Perioperative malnutrition is common in patients with gastroenterological cancer and contributes to postoperative skeletal muscle atrophy, which adversely affects their prognosis. Early assessment of skeletal muscle atrophy is crucial for improving postoperative outcomes. This study aimed to evaluate the efficacy of urinary titin as a biomarker for skeletal muscle atrophy. A prospective observational study was conducted, and a total of 34 gastroenterological cancer patients were included. Urinary titin levels were measured using ELISA at admission, postoperative days (POD) 1, 7, and 14, and at 6 months after surgery. Surgical procedure, operative time, cancer stage, postoperative complications, hospital stay, and preoperative and postoperative body composition were evaluated, along with nutritional status and grip strength from admission to 6 months after surgery. Changes in urinary titin levels were measured at the same time points as described above. Preoperatively, the mean urinary titin level was 5.03 pmol/mg Cr, slightly higher than in healthy subjects. Urinary titin peaked at 33.71 (24.30-66.58) pmol/mg/dL Cr on POD1 and was associated with serum free branched-chain amino acid concentrations. Urinary titin on POD1 was significantly correlated with a decrease in skeletal muscle mass (rs -0.361, p = 0.036) and body cell mass (rs -0.361, p = 0.038) at 6 months postoperatively. The grip strength at 6 months postoperatively tended to decrease (rs -0.342, p = 0.052). BMI and serum LDH at admission were associated with urinary titin on POD1 but were not correlated with skeletal muscle loss at 6 months, suggesting that urinary titin on POD1 is an independent biomarker of skeletal muscle atrophy. These data indicate that urinary titin on POD1 can predict long-term skeletal muscle atrophy.

Lymphocytic infundibulo-neurohypophysitis (LINH) is a rare autoimmune inflammatory process that selectively affects the neurohypophysis and the pituitary stalk, typically presenting with central diabetes insipidus (CDI). LINH is considered underdiagnosed because the definitive diagnosis requires invasive pituitary surgery with a high risk of complications. We present a case of CDI resulting from LINH, which was treated with conservative management, eschewing both glucocorticoid treatment and pituitary surgery. At presentation, the hormonal assessment indicated the presence of CDI without anterior pituitary dysfunction. Magnetic resonance imaging revealed stalk thickening without a posterior pituitary bright spot, and anti-rabphilin-3A antibodies were positive in serum. Collectively, we made a diagnosis of LINH. Considering that the patient did not exhibit any symptoms of mass effect, we chose conservative treatment with desmopressin acetate. One year later, the stalk thickening regressed spontaneously without surgical or glucocorticoid treatment, although the posterior pituitary bright spot remained absent, and CDI did not improve. The inflammatory process of LINH is mostly self-limited and recovers spontaneously, whereas life-long desmopressin treatment may be required because of pituitary stalk fibrosis and atrophy. Our case highlights the importance of noninvasive diagnosis and careful follow-up in preventing unnecessary interventions for patients with LINH.

Functional gonadotroph adenomas (FGAs) are rare, manifesting symptoms like menstrual irregularities or ovarian hyperstimulation syndrome (OHSS). We present a case of OHSS caused by an FGA during the follow-up of a pituitary tumor initially considered nonfunctioning. The patient presented with lower abdominal pain, abdominal swelling, and dyspnea. Magnetic resonance imaging (MRI) revealed 15 cm enlarged ovarian cysts and pleural effusion. Laboratory examination showed an elevated serum estradiol (E2) level (5741.4 pmol/L [1564.0 pg/mL]), suppressed luteinizing hormone, and nonsuppressed follicular-stimulating hormone (FSH). However, no pituitary hormone disorders were observed when a 19 mm pituitary tumor was discovered 11 months prior. Given the absence of human chorionic gonadotropin (hCG) administration, OHSS due to the FGA was suspected. Cabergoline, known for alleviating the severity of OHSS, was administered, but the ovarian cysts continued to enlarge. Subsequently, endoscopic transsphenoidal surgery was performed, and immunohistochemical analysis confirmed the diagnosis of the FSH-producing adenoma. Follow-up MRI scans showed reduced ovarian cysts and successful pituitary tumor resection with a reduced E2 level. This case highlights the importance of considering FGAs when encountering OHSS without hCG administration or following up on pituitary tumors in premenopausal female patients to take appropriate measures for accurate diagnosis and management.

