Mixed-Lineage Leukaemia Gene Regulates Glucose-Sensitive Gene Expression and Insulin Secretion in Pancreatic Beta Cells.

The escalating prevalence of diabetes mellitus underscores the need for a comprehensive understanding of pancreatic beta cell function. Interest in glucose effectiveness has prompted the exploration of novel regulatory factors. The myeloid/lymphoid or mixed-lineage leukaemia gene (MLL) is widely recognised for its role in leukemogenesis and nuclear regulatory mechanisms through its histone methyltransferase activity in active chromatin. However, its function within pancreatic endocrine tissues remains elusive. Herein, we unveil a novel role of MLL in glucose metabolism and insulin secretion. MLL knockdown in ßHC-9 pancreatic beta cells diminished insulin secretion in response to glucose loading, paralleled by the downregulation of the glucose-sensitive genes SLC2a1 and SLC2a2. Similar observations were made in MLL heterozygous knockout mice (MLL+/-), which exhibited impaired glucose tolerance and reduced insulin secretion without morphological anomalies in pancreatic endocrine cells. The reduction in insulin secretion was independent of changes in beta cell mass or insulin granule morphology, suggesting the regulatory role of MLL in glucose-sensitive gene expression. The current results suggest that MLL interacts with circadian-related complexes to modulate the expression of glucose transporter genes, thereby regulating glucose sensing and insulin secretion. Our findings shed light on insulin secretion control, providing potential avenues for therapeutics against diabetes.

Exploring potential correlations between HLA class II and the risk of microvascular complications in Japanese patients with type 1 diabetes.

Managing complications in Type 1 diabetes (T1D) remains challenging. HLA genes, particularly DR and DQ, are linked to T1D susceptibility. We studied 48 Japanese T1D inpatients and revealed associations between DRB1*04:05-DQB1*04:01 and DRB1*09:01-DQB1*03:03 haplotypes and complications, offering a new perspective for future research.

Calorie Restriction Using High-Fat/Low-Carbohydrate Diet Suppresses Liver Fat Accumulation and Pancreatic Beta-Cell Dedifferentiation in Obese Diabetic Mice.

In diabetes, pancreatic ß-cells gradually lose their ability to secrete insulin with disease progression. ß-cell dysfunction is a contributing factor to diabetes severity. Recently, islet cell heterogeneity, exemplified by ß-cell dedifferentiation and identified in diabetic animals, has attracted attention as an underlying molecular mechanism of ß-cell dysfunction. Previously, we reported ß-cell dedifferentiation suppression by calorie restriction, not by reducing hyperglycemia using hypoglycemic agents (including sodium-glucose cotransporter inhibitors), in an obese diabetic mice model (db/db). Here, to explore further mechanisms of the effects of food intake on ß-cell function, db/db mice were fed either a high-carbohydrate/low-fat diet (db-HC) or a low-carbohydrate/high-fat diet (db-HF) using similar calorie restriction regimens. After one month of intervention, body weight reduced, and glucose intolerance improved to a similar extent in the db-HC and db-HF groups. However, ß-cell dedifferentiation did not improve in the db-HC group, and ß-cell mass compensatory increase occurred in this group. More prominent fat accumulation occurred in the db-HC group livers. The expression levels of genes related to lipid metabolism, mainly regulated by peroxisome proliferator-activated receptor α and γ, differed significantly between groups. In conclusion, the fat/carbohydrate ratio in food during calorie restriction in obese mice affected both liver lipid metabolism and ß-cell dedifferentiation.

Influence of diet and body weight in treatment-resistant acquired partial lipodystrophy after hematopoietic stem cell transplantation and its potential for metabolic improvement.

