Downregulation of Krüppel-like factor 15 expression delays endochondral bone ossification during fracture healing.

OBJECTIVE: The role of Krüppel-like zinc finger transcription factor 15 (KLF15) in endochondral ossification during fracture healing remains unexplored. In this study, we aimed to elucidate the impact of KLF15 in a mouse model of tibial transverse fracture. METHODS: We created tamoxifen-inducible, cartilage-specific KLF15 knockout mice (KLF15 KO). KLF15 fl/fl Col2-CreERT mice from the same litters as the KLF15 KO mice, but not treated with 4-hydroxytamoxifen, were used as controls (CT). At 10 weeks, male KLF15 KO and CT mice underwent tibial fracture followed by intramedullary nailing. Both groups were administered tamoxifen at days 0, 3, and 7 after surgery. The tibiae were harvested on post-surgery days 7, 10, and 14 for radiological assessment using micro-computed tomography. Histological staining (Safranin-O) and immunohistochemistry for KLF15, SOX9, Indian hedgehog (IHH), RUNX2, and Osterix were performed. Additionally, cartilage from mouse fetus was cultured for qRT-PCR and western blot analyses of KLF15, SOX9, IHH, Col2, RUNX2, Osterix, TGF-ß, SMAD3, and phosphor-SMAD3. RESULTS: The radiological assessment revealed that immature callus formation was delayed in KLF15 KO, compared with that in CT, peaking on day 14 compared with that on day 10 in CT. KLF15 KO mice exhibited delayed fracture healing and reduced Safranin-O staining at days 7 and 10 post-surgery. The ratio of cells positive for KLF15 and SOX9 was significantly lower in KLF15 KO than in CT, whereas the ratios for IHH, RUNX2, and Osterix showed no significant difference. RT-PCR revealed reduced expression of KLF15, SOX9, and COL2, with no significant changes in IHH, Osterix, RUNX2, TGF-ß, and SMAD3. Western blot analysis indicated decreased SMAD3 phosphorylation in KLF15 KO mice. CONCLUSION: KLF15 regulates SOX9 via the TGF-ß-SMAD3-SOX9 pathway, independent of IHH, in endochondral ossification. The KLF15 deficiency decreases SOX9 expression through reduced SMAD3 phosphorylation, subsequently delaying fracture healing.

Problems in screening for gestational diabetes mellitus by measurement of casual blood glucose levels at 24-28 gestational weeks.

AIMS/INTRODUCTION: This study aimed to evaluate the problems in screening for gestational diabetes mellitus (GDM) by casual blood glucose (CBG) measurements at 24-28 gestational weeks. MATERIALS AND METHODS: Overall, 763 pregnant women who underwent the 50-g glucose challenge test (GCT) at 24-28 gestational weeks were enrolled. The preload blood glucose (0-h BG) level of 50-g GCT was considered as CBG. RESULTS: A total of 240 women with BG levels at 1-h after loading (1-h BG) on 50-g GCT ≥140 mg/dL underwent the 75-g oral glucose tolerance test, and 98 (40.8%) were diagnosed with GDM. Of the 99 women with GDM, 71 (71.7%) had 0-h BG on 50-g GCT <100 mg/dL. CONCLUSIONS: This study, where pregnant women underwent both CBG and 50-g GCT simultaneously, showed that when CBG at 24-28 gestational weeks ≥100 mg/dL alone was used for screening GDM, many pregnant women with GDM were overlooked.

Acquired isolated ACTH deficiency co-occurrence with breast cancer irrespective of paraneoplastic syndrome: coincidence or inevitability.

