Acute effect of fructose, sucrose, and isomaltulose on uric acid metabolism in healthy participants.

Fructose is associated with hyperuricemia and gout development. Focusing on fructose and fructose-containing disaccharides, we investigated the effects of three different types of carbohydrates (fructose, sucrose, and isomaltulose) on uric acid metabolism and gene expression profiling in peripheral white blood cells. In a randomized crossover study, ten healthy participants ingested test drinks of fructose, sucrose, and isomaltulose, each containing 25 g of fructose. Plasma glucose, serum and urine uric acid, and xanthine/hypoxanthine concentrations were measured. Microarray analysis in peripheral white blood cells and real-time reverse transcription polymerase chain reaction were examined at 0 and 120 in after the intake of test drinks. Serum uric acid concentrations for group fructose were significantly higher than group sucrose at 30-120 min and were significantly higher than those for group isomaltulose at 30-240 min. Several genes involved in the "nuclear factor-kappa B signaling pathway" were markedly changed in group fructose. No significant differences in the mRNA expression levels of tumor necrosis factor, nuclear factor-kappa B, interleukin-1ß, and interleukin-18 were noted. This study indicated that fructose intake (monosaccharide) elevated serum uric acid concentrations compared with disaccharide intake. Differences in the quality of carbohydrates might reduce the rapid increase of postprandial serum uric acid concentrations.

The Novel Mechanisms Concerning the Inhibitions of Palmitate-Induced Proinflammatory Factor Releases and Endogenous Cellular Stress with Astaxanthin on MIN6 ß-Cells.

Astaxanthin, an antioxidant agent, can protect pancreatic ß-cells of db/db mice from glucotoxicity and resolve chronic inflammation in adipose tissue. Nonetheless, the effects of astaxanthin on free-fatty-acid-induced inflammation and cellular stress in ß-cells remain to be demonstrated. Meanwhile, palmitate enhances the secretion of pro-inflammatory adipokines monocyte chemoattractant protein-1 (MCP-1) and VEGF120 (vascular endothelial growth factor). We therefore investigated the influence of astaxanthin on palmitate-stimulated MCP-1 and VEGF120 secretion in mouse insulinoma (MIN6) pancreatic ß-cells. Furthermore, whether astaxanthin prevents cellular stress in MIN6 cells was also assessed. Pre-treatment with astaxanthin or with N-acetyl-cysteine (NAC) which is an antioxidant drug, significantly attenuated the palmitate-induced MCP-1 release through downregulation of phosphorylated c-Jun NH2-terminal protein kinase (JNK) pathways, and suppressed VEGF120 through the PI3K/Akt pathways relative to the cells stimulated with palmitate alone. In addition, palmitate significantly upregulated homologous protein (CHOP) and anti-glucose-regulated protein (GRP78), which are endoplasmic reticulum (ER) stress markers, in MIN6 cells. On the other hand, astaxanthin attenuated the increased CHOP content, but further up-regulated palmitate-stimulated GRP78 protein expression. By contrast, NAC had no effects on either CHOP or GRP78 enhancement induced by palmitate in MIN6 cells. In conclusion, astaxanthin diminishes the palmitate-stimulated increase in MCP-1 secretion via the downregulation of JNK pathways in MIN6 cells, and affects VEGF120 secretion through PI3K/Akt pathways. Moreover, astaxanthin can prevent not only oxidative stress caused endogenously by palmitate but also ER stress, which NAC fails to attenuate, via upregulation of GRP78, an ER chaperon.

The association between impaired proinsulin processing and type 2 diabetes mellitus in non-obese Japanese individuals.

