Characteristics of Human Leukocyte Antigen Class II Genes in Japanese Patients with Type 1 Diabetes and Autoimmune Thyroid Disease.

Genetic factors, particularly human leukocyte antigen (HLA) class II genes, are known to significantly influence the onset of type 1 diabetes (T1D). Additionally, patients with T1D often develop autoimmune thyroid diseases (AITD). Despite this association, comprehensive research on individuals with both AITD and T1D in Japan, especially regarding the influence of specific HLA alleles, remains insufficient. In this retrospective study, we analyzed 44 inpatients diagnosed with T1D. These patients were predominantly female, with an average onset age of 35 years, poor blood sugar control, and approximately 43.2% had concurrent AITD. We observed significant associations of HLA-DRB1*04:05, HLA-DRB1*09:01 and HLA-DRB1*15:02 alleles with T1D regardless of AITD presence, which had been previously established for T1D in Japanese. In this context, comparing Japanese patients with AITD alone, we noted AITD comorbidity with T1D results in alterations in the frequencies of HLA-DRB1*09:01, HLA-DRB1*04:03, and HLA-DRB1*15:02. Furthermore, HLA-DRB1*04:05, HLA-DRB1*09:01, HLA-DRB1*13:02, and HLA-DRB1*15:01 alleles may be alleles whose susceptibility varies for both conditions. These findings underscore the importance of understanding the relationship between T1D, AITD, and HLA genetics, which may inform personalized treatment strategies and facilitate the development of targeted therapies. Future research endeavors should aim to elucidate underlying mechanisms and validate these findings in larger cohorts.

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.

The molecular biology of thyrotroph pituitary neuroendocrine tumors.

Pituitary neuroendocrine tumors (PitNETs), which were formerly known as pituitary adenomas, are classified in 5th Edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. Since thyrotroph PitNETs are rare PitNETs, most previous studies about former thyroid stimulating hormone (TSH)-secreting pituitary adenoma have focused on a small number of cases. However, the diagnostic rate of thyrotroph PitNET has increased because of increased sensitivity of serum TSH measurement and widespread recognition that thyrotroph PitNETs are the cause of syndrome of inappropriate secretion of TSH (SITSH). Therefore, knowledge on the molecular mechanism of thyrotroph PitNET is gradually accumulating. Recently, comprehensive chromosomal, genetic, and epigenomic alterations in thyrotroph PitNET have been revealed with the availability of comprehensive gene and protein analyses, and the nature of thyrotroph PitNET is gradually being elucidated. However, further analysis is needed to determine whether the causes of these changes are directly responsible for the development of tumors.

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.

SFPQ associated with a co-activator for PPARγ, HELZ2, regulates key nuclear factors for adipocyte differentiation.

We recently isolated a novel co-activator of peroxisome proliferator-activated receptor γ, helicase with zinc finger 2 (HELZ2). HELZ2 null mice were resistant to diet-induced obesity and NAFFL/NASH, and HELZ2 was phosphorylated at tyrosine residues. In order to find a factor related to HELZ2, we analyzed products co-immunoprecipitated with phosphorylated HELZ2 by mass spectrometry analyses. We identified proline- and glutamine-rich (SFPQ) as a protein associating with tyrosine-phosphorylated HELZ2. The knockdown of SFPQ in 3T3-L1 cells downregulated mRNA levels of transcription factors including Krox20, Cebpß, and Cebpδ: key factors for early-stage adipocyte differentiation. In addition, knockdown of SFPQ inhibited 3T3-L1 cell differentiation to mature adipocytes. These findings demonstrated that SFPQ associating with HELZ2 is an important novel transcriptional regulator of adipocyte differentiation.

Angiotensin receptor blockers significantly reduce hemoglobin level in patients with type 2 diabetes mellitus not suffered chronic cardiac failure and chronic kidney disease.

Anemia due to angiotensin receptor blocker (ARB) therapy has been previously reported in patients with diabetes mellitus with glomerular filtration rates of <60 mL min-1/1.73 m2. However, whether Japanese patients with type 2 diabetes mellitus (T2DM) receiving ARB therapy for chronic cardiac failure and chronic kidney disease develop reduced hemoglobin (Hb) levels has not been elucidated. Thus, this cross-sectional study was conducted, and Hb levels were compared between patients with T2DM with and without ARB administration. No significant difference in the prescribed proportion of antidiabetic medicines such as biguanide, sodium glucose co-transporter 2 inhibitors, and α-glucosidase inhibitors was found between the group treated with ARBs and the group without ARBs. Thus, we considered that the effects of antidiabetic medicines on the results were minimum. In this study, the Hb levels of patients who received ARBs (13.8 ± 1.7 g/dL) were significantly lower than those of patients without ARBs (14.9 ± 1.35 g/dL) (p = 0.034). The difference between this study and a previous study relies on eGFR levels. Thus, the eGFR levels of the patients in this study and the previous study were above 60 and below 60 mL min-1/1.73 m2, respectively. Despite those differences, both studies showed that the use of ARBs was associated with a decrease in Hb levels in patients with T2DM. Thus, the evaluation of glycated Hb levels should be focused on whether ARBs are prescribed for patients with T2DM.