Lipodystrophy is a rare disease characterized by various metabolic complications resulting from the complete or partial loss of adipose tissues and abnormal fat accumulation. Acquired lipodystrophy may occur due to certain drugs, autoimmunity or for unknown reasons. Recently, cases of acquired lipodystrophy after hematopoietic stem cell transplantation (HSCT) have been reported. Leptin administration, used recently to treat generalized lipodystrophy, effectively controlled metabolic complications; however, few reports demonstrated the effectiveness of leptin for acquired partial lipodystrophy. In this report, we present the case of a 17-year-old woman who developed insulin resistance, hypertriglyceridemia, and fatty liver after HSCT. Due to her thin gluteal fat and low blood adiponectin levels, her metabolic abnormalities were attributed to partial lipodystrophy. While both leptin and pemafibrate administration partially attenuated metabolic abnormalities, its effects were relatively limited, probably because the serum leptin levels were maintained, which is not likely in generalized lipodystrophy. Nevertheless, after she developed adjustment disorder and experienced weight loss, along with decreased food intake, her metabolic markers significantly improved. This case suggests the modest effect of leptin and permafibrate in partial lipodystrophy after HSCT, highlighting the importance of diet therapy in metreleptin treatment for acquired partial lipodystrophy.

Hot Water Eliminates the Bitter Taste of Oral Semaglutide: A Report of Four Cases.

Semaglutide is a well-designed drug with a special coating that allows for oral administration to patients with type 2 diabetes mellitus. However, patients taking oral semaglutide complain of its bitter taste. We therefore considered suggesting that patients take oral semaglutide with hot water. When the hot water temperature was increased to above 46.0°C but below 52.0°C, no bitter taste was perceived, with the daily mean interstitial glucose level remaining at the target range. Taking oral semaglutide with hot water helps reduce its bitter taste.

Total Pancreatectomy in a Patient Treated with a Sensor-augmented Pump Showing No Evidence of Hyperglycemia or Ketoacidosis without Any Insulin Administration.

Total pancreatectomy results in complete loss of insulin and glucagon. Sensor-augmented pumps (SAPs) allow fine-tuning of the basal insulin rate, which helps avoid both hypo- and hyperglycemic events. We herein report a case of total pancreatectomy treated with a SAP with no evidence of ketoacidosis without any insulin administration during a certain period of time. Furthermore, we observed a sudden drop in blood glucose levels without insulin, which may have been due to glucose effectiveness. Our case is valuable in arguing the concept of glucose effectiveness in the absence of insulin and glucagon.

Imeglimin Improved Plasma Glucose Levels in Patients With Latent Autoimmune Diabetes of Adults: Report of 2 Cases.

Imeglimin has not been well studied as an oral agent for the treatment of latent autoimmune diabetes of adults (LADA). We treated 2 cases of LADA with imeglimin. The case 1 patient was originally diagnosed with type 2 diabetes (T2D) at age 50 years and was treated with sulfonylurea, biguanide, canagliflozin, imeglimin, and dulaglutide. Before imeglimin, his glycated hemoglobin A1c (HbA1c) change was 94.0 mmol/mol (8.6%) in November 2022, but it dropped to 71.0 mmol/mol (6.5%) in May 2023 after imeglimin was added. The case 2 patient was originally diagnosed with T2D when she was aged 48 years. She was treated with vildagliptin, biguanide, luseogliflozin, and imeglimin. Her HbA1c before imeglimin was 92.9 mmol/mol (8.5%) in January 2023, which decreased to 75.4 mmol/mol (6.9%) in July 2023 after imeglimin was added. Although imeglimin has not been approved for treating type 1 diabetes and LADA, adding imeglimin to the current medication was effective in improving and controlling the patients' plasma glucose.

Role of Fyn and the interleukin-6-STAT-3-autophagy axis in sarcopenia.

