A High-Methionine Diet for One-Week Induces a High Accumulation of Methionine in the Cerebrospinal Fluid and Confers Bipolar Disorder-like Behavior in Mice.

Methionine (Met) is considered the most toxic amino acid in mammals. Here, we investigated biochemical and behavioral impacts of ad libitum one-week feeding of high-Met diets on mice. Adult male mice were fed the standard rodent diet that contained 0.44% Met (1×) or a diet containing 16 graded Met doses (1.2×-13×). High-Met diets for one-week induced a dose-dependent decrease in body weight and an increase in serum Met levels with a 2.55 mM peak (versus basal 53 µM) on the 12×Met diet. Total homocysteine (Hcy) levels were also upregulated while concentrations of other amino acids were almost maintained in serum. Similarly, levels of Met and Hcy (but not the other amino acids) were highly elevated in the cerebrospinal fluids of mice on the 10×Met diet; the Met levels were much higher than Hcy and the others. In a series of behavioral tests, mice on the 10×Met diet displayed increased anxiety and decreased traveled distances in an open-field test, increased activity to escape from water soaking and tail hanging, and normal learning/memory activity in a Y-maze test, which were reflections of negative/positive symptoms and normal cognitive function, respectively. These results indicate that high-Met ad libitum feeding even for a week can induce bipolar disorder-like disease models in mice.

A 7 day inpatient diabetes education program improves quality of life and glycemic control 12 months after discharge.

AIMS: For long-term management of diabetes, patients with type 2 diabetes mellitus require a high level of treatment adherence, which is associated with treatment satisfaction and their quality of life (QOL). To achieve it, patient education about diabetes self-management is essential. We routinely conduct a 7 day inpatient diabetes education program and administer the diabetes treatment-related (DTR)-QOL questionnaire to all participants, both before admission and at discharge. Here, we investigated whether our program improves QOL and post-discharge glycemic control. MATERIALS AND METHODS: This retrospective study utilized data from patients with type 2 diabetes mellitus who participated in our program between July 2017 and March 2020 and who had been treated in our outpatient department for more than 1 year. We evaluated the relationship between at admission and at discharge diabetes treatment-related quality of life scores and glycemic control after discharge. RESULTS: Data from 140 patients were analyzed in this study, which showed a significant improvement in the total, 'Anxiety and dissatisfaction with treatment', and 'Satisfaction-with-treatment' scores. A significant improvement was evident in HbA1c at 12 months after discharge. Multiple regression analysis showed that HbA1c after 12 months was independently associated with gender, duration of diabetes, and HbA1c at admission. CONCLUSIONS: Our program effectively improves quality of life and post-discharge glycemic control in patients with type 2 diabetes mellitus. It is particularly effective in patients of the male gender, with a shorter duration of diabetes mellitus and higher HbA1c at admission.

Postprandial Plasma Glucagon Kinetics in Type 2 Diabetes Mellitus: Comparison of Immunoassay and Mass Spectrometry.

CONTEXT: Accurate glucagon level measurements are necessary for investigation of mechanisms for postprandial hyperglycemia in type 2 diabetes. OBJECTIVE: To evaluate the accuracy of postprandial glucagon level measurements using a sandwich ELISA vs a recently established liquid chromatography-high resolution mass spectrometry (LC-HRMS) method in type 2 diabetes mellitus. DESIGN AND PARTICIPANTS: Twenty patients with type 2 diabetes treated with insulin underwent a meal test before and after administration of the dipeptidyl peptidase-4 inhibitor anagliptin for 4 weeks. Blood samples were taken serially after the meal, and glucagon levels were measured using both ELISA and LC-HRMS. We compared the change from baseline to 4 weeks (Δ0-4W) using the area under the curve for plasma glucagon during the meal test [area under the curve (AUC)0-3h] measured using ELISA and LC-HRMS. RESULTS: ELISA-based glucagon AUC0-3h was higher than LC-HRMS-based AUC0-3h at baseline and 4 weeks. However, differences in Δ0-4W-AUC0-3h measured using ELISA and LC-HRMS were not statistically significant. Additionally, Δ0-4W-AUC0-3h measured using ELISA and LC-HRMS were strongly correlated (r = 0.87, P < 0.001). CONCLUSIONS: Plasma glucagon levels during a meal test in patients with type 2 diabetes measured using ELISA were consistently higher than those measured using LC-HRMS. However, given that the changes in glucagon levels measured using ELISA before and after dipeptidyl peptidase-4 inhibitor therapy were similar to those based on LC-HRMS, this ELISA seems to be useful for evaluating the effect of the drug interventions on postprandial glucagon levels.

2D DIGE proteomic analysis reveals fasting-induced protein remodeling through organ-specific transcription factor(s) in mice.

