Combination of poly-γ-glutamic acid and galactooligosaccharide improves intestinal microbiota, defecation status, and relaxed mood in humans: a randomized, double-blind, parallel-group comparison trial.

The genus Bifidobacterium comprises beneficial intestinal bacteria that play a crucial role in the regulation of human health. Traditional prebiotics are known to increase intestinal bifidobacteria by supplying a carbon source necessary for their growth. However, intestinal bifidobacteria need not only a carbon source but also a nitrogen source for growth. Moreover, the growth of bifidobacteria is known to be inhibited in a culture medium that does not contain glutamic acid. Based on these reports, we hypothesized that the combined intake of traditional prebiotics and glutamic acid would be beneficial for growth of bifidobacteria in the gut. In this study, we investigated the effects of the combination of galactooligosaccharide (GOS; traditional prebiotic material) and poly-γ-glutamic acid (γ-PGA; source of glutamic acid) and only GOS on the intestinal microbiota and health conditions (including intestinal regulation, mood status, gastrointestinal condition, skin condition, and sleep quality) in a randomized, double-blind, parallel-group comparison trial in healthy subjects. The combined intake of GOS and γ-PGA significantly increased the prevalence of B. longum compared to the intake of GOS alone. A minimum effective dose of 2.0 g GOS and 0.3 g γ-PGA improved defecation and mood status. We revealed the combined effects of GOS and γ-PGA on intestinal microbiota as well as physical condition and concluded that the delivery of glutamic acid to the large intestine with traditional prebiotics is useful as an advanced prebiotic.

Effects of Five Amino Acids (Serine, Alanine, Glutamate, Aspartate, and Tyrosine) on Mental Health in Healthy Office Workers: A Randomized, Double-Blind, Placebo-Controlled Exploratory Trial.

BACKGROUND: The importance of maintaining good mental health with overall well-being has recently drawn attention from various spheres of academics and the working population. Amino acid intake has been reported to reduce depression symptoms and other mental health problems. However, the effectiveness of amino acid intake (i.e., single or combined) remains unknown. In this study, we assessed a combination of five amino acids (serine, alanine, glutamate, aspartate, and tyrosine; SAGAT) reported to regulate mental health. METHODS: A randomized, double-blind, placebo-controlled exploratory trial was conducted. Participants, aged between 20 and 65 years with fatigue sensation, were randomized to receive either SAGAT or the placebo and ingested them for four weeks. A transient mental work was loaded at day 0 and after four weeks of intervention. As the primary outcomes, the fatigue sensation was assessed. The mood status, cognitive function, work efficiency, and blood marker were also measured as secondary outcomes. RESULTS: The number of participants analyzed for the efficacy evaluation were 20 in SAGAT and 22 in the placebo. There were no significant differences in the primary outcomes. However, as the secondary outcomes, the SAGAT group showed a significant improvement in motivation and cognitive function in the recovery period after mental work loaded in a four-week intervention compared to the placebo. CONCLUSION: The current findings suggest that SAGAT contributes to maintaining proper motivation and cognitive function. CLINICAL TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (ID: UMIN 000041221).

l-Serine and EPA Relieve Chronic Low-Back and Knee Pain in Adults: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Multisite pain, including low-back and knee pain, is a major health issue that greatly decreases quality of life. OBJECTIVES: This study analyzed the effects of l-serine, which provides necessary components for nerve function, and EPA, which exerts anti-inflammatory properties, on pain scores of adults with pain in at least the low back and knee for ≥3 mo. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group study. The Japan Low Back Pain Evaluation Questionnaire (JLEQ) and Japanese Knee Osteoarthritis Measure (JKOM) were applied as primary outcomes. The Brief Pain Inventory (BPI) and safety evaluation were secondary outcomes. We enrolled 120 participants aged ≥20 y (36 men and 84 women: mean ± SD age = 40.8 ± 10.9 y). The participants were randomly allocated to either the active group (daily ingestion of 594 mg l-serine and 149 mg EPA) or placebo group. The study period consisted of 8-wk dosing and 4-wk posttreatment observation. ANCOVA between groups for each time point was conducted using the baseline scores as covariates. RESULTS: The JLEQ scores (active compared with placebo: 14.2 ± 11.2 compared with 19.0 ± 10.2) at week 8 were lower in the active group (P < 0.001). The JKOM scores at week 4 (11.7 ± 9.0 compared with 13.9 ± 7.9), week 8 (10.4 ± 7.9 compared with 13.1 ± 7.1), and week 12 (10.3 ± 7.4 compared with 13.8 ± 7.5) were lower in the active group (P ≤ 0.04). Additionally, the active group had 11-27% better scores compared with the placebo group for BPI1 (worst pain), BPI3 (average pain), and BPI5D (pain during moving) at week 4 (P ≤ 0.028) and week 8 (P ≤ 0.019), respectively, and BPI5D was 23% better in the active group at week 12 (P = 0.007). No adverse events were observed. CONCLUSIONS: l-Serine and EPA were effective for pain relief in adults with low-back and knee pain after multiplicity adjustment.This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000035056.

Nateglinide prevents fatty liver through up-regulation of lipid oxidation pathway in Goto-Kakizaki rats on a high-fat diet.