Sarcopenia is the progressive loss of muscle mass wherein Fyn regulates STAT3 to decrease autophagy. To elucidate the role of inflammation in Fyn-STAT3-dependent autophagy and sarcopenia, here we aimed to investigate the underlying mechanisms using two mouse models of primary and secondary sarcopenia: (1) tail suspension and (2) sciatic denervation. In wild-type mice, the expression of Fyn and IL-6 increased significantly. The expression and phosphorylation levels of STAT3 were also significantly augmented, while autophagic activity was abolished. To investigate Fyn-dependency, we used tail suspension with Fyn-null mice. In tail-suspended wild-type mice, IL-6 expression was increased; however, it was abolished in Fyn-null mice, which maintained autophagy and the expression and ablation of STAT3 phosphorylation. In conclusion, Fyn was found to be associated with the IL-6-STAT3-autophagy axis in sarcopenia. This finding permits a better understanding of sarcopenia-associated metabolic diseases and the possible development of therapeutic interventions.

Assessment of factors associated with improved glycemic control after switching from intermittently scanned to real-time continuous glucose monitoring in Japanese patients with type 1 diabetes.

The advantages of real-time continuous glucose monitoring (rtCGM) over intermittently scanned CGM (isCGM) reportedly include lower glycated hemoglobin (HbA1c) levels as well as reduced glycemic variability. However, there have been few studies of the effect of switching from isCGM to rtCGM on glycemic control, as well as the specific factors underlying any observed improvements. To that end, all patients with type 1 diabetes mellitus who used the DEXCOM rtCGM device (Terumo Corporation, Tokyo, Japan) at our institution were reviewed, and 16 individuals with type 1 diabetes who switched from isCGM to rtCGM were investigated. The patients' HbA1c decreased in 75% of the cases (p = 0.02). On the other hand, GMI increased in 75% of the cases (p = 0.01). Intriguingly, the percentage of time below range and coefficient of variation were significantly improved with rtCGM compared to isCGM (2.9% vs. 7.6%, p = 0.016 and 35% vs. 40%, p = 0.0019, respectively). We also found that the discrepancy between HbA1c and GMI among users of isCGM was a key indicator that improved when switching to rtCGM. If discrepancies are observed between HbA1c and GMI when using isCGM, switching to rtCGM should be considered for improving glycemic control.

Effect of dipeptidyl peptidase-4 inhibitors on glycated hemoglobin levels relies on dietary sodium intake.

AIMS: Sodium load increases endogenous glucagon-like peptide-1 (GLP-1) levels in humans. Therefore, patients with an increased amount of dietary sodium intake are supposed to have higher endogenous GLP-1 levels compared to those with less dietary sodium intake. Therefore, it can be hypothesized that patients with type 2 diabetes mellitus (T2DM) with more dietary sodium intake show better dipeptidyl peptidase-4 inhibitor (DPP-4i) effect on glycemic control because of the expected higher GLP-1 level. Thus, we performed a single-center cohort study to explore this idea. METHODS: Medical records of patients with T2DM prescribed DPP-4i in the last 11 years were investigated. Dietary sodium intake was measured before the DPP-4i prescription with Tanaka's formula using casual spot urine samples. The effect of DPP-4i on glycemic control was estimated by the subtraction of glycated hemoglobin (HbA1c) before DPP-4i initiation from HbA1c 1 year after DPP-4i administration. We analyzed 50 patients. RESULTS: DPP-4i improved HbA1c by -0.41% ± 0.66%. The effect of DPP-4i on glycemic control was significantly negatively correlated with the dietary sodium intake (r = -0.400). Thus, the more dietary sodium intake, the better the glycemic control by DPP-4i. CONCLUSIONS: Thus, patients can expect better plasma glucose control by DPP-4is if patients are taking increased dietary sodium intake.

Fyn Phosphorylates Transglutaminase 2 (Tgm2) and Modulates Autophagy and p53 Expression in the Development of Diabetic Kidney Disease.

Autophagy is involved in the development of diabetic kidney disease (DKD), the leading cause of end-stage renal disease. The Fyn tyrosine kinase (Fyn) suppresses autophagy in the muscle. However, its role in kidney autophagic processes is unclear. Here, we examined the role of Fyn kinase in autophagy in proximal renal tubules both in vivo and in vitro. Phospho-proteomic analysis revealed that transglutaminase 2 (Tgm2), a protein involved in the degradation of p53 in the autophagosome, is phosphorylated on tyrosine 369 (Y369) by Fyn. Interestingly, we found that Fyn-dependent phosphorylation of Tgm2 regulates autophagy in proximal renal tubules in vitro, and that p53 expression is decreased upon autophagy in Tgm2-knockdown proximal renal tubule cell models. Using streptozocin (STZ)-induced hyperglycemic mice, we confirmed that Fyn regulated autophagy and mediated p53 expression via Tgm2. Taken together, these data provide a molecular basis for the role of the Fyn-Tgm2-p53 axis in the development of DKD.