Summary: A 52-year-old female patient with breast cancer presented with a history of fatigue and malaise 1 year prior. She was diagnosed with isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) on endocrinological examination. Her pituitary gland showed normal morphology. Paraneoplastic IAD associated with breast cancer was suspected; however, immunofluorescence staining revealed no ectopic ACTH or proopiomelanocortin expression in the tumor tissue. Subsequently, the patient was diagnosed with idiopathic acquired IAD concurrent with breast cancer, ruling out paraneoplastic syndrome. Although malignancy should be considered a potential cause of IAD, not all patients with concurrent IAD and malignancy necessarily develop paraneoplastic syndrome. Learning points: Several adrenal insufficiency symptoms are similar to the nonspecific symptoms associated with malignancies, and therefore, the diagnosis of IAD remains challenging, especially in patients with cancer. When we encounter a case of IAD accompanied by a malignant tumor, it is important to suspect that paraneoplastic IAD, a novel clinical condition as secondary hypophysitis, may be the etiologic agent. Although malignant tumours should be considered a potential cause of IAD, not all patients with concurrent IAD and malignancy necessarily develop paraneoplastic autoimmune hypophysitis.

Diagnosis of sarcopenic obesity in Japan: Consensus statement of the Japanese Working Group on Sarcopenic Obesity.

Sarcopenic obesity is the co-existence of obesity and sarcopenia in individuals aged 40-75 years. The Japanese Working Group on Sarcopenic Obesity has developed diagnostic criteria tailored for the Japanese population, considering their unique characteristics compared with European populations. Our algorithm consists of two steps: screening and diagnosis. The screening of obesity mandates using waist circumference and/or body mass index (BMI) based on national standards, while screening for sarcopenia involves the "finger ring test" in addition to the Asian Working Group for Sarcopenia 2019 criteria. The final diagnosis of sarcopenia involves handgrip strength for low muscle strength, the five-times chair stand test for low physical function, and limb skeletal muscle mass (corrected for BMI) for low muscle mass. Obesity is assessed by visceral fat area or body fat percentage. Sarcopenic obesity is then categorized into Stage I, with muscle weakness/loss of function, loss of muscle mass, and obesity; or Stage II, which includes complications. Further clinical validation is needed to refine the consensus and age range. Geriatr Gerontol Int 2024; 24: 997-1000.

Long-term metabolic effectiveness and safety of growth hormone replacement therapy in patients with adult growth hormone deficiency: a single-institution study in Japan.

PURPOSE: To elucidate the long-term efficacy and safety of growth hormone replacement therapy (GHRT) in Japanese patients with adult growth hormone deficiency (AGHD). METHODS: We conducted a retrospective study. A total of 110 patients with AGHD receiving GHRT were enrolled. Clinical and laboratory data were collected annually from the beginning of the study. Statistical analysis was performed using a linear mixed-effects model. RESULTS: Of all patients, 46.4% were males, 70.9% had adult-onset GHD, and follow-up was up to 196 months, with a median of 68 months. The insulin-like growth factor-1 standard deviation score increased after the start of GHRT and remained constant for more than 11 years. Seventeen patients were followed up for more than 11 years. The body mass index increased. Waist circumference decreased in the short term but increased in the long term. The diastolic blood pressure decreased 1-5 years after the start of GHRT, and the systolic blood pressure increased 11 years after GHRT. Moreover, a long-term decrease in low-density lipoprotein cholesterol, an increase in high-density lipoprotein cholesterol, and a decrease in aspartate aminotransferase and alanine aminotransferase levels were observed. The glycosylated hemoglobin level increased after 3 years. The bone mineral density in the lumbar spine and total hip increased significantly 3 years after the start of GHRT. Finally, the number of adverse events was eight. CONCLUSION: We demonstrated the metabolic effectiveness and safety of GHRT in Japanese patients with AGHD over a long follow-up period of 16 years.

Comparison over Time of Adverse Drug Reactions in Diabetes Patients Treated with Sodium-Glucose Cotransporter 2 Inhibitors.