In patients with type 2 diabetes the presence of Hashimoto's thyroiditis reduces the beneficial effect of dipeptidyl peptidase-4 inhibitor on plasma glucose control.

In this study, we compared the efficacy of a dipeptidyl peptidase-4 inhibitor (DPP4i) to improve glucose control in patients with type 2 diabetes mellitus (T2DM) with or without Hashimoto's thyroiditis (HT). First, we compared the change in glycated hemoglobin (HbA1c) between the hypothyroid condition (before levothyroxine sodium hydrate [LT4] treatment) and euthyroid condition (after LT4 treatment when patients had achieved euthyroidism for at least six months) in patients with T2DM and HT. Next, we compared the change in HbA1c levels before and six months of DPP4i treatment in patients with T2DM with and without HT. In hypothyroid condition the change in HbA1c after six months of DPP4i treatment was 0.13% ± 0.86%. The change in HbA1c levels from when patients first achieved euthyroidism to after six months in the euthyroid condition was 0.26% ± 0.90%. DPP4i efficacy in patients with T2DM and HT was reduced compared to patients with T2DM but without HT (-0.40 ± 0.90 vs. -0.99 ± 0.5, p = 0.0032). These data suggest that hypothyroidism does not impact on DPP4i efficacy. However, the effect of DPP4i in patients with T2DM and HT was reduced compared to that in T2DM patients without HT. An estimation of thyroid function before prescribing DPP4i may be useful tool for predicting the efficacy of DPP4i, allowing the ruling out complications from HT.

Position paper from the Japan Thyroid Association task force on the management of low-risk papillary thyroid microcarcinoma (T1aN0M0) in adults.

The incidence of thyroid carcinoma has been increasing worldwide. This is interpreted as an increase in the incidental detection of papillary thyroid microcarcinomas (PTMCs). However, mortality has not changed, suggesting overdiagnosis and overtreatment. Prospective clinical trials of active surveillance for low-risk PTMC (T1aN0M0) have been conducted in two Japanese institutions since the 1990s. Based on the favorable outcomes of these trials, active surveillance has been gradually adopted worldwide. A task force on the management of PTMC in adults organized by the Japan Thyroid Association therefore conducted a systematic review and has produced the present position paper based on the scientific evidence concerning active surveillance. This paper indicates evidence for the increased incidence of PTMC, favorable surgical outcomes for low-risk PTMC, recommended criteria for diagnosis using fine needle aspiration cytology, and evaluation of lymph node metastasis (LNM), extrathyroidal extension (ETE) and distant metastasis. Active surveillance has also been reported with a low incidence of disease progression and no subsequent recurrence or adverse events on survival if conversion surgery was performed at a slightly advanced stage. Active surveillance is a safe and valid strategy for PTMC, because it might preserve physical quality of life and reduce 10-year medical costs. However, some points should be noted when performing active surveillance. Immediate surgery is needed for PTMC showing high-risk features, such as clinical LNM, ETE or distant metastasis. Active surveillance should be performed under an appropriate medical team and should be continued for life.

The Optimal "Time in Range" and "Time below Range" are Difficult to Coordinate in Patients with Type 1 Diabetes.

Achieving the optimal glucose level time in range (TIR), as recently proposed by the "International Consensus on Time in Range," is challenging. We retrospectively analyzed data from 192 patients, including 58 with type 1 diabetes, using the FreeStyle Libre Pro system. This device was used by physicians for continuous glucose monitoring (CGM) and for making therapeutic decisions based on unbiased data, as the patients were blinded to their blood glucose levels during monitoring. The desired 70% TIR among patients with type 2 diabetes corresponded to an HbA1c of 7.7%. Importantly, however, a 70% TIR for patients with type 1 diabetes corresponded to an HbA1c of 6.9%, which diverged markedly from the HbA1c of 7.9% that corresponded to the desired 4% time below range (TBR). Moreover, these dissociations were observed more in patients with type 1 diabetes with a higher % coefficient of variation (> 36%). Hence, while the TIR is strongly correlated with HbA1c, it is difficult to coordinate with the TBR in Japanese patients with type 1 diabetes. As these metrics (which are critical indicators in clinical practice) are rapidly gaining popularity globally, including in Japan, our data strongly support the cautious use of new CGM metrics such as TIR and TBR/time above range, and emphasize the importance of individualized treatment in achieving the optimal TIR and TBR, especially in patients with type 1 diabetes.