We aimed to examine the association between impaired proinsulin processing in pancreatic beta cells and type 2 diabetes mellitus in non-obese Japanese patients. Participants were divided into groups for normal glucose tolerance, prediabetes, and type 2 diabetes based on the oral glucose tolerance test (OGTT). Activities of prohormone convertase (PC) 1/3 and PC2 in fasting states were estimated. Multiple regression analysis was undertaken to ascertain if alteration of the activities of these enzymes contributes to the development of impaired glucose tolerance by comparison with HOMA-ß and the oral disposition index (DI(O)). Overall, 452 subjects were included. PC1/3 activity tended to decrease in type 2 diabetes compared with normal glucose tolerance. PC2 activity showed no difference among the three groups. Decreased estimated PC1/3 activity was significantly associated with type 2 diabetes after adjustment for sex, age, creatinine, triglycerides, HOMA-ß and DI(O). Odds ratios (95% CI) of PC1/3, HOMA-ß, and DI(O) were 2.16 (1.12-4.19), 3.44 (1.82-6.52) and 14.60 (7.87-27.11), respectively. Furthermore, decreased PC1/3(≤1.7) combined with decreased HOMA-ß (≤30) had a sensitivity of 73% and specificity of 62%. Decreased PC1/3 activity may be a useful measurement of beta-cell function alongside decreased HOMA-ß or DI(O). A combined decrease in estimated fasting PC1/3 activity and HOMA-ß measurement led to suspicion of type 2 diabetes in the non-obese Japanese population studied.

The glucagon-like peptide 1 receptor agonist enhances intrinsic peroxisome proliferator-activated receptor γ activity in endothelial cells.

Recent studies have suggested glucagon-like peptide-1 (GLP-1) signaling to exert anti-inflammatory effects on endothelial cells, although the precise underlying mechanism remains to be elucidated. In the present study, we investigated whether PPARγ activation is involved in the GLP-1-mediated anti-inflammatory action on endothelial cells. When we treated HUVEC cells with 0.2ng/ml exendin-4, a GLP-1 receptor agonist, endogenous PPARγ transcriptional activity was significantly elevated, by approximately 20%, as compared with control cells. The maximum PPARγ activity enhancing effect of exendin-4 was observed 12h after the initiation of incubation with exendin-4. As H89, a PKA inhibitor, abolished GLP-1-induced PPARγ enhancement, the signaling downstream from GLP-1 cross-talk must have been involved in PPARγ activation. In conclusion, our results suggest that GLP-1 has the potential to induce PPARγ activity, partially explaining the anti-inflammatory effects of GLP-1 on endothelial cells. Cross-talk between GLP-1 signaling and PPARγ activation would have major impacts on treatments for patients at high risk for cardiovascular disease.

Delayed dinnertime impairs glucose tolerance in healthy young adults.

To explore the relationship between mealtime delays of up to 3 h and subsequent glucose fluctuations, healthy young adults were allocated to three delayed dinnertimes in randomized order. Participants consumed test meals for lunch and dinner. After assessing the glucose responses using intermittently scanned continuous glucose monitoring devices (isCGM), the peak glucose elevation, and incremental area under the curve (iAUC) of postprandial glucose during certain intervals increased significantly when the time between lunch and dinner was delayed by 1 h or more. Our results support the importance of improving irregular mealtime habits, such as late eating.

Post-meal endogenous insulin secretion was significantly lower in head than in body/tail cancer of the pancreas.

THE AIM: Pancreatic cancer, a rapidly progressive malignancy, is often diagnosed in patients with diabetes. The incidence of pancreatic cancer has risen dramatically over recent decades. Early diagnosis of this malignancy is generally difficult because the symptoms do not become apparent until the disease has progressed, generally leading to a poor outcome. To achieve earlier diagnosis, we analyzed the clinical characteristics of pancreatic cancer patients showing deterioration of plasma glucose levels while hospitalized. METHOD: Thirty-six cases were divided into 2 groups;those diagnosed with diabetes more than a year prior to identification of pancreatic cancer and diabetes secondary to pancreatic cancer. These 2 groups were further subdivided according to the tumor site (head or body/tail), allowing analysis of 4 subgroups. Anthropometric measurements, laboratory values were determined. RESULTS: Both groups with diabetes lost at least 4 kg and showed HbA1c deterioration of at least 1% within 5 months of the pancreatic cancer diagnosis. The post-meal elevation of serum C-peptide immunoreactivity (CPR) was significantly decreased in the group with cancer of the pancreatic head, and this was unrelated to tumor size. CONCLUSION: Characteristically, pancreatic head cancer was associated with decreased endogenous insulin secretion as compared to body/tail cancer. J. Med. Invest. 70 : 350-354, August, 2023.

The Urinary Excretion of Magnesium as an Effective Magnesium Deficiency State Indicator: A Controlled Intervention Trial.

