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.

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.

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.

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.

Fluctuations in plasma adrenocorticotropic hormone concentration may predict the onset of immune checkpoint inhibitor-related hypophysitis.

Immune checkpoint inhibitor (ICI)-related hypophysitis (RH) is a common immune-related adverse event. The early detection of ICI-RH prevents life-threatening adrenal insufficiency. However, good predictors of secondary adrenal insufficiency in ICI-RH have not yet been reported. We hypothesized that fluctuations in plasma adrenocorticotropic hormone (ACTH) and cortisol levels occur similarly to those in thyroid-stimulating hormone and thyroid hormone (thyroxine and triiodothyronine) levels in ICI-related thyroiditis. Here, we sought to test this hypothesis. Patients who used ICI and had a history of measurement of plasma ACTH and serum cortisol concentrations were retrieved from electronic medical records, and those with a history of glucocorticoid use were excluded from the analysis. We evaluated fluctuations in plasma ACTH and serum cortisol concentrations and the development of ICI-RH. For patients with ICI-RH, data at three points (before ICI administration (pre), maximum ACTH concentration (peak), and onset of ICI-RH) were analyzed to evaluate hormone fluctuations. A total of 202 patients were retrieved from the medical record. Forty-three patients were diagnosed with ICI-RH. Twenty-six out of 43 patients had sufficient data to evaluate fluctuations in plasma ACTH and serum cortisol concentrations and no history of glucocorticoid use. ACTH concentrations changed from 37.4 (29.9­48.3) (pre) to 64.4 (46.5­106.2) (peak) pg/mL (1.72­fold increase, p=0.0026) in the patients with ICI-RH before the onset. There were no differences in cortisol concentrations between the pre and peak values in patients with ICI-RH. We also evaluated the fluctuations in plasma ACTH and serum cortisol levels in patients who did not receive ICI-RH (62 cases). However, elevation of plasma ACTH levels was not observed in patients without ICI-RH, suggesting that transient elevation of plasma ACTH levels is a unique phenomenon in patients with ICI-RH. In conclusion, plasma ACTH levels were transiently elevated in some patients with ICI-RH before the onset of secondary adrenal insufficiency. Monitoring the ACTH levels and their fluctuations may help predict the onset of ICI-RH.

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.

Effects of the Cortisol Milieu on Tumor-Infiltrating Immune Cells in Corticotroph Tumors.

CONTEXT: Corticotrophs are susceptible to lymphocyte cytotoxicity, as seen in hypophysitis, suggesting that an immunological approach may be a potential strategy for corticotroph-derived tumors. OBJECTIVE: We aimed to clarify whether corticotroph tumors that induce hypercortisolemia (ACTHomas) could be targets for immunotherapy. METHODS: Tumor-infiltrating immune cells were immunohistochemically analyzed. ACTHomas were compared with other pituitary tumors, and further divided into 3 different cortisol-exposed milieus: Naïve (ACTHomas without preoperative treatment), Met (ACTHomas with preoperative metyrapone), and SCA (silent corticotroph adenomas). A 3-dimensional cell culture of resected tumors was used to analyze the effects of immune checkpoint inhibitors. RESULTS: The number of tumor-infiltrating lymphocytes (TILs) was low in ACTHomas. Among these, the number of CD8+ cells was lower in ACTHomas than in both somatotroph and gonadotroph tumors (both P < .01). Then we compared the differences in TILs among Naïve, Met, and SCA. The number of CD4+ cells, but not CD8+ cells, was higher in both Met and SCA than in Naïve. Next, we investigated tumor-associated macrophages, which could negatively affect T cell infiltration. The numbers of CD163+ and CD204+ cells were positively associated with cortisol levels. Moreover, tumor size was positively correlated with the number of CD204+ cells. CONCLUSION: We found the possibility that ACTHomas were immunologically cold in a cortisol-independent manner. In contrast, the tumor infiltration of CD4+ cells and M2-macrophages were associated with the cortisol milieu. Future studies are needed to validate these results and develop effective immunotherapy while considering the cortisol milieu.

The combination of doxazosin and metyrosine as a preoperative treatment for pheochromocytomas and paragangliomas.

