ArticlePDF Available

Manipulating the sequence of food ingestion improves glycemic control in type 2 diabetic patients under free-living conditions


Abstract and Figures

Lipid and protein ingested before carbohydrate reduce postprandial hyperglycemia. We tested feasibility, safety and clinical efficacy of manipulating the sequence of nutrient ingestion in patients with type 2 diabetes (T2D). After a 4-week run-in, 17 T2D patients were randomized to either a control diet (CD) or to an experimental diet (ED) allowing the consumption of high-carbohydrate foods only after high-protein and high-fat foods at each main meal (lunch+dinner). Both diets were accurately followed and neutral on arterial blood pressure, plasma lipids and indices of hepatic and kidney function. After 8 weeks, in spite of a similar reduction of body weight (ED -1.9 95% confidence interval (-3.4/-0.4)kg, P<0.03; CD -2.0 (-3.6/-0.5)kg, P<0.02) and waist circumference (ED -2.9 (-4.3/-1.5)cm, P<0.002; CD -3.3 (-5.9/-0.7)cm, P<0.02), the ED only was associated with significant reductions of HbA1c (-0.3 (-0.50/-0.02)%, P<0.04), fasting plasma glucose (-1.0 (-1.8/-0.3)mmol l(-1), P<0.01), postprandial glucose excursions (lunch -1.8 (-3.2/-0.4)mmol l(-1), P<0.01; dinner: -1.0 (-1.9/-0.1)mmol l(-1), P<0.04) and other indices of glucose variability (s.d.: -0.5 (-0.7/-0.2)mmol l(-1), P<0.02; Coefficient of variation: -6.6 (-10.4/-2.7)%, P<0.02). When compared with the CD, the ED was associated with lower post-lunch glucose excursions (P<0.02) and lower glucose coefficients of variation (P<0.05). Manipulating the sequence of nutrient ingestion might reveal a rapid, feasible, economic and safe strategy for optimizing glucose control in T2D.
Content may be subject to copyright.
Manipulating the sequence of food ingestion improves
glycemic control in type 2 diabetic patients under free-living
D Tricò, E Filice, S Tri and A Natali
Lipid and protein ingested before carbohydrate reduce postprandial hyperglycemia. We tested feasibility, safety and clinical efcacy
of manipulating the sequence of nutrient ingestion in patients with type 2 diabetes (T2D). After a 4-week run-in, 17 T2D patients
were randomized to either a control diet (CD) or to an experimental diet (ED) allowing the consumption of high-carbohydrate foods
only after high-protein and high-fat foods at each main meal (lunch+dinner). Both diets were accurately followed and neutral on
arterial blood pressure, plasma lipids and indices of hepatic and kidney function. After 8 weeks, in spite of a similar reduction of
body weight (ED 1.9 95% condence interval (3.4/ 0.4)kg, Po0.03; CD 2.0 (3.6/ 0.5)kg, Po0.02) and waist circumference
(ED 2.9 (4.3/ 1.5)cm, Po0.002; CD 3.3 (5.9/ 0.7)cm, Po0.02), the ED only was associated with signicant reductions of
HbA1c (0.3 (0.50/ 0.02)%, Po0.04), fasting plasma glucose (1.0 (1.8/ 0.3)mmol l
,Po0.01), postprandial glucose
excursions (lunch 1.8 (3.2/ 0.4)mmol l
,Po0.01; dinner: 1.0 (1.9/ 0.1)mmol l
,Po0.04) and other indices of glucose
variability (s.d.: 0.5 (0.7/ 0.2)mmol l
,Po0.02; Coefcient of variation: 6.6 (10.4/ 2.7)%, Po0.02). When compared with
the CD, the ED was associated with lower post-lunch glucose excursions (Po0.02) and lower glucose coefcients of variation
(Po0.05). Manipulating the sequence of nutrient ingestion might reveal a rapid, feasible, economic and safe strategy for optimizing
glucose control in T2D.
Nutrition & Diabetes (2016) 6, e226; doi:10.1038/nutd.2016.33; published online 22 August 2016
Lipid and protein ingested before carbohydrate, as a preload,
have been shown to acutely improve glucose tolerance, mainly by
delaying gastric emptying and by enhancing insulin secretion.
Indeed, we recently reported that a small mixed non-glucidic
preload markedly improved glucose tolerance by delaying glucose
absorption, enhancing beta cell function and reducing insulin
clearance in patients with type 2 diabetes.
Whether these acute
effects persist over time is unclear.
Furthermore, adding a
nutrient preload to each meal to improve postprandial glucose
control could be unfeasible and/or increase the total daily caloric
intake. As recently suggested by an acute pilot study,
we tested
the hypothesis that manipulating the sequence of food consump-
tion during each main meal (i.e., high-protein and high-lipid foods
before carbohydrate) would exploit the same marked hypogly-
cemic effects of non-glucidic nutrient preloads, revealing a simple,
safe and effective strategy to improve glucose control in type
2 diabetic patients.
Study population
Twenty well-controlled type 2 diabetic patients were enrolled. The
inclusion criteria were age 5075 years, body mass index (BMI)
2635 kg m
, stable weight for at least 6 months, glycated
hemoglobin 4858 mmol mol
, disease duration 5 years. None
had diseases other than diabetes or was taking medications other
than metformin and/or sitagliptin that could potentially interfere
with carbohydrate absorption and/or metabolism. The institutional
Ethics Committee approved the study and all participants provided
written informed consent before inclusion in the study.
Study design
This was a parallel, randomized, open clinical trial. Participants
were evaluated on four consecutive visits separated by 28 ± 2 days
at 08:00 am after an overnight fast. On each occasion, body
weight, fat mass (FM) and basal metabolic rate (BMR) were
assessed by bioelectrical impedance (TBF-300 Body Composition
Analyzer, Tanita Corporation, Arlington Heights, IL, USA); waist and
hip circumferences, and systolic and diastolic blood pressure were
measured according to standard procedures. Blood samples were
collected at study entry (visit 1), after 28 days of run-in (visit 2) and
after 56 days of diet (visit 4) for the measurement of blood
glucose, glycated hemoglobin, total cholesterol, LDL cholesterol,
HDL cholesterol, triglycerides, and standard indices of renal,
hepatic, pancreatic and thyroid function. Volunteers were also
asked to measure their blood glucose concentrations by
glucometer (Contour XT, Bayer HealthCare LLC, Whippany, NJ,
USA) once a week six times in a single day (before and two hours
after breakfast, lunch, and dinner) for the full length of the study.