Assessment of factors that determine the mean absolute relative difference in flash glucose monitoring with reference to plasma glucose levels in Japanese subjects without diabetes.

The Abbott FreeStyle Libre flash glucose monitoring system (FGM) is a recently introduced, but widespread continuous glucose monitoring system. While its mean absolute relative difference (MARD) value indicating its accuracy is acceptable with reference to the self-monitoring of blood glucose (SMBG) levels, few reports have examined the MARD in sensor glucose values of FGM (FGM-SG) with reference to plasma glucose (PG) levels and the factors determining it. We performed oral glucose tolerance tests (OGTTs) in 25 Japanese subjects without diabetes. Parkes error grid analyses showed that FGM-SG with either SMBG or PG levels as a reference met International Organization for Standardization criteria. The MARD in FGM-SG with reference to SMBG levels was 10.9 ± 4.1% during OGTTs. Surprisingly, the MARD in FGM-SG with reference to PG levels was 20.3 ± 10.3% during OGTTs, revealing a discrepancy in the accuracy of FGM-SG compared with that of PG levels; moreover, the MARD showed negative correlations with fasting blood sugar level, homeostasis model assessment insulin resistance index, and body mass index (BMI). Multiple regression analyses revealed that BMI contributed the most to the MARD when FGM-SG and PG level were compared, as lean individuals have a greater MARD regardless of glucose levels. Inaccurate FGM data could potentially increase the risk of inappropriate treatment; consideration of such factors is critical to ensure reliable FGM values.

Usage of continuous glucose monitoring (CGM) for detecting an unrecognized hypoglycemia and management of glucocorticoid replacement therapy in adult patients with central hypoadrenalism.

Patients with adrenal insufficiency require appropriate glucocorticoid replacement therapy; however, reliable biological parameters for optimizing glucocorticoid supplementation are limited. The physician has to rely primarily on clinical judgment, carefully taking into account signs and symptoms potentially suggestive of over- or under-replacement. We have found that some patients who are viewed as receiving sufficient doses of glucocorticoids occasionally exhibit morning headache or morning discomfort, which may be caused by unrecognized nocturnal hypoglycemia. Our aim in this study was to evaluate the usefulness of continuous glucose monitoring (CGM) for detecting unrecognized hypoglycemia and optimizing glucocorticoid replacement therapy in adult patients with central hypoadrenalism. Six patients with central hypoadrenalism of various etiologies were included in this study. All patients exhibited occasional morning headache or discomfort. We performed CGM to measure plasma glucose levels in all patients, and CGM identified unrecognized hypoglycemia episodes at midnight and early in the morning in five patients (83%). The CGM findings were used to fine-tune the dosing and regimens of glucocorticoid replacement and to re-evaluate glucose levels to avoid further unrecognized hypoglycemic events. This optimization of hydrocortisone supplementation prevented additional nocturnal hypoglycemia incidences in all cases. The addition of L-thyroxine with hydrocortisone continued to provide favorable glycemic control. Occasional symptoms also improved after maintenance in all patients. These findings demonstrated that CGM may represent a powerful tool for identifying unrecognized hypoglycemia and for optimizing supplementary hormones in patients with central hypoadrenalism, thereby improving their quality of life.

Transducin ß-like 1, X-linked and nuclear receptor co-repressor cooperatively augment the ligand-independent stimulation of TRH and TSHß gene promoters by thyroid hormone receptors.

