Postprandial hyperglycemia increases the risks of development of type 2 diabetes and cardiovascular diseases. The purpose of this study was to determine whether a 3-day low-carbohydrate/high-fat diet (LC/HFD) alters postprandial plasma glucose and incretin levels during oral glucose tolerance test (OGTT) in healthy men.
Nine healthy young men (age (mean±s.e.), 27±1 years; body mass index, 22±1 kg/m2) consumed either a normal diet (ND: energy from ∼22% fat) or a LC/HFD (energy from ∼69% fat) for 3 days each. The total energy intake from each diet was similar. An OGTT was performed after each 3-day dietary intervention. Postprandial plasma glucose, insulin, free fatty acid and glucagon-like peptide-1 (GLP-1) levels were determined at rest and during the OGTT.
Plasma glucose levels and incremental area under the curve during the OGTT were significantly higher in the LC/HFD trial than in the ND trial (P=0.024). In addition, increase in GLP-1 levels was significantly higher in the LC/HFD trial than in the ND trial (P=0.025). The first-phase insulin secretion indexes were significantly lower in the LC/HFD trial than in the ND trial (P<0.041).
These results demonstrate that even short-term LC/HFD increased postprandial plasma glucose and GLP-1 levels in healthy young men. A decrease in first-phase insulin secretion may partially contribute to the short-term LC/HFD-induced increase in postprandial plasma glucose levels.
Postprandial hyperglycemia is a condition of high blood glucose level after eating a meal, and is an effective predictor of mortality from all causes and cardiovascular diseases (CVD) as well as the risk of developing type 2 diabetes.1, 2, 3 Furthermore, decreasing postprandial hyperglycemia with medications reduces the risks of developing CVD and type 2 diabetes.4, 5, 6 One of the factors explaining the association between postprandial hyperglycemia and the development of CVD and type 2 diabetes is the resulting acute fluctuation in blood glucose levels. Interestingly, acute fluctuation in blood glucose levels suppresses endothelium-dependent vasodilation,7 and increases levels of interleukin-6, tumor necrosis factor-α8 and platelet hyperaggregability9 in healthy men; all these parameters have been associated with the development of CVD. Therefore, it is important to elucidate the factors that elicit postprandial hyperglycemia for the prevention of both CVD and type 2 diabetes.
A low-carbohydrate/high-fat diet (LC/HFD) has a key role in the development of postprandial hyperglycemia. Short-term exposure (1–11 days) to LC/HFD decreases carbohydrate oxidation10, 11, 12, 13, 14, 15, 16 and increases endogenous glucose production.10, 17 In addition, short-term LC/HFD (3–5 days) decreases insulin sensitivity, as measured using the hyperinsulinemic–euglycemic glucose clamp18, 19 and the intravenous glucose tolerance test.20 However, little is known about the effect of LC/HFD on postprandial hyperglycemia. Although the hyperinsulinemic–euglycemic glucose clamp and intravenous glucose tolerance test are widely accepted as the gold standard for quantifying insulin resistance, they may not accurately reflect insulin action and glucose dynamics under postprandial physiological conditions, owing to the fact that insulin secretion and incretins21 contribute to postprandial glucose metabolism. Thus, an oral ingestion test would be more effective to estimate postprandial glucose metabolism. The oral glucose tolerance test (OGTT), which is used as the representative oral ingestion test, can effectively assess the response of postprandial glucose, insulin and incretins (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)) levels under physiological conditions.
To the best of our knowledge, few reports have investigated the effects of short-term LC/HFD on postprandial glucose metabolism using oral ingestion tests. Some studies have shown that LC/HFD for ∼1–5 days decreased glucose disposal during OGTT in healthy22, 23, 24 and aerobically active subjects.25 However, none of the previous studies investigated the effects of short-term LC/HFD on both postprandial glucose and incretin levels. Because incretin can stimulate insulin secretion during the postprandial period,21 a decrease in incretin secretion may indirectly contribute to the increase in postprandial glucose levels in these conditions.
The purpose of this study was to examine the effects of short-term LC/HFD on postprandial glucose, insulin and incretin levels measured using the OGTT in healthy young men.