The total daily caloric need was estimated in each volunteer by
adding the BMR to the individual caloric expenditure during
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. Correspondence: Dr D Tricò, Department of Clinical and Experimental Medicine, University of Pisa,
Via Roma 67, Pisa 56126 Italy.
Received 3 April 2016; revised 1 June 2016; accepted 12 June 2016
Citation: Nutrition & Diabetes (2016) 6, e226; doi:10.1038/nutd.2016.33
working and leisure time physical activity. On visit 2, volunteers
were randomized into two different groups. Subjects from control
group were asked to follow an 8-week standard balanced mild-
hypocaloric diet (control diet (CD)).
Each subject received a
dietary plan with the food composition of three typical meals
(breakfast, lunch and dinner) and a table of possible substitutions
with variable equicaloric amounts of different foods. Meals and
variants were pondered to yield a caloric decit of ~ 200 kcal
per day with respect to the total daily caloric need, to produce an
expected weight loss of ~ 1 kilogram a month. Patients from the
experimental group received the same diet plan in terms of food
quality and quantity (experimental diet, ED). In addition, they
received indications on macronutrient composition of foods and
were strongly recommended to x the sequence of macronutrient
ingestion at each main meal (lunch and dinner), so as to eat high-
carbohydrate-containing foods (e.g., bread, pasta, potatoes)
preferably after the ingestion of high-protein and high-fat foods
(e.g., meat, cheese, sh). A typical main meal in the ED was so
composed of meat as the rst course, then vegetables, bread
and/or pasta and fruit. All volunteers were asked to report their
overall compliance to the caloric content and to the sequence of
nutrients of the prescribed diet by checking on an ad hoc
designed form at each meal.
Statistical analysis
Data are shown as mean ± s.e.m. The changes induced by our
experimental maneuver were evaluated by using either Wilcoxon
signed rank or Mixed-model multivariate analysis of variance
(MANOVA) for repeated measures with time as within-subject
factor, diet as between subjects factor, and the interaction time*diet
as main outcome variable. Data from self-monitoring of blood
glucose were analyzed by calculating mean 2-hours glucose
increments over pre-meal values for each meal (breakfast, lunch,
dinner) and by calculating mean concentrations, s.d. and
percentage coefcients of variation (CV; s.d./mean ratio) of lunch
+dinner glucose values over 4 days (on week apart) during the
run-in, the rst and the second 4 weeks of diet.
Statistical analyses
were performed using JMP 9.0 (SAS Institute Inc., Cary, NC, USA).
A value of P0.05 was considered statistically signicant.
Characteristics of the study population
Three volunteers were excluded due to their poor compliance
to the study protocol, nine were included in the control group
(age 64 ± 8 years, 6 males and 3 females, 4 on metformin and 2 on
metformin+sitagliptin therapy) and eight in the experimental
group (age 65 ±7 years, 6 males and 2 females, 4 on metformin
and 1 on metformin+sitagliptin therapy). Clinical and metabolic
characteristics were similar between the two study groups
(Table 1). Although a proper subgroup analysis was not performed
due to the small number of subjects, neither metformin nor
sitagliptin use has reasonably affected study results, since subjects
taking medications showed no large difference in glycemic
responses compared with other group members. Self-reported
dietary compliance at each main meal was 495% in terms of
caloric intake and 490% in terms of food sequence. None of the
patients randomized to the ED complained of any distress
associated with the xed sequence of nutrient consumption
during their two main meals (lunch and dinner).
Clinical variables
The two diet regimens produced similar (diet and time*diet
effects = ns by MANOVA) and close-to-the-expected reductions in
body weight (ED 1.9 kg, 95% condence interval (CI) (3.4/ 0.4);
CD 2.0 kg, 95% CI (3.6/ 0.5); time effect Po0.003), BMI
(ED 0.7 kg m
, 95% CI (1.2/ 0.2); CD 0.7 kg m
, 95% CI
(1.2/ 0.2); time effect Po0.002), FM (ED 1.5%, 95% CI
(2.8/ 0.3); CD 0.8%, 95% CI (1.8/0.2); time effect Po0.02)
and waist circumference (ED 2.9 cm, 95% CI (4.3/ 1.5); CD
3.3 cm, 95% CI (5.9/ 0.7); time effect Po0.002) (Table 1). No
differences were found in serum lipids or systolic and diastolic
blood pressure values in any of the four visits in the two study
groups (Table 1). Neither diet affected renal, hepatic, pancreatic
and thyroid function indices (data not shown).