Mutations in TBL1X, a component of the nuclear receptor co-repressor (N-CoR) and silencing mediator of retinoic acid and thyroid hormone receptor co-repressor complexes, have recently been implicated in isolated central hypothyroidism (CeH). However, the mechanisms by which TBL1X mutations affect negative feedback regulation in the hypothalamus-pituitary-thyroid axis remain unclear. N-CoR was previously reported to paradoxically enhance the ligand-independent stimulation of TRH and TSHß gene promoters by thyroid hormone receptors (TR) in cell culture systems. We herein investigated whether TBL1X affects the unliganded TR-mediated stimulation of the promoter activities of genes negatively regulated by T3 in cooperation with N-CoR. In a hypothalamic neuronal cell line, the unliganded TR-mediated stimulation of the TRH gene promoter was significantly enhanced by co-transfected TBL1X, and the co-transfection of TBL1X with N-CoR further enhanced promoter activity. In contrast, the knockdown of endogenous Tbl1x using short interfering RNA significantly attenuated the N-CoR-mediated enhancement of promoter activity in the presence of unliganded TR. The co-transfection of N365Y or Y458C, TBL1X mutants identified in CeH patients, showed impaired co-activation with N-CoR for the ligand-independent stimulation of the TRH promoter by TR. In the absence of T3, similar or impaired enhancement of the TSHß gene promoter by the wild type or TBL1X mutants, respectively, was observed in the presence of co-transfected TR and N-CoR in CV-1 cells. These results suggest that TBL1X is needed for the full activation of TRH and TSHß gene promoters by unliganded TR. Mutations in TBL1X may cause CeH due to the impaired up-regulation of TRH and/or TSHß gene transcription despite low T3 levels.

Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations.

Somatic mutations in KCNJ5 gene have been identified in patients with adrenal aldosterone-producing adenomas (APAs). We previously reported that Japanese patients with APAs had distinct characteristics from patients in Western countries; i.e. they had a high frequency of KCNJ5 mutations and exhibited a frequent association with cortisol co-secretion. Therefore, APAs among Japanese patients may have different features from those in Western countries. We added recent cases, examined 47 cases (43% male) of APAs, including clinicopathological features, KCNJ5 mutations, and the mRNA levels of several steroidogenic enzymes, and compared the results obtained to those reported in other countries. While the prevalence of KCNJ5 mutations is approximately 40% in Western countries, 37 APA cases (78.7%) showed mutations: 26 with p.G151R and 11 with p.L168R. Although a significant gender difference has been reported in the frequency of KCNJ5 mutations in Europe, we did not find any gender difference. However, the phenotypes of Japanese patients with mutations were similar to those of patients in Western countries; patients were younger and had higher plasma aldosterone levels, lower potassium levels, and higher diastolic blood pressure. Reflecting these phenotypes, APAs with mutations had higher CYP11B2 mRNA levels. However, in contrast to APAs in Western countries, Japanese APAs with mutations showed lower CYP11B1, CYP17A1, and CYP11A1 mRNA levels. These findings demonstrated that Japanese APA patients may have distinct features including a higher prevalence of KCNJ5 mutations, no gender difference in the frequency of these mutations, and characteristics similar to the zona glomerulosa.

Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma.

The anti-programmed cell death-1 monoclonal antibody (mab), nivolumab has recently been approved for the treatment of unresectable or metastatic malignant melanoma and non-small-cell lung cancers in Japan. Ipilimumab, an anti-cytotoxic T lymphocyte antigen-4 mab for malignant melanoma that was approved earlier than nivolumab in Western countries, is known to frequently cause endocrine immune-related adverse events such as hypophysitis and thyroid dysfunction. We herein report a patient with advanced melanoma who appeared to develop hypophysitis as a consequence of the inhibition of PD-1 by nivolumab. One week after the 6th administration of nivolumab, the patient developed progressive fatigue and appetite loss. Laboratory data on admission for the 7th administration of nivolumab showed eosinophilia and hyponatremia. Since ACTH and cortisol levels were low, nivolumab was discontinued and a large dose of hydrocortisone (100 mg/d) was promptly administered intravenously. A magnetic resonance imaging scan revealed the mild enlargement of the anterior pituitary gland and thickening of the stalk with homogenous contrast. A detailed assessment of anterior pituitary functions with hypothalamic hormone challenges showed that hormonal secretions other than ACTH and TSH were normal. With a replacement dose of hydrocortisone (20 mg/d), the 7th administration of nivolumab was completed without exacerbating the patient's general condition. The present report provides the first detailed endocrinological presentation of nivolumab-induced hypophysitis showing the enlargement of the pituitary gland and stalk in a malignant melanoma patient in Japan. Oncologists and endocrinologists need to be familiar with potentially life-threatening hypophysitis induced by immune-checkpoint inhibitors.

GNAS mutations in adrenal aldosterone-producing adenomas.