BACKGROUNDS: The prescription of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been increasing due to their additional benefits, including weight loss, cardioprotection and renoprotection. Accordingly, there are concerns about the potential rise in severe adverse drug reactions (ADRs), such as urinary tract infections, diabetic ketoacidosis, volume depletion, and hypoglycemia. The Society has announced recommendations on the proper use of SGLT2 inhibitors. We aimed to elucidate the recent occurrence of severe ADRs which need discontinuation of SGLT2 inhibitors or hospitalization. METHODS: In this retrospective cohort study, we identified 391 diabetic patients who were prescribed SGLT2 inhibitors upon admission to our hospital between April 2017 and March 2023. Of these, 68 patients who discontinued SGLT2 inhibitors for reasons other than ADRs were excluded. Patients were classified into the 2017 group and the 2020 group based on the treatment period of SGLT2 inhibitors, and the occurrence of ADRs and patient backgrounds were compared between the two groups. RESULTS: A total of 323 eligible patients were identified. Discontinuations of SGLT2 inhibitors decreased in the 2020 group (p < 0.05). However, discontinuations due to frailty increased (p < 0.05). Hospitalization due to ADRs, specifically those due to urinary tract infections, diabetic ketoacidosis, or volume depletion, did not specifically decrease (p = 0.273). CONCLUSIONS: This study indicated that there has been some improvement in the awareness of the proper use of SGLT2 inhibitors and there is still a need to continue enlightenment activities.

Understanding negative feedback: Changes in high-molecular-weight adrenocorticotropic hormone in adrenocorticotropic hormone-independent Cushing's syndrome.

Cushing's syndrome is characterized by chronic glucocorticoid oversecretion and diverse clinical manifestations. Distinguishing between adrenocorticotropic hormone (ACTH)-independent and ACTH-dependent forms is crucial for determining treatment options. Plasma ACTH levels aid in the differential diagnosis, with undetectable or low levels suggesting ACTH-independent hypercortisolemia. ACTH is derived from pro-opiomelanocortin, and its processing involves prohormone convertase 1/3. High-molecular-weight ACTH is generally found in ACTH-producing pituitary tumors and ectopic ACTH syndrome. The mechanism of negative feedback and the process of high-molecular-weight ACTH alternation during ACTH-independent Cushing's syndrome remain unclear. A 40-year-old woman with hypertension and multiple fractures developed symptoms suggestive of Cushing's syndrome. Computed tomography revealed a left adrenocortical tumor along with atrophy of the right adrenal gland. ACTH levels were undetectable at the previous clinic, indicating ACTH-independent Cushing's syndrome. However, subsequent measurements at our hospital revealed non-suppressed ACTH (18.1 pg/mL), prompting further investigation. Gel exclusion chromatography confirmed the presence of high-molecular-weight ACTH. Metyrapone treatment decreased the cortisol levels. In this situation, in which ACTH levels should be elevated, a decrease in high-molecular-weight ACTH levels was observed. Histological findings revealed cortisol-producing adenoma without ACTH expression. This case highlights the importance of assay differences in evaluating ACTH concentrations and introduces a novel finding of circulating high-molecular-weight ACTH. The observed decline in high-molecular-weight ACTH levels suggests a potential time lag in the negative feedback within the hypothalamic-pituitary-adrenal axis exhibited by glucocorticoids. This temporal aspect of the regulation of ACTH-related molecules warrants further exploration to enhance our understanding of the hypothalamic-pituitary-adrenal axis feedback mechanism.

Impact of early-morning administration of rapid-acting insulin on the increase in blood glucose levels related to the dawn phenomenon in individuals with type 1 diabetes.