Nine healthy young men participated in this study (age (mean±s.e.), 27±1 years; height, 176±1 cm; peak oxygen consumption (VO2 peak), 40.5±2.3 ml/kg/min). The participants had a sedentary lifestyle, that is they did not exercise on a regular basis. The participants had no history of any metabolic diseases or CVD. None of the participants were smokers, and all refrained from taking any medications or supplements known to affect their metabolism. The participant’s body mass (BM) had been stable (<3 kg change) for at least 2 months. The purpose, design and risks of this study were explained to each participant, and written informed consent was obtained. The study conformed the principles outlined in the Helsinki Declaration and was approved by the ethics committees on human research of Waseda University.
All participants performed two experimental trials lasting 4 days each. The trials consisted of consumption of (a) a normal diet (ND) and (b) LC/HFD for 3 consecutive days each. The trial order for each participant was randomized. The two trials were separated by at least 1 week and were performed within 1 month. The day before starting each trial, participants had the same diet and could eat their evening meal at any time up to 2100 h. After this meal, they refrained from consuming any food but could drink water. On the morning of day 1, the participants arrived at the laboratory at 0900 h after an overnight fast (>12 h). After they had rested in a supine position for 30 min, a blood sample was collected to measure baseline metabolite and hormone levels. In addition, BM, fat mass, and fat-free mass were measured by impedance (InnerScan BC-520; Tanita, Tokyo, Japan). After these measurements, the participants consumed ND or LC/HFD in accordance with the allocated trial for 3 days. On day 4 (after 3 days of dietary intervention), the participants arrived at the laboratory at 0900 h after an overnight fast. BM, fat mass and fat-free mass were then measured by impedance (InnerScan BC-520). After the participants had rested in a supine position for 30 min, an intravenous catheter was inserted into the antecubital vein and a baseline blood sample was collected. After the participants ingested 75 g liquid glucose (TRELAN-G75; Ajinomoto, Tokyo, Japan), 2-h OGTT was started. During OGTT, the participants rested in supine position on a bed, and blood samples were withdrawn at 15, 30, 45, 60, 90 and 120 min after ingestion of the liquid glucose.
Diet and physical activity
The food was supplied by the investigators. Each participant received ND or LC/HFD for 3 consecutive days each. Total energy intake per day was similar between ND and LC/HFD, but the percentage of carbohydrate, fat and protein to total energy intake varied. The ND contained ∼67% carbohydrate, ∼22% fat and ∼11% protein, whereas the LC/HFD contained ∼20% carbohydrate, ∼69% fat and ∼11% protein. The total energy intake per day for each participant was estimated using the Dietary Reference Intakes for Japanese equation (basal metabolic rate (reference basal metabolic rate × reference BM) × physical activity level (normal physical activity level: 1.75)).26 These diets did not vary from day to day and were designed to be as common and regular as possible. The menu of both diets was designed using a dietary analysis program (Eiyoukun, version 4.0; Kenpakusya, Tokyo, Japan) by a nutritionist. Participants were instructed to adhere to the provided menus and to check the food intake record. Food records were confirmed at the end of the dietary intervention by the investigators.
Participants were instructed to maintain their usual lifestyle throughout the experiment. The amount of physical activity during the experiment was assessed via interview.
Blood sampling and metabolite and hormone levels
Blood samples were collected in a 8.5-ml tube, containing thrombin for analyzing insulin, c-peptide, free fatty acid (FFA), β-hydroxybutyric acid (β-HBA), triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol, alanine aminotransferase and aspartate aminotransferase levels, and in another 2-ml tube, containing 2.5 mg EDTA, 1000 KIU aprotinin, and 20 μl dipeptidyl peptidase-4 inhibitor (Millipore, Billerica, MA, USA) for analyzing GLP-1 and GIP levels. The blood samples in the 8.5-ml tube were centrifuged (3000 g for 10 min at 4 °C) 30 min after collection, whereas those in the 2-ml tube were kept in ice and centrifuged (3000 g for 10 min at 4 °C) within 30 min of collection. After centrifugation, the serum and plasma from each sample were transferred into a plastic tube and immediately stored at −80 °C until further analysis.