Glucose control variables
After 8 weeks, the ED produced an improvement of the overall
glucose control, as assessed by the reduction of glycated
Table 1. Clinical and metabolic variables
Experimental diet Control diet
4 weeks 0 4 weeks 8 weeks 4 weeks 0 4 weeks 8 weeks
Weight (kg) 85.6 ±2.4 84.9 ±2.3 83.4 ±2.5
83.0 ±2.5
85.3 ±5.1 84.8 ±5.1 83.2 ±4.7
82.7 ±4.7
BMI (kg m
) 31.1 ±1.3 30.9 ±1.3 30.2 ±1.2
30.2 ±1.2
30.5 ±1.2 30.3 ±1.2 29.8 ±1.1
29.6 ±1.2
Fat mass (%) 32.2 ±3.3 31.3 ±2.8 29.9 ±2.8 29.8 ±3.0
31.0 ±2.8 30.9 ±2.7 30.2 ±2.6 30.1 ±2.6
Fat-free mass (%) 60.9 ±1.3 61.0 ±1.1 61.2 ±1.0 61.4 ±1.2 58.9 ±4.2 58.5 ±4.3 58.0 ±3.9 57.8 ±3.9
Waist (cm) 104 ±2 103 ±2 102 ±2 100 ±2
105 ±4 104 ±4 104 ±4 101 ±4
Waist/hip ratio 0.99 ±0.02 0.99 ±0.01 0.98 ±0.02 0.97 ±0.02 1.00 ±0.02 0.99 ±0.02 1.00 ±0.03 0.99 ±0.02
Systolic blood pressure (mm Hg) 134 ±4 136 ±9 125 ±6 131 ±7 129 ±5 127 ±4 133 ±4 128 ±3
Diastolic blood pressure (mm Hg) 86 ±376±781±382±484±483±479±280±1
(%) 6.7 ±0.2 6.7 ±0.2 6.4 ±0.2
6.8 ±0.1 6.8 ±0.1 6.6 ±0.1
(mmol mol
) 49.3 ±1.7 49.4 ±2.0 46.7 ±1.7
51.3 ±1.6 51.2 ±1.6 48.4 ±1.4
Fasting plasma glucose (mmol l
) 6.9 ±0.4 7.1 ±0.5 6.1 ±0.3
6.8 ±0.3 6.4 ±0.3 5.6 ±0.4
PGE breakfast (mmol l
)1.3 ±0.4 0.8 ±0.3 0.5 ±0.3 1.2 ±0.4 0.7 ±0.3 0.9 ±0.5
PGE lunch (mmol l
)2.3 ±0.6 0.8 ±0.3
0.5 ±0.3
1.3 ±0.4 1.5 ±0.5 1.5 ±0.5
PGE dinner (mmol l
)1.5 ±0.5 0.5 ±0.3
0.6 ±0.4
1.7 ±0.6 1.6 ±0.4 1.8 ±0.6
Mean glucose (mmol l
)7.5 ±0.4 6.7 ±0.4
6.7 ±0.3
7.4 ±0.3 6.9 ±0.3 6.9 ±0.3
s.d. (mmol l
)1.5 ±0.2 1.1 ±0.2 0.9 ±0.1
1.7 ±0.2 1.4 ±0.2 1.5 ±0.2
Coefcient of variation (%) 19.6 ±2.2 16.6 ±1.9 13.0 ±1.2
22.9 ±2.1 19.3 ±2.2 21.3 ±2.2
Abbreviations: PGE, postprandial glucose excursions.
4 weeks vs 0, Po0.05;
8 weeks vs 0, Po0.05;
8 weeks vs 4 weeks, Po0.05. PGE are the mean 2-hours
glucose increments over pre-meal values following each meal during the run-in (4 to 0 weeks), the rst (04 weeks) and the second (48 weeks) 4 weeks of
diet. Data are mean ±s.e.m.
Nutrient sequence and glucose control
D Tricò et al
Nutrition & Diabetes (2016), 1 4
hemoglobin (0.3%, 95% CI (0.50/ 0.02), Po0.04 by Wilcoxon)
(Table 1). This was associated to a decline of 1.0 mmol l
(95% CI
(1.8/ 0.3), Po0.01) in fasting plasma glucose and of 0.8
mmol l
(95% CI (1.4/ 0.2), Po0.04) in mean lunch+dinner
glucose (Table 1), and to a marked reduction of postprandial
glucose excursions (lunch: 1.8 mmol l
, 95% CI (3.2/ 0.4),
Po0.01; dinner: 1.0 mmol l
, 95% CI (1.9/ 0.1), Po0.04) and
other indices of glucose variability (SD 0.5 mmol l
, 95%CI
(0.7/ 0.2), Po0.02; CV 6.6%, 95% CI (10.4/ 2.7), Po0.02)
(Figure 1). The CD produced a non-signicant reduction of
glycated hemoglobin (0.3%, 95% CI (0.6/0.1), P= 0.09) and
fasting plasma glucose (0.7 mmol l
, 95% CI (1.6/0.2), P= 0.06),
and it failed to improve postprandial glucose excursions and other
glucose variability indices (Table 1). Among these variables, the
time*diet effect by MANOVA was statistically signicant for post-
lunch glucose excursions (Po0.04) and for the CV of glucose
concentrations (Po0.05).
This study demonstrates that by only manipulating the sequence
of nutrient ingestion it is possible to improve glycemic excursions
in type 2 diabetic patients in free-living conditions, and that this
intervention is safe and well accepted. More in general, it proves
the concept that it is effective and feasible to rely upon the
physiologic responses acutely activated by nutrient ingestion (i.e.,
nutrient sensing
) to improve glucose homeostasis. Participants
were instructed to consume high-carbohydrate-containing foods
only after non-glucidic nutrients, to exploit and combine the
well-known positive effects of lipid and protein on glucose
without increasing the total amount of foods and
without requiring supplements (articial formula) that might be
expensive and poorly accepted. Despite the high variability
inherent to the real-life setting and the small populations, the
time course of blood glucose self-monitoring revealed that an
overall reduction in glycemic variability, particularly at the
manipulated meals (lunch and dinner), was already evident at
the rst month of diet and sustained through the following
4 weeks (Figure 1). Accordingly, the effects of the ED on glucose
variability indices were not related to the extent of individual
weight loss. If applied also to the breakfast (scarcely feasible for
Italian habits), the overall effect of this dietary intervention on
glucose control, namely on glycated hemoglobin, would have
probably been greater. Although conceived on the bases of the
same experimental evidences, our approach may have several
advantages with respect to the already proposed protein
supplement preloads.
First, the physiological combination of
lipid and protein is likely to be more effective, by acting on
multiple targets;
indeed, the effect on glucose tolerance of
protein alone, though persistent, was quantitatively small.
Second, with our approach the daily caloric intake and the
proportions of macronutrients are not altered; as expected, the ED
has no impact on body weight nor it alters body mass
composition, lipid prole or indices of renal function.
In conclusion, this pilot study supports the concept that
manipulating the sequence of nutrient ingestion might reveal a
useful, feasible and inexpensive strategy for long-term manage-
ment of type 2 diabetes and provides encouragement for further
longer-term and larger clinical trial.
The authors declare no conict of interest.
We would like to acknowledge Alberto Tulipani and Angelica Lucchesi from the
Department of Clinical and Experimental Medicine at the University of Pisa for their
assistance with the collection of the data. We would also like to thank all the
volunteers enrolled in this trial. This work was supported by institutional grants from
the University of Pisa (Fondi di Ateneo).