Aims/Introduction: An early-morning elevation of blood glucose levels known as the dawn phenomenon and consequent postbreakfast hyperglycemia occur in some individuals with type 1 diabetes (T1D). Whereas insulin pump therapy can mitigate this phenomenon, some individuals prefer or are limited to alternative treatments. We have now assessed the effectiveness of early-morning administration of rapid-acting insulin for amelioration of the dawn phenomenon in individuals with T1D. Materials and Methods: Thirteen individuals with T1D who experienced the dawn phenomenon as determined by continuous glucose monitoring (CGM) and who received a small dose of rapid-acting insulin on waking were included in this retrospective study. We evaluated the change in sensor glucose levels during a 2-h period from before to after breakfast consumed at 0700 h. The change in blood glucose levels during additional time intervals, average daily sensor glucose values, CGM indices, and insulin dose were also evaluated. Results: The early-morning administration of 0.5-1 unit of rapid-acting insulin was associated with a significant reduction in 2-h glucose variability between before (0700 h) and after breakfast from a median of 90.7-51.0 mg/dL. The glucose variability from 0300 to 0700 or 0900 h was also significantly decreased, from 67.7 to 29.0 mg/dL and from 172.5 to 78.3 mg/dL, respectively. Average sensor glucose levels throughout the day were significantly reduced (from 192.7 to 156.7 mg/dL), as was the daily total insulin dose. Conclusion: Early-morning administration of rapid-acting insulin effectively managed the dawn phenomenon and subsequent postbreakfast hyperglycemia in individuals with T1D. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-024-00709-6.

Diagnostic dilemma in Cushing's syndrome: discrepancy between patient-reported and physician-assessed manifestations.

PURPOSE: Early diagnosis and immediate treatment of Cushing's syndrome (CS) are critical for a better prognosis but remain a challenge. However, few comprehensive reports have focused on this issue or investigated whether patient-reported manifestations are consistent with physician-assessed symptoms of CS. This study aimed to clarify the differences in patient-reported and physician-assessed manifestations of signs and symptoms of CS that prevent early diagnosis. METHODS: This single-center retrospective study included 52 patients with CS (16 with Cushing's disease and 36 with adrenal CS). Upon clinical diagnosis, medical records were used to independently review the patient-reported and physician-assessed manifestations of typical (such as purple striae and proximal myopathy) and nonspecific features (such as hirsutism and hypertension). The correlations and differences between the patient-reported and physician-assessed manifestations were then analyzed. RESULTS: We observed a positive correlation between the total number of manifestations of nonspecific features reported by patients and those assessed by physicians, but not for typical features. Moreover, manifestations reported by the patients were less frequent than those assessed by physicians for typical features, leading to discrepancies between the two groups. In contrast, there were no differences in most nonspecific features between the patient-reported and physician-assessed manifestations. Notably, the concordance between patient-reported and physician-assessed manifestations of typical features was not associated with urinary free cortisol levels. CONCLUSION: Regardless of disease severity, patients often do not complain of the typical features of CS that are crucial for formulating a diagnosis.

Seasonal fluctuations of CGM metrics in individuals with type 1 diabetes using an intermittently scanned CGM device or sensor augmented pump.

OBJECTIVE: To elucidate the fluctuations in glucose levels measured using CGM-metrics during the four distinct seasons of the year in individuals with type 1 diabetes mellitus (T1DM) using an intermittently scanned CGM (isCGM) device or sensor augmented pump (SAP). RESEARCH DESIGN AND METHODS: This retrospective, single-center study enrolled 93 individuals with T1DM who were equipped with an isCGM device or SAP at Kobe University Hospital. The subjects had a median age of 47.0 years [interquartile range, 37.0-62.0 years], 25 individuals (26.9%) were male, median body mass index was 22.0 kg/m2 [20.8-23.8 kg/m2], and median hemoglobin A1c level was 7.4% [6.9-8.0%]. CGM data were reviewed from January to December 2019, and the mean sensor glucose (SG) value, time above range (TAR), time in range (TIR), time below range (TBR), and standard deviation (SD) of SG were calculated for each season (spring, March-May; summer, June-August; autumn, September-November; winter, December-February). RESULTS: Seasonal fluctuations were detected for mean SG, TAR, TIR, and SD, with TIR being lower and mean SG, TAR, and SD being higher in cold seasons (spring or winter) than in warm seasons (summer or autumn). CONCLUSION: Seasonal fluctuations in CGM metrics should be taken into account in future studies performed to evaluate the favorable impact of CGM on glycemic management in individuals with T1DM.