Overnight fasting is a routine procedure before surgery in clinical settings. Intermittent fasting is the most common diet/fitness trend implemented for weight loss and the treatment of lifestyle-related diseases. In either setting, the effects not directly related to parameters of interest, either beneficial or harmful, are often ignored. We previously demonstrated differential activation of cellular adaptive responses in 13 atrophied/nonatrophied organs of fasted mice by quantitative PCR analysis of gene expression. Here, we investigated 2-day fasting-induced protein remodeling in six major mouse organs (liver, kidney, thymus, spleen, brain, and testis) using two-dimensional difference gel electrophoresis (2D DIGE) proteomics as an alternative means to examine systemic adaptive responses. Quantitative analysis of protein expression followed by protein identification using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOFMS) revealed that the expression levels of 72, 26, and 14 proteins were significantly up- or downregulated in the highly atrophied liver, thymus, and spleen, respectively, and the expression levels of 32 proteins were up- or downregulated in the mildly atrophied kidney. Conversely, there were no significant protein expression changes in the nonatrophied organs, brain and testis. Upstream regulator analysis highlighted transcriptional regulation by peroxisome proliferator-activated receptor alpha (PPARα) in the liver and kidney and by tumor protein/suppressor p53 (TP53) in the thymus, spleen, and liver. These results imply of the existence of both common and distinct adaptive responses between major mouse organs, which involve transcriptional regulation of specific protein expression upon short-term fasting. Our data may be valuable in understanding systemic transcriptional regulation upon fasting in experimental animals.

Comparison of sitagliptin with nateglinide on postprandial glucose and related hormones in drug-naïve Japanese patients with type 2 diabetes mellitus: A pilot study.

AIMS/INTRODUCTION: Dipeptidyl peptidase-4 inhibitors and glinides are effective in reducing postprandial hyperglycemia. However, little information is available on the comparative effects of the two drugs on the levels of postprandial glucose. The aim of the present study was to compare the effects of sitagliptin and nateglinide on meal tolerance tests in drug-naïve patients with type 2 diabetes mellitus. MATERIALS AND METHODS: The study participants were 19 patients with type 2 diabetes mellitus, which was inadequately controlled by diet and exercise. An open-label, prospective, cross-over trial was carried out to compare the effects of single-dose sitagliptin and nateglinide on the postprandial glucose level and its related hormones during meal tests. RESULTS: The change in area under the curve (AUC) of glucose from 0 to 180 min (AUC0-180 min) during the meal test by nateglinide was similar to that by sitagliptin. As expected, the change in active glucagon like peptide-1 was significantly higher after a single-dose of sitagliptin than nateglinide. Then, insulin secretion relative to glucose elevation (ISG) (ΔISG0-180 min: ΔAUC0-180 min insulin/AUC0-180 min glucose) was significantly enhanced by nateglinide compared with sitagliptin. Conversely, glucagon level (ΔAUC0-180 min glucagon) was increased by administration of nateglinide, whereas the glucagon level was reduced by administration of sitagliptin. CONCLUSIONS: The effects of sitagliptin on postprandial glucose levels were similar to those of nateglinide in drug-naïve type 2 diabetes patients. However, the induced changes in insulin, active glucagon-like peptide-1 and glucagon during meal loading suggest that reduction of postprandial hyperglycemia was achieved by the unique effect of each drug.

Switching from Twice-Daily Basal Insulin Injections to Once-Daily Insulin Degludec Injection for Basal-Bolus Insulin Regimen in Japanese Patients with Type 1 Diabetes: A Pilot Study.

The aim of this study was to investigate the efficacy of insulin degludec used for basal-bolus insulin regimen after switching from twice-daily basal insulin in Japanese patients with type 1 diabetes mellitus. The subjects were 22 type 1 diabetes patients treated with basal-bolus insulin regimen with twice-daily basal insulin. Basal insulin was switched to once-daily injection of insulin degludec with 10% dose reduction. HbA1c and fasting plasma glucose (FPG) were measured before and 12 weeks after switching. The frequency of hypoglycemic episodes, standard deviation (SD) of blood glucose, and mean of daily difference (MODD) were evaluated by continuous glucose monitoring (CGM) before and 4 weeks after switching. HbA1c and FPG before and 12 weeks after switching were comparable (HbA1c 8.5 ± 1.4 versus 8.7 ± 1.6%, P = 0.28; FPG 203.2 ± 81.2 versus 206.5 ± 122.4 mg/dL, P = 0.91). The frequency of hypoglycemia during nighttime was not significantly different at 4 weeks after switching (14.4 ± 17.0 versus 11.1 ± 15.0%, P = 0.45). In addition, SD and MODD before and 4 weeks after switching were also comparable. In conclusion, glycemic control under once-daily insulin degludec injection was almost comparable to that under twice-daily basal insulin injections in Japanese type 1 diabetes patients. This study was registered with ID: UMIN000010474.