DT conceived, designed and conducted the clinical studies, provided a
substantial contribution to the acquisition, analysis and interpretation of the
data and drafted the manuscript. EF conducted the clinical studies and
provided a substantial contribution to the acquisition of the data. ST conducted
the clinical studies and provided a substantial contribution to the acquisition of
the data. AN conceived and designed the study, provided a substantial
Figure 1. Mean capillary blood glucose concentrations and postprandial glucose excursions (PGE) (top right corner) before and after breakfast
(B), lunch (L) and dinner (D) during the run-in (light gray), the rst 4 weeks (dark gray) and the second 4 weeks (black) of experimental diet (ED,
continuous line) and control diet (CD, dashed line). *Po0.05 by Wilcoxon in comparison with the run-in PGE value.
Nutrient sequence and glucose control
D Tricò et al
Nutrition & Diabetes (2016), 1 4
contribution to the analysis and interpretation of the data. DT and AN are the
guarantors of this work and, as such, had full access to all of the data in the
study and take responsibility for the integrity of the data and the accuracy of
the data analysis. All authors revised the manuscript critically and approved the
nal version of the article.
1 Trico D, Baldi S, Tulipani A, Frascerra S, Macedo MP, Mari A et al. Mechanisms
through which a small protein and lipid preload improves glucose tolerance.
Diabetologia 2015; 58: 25032512.
2 Trico D, Filice E, Baldi S, Frascerra S, Mari A, Natali A. Sustained effects of a protein
and lipid preload on glucose tolerance in type 2 diabetes patients. Diabetes Metab
2016; 16: 3038830393.
3 Welch IM, Bruce C, Hill SE, Read NW. Duodenal and ileal lipid suppresses post-
prandial blood glucose and insulin responses in man: possible implications for the
dietary management of diabetes mellitus. Clin Sci (Lond) 1987; 72:209216.
4 Gentilcore D, Chaikomin R, Jones KL, Russo A, Feinle-Bisset C, Wishart JM et al.
Effects of fat on gastric emptying of and the glycemic, insulin, and incretin
responses to a carbohydrate meal in type 2 diabetes. J Clin Endocrinol Metab 2006;
91: 20622067.
5 Jakubowicz D, Froy O, Ahren B, Boaz M, Landau Z, Bar-Dayan Y et al. Incretin,
insulinotropic and glucose-lowering effects of whey protein pre-load in type 2
diabetes: a randomised clinical trial. Diabetologia 2014; 57: 18071811.
6 Ma J, Stevens JE, Cukier K, Maddox AF, Wishart JM, Jones KL et al. Effects of a
protein preload on gastric emptying, glycemia, and gut hormones after a car-
bohydrate meal in diet-controlled type 2 diabetes. Diabetes Care 2009;
32: 16001602.
7 Ma J, Jesudason DR, Stevens JE, Keogh JB, Jones KL, Clifton PM et al. Sustained
effects of a protein 'preload' on glycaemia and gastric emptying over 4 weeks in
patients with type 2 diabetes: A randomized clinical trial. Diabetes Res Clin Pract
2015; 108: e31e34.
8 Cunningham KM, Daly J, Horowitz M, Read NW. Gastrointestinal adaptation
to diets of differing fat composition in human volunteers. Gut 1991;
9 Shukla AP, Iliescu RG, Thomas CE, Aronne LJ. Food order has a signicant
impact on postprandial glucose and insulin levels. Diabetes Care 2015;
38: e98e99.
10 American Diabetes Association. (4) Foundations of care: education, nutrition,
physical activity, smoking cessation, psychosocial care, and immunization.
Diabetes Care 2015; 38: S20S30.
11 DeVries JH. Glucose variability: where it is import ant and how to measure it.
Diabetes 2013; 62: 14051408.
12 Efeyan A, Comb WC, Sabatini DM. Nutrient-sensing mechanisms and pathways.
Nature 2015; 517:302310.
13 Alsalim W, Tura A, Pacini G, Omar B, Bizzotto R, Mari A et al.. Mixed meal ingestion
diminishes glucose excursion in comparison with glucose ingestion via several
adaptive mechanisms in people with and without type 2 diabetes. Diabetes Obes
Metab 2016; 18:2433.
This work is licensed under a Creative Commons Attribution 4.0
International License. The images or other third party material in this
article are included in the articles Creative Commons license, unless indicated
otherwise in the credit line; if the material is not included under the Creative Commons
license, users will need to obtain permission from the license holder to reproduce the
material. To view a copy of this license, visit
© The Author(s) 2016
Nutrient sequence and glucose control
D Tricò et al
Nutrition & Diabetes (2016), 1 4
... Another novel approach towards the management of postprandial glycemia in T2DM patients is manipulating the order in which foods are consumed during meals. Pre-meal loading with fat and protein has been shown to reduce postprandial glycemia; however, this approach is not a real-life approach and could lead to weight gain if applied systematically [68,69]. On the other hand, separating food sources in meals and manipulating consumption order while eating the same amount of food could overcome that risk. ...
... Similar weight reduction was observed in both groups. HbA1c was reduced by 0.3% in the experimental group, as was postprandial glucose peaks and glucose variability after meals, with no such effect observed in the control group [69]. In another study that involved healthy and 12 T2DM participants, ingesting fish or meat 15 min before rice resulted in delayed gastric emptying in both groups compared with rice 15 min before fish, and significantly reduced glucose iAUC 15-240 min by 6% in the fish-rice condition and 9% in the meat-rice condition compared with the rice-fish condition in T2DM patients. ...
... Appetizers usually consist of protein sources with vegetables and do not include carbs [82]. The studies presented in this review that have manipulated the order of foods consumed in meals (salad or protein first) and have used time spacing of foods in meals (5 to 15 min in between) resemble the latter approach and have reported consistent results regarding acute postprandial responses and long-term glycemia management [69,71,[73][74][75][76][77]. This approach has started gaining wide support [83] given that it has provided consistent results and avoids the ingestion of extra calories compared with the fat and protein preloading approaches [68,84,85]. ...