Glycemic metrics in Japanese isCGM users - Analysis by diabetes type and therapy.

AIMS/INTRODUCTION: The FreeStyle Libre (FSL) intermittently scanned continuous glucose monitoring (isCGM) system continually measures interstitial glucose levels and provides the data to users in numerical and graphical formats that guide users in their daily diabetes self-management. Although numerous studies have demonstrated the glycemic benefits of FSL in pediatric and adult populations, few studies have characterized FSL use specifically by Japanese adults with type 1 or 2 diabetes. We utilized established CGM metrics to assess glycemic control in a large cohort of Japanese adults with type 1 and 2 diabetes. MATERIALS AND METHODS: A total of 3,463 anonymized FSL users provided categorization into one of four therapy groups of interest: type 1 diabetes (n = 1,768), type 2 diabetes-multiple daily injections (MDI) (n = 612), type 2 diabetes-basal (BOI) (n = 343), and type 2 diabetes-non-insulin (NIT) (n = 740). Established CGM metrics were used to assess glycemic control. RESULTS: All study groups showed relatively good glycemic control. Type 1 diabetes users showed the highest glucose variability (SD, 61 mg/dL; and %CV, 40%), above the established target level (%CV ≤ 36%). type 2 diabetes-MDI and type 2 diabetes-BOI users had similar levels of glucose variability (both within target). Type 2 diabetes-NIT users had the highest mean % time in range (TIR) (84.3%) and largest percentage of users that met the target of %TIR > 70% (87.4%). In contrast, type 1 diabetes users had the lowest mean %TIR (62.6%) and the lowest percentage meeting the established %TIR target (30.5%). CONCLUSIONS: By utilizing CGM devices in daily diabetes care, both healthcare professionals and patients can monitor glycemic excursions and gain insights into their historical glucose control patterns.

Dapagliflozin administration to a mouse model of type 2 diabetes induces DNA methylation and gene expression changes in pancreatic islets.

Decreased pancreatic ß-cell volume is a serious problem in patients with type 2 diabetes mellitus, and there is a need to establish appropriate treatments. Increasingly, sodium/glucose cotransporter 2 (SGLT2) inhibitors, which have a protective effect on pancreatic ß-cells, are being prescribed to treat diabetes; however, the underlying mechanism is not well understood. We previously administered SGLT2 inhibitor dapagliflozin to a mouse model of type 2 diabetes and found significant changes in gene expression in the early-treated group, which led us to hypothesize that epigenetic regulation was a possible mechanism of these changes. Therefore, we performed comprehensive DNA methylation analysis by methylated DNA immunoprecipitation using isolated pancreatic islets after dapagliflozin administration to diabetic model mice. As a result, we identified 31 genes with changes in expression due to DNA methylation changes. Upon immunostaining, cystic fibrosis transmembrane conductance regulator and cadherin 24 were found to be upregulated in islets in the dapagliflozin-treated group. These molecules may contribute to the maintenance of islet morphology and insulin secretory capacity, suggesting that SGLT2 inhibitors' protective effect on pancreatic ß-cells is accompanied by DNA methylation changes, and that the effect is long-term and not temporary. In future diabetes care, SGLT2 inhibitors may be expected to have positive therapeutic effects, including pancreatic ß-cell protection.

Adaptive gene expression of alternative splicing variants of PGC-1α regulates whole-body energy metabolism.

The transcriptional coactivator PGC-1α has been implicated in the regulation of multiple metabolic processes. However, the previously reported metabolic phenotypes of mice deficient in PGC-1α have been inconsistent. PGC-1α exists as multiple isoforms, including variants transcribed from an alternative first exon. We show here that alternative PGC-1α variants are the main entity that increases PGC-1α during exercise. These variants, unlike the canonical isoform of PGC-1α, are robustly upregulated in human skeletal muscle after exercise. Furthermore, the extent of this upregulation correlates with oxygen consumption. Mice lacking these variants manifest impaired energy expenditure during exercise, leading to the development of obesity and hyperinsulinemia. The alternative variants are also upregulated in brown adipose tissue in response to cold exposure, and mice lacking these variants are intolerant of a cold environment. Our findings thus indicate that an increase in PGC-1α expression, attributable mostly to upregulation of alternative variants, is pivotal for adaptive enhancement of energy expenditure and heat production and thereby essential for the regulation of whole-body energy metabolism.