AimsTo conduct a study on glycemic control improvement by appropriate re-education on the self-injection technique (SIT) in patients with diabetes mellitus undergoing insulin therapy.MethodsPatients who received appropriate SIT and were treated with insulin for more than a year were re-educated. For the observation period of six months, the subjects' SIT was checked, and hemoglobin A1c (HbA1c) levels were measured at each visit. HbA1c levels, insulin doses, and behavioral changes in SIT were investigated at baseline and at the end of the observation period.ResultsIn the per-protocol set population, the HbA1c level decreased by 0.2 % (2.0 mmol/mol) on average, showing a significant difference (p = 0.009). No significant difference was observed in the proportion of subjects with decreased HbA1c levels, changes in total daily insulin doses, or blood glucose levels. Four of the six SIT items covered by re-education were improved.ConclusionsProviding re-education on insulin SIT was considered effective in reducing HbA1c levels and improving adherence to proper SIT.

Previous studies suggested that β-cell function markers such as fasting and postprandial serum C-peptide and C-peptide increment (FCPR, PCPR, and ΔCPR, respectively) may be useful in estimating glycemic response to glucagon-like peptide-1 receptor agonists. However, it remains elusive whether baseline glycemic control confounds these markers. Here we aimed to identify the least confounded β-cell function markers and investigate whether these markers could predict glycemic response to dulaglutide. We evaluated FCPR, PCPR, and ΔCPR levels in patients with type 2 diabetes who initiated dulaglutide treatment after a standardized meal tolerance test (MTT). We first investigated the confounding effects of baseline HbA1c on β-cell function markers using Pearson’s correlation test. Then, we evaluated the association between each β-cell function marker and glycemic response (HbA1c change 0–6 months) to dulaglutide using generalized linear model and logistic regression analysis with adjustment for baseline HbA1c. In 141 patients, baseline HbA1c was significantly inversely correlated with PCPR and ΔCPR (P < 0.01 for both) but not with FCPR (r = 0.02; P = 0.853), suggesting that FCPR was the marker least confounded by baseline glycemic control. Of all patients, 59 continued dulaglutide for at least 6 months without initiating any additional glucose-lowering medications. Mean ± SE HbA1c change 0–6 months was − 1.16 ± 0.17% (P < 0.001 vs. baseline). The β-cell function markers were significantly associated with HbA1c change 0–6 months in the generalized linear model. FCPR was also a significant predictor for achieving a reduction in HbA1c of at least 1% (P = 0.044) with an area under the receiver operating characteristic curve of 0.83 (sensitivity = 0.81 and specificity = 0.79). Fasting and meal-induced C-peptide levels are associated with glycemic response to dulaglutide, among which FCPR is least confounded by baseline glycemic control, suggesting its utility as a marker for glycemic response to dulaglutide.

ABSTRACT Plant sterol intake is widely recommended for patients with cardiovascular risk factors based on the inhibitory effect on intestinal cholesterol absorption. Although plant sterols, once absorbed, can promote atherosclerosis, their intake is believed to be safe because of poor absorption, except in rare hyperabsorbers with homozygous ABCG5/8 mutations. We report a case of new‐onset type 1 diabetes accompanied by hypercholesterolemia. At the initial presentation with diabetic ketoacidosis, the patient showed marked hypercholesterolemia. Whole‐exome sequencing revealed a heterozygous pathogenic variant in ABCG5 (p.R419H). The initial serum plant sterol levels were markedly high (sitosterol 32.5 μg/mL, campesterol 66.0 μg/mL), close to the range observed in patients with homozygous ABCG5/8 mutations, which were largely reduced by insulin treatment without ezetimibe. The addition of ezetimibe normalized plant sterol levels. These findings provide the first evidence that uncontrolled diabetes plays a causal role in the pathogenesis of phytosterolemia.

Context Sporadic pseudohypoparathyroidism type 1B (sporPHP1B) is an imprinting disease without a defined genetic cause, characterized by broad methylation changes in differentially methylated regions (DMRs) of the GNAS gene. Objective This work aims to provide insights into the causative event leading to the GNAS methylation defects through comprehensive molecular genetic analyses of a pair of female monozygotic twins concordant for sporPHP1B who were conceived naturally, that is, without assisted reproductive techniques. Methods Using the leukocyte genome of the twins and family members, we performed targeted bisulfite sequencing, methylation-sensitive restriction enzyme (MSRE)-quantitative polymerase chain reaction (qPCR), whole-genome sequencing (WGS), high-density single-nucleotide polymorphism (SNP) array, and Sanger sequencing. Results Methylation analyses by targeted bisulfite sequencing and MSRE-qPCR revealed almost complete losses of methylation at the GNAS AS, XL, and A/B DMRs and a gain of methylation at the NESP55 DMR in the twins, but not in other family members. Except for the GNAS locus, we did not find apparent methylation defects at other imprinted genome loci of the twins. WGS, SNP array, and Sanger sequencing did not detect the previously described genetic defects associated with familial PHP1B. Sanger sequencing also ruled out any novel genetic alterations in the entire NESP55/AS region. However, the analysis of 28 consecutive SNPs could not exclude the possibility of paternal heterodisomy in a span of 22 kb comprising exon NESP55 and AS exon 5. Conclusion Our comprehensive analysis of a pair of monozygotic twins with sporPHP1B ruled out all previously described genetic causes. Twin concordance indicates that the causative event was an imprinting error earlier than the timing of monozygotic twinning.