The plasma glucose level was immediately analyzed using a glucose autoanalyzer (Niporo; FreeStyle Freedom, Osaka, Japan). The serum insulin level was measured using an electrochemiluminescence immunoassay kit (Roche Diagnostics; Tokyo, Japan). The serum c-peptide level was measured using a chemiluminescent immunoassay kit (Roche Diagnostics). The serum FFA level was measured by an enzymatic colorimetric method (Wako Pure Chemical Industries; Osaka, Japan). The serum β-HBA level was measured by an enzymatic cycling method (Kainos Laboratories; Tokyo, Japan). The serum TG level was measured by an enzymatic colorimetric method (Kyowa Medex; Tokyo, Japan). Total cholesterol and high-density lipoprotein cholesterol level were measured by an enzymatic method (Kyowa Medex). Low-density lipoprotein cholesterol (LDLC) level was calculated according to the equation of Friedewald et al.27 The alanine aminotransferase and aspartate aminotransferase level were determined by the Japan Society of Clinical Chemistry transferable method (Wako Pure Chemical Industries). Plasma GLP-1 (7–36 amide and 7–37) and GIP levels were measured using the ELISA kit (Millipore).
Homeostasis model assessment ratio (HOMA-R) was calculated according to Matthews et al.28 The incremental area under the curves (iAUC) for glucose, insulin, FFA, β-HBA, TG, GLP-1 and GIP levels during the 2-h OGTT were obtained using the trapezoidal rule. Oral glucose insulin sensitivity was calculated from plasma glucose and insulin levels before and during the OGTT to assess insulin sensitivity according to Mari et al.29 The insulinogenic index and Stumvoll first-phase insulin release index30 were used to estimate first-phase insulin release.
All data are shown as mean±s.e. Statistical analyses were performed using SPSS software (version 18; IBM, Tokyo, Japan). A two-way analysis of variance for repeated measures (trial × time) with Bonferroni post hoc analysis was used to compare changes in characteristics and metabolite levels between two trials over time. Paired t-test was used to analyze differences in iAUC of metabolites and hormones, and insulinogenic index and Stumvoll first-phase insulin release index between the two trials. Pearson’s product–moment correlation coefficient was used to determine the relationship among glucose, incremental area under the curves insulinogenic index and Stumvoll first-phase insulin release index during OGTT. The sample size was determined by a statistical power analysis (β=0.2, α=0.05) of an expected difference in metabolite variables based on our preliminary data. To interpret the magnitude of difference and correlation coefficient, effect size (ES) on the basis of Cohen31 was calculated. ES was classified as small (paired t-test: <0.20, Pearson’s product–moment correlation coefficient: <0.10), as moderate (paired t-test: 0.20–0.79, Pearson’s product–moment correlation coefficient: 0.10–0.49) and as large (paired t-test: >0.80, Pearson’s product–moment correlation coefficient: >0.50). Statistical significance was set at <0.05.
Total energy intake per day was not significantly different between the ND and LC/HFD trials (ND, 11694±218 kJ/day; LC/HFD, 11823±260 kJ/day). Moreover, these values were not different from the energy intake per day estimated by the Dietary Reference Intakes for Japanese 2010 (11627±285 kJ/day). The percentages of carbohydrate and fat intakes were significantly different between two trials (P<0.05), but the intake of protein to total energy intake was similar (ND: carbohydrate, 66±0.1%; fat, 22±0.4%; protein, 11±0.1%; LC/HFD: carbohydrate, 20±0.3%; fat, 69±0.3%; protein, 11±0.1%).
Percentage of fat and fat mass remained unchanged with both the ND and LC/HFD trials (Table 1). BM and fat-free mass slightly decreased after both trials (P<0.05), but the changes were similar (BM: ND, −1.1±0.3%; LC/HFD, −1.3±0.3%; fat-free mass: ND, −0.9±0.2%; LC/HFD, −0.8±0.6%; Table 1).