Acquired thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone deficiencies with circulating anti-glycoprotein hormones alpha chain-positive cell antibodies.

BACKGROUND: A patient with systemic lupus erythematosus (SLE) suffered from acquired thyroid-stimulating hormone (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) deficiencies. MRI findings revealed a slight atrophy of the pituitary gland. Further, the serum concentration of the covalent alpha subunit (glycoprotein hormones alpha chain [CGA]) in TSH-, LH-, and FSH-positive cells was below the detectable range. Because SLE is an autoimmune disorder, autoimmunity against the pituitary gland was suspected as the cause of pituitary deficiency. METHODS AND RESULTS: Immunofluorescence analysis showed that the patient's immunoglobulin G recognized CGA-positive cells in the pituitary gland; therefore, autoimmunity against CGA-positive cells may have caused TSH, LH, and FSH deficiencies in this patient. Moreover, cell-specific autoimmunity impairs pituitary hormone levels. Further research is required to clarify whether acquired TSH, LH, and FSH deficiencies are common in patients with SLE or other autoimmune diseases. CONCLUSION: Our findings highlight a unique case of acquired TSH, LH, and FSH deficiencies caused by circulating anti-CGA-positive cell antibodies, introducing a novel clinical concept of acquired hypopituitarism.

A multicenter, open-label, single-arm trial of the long-term safety of empagliflozin treatment for refractory diabetes mellitus with insulin resistance (EMPIRE-02).

AIMS/INTRODUCTION: Insulin resistance syndrome and lipoatrophic diabetes are rare conditions characterized by the development of treatment-refractory diabetes with severe insulin resistance. We recently conducted a 24 week, multicenter, single-arm trial (EMPIRE-01) that demonstrated a certain level of effectiveness and safety of empagliflozin for these conditions. To evaluate treatment safety over a longer period, we have now performed an additional 28 week trial (EMPIRE-02) that followed on from EMPIRE-01. MATERIALS AND METHODS: The primary and secondary outcomes were safety and efficacy evaluations, respectively. All eight subjects of the EMPIRE-01 trial participated in EMPIRE-02. RESULTS: Twenty adverse events (AEs) were recorded among five individuals during the combined 52 week treatment period of both trials. Whereas one case of chronic hepatitis B was moderate in severity, all other AEs were mild. There were thus no serious AEs or events necessitating discontinuation or suspension of treatment or a reduction in drug dose. Whereas ketoacidosis or marked increases in serum ketone body levels were not observed, the mean body mass of the subjects was decreased slightly after completion of EMPIRE-02. The improvement in mean values of glycemic parameters observed in EMPIRE-01 was not sustained in EMPIRE-02, mostly because of one individual whose parameters deteriorated markedly, likely as a result of nonadherence to diet therapy. The improvement in glycemic parameters was sustained during EMPIRE-02 after exclusion of this subject from analysis. CONCLUSIONS: Empagliflozin demonstrated a certain level of safety and efficacy for the treatment of insulin resistance syndrome and lipoatrophic diabetes over 52 weeks, confirming its potential as a therapeutic option.

Thyroid dysfunction due to trace element deficiency-not only selenium but also zinc.