CONTEXT:The PDX1 gene encodes pancreatic and duodenal homeobox, a critical transcription factor for pancreatic β-cell differentiation and maintenance of mature β-cells. Heterozygous loss-of-function mutations cause PDX1-MODY (MODY4). CASE DESCRIPTION:Our patient is an 18-year-old lean man who developed diabetes at 16 years of age. Given his early-onset age and leanness, we performed genetic testing. Targeted next-generation sequencing and subsequent Sanger sequencing detected a novel heterozygous frameshift mutation (NM_00209.4:c.218delT. NP_000200.1: p.Leu73Profs*50) in the PDX1 transactivation domain that resulted in loss-of-function and was validated by an in vitro functional study. The proband and his 56-year-old father, who had the same mutation, both showed markedly reduced insulin and gastric inhibitory polypeptide (GIP) secretion compared with the dizygotic twin sister, who was negative for the mutation and had normal glucose tolerance. The proband responded well to sitagliptin, suggesting its utility as a treatment option. Notably, the proband and his father showed intriguing phenotypic differences: the proband had been lean for his entire life but developed early-onset diabetes requiring an antihyperglycemic agent. In contrast, his father was overweight, developed diabetes much later in life, and did not require medication, suggesting the oligogenic nature of PDX1-MODY. A review of all reported cases of PDX1-MODY also showed heterogeneous phenotypes regarding onset age, obesity, and treatment, even in the presence of the same mutation. CONCLUSIONS:We identified the first Japanese family with PDX1-MODY. The similarities and differences found among the cases highlight the wide phenotypic spectrum of PDX1-MODY.

Aims: The effect of β-cell function on glycemic response to dulaglutide (DU) is not fully understood in clinical settings. We explored a suitable clinical marker of β-cell function to predict glycemic response to DU in patients with type 2 diabetes (T2D). Methods: We retrospectively analyzed 141 patients who commenced once-weekly DU 0.75 mg after undergoing a meal tolerance test (MTT) with a standardized meal from September 2015 to December 2019 at our hospital. β-cell function was assessed by fasting and 2h postprandial serum C-peptide immunoreactivity (CPR) as well as increment of CPR (dCPR) in the MTT. We analyzed the suitability of each measurement as a marker for β-cell function and its association with glycemic response to DU using linear and logistic regression with adjustment for baseline HbA1c. Results: In 141 patients, 2h postprandial CPR (PCPR) and dCPR showed significant inverse correlation with baseline HbA1c (r = -0.25 and -0.33, respectively; P < 0.01 for both), while fasting CPR (FCPR) did not (r = 0.02; P = 0.853). Given the association of high baseline HbA1c and impairment of meal-stimulated insulin secretion measured with PCPR and dCPR, we adopted FCPR as a marker for β-cell function with less influence from baseline HbA1c in the following analysis. Of the 141 patients, 59 patients continued DU without initiating any additional glucose-lowering agents for more than 6 months. The baseline mean ± SD HbA1c, fasting plasma glucose, and FCPR of the 59 patients were 8.9 ± 1.2%, 9.2 ± 2.3 mmol/L, 0.50 ± 0.29 nmol/L, respectively. The mean ± SE change in HbA1c 0-6 months was -1.2 ± 0.2%. FCPR was significantly associated with a reduction in HbA1c (P = 0.031). Furthermore, FCPR was a significant predictor for achieving a reduction in HbA1c ≥ 1% over 6 months (OR, 1.40; 95% CI, 1.14-1.71; P = 0.039) with the area under the receiver operating characteristics curve of 0.83. Conclusions: FCPR is less affected by baseline HbA1c than PCPR and dCPR, and can be a useful marker for predicting glycemic response to DU. Disclosure M. Hasebe: None. S. Honjo: None. J. Fujikawa: None. A. Hamasaki: None. S. Yoshiji: None. Y. Iwasaki: None. S. Kimura: None. Y. Seno: None. Y. Keidai: None. T. Haraguchi: None. K. Iwasaki: None. Y. Wada: None.