The Impact of Age- and Sex-Specific Reference Ranges for Serum Thyrotropin and Free Thyroxine on the Diagnosis of Subclinical Thyroid Dysfunction: A Multicenter Study from Japan.

Background: Reference ranges for serum thyrotropin (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) established without considering age- and sex-based differences are currently used to evaluate thyroid function. Therefore, we investigated age- and sex-based differences in serum TSH and thyroid hormone levels in euthyroid individuals. Methods: We performed cross-sectional analyses of retrospective data collected from two Japanese institutions. We estimated sex-specific 95% reference ranges for TSH and fT4 according to age strata. Results: We included data from 14,860 participants undergoing screening with a Siemens thyroid testing kit and 8,132 participants undergoing screening with an Abbott kit during annual health check-ups at Takasaki Hidaka Hospital. In addition, 515 participants visiting a specialized thyroid-focused hospital were evaluated using Tosoh kits. The median TSH level of women in their 30s was 1.5 mIU/L (2.5th percentile, 0.5; 97.5th percentile, 4.6) using the Siemens kit, while that of women in their 60s was 1.9 (0.7-7.8) mIU/L. The corresponding levels were lower in men; the age-associated increase was small. The median serum fT4 level of men in their 30s was 1.3 (1.0-1.7) ng/dL and that of men in their 60s was 1.2 (1.0-1.6) ng/dL. These levels gradually but significantly decreased with age. fT4 levels in women were lower than those in men and remained consistent with age. Serum fT3 levels were significantly higher in men than in women and gradually but significantly decreased with age. The Abbott and Tosoh kits showed similar results. When using the Siemens kit, ∼60% (216/358) of women diagnosed with subclinical hypothyroidism using manufacturer-recommended reference ranges had normal results when age- and sex-specific reference ranges were applied, demonstrating the high percentage of overdiagnosis, especially in those aged ≥60 years. Conversely, some middle-aged individuals with normal thyroid function were reassessed and classified as having subclinical hyperthyroidism by age- and sex-specific reference ranges. Conclusions: Age- and sex-specific reference ranges should be used to avoid over- and underdiagnosis of subclinical thyroid dysfunction and appropriate therapies.

The ratio of free triiodothyronine to free thyroxine is regulated differently in patients with type 2 diabetes mellitus treated and not treated with sodium glucose cotransporter 2 inhibitors.

BACKGROUND AND AIMS: Triiodothyronine reduces sodium glucose cotransporter 2 expression in the kidney and increased glucose excretion in urine of alloxan-induced diabetic rats. Free thyroxine is also negatively associated with islet beta-cell function in euthyroid subjects. However, the influence of sodium glucose cotransporter 2 inhibitor on thyroid function in patients with type 2 diabetes mellitus has not been established. METHODS: We investigated thyroid function in patients with type 2 diabetes mellitus in the presence or absence of sodium glucose cotransporter 2 inhibitor in a multicenter retrospective study conducted between 2019 and 2021. All participants visited the hospital monthly for type 2 diabetes mellitus treatment and plasma glucose and glycated hemoglobin level measurements. Furthermore, thyroid-stimulating hormone, free triiodothyronine, and free thyroxine levels were measured annually. RESULTS: Free triiodothyronine level and the free triiodothyronine:free thyroxine ratio in the group treated with sodium glucose cotransporter 2 inhibitor were significantly higher than the levels in the group not treated with sodium glucose cotransporter 2 inhibitor. Free triiodothyronine levels in the group treated with sodium glucose cotransporter 2 inhibitor were significantly higher than the levels in the group not treated with sodium glucose cotransporter 2 inhibitor (p = 0.040). Free thyroxine levels in the group treated with sodium glucose cotransporter 2 inhibitor were significantly lower than the levels in the group not treated with sodium glucose cotransporter 2 inhibitor (p = 0.002). Thyroid-stimulating hormone levels did not differ significantly between the two groups. CONCLUSIONS: Our findings show that sodium glucose cotransporter 2 inhibitor affects free triiodothyronine levels free thyroxine levels, and the free triiodothyronine:free thyroxine ratio.