Dyslipidemia and fatty liver are important components of the metabolic syndrome and are the factors most commonly associated with the development of nonalcoholic fatty liver disease. Delayed and excessive insulin secretion in response to food intake is a key element in the onset of these risk factors. Nateglinide (NAT) is known to restore early-phase insulin secretion. We assessed the effect of NAT on postprandial hypertriglyceridemia and fatty liver in type 2 diabetic Goto-Kakizaki (GK) rats. The GK rats fed a high-fat diet containing 30% beef tallow twice a day were administered either the vehicle alone or NAT (50 mg/kg) before each meal for 12 weeks. Delayed insulin secretion and an increase of total insulin release were caused by feeding 30% beef tallow to the rats. This diet also induced postprandial hypertriglyceridemia and increased the hepatic triglyceride content. Treatment with NAT restored early-phase insulin secretion without any increase of total insulin release and also reduced postprandial hypertriglyceridemia and the hepatic triglyceride content. There was up-regulation of the hepatic expression of peroxisome proliferators-activated receptor alpha and its downstream enzymes after 12 weeks of NAT treatment, as well as normalization of the plasma total ketone body level. Furthermore, NAT also up-regulated hepatic expression of the adiponectin receptor AdipoR2, although there was no effect on the plasma adiponectin level. These findings indicate that long-term treatment with NAT prevented the development of fatty liver through the up-regulation of hepatic lipid oxidation pathways. Restoration of early-phase insulin secretion and suppression of recurrent postprandial hypertriglyceridemia might be involved in these effects of NAT. The present results may support the use of NAT to prevent the onset and progression of the metabolic syndrome and chronic liver disease.

Repetitive fluctuations in blood glucose enhance monocyte adhesion to the endothelium of rat thoracic aorta.

BACKGROUND: The aim of this study was to elucidate the effect of repetitive fluctuations in blood glucose concentrations on monocyte adhesion to the aortic endothelium. METHODS AND RESULTS: Nonobese type 2 diabetes, Goto-Kakizaki (GK) rats were fed twice daily to induce repetitive postprandial glucose spikes. Then, we compared the number of monocytes adherent to the endothelium of thoracic aorta in these rats with that in rats fed ad libitum. To suppress the glucose spikes, rats were injected with an inhibitor of sodium-glucose transporter, phloridzin, just before each meal for 12 weeks. GK rats fed twice daily showed significantly lower HbA1c than GK rats fed ad libitum. However, the former group showed markedly higher number of monocytes adherent to the endothelium than the latter, together with increased arterial intimal thickening. Phloridzin significantly reduced the number of adherent monocytes in GK rats fed twice daily. CONCLUSIONS: Our data demonstrated that repetitive postprandial fluctuation in glucose concentration evokes monocyte adhesion to endothelial cells that was worse than that induced by stable hyperglycemia in vivo. Suppression of such fluctuations efficiently suppressed monocyte adhesion to the aortic endothelium.

Nateglinide suppresses postprandial hypertriglyceridemia in Zucker fatty rats and Goto-Kakizaki rats: comparison with voglibose and glibenclamide.

Postprandial hypertriglyceridemia, as well as postprandial hyperglycemia, are important factors contributing to the development of cardiovascular disease in patients with type 2 diabetes. Nateglinide is a recently approved antidiabetic that suppresses postprandial hyperglycemia by stimulating the early phase of insulin secretion. In the present study, we investigated the effects of nateglinide on postprandial hypertriglyceridemia in obese Zucker fatty (ZF) rats and non-obese diabetic Goto-Kakizaki (GK) rats. Administration of an oral fat load caused marked hypertriglyceridemia with a peak at 2 h in ZF and GK rats. Nateglinide (50 mg/kg) significantly suppressed the increase of plasma triglycerides after fat loading in both types of rat (delta AUC [0-4 h]: 15+/-69 mg.h/dl for nateglinide vs. 838+/-100 mg.h/dl for vehicle in ZF rats; p<0.01, 81+/-22 mg x h/dl for nateglinide vs. 164+/-17 mg.h/dl for vehicle in GK rats; p<0.01). In contrast, other antidiabetic agents (voglibose and glibenclamide) did not show a significant effect on the increase of triglycerides after fat loading. The triglyceride components suppressed by nateglinide were mainly at the origin and in the pre beta subfraction on agarose gel electrophoresis, suggesting that chylomicrons and very low density lipoproteins were decreased. Plasma insulin levels were significantly increased at 30 min in nateglinide-treated rats, but not in voglibose- or glibenclamide-treated rats. These results suggest that nateglinide not only suppresses postprandial hyperglycemia, but also suppresses postprandial hypertriglyceridemia, by promoting rapid and pulsatile insulin secretion in patients with type 2 diabetes.

Decreased blood glucose excursion by nateglinide ameliorated neuropathic changes in Goto-Kakizaki rats, an animal model of non-obese type 2 diabetes.

In the present study, we examined the effect of long-term suppression of postprandial hyperglycemia and glycemic fluctuation in Goto-Kakizaki (GK) rats, a type 2 diabetic animal model, by nateglinide (NG), a fast-acting hypoglycemic agent, on some measures of neuropathy and compared the outcome with the slow-acting effect of glibenclamide (GC). GK rats fed twice daily were given NG (50 mg/kg) or GC (1 mg/kg) orally before each meal for 24 weeks. The dose of NG and GC was determined by the data of their comparable suppressive effects on hyperglycemia as a total sum of glucose values after glucose load. At the end, there was no significant influence of treatment with NG or GC on body weight, fasting blood glucose, and glycated hemoglobin in GK rats. However, NG treatment suppressed postprandial hyperglycemia by 50% throughout the observation period, whereas this effect was not apparent in GC-treated rats. Delayed motor nerve conduction velocity was normalized by NG treatment, while GC had a partial (50%) effect. GK rats showed elevated contents of sorbitol and 3-deoxyglucosone in the sciatic nerve, and these changes were inhibited by NG treatment. Reduced Na(+)/K(+)-adenosine triphosphatase (ATPase) activity in GK rats was not affected by either NG or GC treatment. These results suggest that meticulous control of postprandial hyperglycemia is essential to inhibit the development of neuropathy in type 2 diabetes.