PURPOSE: Preoperative medical management is critical to prevent intraoperative cardiovascular complications in patients with pheochromocytomas and paragangliomas (PPGLs). Initial treatment involves α-adrenergic receptor blockers. However, while the routine use of metyrosine alongside these blockers is not strongly recommended due to a lack of evidence supporting its efficacy and associated safety concerns, there are previous studies on combination therapy with phenoxybenzamine and metyrosine. There are few reports on combination therapy with the selective α1-adrenergic receptor blocker doxazosin. Therefore, we investigated this combination treatment, which theoretically can affect perioperative outcomes in patients with PPGLs. To our knowledge, this is the first such study. METHODS: This retrospective single-center observational study involved 51 patients who underwent surgical resection of PPGLs at Kobe University Hospital between 2014 and 2022. All patients received doxazosin at maximum doses. Fourteen patients received concomitant metyrosine, while 37 received doxazosin alone. Their perioperative outcomes were compared. RESULTS: No severe event, such as acute coronary syndrome, was observed in either group. Intraoperatively, the doxazosin + metyrosine group exhibited a lower median minimum systolic blood pressure (56 [54-60] vs. 68 [59-74] mmHg, P = 0.03) and required lower median remifentanil (P = 0.04) and diltiazem (P = 0.02) doses than the doxazosin-alone group. CONCLUSION: The combination of metyrosine and doxazosin as a preoperative treatment for PPGLs affects intraoperative circulatory hemodynamics, such as a reduced occurrence of blood pressure elevation during surgery. Further research is necessary to identify patients who will benefit most from this combination treatment.

Type 1 diabetes mellitus affected by potential toxicity from long-term use of nivolumab.

We present a case of type 1 diabetes mellitus (T1DM) that developed in a 53-year-old man after long-term treatment with nivolumab. The patient underwent total gastrectomy for gastric cancer at 40 years of age, and he was started on nivolumab at age 48 years for treatment of a recurrent lesion that proved resistant to standard chemotherapy. Nivolumab treatment resulted in complete response, but, after the 136th infusion of the drug at age 53 years, the patient was hospitalized for sudden onset of diabetic ketoacidosis. He was diagnosed with immune checkpoint inhibitor-induced T1DM (ICI-DM), which developed 1988 days (284 weeks) after initiation of nivolumab. HLA typing revealed disease susceptibility alleles for both fulminant T1DM and ICI-DM. With the increased survival after the ICI treatment, delayed-onset irAEs after long-term use of ICI have been reported; however, delayed-onset ICI-DM remains to be elucidated. This case provides important insight into ICI-DM that develops after prolonged ICI administration, and it suggests that patients should be monitored for ICI-DM regardless of the duration of ICI therapy.

A Multicenter, Open-Label, Single-Arm Trial of the Efficacy and Safety of Empagliflozin Treatment for Refractory Diabetes Mellitus with Insulin Resistance (EMPIRE-01).

INTRODUCTION: Insulin resistance syndrome and lipoatrophic diabetes are characterized by severe insulin resistance and are often refractory to treatment. Trials assessing the efficacy of antidiabetes drugs for these rare conditions have been limited, however. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which lower glycemia independently of insulin action, have shown efficacy for type 2 diabetes with insulin resistance. We here investigated the efficacy and safety of the SGLT2 inhibitor empagliflozin for treatment of insulin resistance syndrome and lipoatrophic diabetes. METHODS: The trial was conducted at five academic centers in Japan and included seven patients with insulin resistance syndrome and one patient with lipoatrophic diabetes. Participants received 10 mg of empagliflozin daily. If the hemoglobin A1c (HbA1c) level was ≥ 7.0% (52 mmol/mol) after 12 weeks, the dose was adjusted to 25 mg. The study duration was 24 weeks, and the primary outcome was the change in HbA1c level by the end of the treatment period. Safety evaluations were performed for all participants. RESULTS: By the end of the 24-week treatment period, the mean HbA1c level for all eight patients had decreased by 0.99 percentage points (10.8 mmol/mol) (95% confidence interval [CI], 0.59 to 1.38 percentage points, 6.6 to 14.9 mmol/mol) and the mean fasting plasma glucose concentration had declined by 63.9 mg/dL (3.55 mmol/L) (95% CI 25.5 to 102.3 mg/dL, 1.42 to 5.68 mmol/L). Continuous glucose monitoring revealed a reduction in mean glucose levels from 164.3 ± 76.1 to 137.6 ± 46.6 mg/dL (9.13 ± 4.23 to 7.65 ± 2.59 mmol/L) as well as an increase in the time in range (70-180 mg/dL) from 58.9 ± 36.1% to 70.8 ± 18.3%. Seventeen mild adverse events were recorded in five individuals throughout the study period. No severe events were reported. The mean body mass showed a slight decrease and the mean serum ketone body concentration showed a slight increase during treatment. CONCLUSION: Our results demonstrate that empagliflozin shows a certain level of efficacy and safety for treatment of insulin resistance syndrome and lipoatrophic diabetes. TRIAL REGISTRATION: jRCTs2051190029 and NCT04018365.

