Acute metabolic responses to a high-carbohydrate meal in outpatients with type 2 diabetes treated with a low-carbohydrate diet: a crossover meal tolerance study

Low-carbohydrate diets (LCDs) are known to be more effective than high-carbohydrate diets (HCDs) in improving glycemic control in type 2 diabetes mellitus (T2DM) [1, 2]. Our carbohydrate-reduced diet (CARD) also showed efficacy and safety over 2 years in mild T2DM [3], with an efficacy comparable to that provided by insulin therapy in severe T2DM [4]. An important problem with LCDs, however, is the high attrition rate [2, 3, 5]. Even patients who strictly conform to LCDs sometimes crave a high-carbohydrate meal (HCM), which often triggers the patients to drop out from the LCDs.

Although a key adaptation of LCDs is the production and utilization of ketone bodies [6, 7], the potential of such bodies for uses other than as fuels remains unclear [7]. Even moderate LCDs (30-45% carbohydrate diets) are highly effective for T2DM and dyslipidemia [2, 3, 8]. Thus, patients on a less-strict LCD sometimes eat HCMs because they are not required to strictly limit carbohydrates. Nevertheless, little is known about the acute metabolic changes resulting from the change in carbohydrate conditions in such patients.

In the present study, our subjects, T2DM outpatients on CARD, underwent crossover meal tolerance tests (HCM vs. a low-carbohydrate meal, LCM) to compare the acute effects of HCMs and LCMs on postprandial serum ketone bodies, free fatty acids (FFAs) and triglycerides. We also compared acute responses between subjects on moderate (non-ketogenic) and strict (ketogenic) CARD. Furthermore, for HCMs, we examined the correlation of postprandial changes in serum ketone bodies, FFAs and triglycerides with an increase in postprandial plasma glucose, insulin secretory capacity and background dietary %carbohydrate.

Thirty-one volunteer T2DM outpatients from the Haimoto Clinic participated in the study (Table 1). All patients were Japanese. Patients with severe diabetes complications were excluded. The participants achieved relatively good glycemic control (mean hemoglobin A1c (HbA1c) level: 6.9 ± 0.4%) by implementing CARD for a mean duration of 22 months. They received no insulin, sulfonylurea or nateglinide treatment, and their mean HbA1c level before CARD was 8.9 ± 2.0%. Based on their initial HbA1c levels, 18 were assigned moderate CARD and 13 strict CARD [3, 4]. Nine subjects took glucose-lowering medication (miglitol, metformin and pioglitazone).

The HCMs and LCMs were prepared at the Haimoto Clinic by an experienced dietitian. The total energy of the two meals was identical, while the macronutrient composition was contrastive (Table 2). The target HCM macronutrient composition followed the guidelines of the Japan Diabetes Society [9]. The background dietary intake of the subjects was assessed using 3-day food records.

All 31 participants underwent two-meal tolerance tests at intervals of 7-14 days. They were randomly assigned to two groups: 15 subjects took HCMs and LCMs in the first and second tests, respectively, while 16 subjects received LCMs and HCMs in the first and second sessions, respectively. Each meal test was conducted after a 12-hour overnight fast. The subjects were asked to continue their CARD and physical activity during the study period. After blood sampling at baseline (0 minutes), the subjects were asked to consume the test meal in 10 minutes, and blood was collected after 30, 60 and 120 minutes. All antidiabetic and lipid-lowering drugs were stopped for 24 hours before each tolerance test.

Plasma glucose concentration was determined by enzymatic methods (Shino-Test Co. Kanagawa, Japan). Serum immunoreactive insulin was measured using the standard double antibody radioimmunoassay method (Fujirebio Inc. Tokyo, Japan). Enzymatic methods were used to measure serum total cholesterol (Sysmex Co., Hyogo, Japan), triglycerides (Daiichi Pure Chemicals Co., Tokyo, Japan), free fatty acids (Eiken Chemicals Co., Tokyo, Japan), β-hydroxybutyrate and acetoacetate (Kainos Laboratories Inc., Tokyo, Japan). Direct methods were used to assay serum LDL-cholesterol and HDL-cholesterol (Daiichi Pure Chemicals Co., Tokyo, Japan). HbA1c level was measured by high-performance liquid chromatography (Arkley Co., Kyoto, Japan).