INTRODUCTION: Levels of serum selenium (Se) and zinc (Zn) decrease when total parental nutrition (TPN) is administered without trace element supplementation for just a few weeks. These trace elements are involved in thyroid hormone metabolism and their deficiencies cause thyroid dysfunction. However, there have been few reports on the details of its clinical course. CASE PRESENTATION: A 50-year-old man presented with thyroid dysfunction due to Se and Zn deficiency. He had an approximately 70-cm residual small intestine after undergoing intestinal resection and he received TPN without trace element supplementation for one and a half months. Blood tests revealed high levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) and low levels of free triiodothyronine (FT3). An abnormal pattern of thyroid function led to suspicion of Se deficiency. Se supplementation raised FT3 levels and lowered FT4 levels to within their respective reference ranges; however, subclinical hypothyroidism persisted with transient TSH elevation. We suspected that Zn deficiency also contributed to the hypothyroidism and, therefore, initiated Zn supplementation, which resulted in normalization of thyroid function. DISCUSSION: Although thyroid dysfunction has been reported in many studies conducted on Se and Zn deficiencies, hormonal patterns vary between reports. Further accumulation of cases, including detailed data on nutritional status, would be of benefit to elucidate the clinical reality. CONCLUSION: It is important to consider Se and Zn deficiencies when TSH and FT4 levels are elevated. It should also be noted that transient TSH elevation may be observed with Se supplementation.

The early-stage clinical course of anti-pituitary-specific transcription factor-1 hypophysitis diagnosed post-immune checkpoint inhibitor treatment: A case with review of literature.

Anti-pituitary-specific transcription factor-1 (PIT-1) hypophysitis, a paraneoplastic syndrome resulting from an autoimmune response against PIT-1, typically manifests with undetectable levels of growth hormone (GH) and prolactin (PRL), and significantly low levels of serum thyroid-stimulating hormone (TSH) at diagnosis. These hormonal levels are highly specific to this disease and serve as key diagnostic indicators. Herein, we present a detailed clinical course of a 69-year-old male with a history of gastric cancer and lymph node metastases who developed anti-PIT-1 hypophysitis after the initiation of immune checkpoint inhibitor (ICI) therapy, specifically nivolumab, oxaliplatin, and capecitabine. The patient was referred to our department owing to decreased TSH, free triiodothyronine (T3), and free thyroxine (T4) levels after two doses of nivolumab. Initially suspected as central hypothyroidism due to ICI-related hypophysitis, further assessment confirmed the diagnosis of anti-PIT-1 hypophysitis. Notably, GH, PRL, and TSH levels markedly declined, leading to complete deficiencies 2 months after the first nivolumab dose-a pattern consistent with that of previous cases of anti-PIT-1 hypophysitis. Therefore, this report not only presents an atypical subset of ICI-related hypophysitis but also delineates the process of hormone impairment leading to complete deficiencies in anti-PIT-1 hypophysitis. This case highlights the importance of vigilant monitoring for endocrine issues in patients undergoing ICI therapy, given the escalating incidence of immune-related adverse events associated with the extensive use of ICI therapy for various cancers.

Mathematical Models of the Effect of Glucagon on Glycemia in Individuals With Type 2 Diabetes Treated With Dapagliflozin.

Context: Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels by promoting urinary glucose excretion, but their overall effects on hormonal and metabolic status remain unclear. Objective: We here investigated the roles of insulin and glucagon in the regulation of glycemia in individuals treated with an SGLT2 inhibitor using mathematical model analysis. Methods: Hyperinsulinemic-euglycemic clamp and oral glucose tolerance tests were performed in 68 individuals with type 2 diabetes treated with the SGLT2 inhibitor dapagliflozin. Data previously obtained from such tests in 120 subjects with various levels of glucose tolerance and not treated with an SGLT2 inhibitor were examined as a control. Mathematical models of the feedback loops connecting glucose and insulin (GI model) or glucose, insulin, and glucagon (GIG model) were generated. Results: Analysis with the GI model revealed that the disposition index/clearance, which is defined as the product of insulin sensitivity and insulin secretion divided by the square of insulin clearance and represents the glucose-handling ability of insulin, was significantly correlated with glycemia in subjects not taking an SGLT2 inhibitor but not in those taking dapagliflozin. Analysis with the GIG model revealed that a metric defined as the product of glucagon sensitivity and glucagon secretion divided by glucagon clearance (designated production index/clearance) was significantly correlated with blood glucose level in subjects treated with dapagliflozin. Conclusion: Treatment with an SGLT2 inhibitor alters the relation between insulin effect and blood glucose concentration, and glucagon effect may account for variation in glycemia among individuals treated with such drugs.

