-75 years, HbA1c 9.0% (75 mmol/mol) or less, and BMI 35 kg/m(2) or less, were randomised evenly to two groups by use of stratified randomisation, and subjected to meal sequence tests on three separate mornings; days 1 and 2, rice before fish (RF) or fish before rice (FR) in a crossover fashion; and day 3, meat before rice (MR). Pre- and postprandial levels of glucose, insulin, C-peptide and glucagon as well as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide were evaluated. Gastric emptying rate was determined by (13)C-acetate breath test involving measurement of (13)CO2 in breath samples collected before and after ingestion of rice steamed with (13)C-labelled sodium acetate. Participants, people doing measurements or examinations, and people assessing the outcomes were not blinded to group assignment.
  
  
  RESULTS
  FR and MR in comparison with RF ameliorated postprandial glucose excursion (AUC-15-240 min-glucose: type 2 diabetes, FR 2,326.6 ± 114.7 mmol/l × min, MR 2,257.0 ± 82.3 mmol/l × min, RF 2,475.6 ± 87.2 mmol/l × min [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 1,419.8 ± 72.3 mmol/l × min, MR 1,389.7 ± 69.4 mmol/l × min, RF 1,483.9 ± 72.8 mmol/l × min) and glucose variability (SD-15-240 min-glucose: type 2 diabetes, FR 1.94 ± 0.22 mmol/l, MR 1.68 ± 0.18 mmol/l, RF 2.77 ± 0.24 mmol/l [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 0.95 ± 0.21 mmol/l, MR 0.83 ± 0.16 mmol/l, RF 1.18 ± 0.27 mmol/l). FR and MR also enhanced GLP-1 secretion, MR more strongly than FR or RF (AUC-15-240 min-GLP-1: type 2 diabetes, FR 7,123.4 ± 376.3 pmol/l × min, MR 7,743.6 ± 801.4 pmol/l × min, RF 6,189.9 ± 581.3 pmol/l × min [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 3,977.3 ± 324.6 pmol/l × min, MR 4,897.7 ± 330.7 pmol/l × min, RF 3,747.5 ± 572.6 pmol/l × min [p < 0.05 for MR vs RF and MR vs FR]). FR and MR delayed gastric emptying (Time50%: type 2 diabetes, FR 83.2 ± 7.2 min, MR 82.3 ± 6.4 min, RF 29.8 ± 3.9 min [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 66.3 ± 5.5 min, MR 74.4 ± 7.6 min, RF 32.4 ± 4.5 min [p < 0.05 for FR vs RF and MR vs RF]), which is associated with amelioration of postprandial glucose excursion (AUC-15-120 min-glucose: type 2 diabetes, r = -0.746, p < 0.05; healthy, r = -0.433, p < 0.05) and glucose variability (SD-15-240 min-glucose: type 2 diabetes, r = -0.578, p < 0.05; healthy, r = -0.526, p < 0.05), as well as with increasing GLP-1 (AUC-15-120 min-GLP-1: type 2 diabetes, r = 0.437, p < 0.05; healthy, r = 0.300, p = 0.107) and glucagon (AUC-15-120 min-glucagon: type 2 diabetes, r = 0.399, p < 0.05; healthy, r = 0.471, p < 0.05). The measured outcomes were comparable between the two randomised groups.
  
  
  CONCLUSIONS
  Meal sequence can play a role in postprandial glucose control through both delayed gastric emptying and enhanced incretin secretion. Our findings provide clues for medical nutrition therapy to better prevent and manage type 2 diabetes.
  
  
  BACKGROUND
  UMIN Clinical Trials Registry UMIN000017434.
  
  
  BACKGROUND
  Japan Society for Promotion of Science, Japan Association for Diabetes Education and Care, and Japan Vascular Disease Research Foundation.
authors.affiliation: Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, 1-5-6 Minatojimaminamimachi, Chuo-ku, Kobe, 650-0047, Japan.|Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Osaka, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kuwata
authors.affiliation: Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, 1-5-6 Minatojimaminamimachi, Chuo-ku, Kobe, 650-0047, Japan.|Center for Metabolism and Clinical Nutrition, Kansai Electric Power Hospital, Osaka, Japan.|Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwasaki
authors.affiliation: Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, 1-5-6 Minatojimaminamimachi, Chuo-ku, Kobe, 650-0047, Japan.|Department of Clinical Laboratory, Kansai Electric Power Hospital, Osaka, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Minami
authors.affiliation: Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Haruyo
authors.initials: H
authors.lastname: Maeda
authors.affiliation: Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
authors.affiliation: Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Nakada
authors.affiliation: Kyowa Hakko Kirin Co. Ltd, Tokyo, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Nosaka
authors.affiliation: Division of Biostatistics, Clinical Research Center, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Murotani
authors.affiliation: Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, 1-5-6 Minatojimaminamimachi, Chuo-ku, Kobe, 650-0047, Japan.|Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kurose
authors.affiliation: Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, 1-5-6 Minatojimaminamimachi, Chuo-ku, Kobe, 650-0047, Japan.|Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Osaka, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Seino
authors.affiliation: Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, 1-5-6 Minatojimaminamimachi, Chuo-ku, Kobe, 650-0047, Japan. ydaisuke-kyoto@umin.ac.jp.|Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Osaka, Japan. ydaisuke-kyoto@umin.ac.jp.|Center for Metabolism and Clinical Nutrition, Kansai Electric Power Hospital, Osaka, Japan. ydaisuke-kyoto@umin.ac.jp.|Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan. ydaisuke-kyoto@umin.ac.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yabe
mesh_terms: D000328:Adult; D000368:Aged; D002096:C-Peptide / Q000378:metabolism; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000378:metabolism* / Q000503:physiopathology; D004032:Diet; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D054795:Incretins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007564:Japan; D008297:Male; D062407:Meals / Q000502:physiology; D008875:Middle Aged; D019518:Postprandial Period / Q000502:physiology
chemical_list: D002096:C-Peptide; D054795:Incretins; D007328:Insulin; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose
keywords: GIP; GLP-1; Gastric emptying; Meal sequence; Postprandial glucose variability