Mutations in GNAS, which encodes Gsα, have been documented in detail, particularly in human pituitary GH-secreting adenomas. Mutations have also recently been reported in adrenal cortisol-producing adenomas (CPAs), in addition to those in the PRKACA gene. However, mutations have not yet been examined in aldosterone-producing adenomas (APAs). Therefore, we herein investigated mutations in the GNAS gene in APAs. Two of the 15 (13%) CPAs with overt Cushing's syndrome and one of the 9 (11%) CPAs with subclinical Cushing's syndrome examined had the somatic mutations, p.R201S and p.R201C in the GNAS gene. We identified mutations in the GNAS gene (p.R201C) in 2 out of the 33 (6%) APAs tested, both of which showed autonomous cortisol secretion, while 24 APAs had mutations in the KCNJ5 gene (18 with p.G151R and 6 with p.L168R). These GNAS and KCNJ5 mutations were mutually exclusive in these adenomas. We herein demonstrated for the first time the presence of GNAS mutations in APAs, as well as in some cortisol-secreting adenomas. Our results suggest that these mutations, in addition to mutations in the KCNJ5 gene and other genes such as ATP1A1, ATP2B3 and CACNA1D, may be responsible for the tumorigenesis of APAs and CPAs with subclinical Cushing's syndrome.

Coordinated regulation of transcription and alternative splicing by the thyroid hormone receptor and its associating coregulators.

Emerging evidence has indicated that the transcription and processing of precursor mRNA (pre-mRNA) are functionally coupled to modulate gene expression. In collaboration with coregulators, several steroid hormone receptors have previously been shown to directly affect alternative pre-mRNA splicing coupled to hormone-induced gene transcription; however, the roles of the thyroid hormone receptor (TR) and its coregulators in alternative splicing coordinated with transcription remain unknown. In the present study, we constructed a luciferase reporter and CD44 alternative splicing (AS) minigene driven by a minimal promoter carrying 2 copies of the palindromic thyroid hormone-response element. We then examined whether TR could modulate pre-mRNA processing coupled to triiodothyronine (T3)-induced gene transcription using luciferase reporter and splicing minigene assays in HeLa cells. In the presence of cotransfected TRß1, T3 increased luciferase activities along with the inclusion of the CD44 variable exons 4 and 5 in a dose- and time-dependent manner. In contrast, cotransfected TRß1 did not affect the exon-inclusion of the CD44 minigene driven by the cytomegalovirus promoter. T3-induced two-exon inclusion was significantly increased by the cotransfection of the TR-associated protein, 150-kDa, a subunit of the TRAP/Mediator complex that has recently been shown to function as a splicing factor. In contrast, T3-induced two-exon inclusion was significantly decreased by cotransfection of the polypyrimidine tract-binding protein-associated splicing factor, which was previously shown to function as a corepressor of TR. These results demonstrated that liganded TR in cooperation with its associating cofactors could modulate alternative pre-mRNA splicing coupled to gene transcription.

Somatic mutations of the catalytic subunit of cyclic AMP-dependent protein kinase (PRKACA) gene in Japanese patients with several adrenal adenomas secreting cortisol [Rapid Communication].

Somatic mutations of the catalytic subunit of the cyclic AMP-dependent protein kinase (PRKACA) gene have recently been identified in about 35% of cortisol-producing adenomas (CPAs), with the affected patients showing overt Cushing's syndrome. Since we recently reported higher prevalence of mutations of the KCNJ5 gene and associations with autonomous cortisol secretion in Japanese aldosterone-producing adenomas than in Western countries, there might be different features of CPAs between Japan and the West. We therefore investigated mutations of the PRKACA gene in Japanese patients with several adrenal tumors secreting cortisol, including overt Cushing's syndrome, subclinical Cushing's syndrome, and aldosterone-producing adenomas (APAs) co-secreting cortisol operated on at Gunma University Hospital. Of the 13 patients with CPA who showed overt Cushing's syndrome, 3 (23%) had recurrent somatic mutations of the PRKACA gene, p.L206R (c.617 T>G), and there were no mutations in subclinical Cushing's syndrome. Among 33 APAs, 24 had somatic mutations of the KCNJ5 gene, either G151R or L168R, 11 (33%) had autonomous cortisol secretion, but there were no mutations of the PRKACA gene. We established a PCR-restriction fragment length polymorphism assay and revealed that the mutated allele was expressed at a similar level to the wild-type allele. These findings demonstrated that 1) the prevalence of Japanese patients with CPA who showed overt Cushing's syndrome and whose somatic mutations in the PRKACA gene was similar to that in Western countries, 2) the mutation might be specific for CPAs causing overt Cushing's syndrome, and 3) the mutant PRKACA allele was expressed appropriately in CPAs.

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.

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.

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.