With the western influence in our diets, food consumption has changed, and our magnesium (Mg) intake is no longer optimal. Serum Mg (S-Mg) level is currently used as an indicator of Mg deficiency and is strictly regulated via compensatory mechanisms. It is believed that a 24-h urine collection can be used to evaluate potential Mg deficiency. This study aimed to assess whether Mg deficiency state as found in urine Mg (U-Mg) excretion and improving such deficiency with a diet that meets the Recommended Dietary Allowances (RDAs) of Mg for 15 d. Healthy Japanese women were recruited for Study 1 (n=22) and Study 2 (n=10). Study 1 was 1-d balance test, where fasting blood and 24-h urine samples were collected. Study 2 was 15-d diet load test, where fasting blood (days 1, 7, and 15) and 24-h urine (odd days) were collected. All test meals were made certain to have met the RDA for Mg for women in their 20s. In Studies 1 and 2, S-Mg was within the normal range. In Study 1, U-Mg excretion was 67.7±17.0 mg/d, with a large dispersion. In Study 2, U-Mg excretion on days 7 and 15 was significantly higher than on day 1, but have no significant differences in U-Mg excretion between days 7-15. U-Mg excretion can be a valuable indicator to evaluate Mg state. In young women, improvements in Mg deficient state were observed after 7-15 d of taking meals that met the RDAs of Mg.

Insulin signaling and its application.

The discovery of insulin in 1921 introduced a new branch of research into insulin activity and insulin resistance. Many discoveries in this field have been applied to diagnosing and treating diseases related to insulin resistance. In this mini-review, the authors attempt to synthesize the updated discoveries to unravel the related mechanisms and inform the development of novel applications. Firstly, we depict the insulin signaling pathway to explain the physiology of insulin action starting at the receptor sites of insulin and downstream the signaling of the insulin signaling pathway. Based on this, the next part will analyze the mechanisms of insulin resistance with two major provenances: the defects caused by receptors and the defects due to extra-receptor causes, but in this study, we focus on post-receptor causes. Finally, we discuss the recent applications including the diseases related to insulin resistance (obesity, cardiovascular disease, Alzheimer's disease, and cancer) and the potential treatment of those based on insulin resistance mechanisms.

Hypoglycemic effects of colestimide on type 2 diabetic patients with obesity.

Recent studies have shown colestimide, a bile acid-binding resin, to also exert a glucose-lowering effect via amelioration of insulin resistance. To evaluate the effects of colestimide on glucose metabolism and to elucidate the underlying mechanism, we conducted a 6-month, open-label pilot study on 43 type 2 diabetic patients with obesity (BMI ≥ 25). The subjects were randomized to either treatment with colestimide 4g/day (T group, n=23) or continuation of their current therapy (C group, n=20). In the T group patients, mean HbA1c and fasting glucose improved markedly (from 7.71 ± 0.32% to 6.97 ± 0.20%; from 147.4 ± 7.3mg/dL to 127.0 ± 5.0mg/dL, respectively), while obesity-related parameters, i.e. body weight, waist circumference, and visceral fat and subcutaneous fat as determined by umbilical slice abdominal CT, showed no significant changes. Fractionation analyses of serum bile acids revealed significantly increased cholic acids (CA) and decreased chenodeoxycholic acids (CDCA) in the T group patients. However, no correlation was observed between these changes and ΔHbA1c. According to logistic regression analysis, baseline HbA1c was the only variable predicting the decrease of HbA1c (>0.5%) among sex, age, BMI, total cholesterol, ΔCA and ΔCDCA. The index of insulin resistance, i.e. HOMA-R, did not improve, and the index of ß cell function, i.e. HOMA-ß, actually increased significantly. These results suggests that, in obese patients with type 2 diabetes, the mechanism underlying improved glycemic control with colestimide treatment involves enhanced ß cell activity rather than improved insulin resistance.

Serum YKL-40 Level is Associated with Geriatric Nutritional Risk Index (GNRI) and γ-GTP in Hemodialysis Patients.