A variety of eating patterns are recommended by international guidelines to help people with type 2 diabetes mellitus (T2DM) achieve general health and glycemia goals. Apart from eating patterns, there is evidence that other approaches related to the everyday application of dietary advice, such as meal frequency, breakfast consumption, daily carbohydrate distribution, and order of food consumption during meals, have significant effects on glycemia management. The aims of this review were to examine published diabetes nutrition guidelines concerning specific recommendations with regard to the above approaches, as well as to review evidence from studies that have investigated their effect on glycemia in T2DM. The data suggest that eating breakfast regularly, consuming most carbohydrates at lunch, avoiding large dinners late at night, and applying the carbohydrate-last meal pattern are effective practices towards better nutritional management of T2DM.
... MNT is aimed at reducing high glycemic index carbohydrates in an attempt to minimize post-meal glucose "spikes" [44••] while maintaining optimal nutrition. This includes several key components: (1) measured portions of low-glycemic index carbohydrates, (2) intake of healthy fats, (3) eating protein first [45], with total intake up to 1.5 g/kg ideal body weight [46], and (4) dividing food intake into 6 small meals and snacks, spaced every 3-4 h. While there currently are no published reports on utilization of principles of the food matrix effect in individuals with PBH, the physical properties of foods and their relationship to the nutrients contained within are integrated into MNT recommendations. ...
Full-text available
Purpose of Review This manuscript provides a review of post-bariatric hypoglycemia (PBH) with a special focus on the role of the registered dietitian-nutritionist (RDN) and medical nutrition therapy (MNT) recommendations as foundational for management. Recent Findings As the number of bariatric surgeries rises yearly, with 256,000 performed in 2019, PBH is an increasingly encountered late complication. Following Roux-en-Y (RYGB) or vertical sleeve gastrectomy (VSG), about 1/3 of patients report symptoms suggestive of at least mild postprandial hypoglycemia, with severe and/or medically confirmed hypoglycemia in 1–10%. Anatomical alterations, changes in GLP1 and other intestinally derived hormones, excessive insulin response, reduced insulin clearance, impaired counterregulatory hormone response to hypoglycemia, and other factors contribute to PBH. MNT is the cornerstone of multidisciplinary treatment, with utilization of personal continuous glucose monitoring to improve safety when possible. While many individuals require pharmacotherapy, there are no currently approved medications for PBH. Summary Increasing awareness and identification of individuals at risk for or with PBH is critical given the potential impact on safety, nutrition, and quality of life. A team-based approach involving the individual, the RDN, and other clinicians is essential in providing ongoing assessment and individualization of MNT in the long-term management of PBH.
... The approach of eating vegetables before carbohydrates is easier to understand and to attain in making appropriate behavioral changes than other dietary approaches for patients with T2DM [11,12,15,26]. Since we published our studies showing the effect of food order (meal sequence) on glycemic control [11,12,15,26,27], the effect of food order has been discussed and confirmed internationally [28][29][30][31][32][33][34]. Particularly, this approach is also beneficial for medical professionals, especially for dietitians, because this nutrition therapy is easy to teach and takes only 20 min for each session. ...
Full-text available
The aim of this retrospective cohort study was to evaluate the effect of 5-year follow-up of dietitian-led medical nutrition therapy (eating vegetables before carbohydrates) on glycemic control in outpatients with type 2 diabetes (T2DM) at a primary care clinic. A total of 138 patients with dietitian-led medical nutrition therapy (intervention group) and 104 patients without dietitian-led nutrition therapy (control group) were compared for glycemic control, serum lipid, blood pressure, and diabetic complications for 5 years. Each patient in the intervention group received dietary education focused on food order (eating vegetables before carbohydrates) by dietitians. A significant improvement in HbA1c after 5 years in the intervention group [8.5 ± 1.7% (69 mmol/mol) to 7.6 ± 1.1% (59 mmol/mol), p < 0.001] was observed, whereas no change was observed in the control group [7.9 ± 1.2% (62 mmol/mol) to 8.0 ± 1.2% (63 mmol/mol)]. Dietary intake of protein, fat, carbohydrates, cholesterol, and salt in the intervention group demonstrated significant reduction, while the intake of dietary fiber significantly increased after the dietary education. Simple dietary education of ‘eating vegetables before carbohydrates’ presented by dietitians achieved good glycemic control after a 5-year period in outpatients with T2DM at primary care clinic.
... Billede af en stikprøve med vaegt af det standardiserede julemåltid for 1 person, som blev indtaget på dag 1, 3 og [11,12] og vaegten [13]. ...
Full-text available
Introduction The glucose-lowering effect of cinnamon is well known and has been used for this purpose since ancient times. Other christmassy spices, like ginger and cloves, have also been shown to affect blood glucose levels but are not as extensively examined. We aimed to explore the potential glucose-lowering effects of cinnamon, ginger and cloves by postprandial glucose excursions (PPGE) and maximum glucose level during rice pudding intake in healthy participants with use of continuous glucose monitoring during ingestion of the traditional Danish Christmas dish, rice pudding. Methods Participants wore an intermittently scanned continuous glucose monitor for five days in total. Day 0 was a 24h run-in stabilization period. Day 1 was used for baseline with ingestion of a standardized rice pudding meal without any spices. On days 2-4, participants had the same standardized rice pudding with one of the three Christmas spices on top. The participants ate rice pudding for breakfast (low-dose spice) and lunch (high-dose spice). A questionnaire was also developed to investigate the satisfaction level with the rice pudding and spice combinations. Results Data from 12 people were analyzed with mean age (range) of ~ 42 (25-63) years. Mean fasting glucose level (95% CI) was 4.7 (4.0-5.5) mmol/l. PPGE levels were higher for 6 g of ginger, compared to 3 g of ginger with mean difference of 1.02 mmol/l (0.12-1.92) (p = 0.030). No other differences between the different doses of spices or between spices and baseline were found regarding PPGE or the maximum glucose-level during intake of rice pudding. Most people preferred cinnamon on top of the rice pudding, however, eight out of 12 would rather risk complications from a higher blood glucose than eating Christmas spices on top of their rice pudding. Conclusion Putting christmassy spices on top of rice pudding did not have a glucose-lowering effect in this study. This was probably for the best, since we learned from the questionnaire, that the use of Christmas spices on top of rice pudding was rated worse than the risk of complications from having high blood glucose levels. Thus, implementation of Christmas spices as a preventative strategy is not recommended. Funding none. Trial registration none.