A case of insulinoma-induced hypoglycemia managed by Dexcom G4 Platinum.

This report details the case of a 41-year-old woman who was diagnosed with insulinoma. As the patient developed severe life-threatening hypoglycemia, we introduced Dexcom G4 Platinum (DG4P), a modern continuous glucose-monitoring system (CGM). The algorithm of the sensor glucose (SG) values of CGM is based on patients with diabThis report details the case of a 41-year-old woman who was diagnosed with insulinoma. As the patient developed severe life-threatening hypoglycemia, we introduced Dexcom G4 Platinum (DG4P), a modern continuous glucose-monitoring system (CGM). The algorithm of the sensor glucose (SG) values of CGM is based on patients with diabetes; therefore, we evaluated the accuracy of DG4P in this patient. The mean absolute relative differences and absolute differences between SG of DG4P and self-monitoring of blood sugar values were 10.8%±8.3% and 6.8±5.7 mg/dL, respectively, in the hypoglycemic region, which verifies DG4P's accuracy. DG4P was found to be useful for monitoring hypoglycemia not only in patients with diabetes but also in those with insulinoma.etes; therefore, we evaluated the accuracy of DG4P in this patient. The mean absolute relative differences and absolute differences between SG of DG4P and self-monitoring of blood sugar values were 10.8%±8.3% and 6.8±5.7 mg/dL, respectively, in the hypoglycemic region, which verifies DG4P's accuracy. DG4P was found to be useful for monitoring hypoglycemia not only in patients with diabetes but also in those with insulinoma.

FAM83G-based Peptide Induces Apoptosis on Cultured Liver Cancer Cell.

BACKGROUND: Previously, AF-956, which contains S356 of FAM83G and an N-terminal antenna peptide for entry into colon cancer cells, is markedly antiproliferative compared to a control peptide (AF-859), which lacks the N-terminal antenna peptide, by inducing apoptosis via the inhibition of HSP27 phosphorylation at residues S15 and S82. OBJECTIVE: Because FAM83G-derived peptides are promising lead compounds for colon cancer treatment, we reanalyzed the effect of AG-066, which contains S356 of FAM83G and an N-terminal antenna peptide for entry into the liver cancer cells. METHODS: HepG2 liver cancer cells were incubated with either AF-859 or AG-066 at a concentration of 54 µM at 37 °C for 24, 48, and 72 h. The effects of AF-859 and AG-066 on the cultured HepG2 cells were estimated using an inverted light microscope. Furthermore, the DNA ladder method and the dead cell assay were performed by applying Live/Dead Cell Staining Kit II. Erk phosphorylation was estimated by western blotting. RESULTS: Treatment with AG-066 markedly reduced HepG2 viable cell counts compared to the AF- 859-treated HepG2 cells, as evident from the significantly increased number of dead cells in the culture medium. Additionally, AG-066 treatment increased cellular DNA laddering. We found no difference in Erk phosphorylation status between the AG-066- and AF-859-treated groups. CONCLUSION: This study illustrated that the peptide with a structure based on FAM83G functions as a spontaneous apoptosis inducer for liver cancer cells. Hence, it is a promising lead compound for the treatment of liver cancer.

Maternal hypothyroidism is associated with M-opsin developmental delay.