Chitinase-3-like protein 1 (YKL-40) is a glycoprotein associated with inflammation and tissue remodeling that has recently been used as a marker of inflammation in hemodialysis (HD) patients. In this study, we aimed to determine whether YKL-40 has potential to serve as a nutritional parameter in Japanese HD patients. The serum YKL-40 concentration, hematological parameters, inflammatory marker levels, anthropometric measurements, and laboratory values were measured in 88 patients receiving HD. The geriatric nutritional risk index (GNRI) was used as a nutritional assessment tool. 45.4% of patients were malnourished. YKL-40 correlated positively with age, alkaline phosphatase, alanine transaminase and γ-glutamyl transpeptidase (γ-GTP) levels, but not with nutritional status, and correlated inversely with ankle brachial index score, a predictor of atherosclerosis. Furthermore, multiple regression analysis confirmed that γ-GTP, GNRI and age correlated with YKL-40. YKL-40 elevation was associated with γ-GTP, GNRI and age in HD patients. J. Med. Invest. 69 : 101-106, February, 2022.

Vimentin binds IRAP and is involved in GLUT4 vesicle trafficking.

Insulin-responsive aminopeptidase (IRAP) and GLUT4 are two major cargo proteins of GLUT4 storage vesicles (GSVs) that are translocated from a postendosomal storage compartment to the plasma membrane (PM) in response to insulin. The cytoplasmic region of IRAP is reportedly involved in retention of GSVs. In this study, vimentin was identified using the cytoplasmic domain of IRAP as bait. The validity of this interaction was confirmed by pull-down assays and immunoprecipitation in 3T3-L1 adipocytes. In addition, it was shown that GLUT4 translocation to the PM by insulin was decreased in vimentin-depleted adipocytes, presumably due to dispersing GSVs away from the cytoskeleton. These findings suggest that the IRAP binding protein, vimentin, plays an important role in retention of GSVs.

Dietary deoxynucleic acid induces type 2 T-helper immune response through toll-like receptor 9 in mice.

BACKGROUND: It has been shown that dietary nucleotides modulate immune response. Due to their unique properties in immune responses, nucleotides are used as immunonutrition in the field of clinical nutrition. AIM OF THE STUDY: In this study, we examined the effect of dietary deoxynucleic acid (DNA) on antigen (Ag)-specific immune response in ovalbumin (OVA)-immunized BALB/c mice and determined the mechanism using toll-like receptor 9 (TLR9) knock-out (KO) mice. METHODS: BALB/c or TLR9 KO mice were fed control and 1% DNA diets and immunized with OVA. Spleen cells from OVA-immunized mice were stimulated with OVA in vitro, and the contents of IFN-γ and IL-4 in supernatants were measured by an ex vivo system. CD11c(+) dendritic cells were purified, and ability of cytokine induction to CD4(+) cells was examined. RESULTS: The level of OVA-specific IL-4 production in the DNA group was significantly higher than that in the control group. In contrast, the level of OVA-specific IFN-γ production in the DNA group was lower than that in the control group. The DNA diet decreased Ag-specific IL-4 production and enhanced Ag-specific IFN-γ production in TLR9 KO mice. CD11c(+) DCs from mice fed the DNA diet had a greater ability than CD11c(+) DCs from mice fed the control diet to induce the production of IL-4 from DO11.10 CD4(+) T cells. CONCLUSIONS: Dietary DNA increases Ag-specific IL-4 production and decreases IFN-γ production through a TLR9-dependent pathway. CD11c(+) dendritic cells are target cells in dietary DNA-induced immune regulation.

Soy isoflavone equol perpetuates dextran sulfate sodium-induced acute colitis in mice.

The effects of the soy isoflavones, genistein, daidzein and equol, on experimental colitis were examined. Equol severely perpetrated dextran sulfate sodium (DSS)-induced colitis as evaluated by the weight loss. Production of the anti-inflammatory cytokine, IL-10, from T cells was decreased in the equol-treated mice. The results show that the soy isoflavone, equol, played an important role in the inflammatory response in the gastrointestinal tract.

Suppression of oral tolerance by Lactococcus lactis in mice.

Although oral ovabumin (OVA) administration suppressed the antibody (Ab) response in OVA-immunized mice, Lactococcus lactis increased OVA-specific IgG2a in these mice. L. lactis increased the casein-specific IgG level in NC/Nga mice fed on a casein diet. The percentage of CD4(+)CD25(+) cells was increased in DO11.10 mice orally given OVA, but this increase of CD4(+)CD25(+) cells were suppressed in L. lactis-fed DO11.10 mice.