Fasting metabolite and hormone levels
Fasting plasma glucose (P<0.01), serum insulin (P<0.01), HOMA-R (P<0.01) and c-peptide levels (P<0.05) significantly decreased with both the ND and LC/HFD trials, but the changes were similar in both trials (P>0.05; Table 1). Contrary to this, the FFA levels significantly increased with both the ND and LC/HFD trial (P<0.05), but with no differences between two trials (P>0.05; Table 1). The GLP-1 levels remained unchanged before and after both trials (P>0.05), but the GIP level increased after only the LC/HFD trial (P<0.05; Table 1). β-HBA remained unchanged in the ND trial (P>0.05), but it significantly increased after LC/HFD trial (P<0.05; Table 1). The TG level before both trials was identical, but it significantly decreased after the LC/HFD trial (P<0.05). Total cholesterol (P>0.05) and high-density lipoprotein cholesterol levels (P>0.05) remained unchanged before and after the ND and LC/HFD trial. The LDLC level before the ND and LC/HFD trial was lower than that after both trials (P<0.05). Alanine aminotransferase (P>0.05) and aspartate aminotransferase levels (P>0.05) remained unchanged before and after both trials.
Metabolite and hormone levels during oral glucose tolerance test
Plasma glucose levels during OGTT were significantly higher in the LC/HFD trial than in the ND trial (P<0.05; Figure 1a). Glucose iAUC was significantly greater in the LC/HFD trial than in the ND trial (P<0.05; ES, 0.91, Figure 1a). Serum insulin levels during OGTT did not differ between the ND and LC/HFD trials (Figure 1b). The GLP-1 levels during OGTT were significantly higher in the LC/HFD than in the ND trial (P<0.05; Figure 2a), and GLP-1 iAUC was significantly greater in the LC/HFD trial than in the ND trial (P<0.05, ES, 0.92; Figure 2a). The GIP levels during OGTT were similar between the ND and LC/HFD trials, and GIP iAUC did not differ between the two trials (Figure 2b). The response of FFA levels during OGTT did not differ between the ND and LC/HFD trials (Table 2). β-HBA levels during OGTT were significantly higher in the LC/HFD trial than in the ND trial (P<0.05; ES, 0.90; Table 2), and β-HBA iAUC was also significantly greater in the LC/HFD trial than in the ND trial (P<0.05; Table 2). TG levels during OGTT were significantly lower in the LC/HFD trial than in the ND trial (P<0.05; Table 2).
Insulin sensitivity and insulin first-phase release
Oral glucose insulin sensitivity was not significantly different between the ND and LC/HFD trial (Figure 3a). The insulinogenic index and Stumvoll first-phase insulin release index were significantly lower in LC/HFD than in ND trial (insulinogenic index: P<0.05, ES, 0.81; Stumvoll first-phase insulin release index: P<0.05, ES, 0.82; Figures 3b and c).
Relationship between glucose incremental area under the curve and first-phase insulin release
Glucose iAUC for the ND and LC/HFD trials were negatively correlated with the insulinogenic index (r=−0.71; P=0.001; ES, 0.70) and the Stumvoll first-phase insulin release index (r=−0.54; P=0.02; ES, 0.54).
The primary purpose of this study was to compare the effects of a short-term ND and LC/HFD on postprandial glucose, insulin and incretin responses. Our findings demonstrated that short-term LC/HFD increased postprandial plasma glucose and GLP-1 levels and decreased first-phase insulin release in healthy young men.
Plasma glucose levels and iAUC during OGTT increased after 3 days of LC/HFD. This result is in agreement with some short-term dietary intervention studies.22, 23, 24, 25 Increase in postprandial glucose level would be determined by the amount of carbohydrate22 or fat23 in diet. However, it is difficult to isolate the effect of the amount of carbohydrate or fat on postprandial glucose metabolism from the current study.
