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.

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.

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.

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.

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.

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.

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.

Serum lactate levels are associated with serum alanine aminotransferase and total bilirubin levels in patients with type 2 diabetes mellitus: A cross-sectional study.

AIMS: It was recently reported that lactate acts as a metabolic mediator and rises in the diabetic state, but the physiological effects are as yet poorly understood. The objective of the current study was to evaluate the significance of serum lactate elevation in type 2 diabetes mellitus (T2DM) patients. METHODS: Fasting serum lactate levels, hematological and inflammatory serum markers and anthropometric parameters, obtained employing bioelectric impedance analysis, were measured in 103 patients with T2DM. RESULTS: Statistically significant correlations of serum lactate levels with C-reactive peptide, insulin, aspartate aminotransferase, alanine aminotransferase (ALT), serum lipids, total bilirubin, adiponectin, homeostasis model assessment-insulin resistance, body weight, body mass index and body fat (weight or percentage of subcutaneous fat, visceral fat or total body fat), but neither fasting plasma glucose nor HbA1c, were detected. Stepwise regression analysis showed ALT to be independently positively associated with total bilirubin, while being negatively associated with serum lactate levels. Furthermore, serum lactate levels were significantly higher in patients with ALT-predominant liver dysfunction. CONCLUSION: We found fasting serum lactate elevation in T2DM patients to be associated with the serum levels of ALT and total bilirubin independently of blood glucose control. TRIAL REGISTRATION: UMIN clinical trials registry (UMIN000029178).

Novel Mechanisms Modulating Palmitate-Induced Inflammatory Factors in Hypertrophied 3T3-L1 Adipocytes by AMPK.

OBJECTIVE: A growing body of evidence indicates that AMP-activated protein kinase (AMPK) contributes to not only energy metabolic homeostasis but also the inhibition of inflammatory responses. However, the underlying mechanisms remain unclear. To elucidate the role of AMPK, in this study, we observed the effects of AMPK activation on monocyte chemoattractant protein-1 (MCP-1) release in mature 3T3-L1 adipocytes. METHODS: We observed signal transduction pathways regulating MCP-1, which increased in obese adipocytes, in an in vitro model of hypertrophied 3T3-L1 adipocytes preloaded with palmitate. RESULTS: Palmitate-preloaded cells exhibited significant increase in MCP-1 release and triglyceride (TG) deposition. Increased MCP-1 release and TG deposition were significantly decreased by an AMPK activator. In addition, the AMPK activator not only markedly diminished MCP-1 secretion but also augmented phosphorylation of nuclear factor-κB (NF-κB) and extracellular signal-regulated kinase (ERK) 1/2. In contrast, MCP-1 release suppression was abolished by the AMPK inhibitor compound C and the MEK inhibitor U0126. CONCLUSIONS: MCP-1 release from hypertrophied adipocytes is suppressed by AMPK activation through the NF-κB and ERK pathways. These findings provide evidence that AMPK plays a crucial role in ameliorating obesity-induced inflammation.

Metabolic effects of Tofogliflozin are efficiently enhanced with appropriate dietary carbohydrate ratio and are distinct from carbohydrate restriction.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exert their antidiabetic effects by promoting urinary glucose excretion. Nutrition therapy is obviously important, but little is known about the interactions between SGLT2i agents and carbohydrate restriction. Therefore, we studied these interactions using an obese diabetic animal model. KK-Ay mice were pair-fed normal chow [NC; carbohydrate: fat: protein = 65:15:20], low carbohydrate [LC; 43:42:15] or severely carbohydrate restricted diets [SR; 12:45:43] for 12 weeks. Tofogliflozin (Tofo) was administered as the SGLT2i in the NC and LC diet groups. Blood glucose levels were significantly increased in the SR group. Tofo reduced blood glucose levels significantly in the NC group during the experiment and in the LC group at 2-6 weeks. Plasma triglycerides were markedly elevated in the SR group without Tofo, but decreased in response to Tofo administration. Hepatic triglyceride contents were not changed by the LC or the SR diet alone. However, Tofo ameliorated hepatosteatosis in NC-fed animals. Consistent with the downregulation of stearoyl-CoA desaturase 1, the ratio of plasma monounsaturated to saturated fatty acids was significantly reduced in the LC with Tofo and in the SR alone groups, but was not altered in the NC with Tofo group. In summary, metabolism of glucose and lipids was improved by Tofo but not by the SR diet. Furthermore, Tofo improved these parameters more effectively in the NC than in the LC diet group. These data suggest that the effects of SGLT2i are distinct from those of carbohydrate restriction and that a nonrestricted dietary carbohydrate composition is essential for SGLT2i treatment to be effective.

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.

Correction: Long-Term Low Carbohydrate Diet Leads to Deleterious Metabolic Manifestations in Diabetic Mice.

[This corrects the article DOI: 10.1371/journal.pone.0104948.].

Clinical effect of real time pulse rate monitoring with a portable pulsimeter on physical exercise therapy for male patients with type 2 diabetes.