Acute effect of green tea catechins on uric acid metabolism after alcohol ingestion in Japanese men.

INTRODUCTION/OBJECTIVES: Alcohol consumption is associated with hyperuricemia and gout. Previous studies have indicated a role for green tea catechins in uric acid (UA) metabolism. This study aimed to elucidate the acute effect of green tea catechins in terms of enhancing urinary excretion of UA and xanthine/hypoxanthine (Xa/HX; UA precursors) after alcohol ingestion. METHODS: In a randomized crossover study, ten healthy Japanese subjects consumed test meals, including a Japanese distilled spirit (Shochu) with water (SW) or Shochu with catechin-rich green tea (SC), each containing 20 g of alcohol. The SC contained 617 mg of catechin in total. Serum and urine UA and Xa/HX concentrations were measured. Blood samples were collected after 2.5 h, and urine samples were collected between 0 and 5 h after consuming the test meal. RESULTS: Urine UA and Xa/HX excretions were significantly higher in the SC group than in the SW group (UA: SW, 0.45 ± 0.08; SC, 0.52 ± 0.09; Xa/HX: SW, 0.08 ± 0.04; SC, 0.16 ± 0.05 mg/kg/h). UA clearance (CUA) and fractional UA excretion (FEUA) tended to increase more in the SC group than in the SW group (CUA: SW, 7.76 ± 2.14; SC, 8.75 ± 2.23 mL/min/1.73 m2; FEUA: SW, 6.08 ± 1.36; SC, 6.64 ± 1.42%). No significant differences in serum UA and Xa/HX concentrations were observed between two groups. CONCLUSIONS: It was concluded that green tea catechins can enhance the excretion of UA and Xa/HX, even though alcohol is ingested. TRIAL REGISTRATION NUMBER: UMIN000040076. Retrospectively registered 7 April 2020. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000045687 Key Points • Green tea catechins enhance the excretion of uric acid and xanthine/hypoxanthine, even when alcohol is ingested simultaneously. • In case of non-adherence of limiting alcohol intake, catechin-rich green tea may be an effective dietary component to continue dietary therapy.

Identification of cis-acting promoter sequences required for expression of the glycerol-3-phosphate acyltransferase 1 gene in mice.

Glycerol-3-phosphate acyltransferase 1 (GPAT1) is a rate limiting enzyme in de novo glycerophospholipid synthesis. The murine GPAT1 promoter sequence (the "classical" sequence) was reported previously. However, the organization of this DNA sequence does not fully match the mouse genome sequences on NCBI/GenBank. Here we have identified net cis-acting promoter sequences for the mouse GPAT1 gene: promoter 1a which includes part of the classical sequence and the downstream promoter 1b. Promoter 1a facilitates transcription of two alternative GPAT1 transcript variants, GPAT1-V1 and V2, while promoter 1b produces a third transcript variant, GPAT1-V3. Upstream stimulating factor-1 (USF-1) controlled both promoters whereas sterol regulatory element-binding protein-1 (SREBP-1) exclusively regulated promoter 1a activity in vitro. Feeding increased GPAT1-V1 and V2, but not V3 mRNA levels in mouse liver. The obese condition of db/db mice did not alter the hepatic expression levels of any of the three GPAT1 variants. Feeding enhanced hepatic mRNA levels, intranuclear protein levels and promoter 1a-binding levels of SREBP-1, but not of USF-1. Thus, promoter 1a was exclusively activated by routine feeding in vivo. Our results indicate differential roles of the two promoters in the regulation of hepatic GPAT1 gene expression in mice.

Myosin IIA participates in docking of Glut4 storage vesicles with the plasma membrane in 3T3-L1 adipocytes.