Composite paraganglioma-ganglioneuroma with atypical catecholamine profile and phenylethanolamine N-methyltransferase expression: a case report and literature review.

Pheochromocytomas and paragangliomas (PPGLs) are rare tumors that secrete catecholamines and arise from the adrenal medulla or extra-adrenal sympathetic ganglia. These tumors secrete adrenaline and noradrenaline, but paragangliomas usually produce only noradrenaline because of the lack of phenylethanolamine N-methyltransferase (PNMT) expression. Composite paragangliomas, which are complex tumors consisting of multiple types of neuroblastic cells, are extremely rare. We present the case of a 46-year-old woman with an atypical catecholamine profile who was preoperatively diagnosed with pheochromocytoma. However, postoperative pathology revealed that the patient had an extra-adrenal paraganglioma accompanied by a ganglioneuroma, which led to the diagnosis of a composite tumor. Interestingly, PNMT is expressed in both paragangliomas and ganglioneuromas. In addition, we reviewed reported composite paragangliomas and compared their clinical features with those of composite pheochromocytomas. We also discuss various aspects of the etiology of composite paragangliomas and the mechanism by which PNMT is expressed in tumors.

Thrombospondin-1 promotes liver fibrosis by enhancing TGF-ß action in hepatic stellate cells.

Insulin resistance in adipose tissue is thought to be a key contributor to the pathogenesis of various metabolic disorders including metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH), but the mechanism underlying this contribution to MASLD/MASH has remained unknown. We previously showed that dysregulation of the PDK1-FoxO1 signaling axis in adipocytes plays a role in the development of MASLD/MASH by analysis of adipocyte-specific PDK1 knockout (A-PDK1KO) and adipocyte-specific PDK1/FoxO1 double-knockout (A-PDK1/FoxO1DKO) mice. We here focused on the role of the extracellular matrix protein thrombospondin-1 (TSP-1) as a secreted factor whose expression in adipose tissue is increased in A-PDK1KO mice and normalized in A-PDK1/FoxO1DKO mice. Genetic ablation of TSP-1 markedly ameliorated liver fibrosis in A-PDK1KO mice fed a high-fat diet. With regard to the potential mechanism of this effect, TSP-1 augmented the expression of fibrosis-related genes induced by TGF-ß in LX-2 human hepatic stellate cells. We also showed that TSP-1 expression and secretion were negatively regulated by insulin signaling via the PDK1-FoxO1 axis in cultured adipocytes. Our results thus indicate that TSP-1 plays a key role in the pathogenesis of liver fibrosis in MASH. Regulation of TSP-1 expression by PDK1-FoxO1 axis in adipocytes may provide a basis for targeted therapy of hepatic fibrosis in individuals with MASH.

Krüppel-like factor 15 deficiency exacerbates osteoarthritis through reduced expression of peroxisome proliferator-activated receptor gamma signaling in mice.

OBJECTIVE: Krüppel-like zinc finger transcription factors (KLFs) play diverse roles in mammalian cell differentiation and development. In this study, we investigated the function of KLF15 in the progression of osteoarthritis (OA). METHODS: 0Destabilization of the medial meniscus (DMM) surgery was performed in 10-week-old male wild-type control (WT) mice and cartilage-specific KLF15 knockout (KO) mice. Histological analysis, immunohistochemistry, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining were performed. Morphological changes were measured using microcomputed tomography. Six mice from each group were analyzed (total number of mice analyzed: 60). In vitro, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blot analyses were performed. RESULTS: KLF15 KO DMM mice exhibited significant cartilage degradation compared to WT mice. According to the Osteoarthritis Research Society International cartilage OA-histopathology scoring system, the mean sum score in KLF15 KO mice was significantly higher than that in WT mice at 8 weeks after surgery. Immunohistochemistry results revealed KLF15 KO mice exhibited reduced peroxisome proliferator-activated receptor gamma (PPARγ) expression, increased pIKKα/ß, a disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTS) 5, and Matrix metalloproteinases (MMP13) expression, and reduced Forkhead box O (FOXO1) and Light chain 3B (LC3B) expression. Inhibition of PPARγ phosphorylation accelerated the effects of interleukin (IL) 1ß-treatment in both KLF15 KO and WT chondrocytes, and activation of PPARγ expression canceled the IL1ß-induced catabolic effects. CONCLUSION: Our results indicated that the OA phenotype of KLF15 KO DMM mice was influenced by reduced PPARγ expression, including enhanced pIKKα/ß, ADAMTS5, and MMP13 expression, reduced autophagy, and increased apoptosis. KLF15 regulation may constitute a possible therapeutic strategy for the treating OA.