In patients with type 2 diabetes, it is recommended that exercise therapy is performed using heart rate as an index of exercise intensity. This study was designed to clinically evaluate whether continuous exercise therapy with a portable pulsimeter for self-monitoring of the pulse rate influences glycemic control in patients with type 2 diabetes. We randomly assigned 23 male patients to a pulse displayed group (in which the portable pulsimeter displayed a pulse rate) or a pulse non-displayed group (in which the portable pulsimeter only recorded the data and did not display a pulse rate). The patients then received exercise therapy for 1 month. Patients in the pulse displayed group were instructed to regulate their walking speed by maintaining their portable pulsimeter in the target pulse rate zone, whereas patients in the pulse non-displayed group were instructed to regulate their walking speed while taking their pulse rate and using the Borg scale to maintain the target pulse rate zone using the conventional method. We found the mean walking time within the target pulse rate zone during exercise therapy was significantly increased in the pulse displayed group (p < 0.01). Similarly, glycoalbumin and 1,5-anhydro-D-glucitol improved significantly in the pulse displayed group after 1 month of exercise therapy (p < 0.01, respectively). Our results suggest that this therapeutic device might be useful for improving glycemic control in patients with type 2 diabetes.

Influence of Treatment with Extracts of Hypsyzigus marmoreus Mushroom on Body Composition during Obesity Development in KK-A(y) Mice.

Hypsyzigus marmoreus (HM), an edible mushroom, has several effects, including antitumor, antioxidant and anti-allergy properties. On the other hand, the possibly useful effect of HM in diabetic mice has not as yet been elucidated. In this study, we showed treatment with a water soluble extract from HM (EHM) to reduce fat deposits without affecting body weight loss in KK-A(y) mice. EHM treatment also abolished the expressions of pro-inflammatory adipokines, such as tumor necrosis factor α and monocyte chemoattractant protein 1, as compared with vehicle treatment. The expressions of uncoupling protein 3 and peroxisome proliferator-activated receptor gamma coactivator 1α in the soleus muscles of EHM treatment groups were significantly elevated as compared to those in vehicle-treated muscle tissues. These results raise the possibility that EHM can regulate both obesity and insulin resistance.

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.

Bifidobacterium species lower serum glucose, increase expressions of insulin signaling proteins, and improve adipokine profile in diabetic mice.

This study, using C57BL/6J mice with streptozotocin (STZ)-induced diabetes, aimed to determine whether Bifidobacterium species (spp.) both induces the expressions of proteins in the insulin signaling pathway and enhances the expressions of certain adipocytokines. The protein expressions of IκB kinase alpha (IKKα), IκB kinase beta (IKKß), nuclear factor-kappaB inhibitor alpha (IκBα), and the mitogen-activated protein kinase (MAPK) pathway were also investigated. Oral administration of Bifidobacterium spp. reduced blood glucose levels significantly and increased the protein expressions of insulin receptor beta, insulin receptor substrate 1, protein kinase B (Akt/PKB), IKKα, and IκBα. Extracellular-signal-regulated kinase 2 (ERK2) showed increased expression. Bifidobacterium spp. also induced the adiponectin expression and decreased both macrophage chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) expression. In addition, IKKß, c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase expressions showed no significant changes in both groups. In conclusion, Bifidobacterium spp. may be the promising bacteria for treating diabetes.

Oral administration of Bifidobacterium spp. improves insulin resistance, induces adiponectin, and prevents inflammatory adipokine expressions.

The intestinal microbiome might be an important contributor to the development of type 2 diabetes. This study was designed to test the hypothesis that oral administration of Bifidobacterium species (spp.) (including B. longum, B. bifidum, B. infantis, and B. animalis) may both ameliorate insulin resistance and reduce the expressions of inflammatory adipocytokines. Male Swiss-Webster mice fed a high-fat diet with or without oral administration of Bifidobacterium spp. for 5 weeks were subjected to an insulin tolerance test and an oral glucose tolerance test. Plasma levels of glucose at 30, 60, 90 and 120 min after insulin injection or glucose administration were significantly lower in the Bifidobacterium spp. than in the control group (P < 0.05), showing the beneficial effect of oral administration on insulin resistance in obese Swiss mice. In addition, Bifidobacterium spp. increased the adiponectin mRNA level and decreased those of monocyte chemoattractant protein 1 and interleukin 6 in non-diabetic C57BL/6J mice fed a normal diet, indicating a molecular mechanism which may ameliorate the inflammatory state, thereby reducing insulin resistance. In conclusion, oral administration of Bifidobacterium spp. improves insulin resistance and glucose tolerance in obese mice by reducing inflammation, as it does in the lean state.

Treatment with buckwheat bran extract prevents the elevation of serum triglyceride levels and fatty liver in KK-A(y) mice.

Buckwheat powder or protein has been shown to decrease the total serum cholesterol level in non-diabetic mice or rats. However, the lipid-lowering effect of buckwheat bran extract (BBE) in diabetic mice has not been fully elucidated. KK-A(y) mice that received six-week treatment with BBE showed decreased body weight and liver weight compared to those of control (vehicle) mice. However, there was no significant difference in food intake. BBE treatments prevented liver triglyceride accumulation and decreased the serum level of triglycerides. In addition, mRNA expression levels lipogenic enzyme genes, fatty acid synthase, acetyl-coenzyme a oxidase and stearyl-coenzyme a desaturase 1, but not those of ß-oxidized enzyme genes, were decreased in BBE-treated mice. Level of transcription factors ChREBP and SREBP1c, transcripts of lipogenic genes, were also decreased in BBE-treated mice. These results suggest that chronic treatment with BBE derivatives could have beneficial effects on hypertriglycemia in patients with type 2 diabetes mellitus.