... Therefore, insulin resistance may have been involved in the association between glucose variability and atherosclerosis. In addition, it was reported that a healthy lifestyle, including a healthy diet, moderated the relationship between CVD and its risk factors [56], and that dietary interventions, such as a low carbohydrate diet [57], the consumption of low glycemic index food [58], and food order [59], reduced glucose variability. Thus, it was possible that these diets were associated with the tissue characteristics of the carotid artery wall; however, we did not have sufficient data about these diets. ...
Full-text available
Abstract Background The association between glucose variability and the progression of atherosclerosis is not completely understood. We aimed to evaluate the associations of glucose variability with the progression of atherosclerosis in the early stages. Methods We conducted a cross-sectional analysis to investigate the associations of glucose variability, assessed by continuous glucose monitoring, with intima-media thickness (IMT) and gray-scale median (GSM) of the carotid arteries, which are different indicators for the progression of atherosclerosis. We used baseline data from a hospital-based multicenter prospective observational cohort study among Japanese patients with type 2 diabetes without a history of cardiovascular diseases aged between 30 and 80 years. Continuous glucose monitoring was performed by Freestyle Libre Pro, and glucose levels obtained every 15 min for a maximum of eight days were used to calculate the metrics of glucose variability. IMT and GSM were evaluated by ultrasonography, and the former indicates thickening of intima-media complex in the carotid artery wall, while the latter indicates tissue characteristics. Results Among 600 study participants (age: 64.9 ± 9.2 (mean ± SD) years; 63.2%: men; HbA1c: 7.0 ± 0.8%), participants with a larger intra- and inter-day glucose variability had a lower GSM and most of these associations were statistically significant. No trend based on glucose variability was shown regarding IMT. Standard deviation of glucose (regression coefficient, β = − 5.822; 95% CI − 8.875 to − 2.768, P
... Indeed, dietary intake of monounsaturated fatty acids (MUFA) and n-3 polyunsaturated fatty acids (n-3 PUFA), which is especially high in the Mediterranean area, was associated with positive 7-year longitudinal changes in model-derived markers of β-cell function (i.e., β-cell glucose sensitivity and rate sensitivity) in a population-based study [54]. Furthermore, protein and amino acid consumption is known to enhance insulin secretion in both healthy [55][56][57][58] and diabetic individuals [59][60][61][62][63]. In line with this indirect evidence, previous randomized clinical trials in insulin-resistant subjects demonstrated an increase in surrogate markers of β-cell function after a Med diet [26] or LC diet [25]. ...
Full-text available
Low-calorie Mediterranean-style or low-carbohydrate dietary regimens are widely used nutritional strategies against obesity and associated metabolic diseases, including type 2 diabetes. The aim of this study was to compare the effectiveness of a balanced Mediterranean diet with a low-carbohydrate diet on weight loss and glucose homeostasis in morbidly obese individuals at high risk to develop diabetes. Insulin secretion, insulin clearance, and different β-cell function components were estimated by modeling plasma glucose, insulin and C-peptide profiles during 75-g oral glucose tolerance tests (OGTTs) performed at baseline and after 4 weeks of each dietary intervention. The average weight loss was 5%, being 58% greater in the low-carbohydrate-group than Mediterranean-group. Fasting plasma glucose and glucose tolerance were not affected by the diets. The two dietary regimens proved similarly effective in improving insulin resistance and fasting hyperinsulinemia, while enhancing endogenous insulin clearance and β-cell glucose sensitivity. In summary, we demonstrated that a low-carbohydrate diet is a successful short-term approach for weight loss in morbidly obese patients and a feasible alternative to the Mediterranean diet for its glucometabolic benefits, including improvements in insulin resistance, insulin clearance and β-cell function. Further studies are needed to compare the long-term efficacy and safety of the two diets.
... A number of other studies support the beneficial effect of fiber to lower postprandial glycemia (59,61). As compared with the preload, this approach has the indirect advantage of not involving additional energy intake (70,89). Along with a reduction of PPG excursions, intake of vegetables before carbohydrates may per se also reduce the risk of other metabolic disorders, including cardiovascular disease (90). ...
Full-text available
Postprandial glycemic control is an important target for optimal type 2 diabetes management, but is often difficult to achieve. The gastrointestinal tract plays a major role in modulating postprandial glycaemia in both health and diabetes. The various strategies that have been proposed to modulate gastrointestinal function, particularly by slowing gastric emptying and/or stimulating incretin hormone GLP-1, are summarized in this review.
Background: Diurnal glucose fluctuations are increased in prediabetes and might be affected by specific dietary patterns. Aim: The present study assessed the relationship between glycemic variability (GV) and dietary regimen in people with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT). Materials and methods: Forty-one NGT (mean age 45.0±9.0yrs, mean BMI 32.0±7.0kg/m2) and 53 IGT (mean age 48.4±11.2yrs, mean BMI 31.3±5.9kg/m2) subjects were enrolled in this cross-sectional study. FreeStyleLibre Pro sensor was used for 14-days and several parameters of GV were calculated. Participants were provided with a diet diary to record all meals. ANOVA analysis, Pearson correlation and Stepwise forward regression were performed. Results: Despite there was no difference in diet patterns between the two groups, GV parameters were higher in IGT. GV worsened with the increase of overall daily CHO and refined grains consumption and improved with the increase of whole grains intake in IGT. GV parameters were positively (r= 0.14 to 0.53; all p<0.02 for SD, CONGA1, J-index, LI, GRADE, M-Value, MAG) and LBGI inversely (r=-0.37, p=0.006) related to total percentage of CHO, but not to distribution of CHO between the main meals in IGT group. There was a negative relationship between total protein consumption and GV indices (r=-0.27 to -0.52; p<0.05 for SD, CONGA1, J-index, LI, M-Value, MAG). The total energy intake was related to GV parameters (r=0.27 to 0.32; p<0.05 for CONGA1, J-index, LI, M-Value; and r=-0.30, p=0.028 for LBGI). Conclusion: The results on the primary outcomes show that both insulin sensitivity and calorie and CHO content are predictors of GV in individuals with IGT. The secondary analyses imply that overall CHO and refined grains daily consumption might be associated with higher GV, whilst whole grains and protein daily intake is related to lower GV in people with IGT.