In adipocytes and myocytes, insulin stimulation translocates glucose transporter 4 (Glut4) storage vesicles (GSVs) from their intracellular storage sites to the plasma membrane (PM) where they dock with the PM. Then, Glut4 is inserted into the PM and initiates glucose uptake into these cells. Previous studies using chemical inhibitors demonstrated that myosin II participates in fusion of GSVs and the PM and increase in the intrinsic activity of Glut4. In this study, the effect of myosin IIA on GSV trafficking was examined by knocking down myosin IIA expression. Myosin IIA knockdown decreased both glucose uptake and exposures of myc-tagged Glut4 to the cell surface in insulin-stimulated cells, but did not affect insulin signal transduction. Interestingly, myosin IIA knockdown failed to decrease insulin-dependent trafficking of Glut4 to the PM. Moreover, in myosin IIA knockdown cells, insulin-stimulated binding of GSV SNARE protein, vesicle-associated membrane protein 2 (VAMP2) to PM SNARE protein, syntaxin 4 was inhibited. These data suggest that myosin IIA plays a role in insulin-stimulated docking of GSVs to the PM in 3T3-L1 adipocytes through SNARE complex formation.

Impact of Meal Timing on Postprandial Interstitial Fluid Glucose Levels in Young Japanese Females.

Flash glucose monitoring (FGM) provides continuous and accessible measurement of the interstitial fluid glucose (ISFG) level and this system is useful for understanding blood glucose fluctuations. We examined differences in postprandial ISFG after the main mealtimes (breakfast, lunch, and dinner) in healthy young Japanese females. Nine healthy young females (aged 21.5±0.6 y old) were enrolled in this study. ISFG was continuously measured by FGM. Participants ate the same meal three times a day consecutively, thereby satisfying their daily energy requirements. Postprandial ISFG fluctuations were evaluated for 4 h after each meal. There were no significant differences in ISFG before the 3 main meals. The postprandial ISFG peak was the lowest after breakfast, increasing in the order of lunch and then dinner. The area under the curve of the 4-h postprandial ISFG was higher after lunch and dinner than after breakfast. The results of this study suggest that postprandial ISFG differ depending on mealtimes in young Japanese females.

Exendin-4, a GLP-1 receptor agonist, directly induces adiponectin expression through protein kinase A pathway and prevents inflammatory adipokine expression.

Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist that has been used as a drug injected subcutaneously for treatment of type 2 diabetes. Many studies have revealed molecular targets of Ex-4, but its influence on adipokines has not been determined. Our study showed that Ex-4 induced secretion of adiponectin into the culture medium of 3T3-L1 adipocytes. This effect of Ex-4 is due to increased adiponectin mRNA level through the GLP-1R. Both forskolin and 3-isobutyl-1-methylxanthine (IBMX), which may finally elevate cyclic adenosine monophosphate (cAMP) concentration, prevented the induction of adiponectin expression by Ex-4. Moreover, H89, a protein kinase A inhibitor, blocked the effect of Ex-4 on adiponectin. On the other hand, Ex-4 decreased the mRNA levels of inflammatory adipokines. The results indicate that Ex-4 directly promotes adiponectin secretion via the protein kinase A pathway in 3T3-L1 adipocytes and may ameliorate insulin resistance.

The Rab GTPase-activating protein AS160 as a common regulator of insulin- and Galphaq-mediated intracellular GLUT4 vesicle distribution.

Akt substrate of 160kDa (AS160) is a Rab GTPase activating protein (GAP) and was recently identified as a component of the insulin signaling pathway of glucose transporter type 4 (GLUT4) translocation. We and others, previously reported that the activation of Galphaq protein-coupled receptors (GalphaqPCRs) also stimulated GLUT4 translocation and glucose uptake in several cell lines. Here, we report that the activation of GalphaqPCRs also promoted phosphorylation of AS160 by the 5'-AMP activated protein kinase (AMPK). The suppression of AS160 phosphorylation by the siRNA mediated AMPKalpha1 subunit knockdown promoted GLUT4 vesicle retention in intracellular compartments. This suppression did not affect the ratio of non-induced cell surface GLUT4 to Galphaq-induced it. Rat 3Y1 cells lacking AS160 did not show insulin-induced GLUT4 translocation. The cells stably expressing GLUT4 revealed GLUT4 vesicles that were mainly localized in the perinuclear region and less frequently on the cell surface. After expression of exogenous AS160, GLUT4 on the cell surface decreased and GLUT4 vesicles were redistributed throughout the cytoplasm. Although PMA-induced or sodium fluoride-induced GLUT4 translocation was significantly increased in these cells, insulin did not affect GLUT4 translocation. These results suggest that AS160 is a common regulator of insulin- and GalphaqPCR activation-mediated GLUT4 distribution in the cells.