Thyroid hormones are critical for the development of opsins involved in color vision. Hypothyroid mice show delayed M-opsin development and expanded distribution of S-opsin on the retina. However, the effects of maternal hypothyroidism on opsin development remain unknown. This study investigates the effects of congenital central hypothyroidism and maternal hypothyroidism on opsin development in thyrotropin-releasing hormone knockout (TRH-/-) mice. We examined the mRNA expression and protein distribution of S/M-opsin on postnatal days (P)12 and 17, as well as mRNA expression of type 2 and 3 iodothyronine deiodinase (DIO2 and DIO3, respectively) in the retina and type 1 iodothyronine deiodinase (DIO1) in the liver at P12 in TRH+/- mice born to TRH+/- or TRH-/- dams, and conducted S/M-opsin analysis in TRH+/+ or TRH-/- mice born to TRH+/- dams at P12, P17, and P30. M-opsin expression was lower in TRH+/- mice born to TRH-/- dams than in those born to TRH+/- dams, whereas S-opsin expression did not significantly differ between them. DIO1, DIO2, and DIO3 mRNA expression levels were not significantly different between the two groups; therefore, thyroid function in peripheral tissues in the pups was similar. S/M-opsin expression did not significantly differ between the TRH+/+ and TRH-/- mice born to TRH+/- dams on any postnatal day. These results demonstrate that maternal hypothyroidism causes M-opsin developmental delay during the early developmental stages of neonatal mice, and TRH-/- mice, a model of congenital central hypothyroidism, born to a euthyroid dam do not have delayed opsin development.

Casual C peptide index: Predicting the subsequent need for insulin therapy in outpatients with type 2 diabetes under primary care.

BACKGROUND: Evaluation of residual beta cell function is indispensable in patients with type 2 diabetes as it informs not only diagnoses but also appropriate treatment modalities. However, there is a lack of convenient biomarkers for residual beta cell function. Therefore, we evaluated endogenous insulin level as a biomarker in outpatients who were being treated with insulin therapy and in patients who were introduced to insulin therapy after 4 years. METHODS: Data of 174 outpatients with type 2 diabetes (50% male) whose glycemia was moderately controlled (glycated A1c 7.3% [5.2%-14.8%]) were reviewed. Twenty patients whose estimated glomerular filtration rate was lower than 30 ml/min/1.73 m2 were excluded from the evaluation of endogenous insulin level with both casual C-peptide index (C-CPI) and urinary C-peptide/creatinine ratio (determined at any time, generally 1-2 h after breakfast). Patients were stratified based on the provision of insulin therapy. RESULTS: C-CPI and UCPCR were significantly lower in the insulin-treated patients than in the insulin-untreated patients (0.9 vs. 2.2, p < 0.0001; 24.7 vs. 75.5, p = 0.0003, respectively). Moreover, C-CPI were significantly lower in the insulin-requiring patients for 4 years than in the insulin-unrequiring patients (1.0 vs. 1.7, p = 0.0184). The multivariate logistic regression analysis revealed that both indicators of insulin secretion influenced the requirement for insulin therapy, but C-CPI could serve as the most convenient and useful biomarker for not only current insulin therapy requirements (p = 0.0002) but also the subsequent requirement for insulin therapy (p = 0.0008). CONCLUSIONS: C-CPI could be determined easily, and it was found to be a more practical marker for outpatients; therefore, our findings would have critical implications for primary care.

Superior Mesenteric Artery Syndrome Accompanied by Acute-onset Type 1 Diabetes Complicated with Graves' Disease.

A 35-year-old man experienced general fatigue and could not eat solid food because of nausea and vomiting. His weight abruptly decreased from 49 to 45 kg after 2 weeks. A detailed examination indicated superior mesenteric artery syndrome (SMAS) accompanied by acute-onset type 1 diabetes complicated by Graves' disease, referred to as autoimmune polyglandular syndrome type 3A (APS3A). Although SMAS has a good prognosis, some cases require emergency surgery, especially when complicated by gastric perforation. In our case, APS3A and SMAS developed rapidly and at approximately the same time, resulting in a cycle of mutual exacerbation.