The study protocol was approved by the Ethical Committee of the Nagoya Tokusyukai General Hospital, and all participants provided written informed consent.

The limitations of the present study are its very short term and the large SD in serum ketone body levels before the meal tests. Large between-person variations in fasting serum β-hydroxybutyrate levels have been previously reported in outpatients after long-term LCD treatment [10, 11]. Another limitation is that the use of glucose and lipid-lowering drugs may have affected the results.

Nevertheless, the present study demonstrated that HCMs including 59% carbohydrates rapidly decreased postprandial serum ketone body and FFA concentrations within 2 hours in T2DM outpatients on CARD. The decrease can be explained in terms of the metabolic changes of ketone bodies and FFAs to glucose to be used as fuel [12], which is well-known to be largely determined by insulin secretion after the intake of large amounts of carbohydrates [12, 13]. However, our study clarified that the decrease in serum ketone body levels was much more rapid than expected from starvation conditions [12, 14] and was more remarkable in strict (ketogenic) CARD subjects than in moderate (non-ketogenic) CARD subjects. Carbohydrate or glucose administration to fasting normals causes serum ketone body levels to decrease in a few days [12, 14]. Under low-carbohydrate conditions, unlike under starvation conditions, a sufficient intake of protein and fat is likely to be involved in the rapid decrease of serum ketone body levels.

The present study also demonstrated that the insulinogenic index was strongly and positively correlated with Δketone bodies while concomitantly showing a strong and inverse correlation with baseline ketone body levels, but total insulin secretory capacity (AUC-insulin) was not significantly correlated with Δketone bodies. A possible interpretation of these findings is that under low-carbohydrate conditions, a lower insulinogenic index is probably a factor in maintaining a high level of baseline ketone bodies independent of dietary %carbohydrate; then, the initial secretion of only a small amount of insulin after the intake of LCMs leads to rapid decreases of serum postprandial ketone body levels.

Postprandial triglyceride levels have attracted much attention as a cardiovascular risk factor [15, 16], and LCDs are well known to improve serum triglyceride profiles compared to HCDs [7, 13, 17]. Small amounts of dietary fats (15 g) slightly increase postprandial serum triglyceride levels, but never decrease them in normolipidemic adults [18]. Interestingly, the present study demonstrated that small amounts of fat (12 g) in HCMs slightly decreased these levels over 2 hours in the strict CARD group in contrast to causing a slight increase in the moderate group. Moreover, Δtriglyceride was strongly and positively correlated with background dietary %carbohydrate, but not with an increase in postprandial plasma glucose and serum insulin, insulinogenic index or total insulin secretory capacity. Specifically, postprandial triglyceride levels decreased more in strict CARD subjects with lower %carbohydrate levels, and such patients had higher baseline ketone body levels. Given that ketone bodies provide the same metabolic effects as insulin and inhibit lipolysis [7, 19, 20], serum ketone bodies may play a role in decreasing postprandial triglyceride levels. In contrast, large amounts of fat (42 g) in LCMs increased triglyceride concentrations in both CARD groups. These results raise the possibility of a threshold in the dietary fat level under which postprandial triglyceride levels are not elevated [21].

In summary, when T2DM patients treated with CARD ingested HCMs, rapid metabolic change was induced within 2 hours; a rapid decrease in serum ketone bodies and FFA levels was found in conjunction with an increase in postprandial glucose and insulin levels. The decrease in ketone bodies was more remarkable in strict than in moderate CARD subjects. The parameter Δketone bodies was significantly correlated with the insulinogenic index, but not with total insulin secetory capacity. HCMs gradually decreased postprandial triglyceride levels in strict CARD subjects in contrast to causing a slight increase in moderate CARD subjects. The parameter Δtriglyceride was significantly correlated with dietary %carbohydrate.