Objective Aberrations in glucose, insulin, and other postprandial (PP) markers are common in obesity and cardiometabolic disorders. One potentially simple lifestyle/dietary modification to manage these issues is to change the order in which foods are consumed within meals. Carbohydrate exerts the largest effect on PP glucose, and there is some evidence that ingesting dietary fat or protein before carbohydrate delays gastric emptying of carbohydrate and reduces PP glucose. Additionally, certain dietary proteins may augment insulin release if ingested with carbohydrate, thereby improving blood glucose clearance. This review aimed to systematically evaluate evidence from acute experiments that modified the order in which foods were consumed in isocaloric meals. Methods Outcomes of interest were PP glucose and insulin (including area under the curve for both), C-peptide, gut hormones, and perceptual responses. Three databases were searched (PubMed, Cochrane CENTRAL, Web of Science) in February 2022. Additionally, reference lists of identified reports were searched, and an author of several studies was consulted to verify that relevant literature was included. The review included acute interventions that administered isocaloric meals of the same foods but with foods eaten in different orders. Studies were not excluded based on participant characteristics. Results Eleven reports were identified. All reports that assessed glucose and insulin showed a tendency toward lower levels, at least over parts of the PP period, by consuming carbohydrates last. GLP-1 tended to be higher in carbohydrate-last conditions, though this was only measured in a few studies. Perceptual responses (hunger, fullness, etc.) were not consistently different between conditions in two studies, but the certainty of evidence was very low. Conclusions Findings indicate that, at least acutely, there may be benefits to eating carbohydrate after vegetable and/or protein-rich foods. The most consistent effect (judged as moderate certainty) is that carbohydrate-last meal orders tend to lower blood glucose and insulin excursions.
Full-text available
Introduction This systematic review investigated the efficacy of a meal sequence, the carbohydrate-later meal pattern (CL), on type 2 diabetes mellitus (T2DM). Research design and methods We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, WHO International Clinical Trials Registry Platform, and until April 2020 to perform meta‐analyses using random-effects models. Primary outcomes were hemoglobin A1c (HbA1c) and quality of life. Secondary outcomes were plasma concentrations of glucose, insulin and incretin 120 min after a meal, and any adverse outcomes. The revised Cochrane risk-of-bias tool and Grading of Recommendations, Assessment, Development, and Evaluation approach were used to assess the quality of individual studies and the body of evidence, respectively. The present study was registered in the UMIN Clinical Trials Registry. Results We included 230 participants in eight trials, including both trials that examined long-term changes (more than 2 months and less than 2 years) and short-term changes (in 2-hour postprandial values). CL resulted in a slight to no difference in HbA1c (mean difference (MD), −0.21% in the intervention group; 95% CI −0.44% to+0.03%), plasma glucose (MD,+4.94 mg/dL; 95% CI −8.34 mg/dL to +18.22 mg/dL), plasma insulin (MD, −3.63 μIU/mL; 95% CI −11.88 μIU/mL to +4.61 μIU/mL), plasma GLP-1 (MD, +0.43 pmol/L; 95% CI −0.69 pmol/L to +1.56 pmol/L), and plasma GIP (MD, −2.02 pmol/L; 95% CI −12.34 pmol/L to +8.31 pmol/L). All of these outcomes were of low-certainty evidence or very low-certainty evidence. None of the trials evaluated quality of life or adverse events. Conclusions There was no evidence for the potential efficacy of recommending CL beyond standard dietary advice on T2DM. Trial registration number UMIN000039979.
Full-text available
Small protein or lipid preloads are able to improve glucose tolerance to a different extent and through different and poorly defined mechanisms. We aimed at quantifying the effect of a mixed protein and lipid preload and at evaluating the underlying mechanisms. Volunteers with normal (NGT, n = 12) or impaired (IGT, n = 13) glucose tolerance and patients with type 2 diabetes (n = 10) underwent two OGTTs coupled to the double glucose tracer protocol, preceded by either 50 g of parmesan cheese, a boiled egg and 300 ml of water, or 500 ml of water. We measured plasma glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), pancreatic polypeptide (PP), NEFA and glucose tracers, and calculated glucose fluxes, beta cell function variables, insulin sensitivity and clearance. After the nutrient preload, the OGTT-induced rise of plasma glucose was lower than after water alone in each study group. This reduction-more pronounced across classes of glucose tolerance (NGT -32%, IGT -37%, type 2 diabetes -49%; p < 0.002)-was the result of different combinations of slower exogenous glucose rate of appearance, improved beta cell function and reduced insulin clearance, in this order of relevance, which were associated with an only mild stimulation of GIP and GLP-1. After a non-glucidic nutrient preload, glucose tolerance improved in proportion to the degree of its baseline deterioration through mechanisms that appear particularly effective in type 2 diabetes. Exploiting the physiological responses to nutrient ingestion might reveal, at least in the first stages of the diabetic disease, a potent tool to improve daily life glycaemic control. NCT02342834 FUNDING: : This work was supported by grants from the University of Pisa (Fondi di Ateneo) and by FCT grant (PIC/IC/82956/2007).
Full-text available
Aims/hypothesis: Since protein ingestion is known to stimulate the secretion of glucagon-like peptide-1 (GLP-1), we hypothesised that enhancing GLP-1 secretion to harness its insulinotropic/beta cell-stimulating activity with whey protein pre-load may have beneficial glucose-lowering effects in type 2 diabetes. Methods: In a randomised, open-label crossover clinical trial, we studied 15 individuals with well-controlled type 2 diabetes who were not taking any medications except for sulfonylurea or metformin. These participants consumed, on two separate days, 50 g whey in 250 ml water or placebo (250 ml water) followed by a standardised high-glycaemic-index breakfast in a hospital setting. Participants were randomised using a coin flip. The primary endpoints of the study were plasma concentrations of glucose, intact GLP-1 and insulin during the 30 min following meal ingestion. Results: In each group, 15 patients were analysed. The results showed that over the whole 180 min post-meal period, glucose levels were reduced by 28% after whey pre-load with a uniform reduction during both early and late phases. Insulin and C-peptide responses were both significantly higher (by 105% and 43%, respectively) with whey pre-load. Notably, the early insulin response was 96% higher after whey. Similarly, both total GLP-1 (tGLP-1) and intact GLP-1 (iGLP-1) levels were significantly higher (by 141% and 298%, respectively) with whey pre-load. Dipeptidyl peptidase 4 plasma activity did not display any significant difference after breakfast between the groups. Conclusions/interpretation: In summary, consumption of whey protein shortly before a high-glycaemic-index breakfast increased the early prandial and late insulin secretion, augmented tGLP-1 and iGLP-1 responses and reduced postprandial glycaemia in type 2 diabetic patients. Whey protein may therefore represent a novel approach for enhancing glucose-lowering strategies in type 2 diabetes. Trial registration NCT01571622 Funding The Israeli Ministry of Health and Milk Council funded the research.