Sodium-glucose cotransporter 2 inhibitors influence skeletal muscle pathology in patients with heart failure and reduced ejection fraction.

AIMS: Patients with heart failure and reduced ejection fraction (HFrEF) exhibit skeletal muscle pathology, which contributes to symptoms and decreased quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in HFrEF but their mechanism of action remains poorly understood. We aimed, therefore, to determine whether SGLT2i influence skeletal muscle pathology in patients with HFrEF. METHODS AND RESULTS: Muscle biopsies from 28 male patients with HFrEF (New York Heart association class I-III) treated with SGLT2i (>12 months) or without SGLT2i were compared. Comprehensive analyses of muscle structure (immunohistochemistry), transcriptome (RNA sequencing), and metabolome (liquid chromatography-mass spectrometry) were performed, and serum inflammatory profiling (ELISA). Experiments in mice (n = 16) treated with SGLT2i were also performed. Myofiber atrophy was ~20% less in patients taking SGLT2i (p = 0.07). Transcriptomics and follow-up measures identified a unique signature in patients taking SGLT2i related to beneficial effects on atrophy, metabolism, and inflammation. Metabolomics identified influenced tryptophan metabolism in patients taking SGLT2i: kynurenic acid was 24% higher and kynurenine was 32% lower (p < 0.001). Serum profiling identified that SGLT2i treatment was associated with lower (p < 0.05) pro-inflammatory cytokines by 26-64% alongside downstream muscle interleukin (IL)-6-JAK/STAT3 signalling (p = 008 and 0.09). Serum IL-6 and muscle kynurenine were correlated (R = 0.65; p < 0.05). Muscle pathology was lower in mice treated with SGLT2i indicative of a conserved mammalian response to treatment. CONCLUSIONS: Treatment with SGLT2i influenced skeletal muscle pathology in patients with HFrEF and was associated with anti-atrophic, anti-inflammatory, and pro-metabolic effects. These changes may be regulated via IL-6-kynurenine signalling. Together, clinical improvements following SGLT2i treatment in patients with HFrEF may be partly explained by their positive effects on skeletal muscle pathology.

The humanistic and societal impact of obesity in Japan: a targeted literature review.

Obesity is a focus of Japanese public health policy, due to Japanese individuals' high susceptibility to weight-related conditions. In contrast to global definitions, obesity is defined as a body-mass-index (BMI) of ≥25 kg/m2 in Japan. Despite public efforts, rates of obesity have not decreased over the past decade. To better understand its societal impact, we examined the economic, quality of life (QoL), and complications burden of obesity in Japan. Electronic databases were searched for English and Japanese-language publications from 2005 to December 2020 reporting on adults with obesity in Japan; other diseases were excluded, with no restriction on intervention. Outcomes of interest included costs or resource use, QoL, risk of complications, and other clinical outcomes. We identified 137 studies, including 19 reporting on economic evidence, eight reporting on QoL, and 115 reporting on the relationship between obesity and the risk of complications or mortality. The studies consistently showed that Japanese adults with obesity (BMI ≥25 kg/m2) are at increased risk of complications vs. normal weight adults. They also confirmed higher total and medical costs, resource use, and hospitalization costs among adults with obesity vs. normal weight adults. In addition, the studies confirmed a considerable impact of obesity on physical and mental aspects of QoL. Overall, this study found that obesity in Japan is associated with a substantial burden. Japanese people are at risk even with BMI ≥25-<30 kg/m2, which are generally considered as pre-obese in other countries.