Abstract Background: Pseudohypoparathyroidism (PHP) 1B is an imprinting disorder characterized by renal resistance to parathyroid hormone (PTH) without Albright Hereditary Osteodystrophy (AHO). PHP1B is associated with methylation defects at the GNAS differentially methylated regions (DMRs). In sporadic cases with PHP1B, the mechanistic basis of methylation defects remains to be solved, except in rare cases with uniparental disomy of chromosome 20. In addition, to date, monozygotic twin cases with sporadic PHP1B have not been reported. Clinical Case: The patients were 26-year-old Japanese female monozygotic twins. They had been born to nonconsanguineous parents after an uneventful pregnancy. Both twins had common biochemical features, including hypocalcemia, hyperphosphatemia, elevated PTH levels, and impaired urinary excretion of phosphorus and cAMP in response to teriparatide. They showed no signs of AHO. The serum calcium levels of their parents and brother were within the normal range, and family history was unremarkable. Based on these findings, the twins were diagnosed with PHP1B. Targeted bisulfite sequencing of the GNAS DMRs in all family members revealed almost complete gain-of-methylation at the NESP55 DMR, and loss-of-methylation at the AS, XL, and A/B DMRs in the twins, but not in other family members. Except for the GNAS locus, we did not find clear methylation defects in other imprinted genome loci in the twins. Methylation defects at the GNAS locus were further confirmed by methylation-sensitive restriction enzyme-qPCR. Whole-genome sequencing of the twins showed no pathogenic variants in the GNAS exons encoding the Gs alpha subunit. No large deletions or insertions were found at the STX16 locus or in the region from AS exon 5 to XL. Based on the SNP genotyping results, large paternal isodisomies in the GNAS DMRs were unlikely. Collectively, these results suggested that the twins had concordant methylation defects that are seen in the sporadic form of PHP1b. We speculate that an early developmental event before the twin splitting is responsible for the abnormal methylation of the GNAS DMRs. Conclusion: We report, for the first time, monozygotic twins with sporadic PHP1B who were phenotypically and epigenetically concordant. Our comprehensive molecular genetic analyses have thus far ruled out the previously described genetic defects underlying PHP1B. The current findings provide new insights into the mechanistic basis of the GNAS methylation defects in sporadic PHP1B.

Klinefelter syndrome (KS) is frequently complicated by diabetes. However, it is severely underdiagnosed due to a lack of reliable screening methods. We diagnosed two patients with KS at the Center for Diabetes and Endocrinology, Tazuke Kofukai Medical Research Institute Kitano Hospital, Osaka, Japan. By comparing the patients with 39 non-KS patients with diabetes, we propose a screening tool for KS in patients with diabetes.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder caused by mutations of the tumor suppressor gene MEN1. Most of the germline MEN1 gene mutations have been small mutations, and the whole gene deletion is rarely observed. In the present study, we revealed Alu retrotransposon-mediated de novo germline deletion of the whole MEN1 gene and somatic copy-neutral loss of heterozygosity (LOH) in a patient with MEN1. The patient is a 39-year-old woman who was referred to our department for the management of prolactinoma. She was also diagnosed with primary hyperparathyroidism and suspected of MEN1. Although nucleotide sequencing did not detect any MEN1 gene mutations, multiplex ligation-dependent probe amplification (MLPA) revealed a large germline deletion of the MEN1 gene. Subsequent quantitative polymerase chain reaction (qPCR)-based copy number mapping showed a monoallelic loss of approximately 18.5-kilobase region containing the whole MEN1 gene. Intriguingly, the 2 breakpoints were flanked by Alu repetitive elements, suggesting the contribution of Alu/Alu-mediated rearrangements (AAMR) to the whole MEN1 gene deletion. Furthermore, copy number mapping using MLPA and qPCR in combination with single nucleotide polymorphism analysis revealed copy-neutral LOH as a somatic event for parathyroid tumorigenesis. In conclusion, copy number mapping revealed a novel combination of Alu/Alu-mediated de novo germline deletion of the MEN1 gene and somatic copy-neutral LOH as a cytogenetic basis for the MEN1 pathogenesis. Moreover, subsequent in silico analysis highlighted the possible predisposition of the MEN1 gene to Alu retrotransposon-mediated genomic deletion.