Full-text available
Glucose variability predicts hypoglycemia in both type 1 and type 2 diabetes and has consistently been related to mortality in nondiabetic patients in the intensive care unit. SD and mean amplitude of glycemic excursions have historically been very popular measures of glucose variability. For reasons outlined in this counterpoint, I propose to use coefficient of variation and the mean absolute glucose change as preferred measures of glucose variability.
Full-text available
We evaluated whether a whey preload could slow gastric emptying, stimulate incretin hormones, and attenuate postprandial glycemia in type 2 diabetes. Eight type 2 diabetic patients ingested 350 ml beef soup 30 min before a potato meal; 55 g whey was added to either the soup (whey preload) or potato (whey in meal) or no whey was given. Gastric emptying was slowest after the whey preload (P < 0.0005). The incremental area under the blood glucose curve was less after the whey preload and whey in meal than after no whey (P < 0.005). Plasma glucose-dependent insulinotropic polypeptide, insulin, and cholecystokinin concentrations were higher on both whey days than after no whey, whereas glucagon-like peptide 1 was greatest after the whey preload (P < 0.05). Whey protein consumed before a carbohydrate meal can stimulate insulin and incretin hormone secretion and slow gastric emptying, leading to marked reduction in postprandial glycemia in type 2 diabetes.
Background: Small amounts of nutrients given as a 'preload' can reduce post-meal hyperglycaemic peaks in type 2 diabetes (T2D) patients by activating a number of mechanisms involved in glucose homoeostasis. This study was undertaken to ascertain whether this positive effect extends to the late absorptive phase and to identify the main mechanisms involved. Material and methods: Eight well-controlled T2D patients, aged 40-70 years, were randomized to consume a 'preload' of either water or non-glucidic nutrients (50g of Parmesan cheese, one boiled egg) 30min before a 300-min oral glucose tolerance test. Results: After the nutrient preload, significant reductions were observed in peak glucose (-49%; P<0.02), total plasma glucose (iAUC: -28%; P<0.03), exogenous glucose (iAUC: -30%; P<0.03) and insulin clearance (-28%; P<0.04), with enhancement of insulin secretion (iAUC: +22%; P<0.003). These effects were associated with higher plasma levels of GLP-1 (iAUC: +463%; P<0.002), GIP (iAUC: +152%; P<0.0003) and glucagon (iAUC: +144%; P<0.0002). Conclusion: In T2D patients, a protein and lipid preload improves glucose tolerance throughout the whole post-absorptive phase mainly by reducing the appearance of oral glucose, and improving both beta-cell function and insulin bioavailability.
AimsTo study the integrative impact of macronutrients on postprandial glycemia, β-cell function, glucagon and incretin hormones in man.Methods Macronutrients were ingested alone (glucose 330kcal, protein 110kcal or fat 110kcal) or together (550kcal) by healthy subjects (n=18) and by subjects with drug-naïve type 2 diabetes (n=18). ß-cell function and insulin clearance were estimated by modeling glucose, insulin and C-peptide data. Secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured and administered paracetamol estimated gastric emptying.ResultIn both groups, mixed meal diminished glucose excursion compared to glucose alone, and insulin levels, but not C-peptide levels, rose more than after glucose alone. β-cell function was augmented, insulin clearance was reduced and glucagon levels were higher after mixed meal compared to glucose. GLP-1 and GIP levels increased after all challenges and GIP secretion was markedly higher after mixed meal than after glucose alone. Appearance of paracetamol was delayed after mixed meal compared to glucose alone.Conclusions Adding protein and fat macronutrients to glucose in a mixed meal diminishes glucose excursion in association with increased β-cell function, reduced insulin clearance, delayed gastric emptying and augmented glucagon and GIP secretion. This suggests that the macronutrient composition regulates glycemia though both islet and extra-islet mechanisms in both healthy subjects and in type 2 diabetes.
Postprandial hyperglycemia is an important therapeutic target for optimizing glycemic control and for mitigating the proatherogenic vascular environment characteristic of type 2 diabetes. Existing evidence indicates that the quantity and type of carbohydrate consumed influence blood glucose levels and that the total amount of carbohydrate consumed is the primary predictor of glycemic response (1). Previous studies have shown that premeal ingestion of whey protein, as well as altering the macronutrient composition of a meal, reduces postmeal glucose levels (2–4). There are limited data, however, regarding the effect of food order on postprandial glycemia in patients with type 2 diabetes (5). In this pilot study, we sought to examine the effect of food order, using a typical Western meal, incorporating vegetables, protein, and carbohydrate, on postprandial glucose and insulin excursions in overweight/obese adults with type 2 diabetes. A total of 11 subjects (6 female, 5 male) with metformin-treated type 2 diabetes were studied …
We have shown that the capacity of 25g whey preloads to slow gastric emptying and reduce postprandial glycaemia persists after 4 weeks regular exposure in patients with diet-controlled type 2 diabetes. This dietary strategy therefore appears feasible for larger clinical trials to evaluate beneficial effects on long-term glycaemic control. Registered with the Australian New Zealand Clinical Trials Registry: ACTRN12614000831684. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
The ability to sense and respond to fluctuations in environmental nutrient levels is a requisite for life. Nutrient scarcity is a selective pressure that has shaped the evolution of most cellular processes. Different pathways that detect intracellular and extracellular levels of sugars, amino acids, lipids and surrogate metabolites are integrated and coordinated at the organismal level through hormonal signals. During food abundance, nutrient-sensing pathways engage anabolism and storage, whereas scarcity triggers homeostatic mechanisms, such as the mobilization of internal stores through autophagy. Nutrient-sensing pathways are commonly deregulated in human metabolic diseases.