Three-day LC/HFD led to increase in postprandial glucose level. One possible mechanism may be the loss of first-phase insulin release, which leads to a decrease in postprandial glucose disposal due to the reduction of peripheral glucose uptake, hepatic glucose uptake and suppression of hepatic glucose production.32 In support of this hypothesis, the insulinogenic index and the Stumvoll first-phase insulin release index were significantly lower in LC/HFD than in ND trial with no difference in the oral glucose insulin sensitivity between two trials. Moreover, the negative relationships between plasma glucose iAUC and the first-phase insulin release indexes were observed. These data are supported by the results of Swinburn et al.33 They reported that a high-fat modern diet decreased glucose tolerance and β-cell sensitivity to glucose without change in insulin sensitivity in both Pima Indians and Caucasians. Nevertheless, the reasons for the reduction in the first-phase insulin release are unclear. Although the effects of elevated plasma FFA on insulin secretion are controversial, prolonged elevation of FFA levels impaires insulin secretion.34 In the current study, the increase in fasting FFA levels was similar between ND and LC/HFD, but they negatively correlated with first-phase insulin release indexes. Therefore, it is likely that FFA levels are a contributing factor in the regulation of first-phase insulin release.
The fasting GIP levels increased only with the LC/HFD trial. Similarly, the increased GLP-1 level during OGTT was higher in the LC/HFD trial than in the ND trial. A previous study reported an increase in fasting GIP levels after high-fat overfeeding.17 However, to our knowledge, the finding that GLP-1 levels are increased in response to short-term LC/HFD is novel. The greater increase in postprandial GLP-1 levels could be explained by the change in the rate of gastric emptying. Although this parameter was not measured in the present study, the rate of gastric emptying influences the release of GLP-1. In fact, when the rate of gastric emptying increased and the rate of glucose entry into small intestine enhanced, increases in plasma GLP-1 level were promoted in healthy men.35 Moreover, the rate of gastric emptying was accelerated after a 3-day high-fat diet intake.36 Therefore, our data suggest that a LC/HFD could partly contribute to promoting the release of GLP-1 by affecting the rate of gastric empting.
GLP-1 and GIP are gut hormones that stimulate postprandial insulin secretion.21 The greater increase in GIP and GLP-1 level after LC/HFD appears to facilitate postprandial endogenous insulin secretion. However, there was no difference in the response of serum insulin levels between ND and LC/HFD. The reasons for this remain unclear. Nevertheless, it is believed that the increase in postprandial GLP-1 levels represents an adaptive response to promote declined insulin secretion for the replenishment of glycogen levels depleted in the liver and muscles.
The decrease in the fasting TG levels, which was maintained during the OGTT, was only observed with the LC/HFD. Because a LC/HFD contains little carbohydrate, it reduces blood glucose availability and glucose oxidation gradually decreases. In contrast, fat oxidation gradually increases12, 13, 16 and the contribution of TG-derived fatty acid oxidation to total fat oxidation increases with a LC/HFD.37 The increased contribution of TG-derived fatty acid oxidation is involved in the increase in lipoprotein lipase (LPL) activity in the muscle capillary bed with high-fat diet.38 LPL facilitates the release of fatty acid from TG within the muscle and very low-density lipoprotein, and increases fat oxidation.38 Considering that fasting TG is mainly delivered along with very low-density lipoprotein, although the contribution of TG in the muscle and very low-density lipoprotein to total fat oxidation is unclear, the increase in oxidation of fatty acid released from TG may decrease the fasting TG level after 3-day LC/HFD.
In conclusion, short-term LC/HFD increased postprandial glucose and GLP-1 levels in healthy young men. Impaired glucose tolerance was partly explained by reduction in insulin release. These findings demonstrated that even a short-term (3 days) excess fat intake could cause postprandial hyperglycemia in healthy young men under physiological conditions.
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This work was supported in part by a Grant-in-Aid for the Young Scientists (B) (22700703) and for the Global COE program ‘Sport Sciences for the promotion of Active Life’ (2010–2011) awarded by Ministry of Education, Culture, Sports Science and Technology of Japan.
The authors declare no conflict of interest.
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Cite this article
Numao, S., Kawano, H., Endo, N. et al. Short-term low carbohydrate/high-fat diet intake increases postprandial plasma glucose and glucagon-like peptide-1 levels during an oral glucose tolerance test in healthy men. Eur J Clin Nutr 66, 926–931 (2012). https://doi.org/10.1038/ejcn.2012.58
- postprandial hyperglycemia
- impaired glucose tolerance
- glucose-dependent insulinotropic polypeptide
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