Background: The efficacy and safety of incretin-based therapies for glucocorticoid-induced hyperglycemia, for which insulin is often used, remain to be established in real-world clinical settings. We aimed to study whether a once-weekly GLP-1 receptor agonist improves glycemic control in patients on glucocorticoid therapy compared with a DPP-4 inhibitor. Methods: We retrospectively compared the 12-week efficacy and safety of dulaglutide versus sitagliptin in patients with diabetes on prednisolone treatment (4-40 mg/day) who visited our hospital from 2015 to 2018. Results: Among 73 patients who started dulaglutide or sitagliptin for glucocorticoid-induced hyperglycemia while on prednisolone treatment (4-40 mg/day), 40 patients continued dulaglutide or sitagliptin along with prednisolone (4-40 mg/day) for the entire treatment period of 12 weeks (n =16, 24, respectively). The baseline characteristics and change in prednisolone doses from baseline to 1-12 weeks were comparable between the two groups. Dulaglutide significantly reduced the HbA1c and total daily insulin doses per bodyweight from baseline to 12 weeks (-0.78, p = 0.034; -0.29, p = 0.001, respectively), whereas neither was achieved by sitagliptin (-0.26, p = 0.088; -0.12, p = 0.105). A significantly higher proportion of patients were insulin-free at 12 weeks in the dulaglutide group than in the sitagliptin group (61.5% vs. 20.0%, p = 0.046). As for adverse events, nausea and vomiting were observed in 11.1% of the dulaglutide group. Hypoglycemia was not observed in either group. Conclusions: Compared with sitagliptin, dulaglutide can be an effective option for glucocorticoid-induced hyperglycemia with acceptable tolerability in real-world clinical settings. Disclosure S. Yoshiji: None. Y. Iwasaki: None. K. Iwasaki: None. M. Aizawa-Abe: None. S. Honjo: None. Y. Wada: None. J. Fujikawa: None. A. Hamasaki: None.

Recently, sodium-glucose cotransporter 2 (SGLT2) inhibitors is expected its hematopoietic effect for treatment of the anemia in chronic renal failure. However, it is still unclear whether the effect is independent from its antidiabetic effect. In this study, we investigated correlations between hematocrit elevation, HbA1c reduction or parameters reflecting diuretic change in patients with type 2 diabetes (T2D). A total of 46 patients (male: n = 33, age: 54.6 ± 10.4 [mean ± SD] years, BMI: 29.2 ± 4.3 kg/m2, HbA1c: 8.7 ± 1.0%) with T2D who were newly administered SGLT2 inhibitors from July 2014 to November 2016 were retrospectively identified. The patients with HbA1c less than 7.0% at the baseline or who showed decrease in hematocrit or increase in HbA1c were excluded. Changes in HbA1c, hematocrit, urine specific gravity, uric acid, serum creatinine and plasma osmolarity levels between before and 30 days after the administration of the drugs were evaluated. Plasma osmolarity was calculated by the formula (2 x (Na [mEq/l] + K [mEq/l])) + (BUN [mg/dl]/2.8) + (glucose [mg/dl]/18). HbA1c was decreased (-0.68 ± 0.50%; p = 0.001) and hematocrit (2.1 ± 1.4%; p = 0.002) and urine specific gravity (0.008 ± 0.009 g/ml; p < 0.001) were increased significantly. However, uric acid, serum creatinine and plasma osmolarity did not show change. Changes in HbA1c and plasma osmolarity showed significant correlation (r = -0.31; p = 0.03) whereas changes in hematocrit and plasma osmolarity did not (r = -0.01; p = 0.94). HbA1c showed no significant correlation with hematocrit, serum creatinine, uric acid or urine specific gravity; hematocrit also did not have significant correlation with serum creatinine, uric acid or urine specific gravity. In conclusion, our data suggest that the elevation of hematocrit and decrease in HbA1c after the administration of SGLT2 inhibitors have different relation with parameters reflecting diuretic effects. Disclosure Y. Wada: None. Y. Hamamoto: Speaker’s Bureau; Self; Novo Nordisk A/S. Y. Nakatani: None. J. Fujikawa: None. Y. Iwasaki: None. S. Yoshiji: None. M. Aizawa-Abe: None. K. Iwasaki: None. S. Honjo: None. A. Hamasaki: None.

A patient with mitochondrial diabetes mellitus developed diabetic ketoacidosis. During insulin treatment, although diabetic ketoacidosis improved, lactic acidosis unexpectedly worsened. This clinical course, named "switched metabolic acidosis," could reflect the unique pathophysiology of the mitochondrial disorder.

Klinefelter syndrome (KS) is frequently complicated by diabetes. However, it is severely underdiagnosed due to a lack of reliable screening methods. We diagnosed two patients with KS at the Center for Diabetes and Endocrinology, Tazuke Kofukai Medical Research Institute Kitano Hospital, Osaka, Japan. By comparing the patients with 39 non-KS patients with diabetes, we propose a screening tool for KS in patients with diabetes.