Newer parameters of the octreotide test in patients with acromegaly.

PURPOSE: Predicting the therapeutic effects of first-generation somatostatin receptor ligands (fg-SRLs) is important when assessing or planning effective treatment strategies in patients with acromegaly. The oft-used maximum growth hormone (GH) suppression rate parameter of the octreotide test has a suboptimal predictive value. Therefore, this study explored newer parameters of the octreotide test for predicting the therapeutic effect of long-acting fg-SRLs. METHODS: In this single-center retrospective study, the octreotide test parameters and the therapeutic effects of fg-SRL at 3 months were investigated in 45 consecutive treatment-naïve patients with acromegaly between April 2008 and March 2023. Additionally, the relationship between the octreotide test parameters and the therapeutic effects of fg-SRLs was investigated. Tumor shrinkage was evaluated based on changes in the longitudinal diameter of the macroadenomas. The area GH suppression rate-time under the curve (AUC) and the time to nadir GH level were calculated and compared with the maximum GH suppression rate. RESULTS: The AUC estimated reductions in serum insulin-like growth factor I, and tumor shrinkage. The time to nadir GH level predicted tumor shrinkage more robustly than the maximum GH suppression rate in patients with macroadenoma. CONCLUSION: The AUC and time to nadir GH level may potentially be newer parameters of the octreotide test for estimating the therapeutic effect of fg-SRLs.

Continuous glucose monitoring metrics following sub-Tenon's injection of triamcinolone acetonide for diabetic macular edema.

PURPOSE: This pilot study aims to comprehensively evaluate the effects of sub-Tenon's injection of triamcinolone acetonide (STTA) on glycemic control in patients with diabetic macular edema (DME) using professional continuous glucose monitoring (CGM). METHODS: This retrospective study analyzed changes in glycemic control in 20 patients with type 2 mellitus and DME following single STTA (20 mg/0.5 mL) using The FreeStyle Libre Pro system. Professional CGM provides core CGM metrics such as the percentage of time that glucose levels fall within a target range and include the time in range (TIR) (70-180 mg/dL), time above range (TAR) (> 180 mg/dL), and time below range (TBR) (< 70 mg/dL). Outcome measures were the changes in CGM metrics (TIR, TAR and TBR) and the percentage of patients in whom TAR increased by at least 10 percentage points (ppt) 4 days before to 4 days after STTA administration. RESULTS: The mean CGM metrics (TIR/TAR/TBR) were 75.5%/19.9%/4.4% 4 days before STTA and 73.7%/22.4%/3.5% 4 days after STTA; the metrics 4 days before and 4 days after STTA were not significantly different (P = 0.625 for TIR, P = 0.250 for TAR, and P = 0.375 for TBR). TAR increased by more than 10 ppt in four (20%) patients treated with sulfonylurea and/or insulin. CONCLUSION: Although there were no significant changes in the CGM metrics, four patients developed CGM-measured hyperglycemia after STTA for DME.

Definition, criteria, and core concepts of guidelines for the management of obesity disease in Japan.

To identify those who might benefit from weight reduction within a large population of obese individuals, Japan Society for the Study of Obesity (JASSO) advocated the concept of "obesity disease." Here we summarize the definition, criteria, and core concepts for the management of obesity disease based on JASSO's latest guideline. JASSO defines obesity as excessive fat storage in adipose tissue associated with a BMI of ≥25 kg/m2. The threshold BMI of obesity is low as compared to Western countries given that Japanese individuals tend to develop obesity-related health disorders at lower BMI. Obesity with a BMI of ≥35 kg/m2 is referred to as "high-degree obesity" as treatment strategies vary based on the degree of obesity. Obesity is diagnosed as "obesity disease" if accompanied by any of the 11 specific obesity-related health disorders that weight reduction can prevent or alleviate, or if it meets the criteria for visceral fat obesity with a visceral fat area of ≥100 cm2. The initial weight reduction goals for high-degree obesity disease range from 5% to 10% of their current body weight, depending on the associated health disorders. That for those with obesity disease who do not qualify as high-degree is 3% or more. If these initial goals are not achieved, intensifying dietary therapy or introducing drug therapy (or both) may be necessary. While surgical treatment is primarily indicated for high-degree obesity disease, it might be appropriate for cases of obesity disease with a BMI <35 kg/m2, depending on the accompanying health disorders. Enhancing the quality of life for individuals with obesity or obesity disease necessitates a broader societal approach, emphasizing the resolution of related stigma.

Clinical features of anti-pituitary-specific transcription factor-1 (PIT-1) hypophysitis: a new aspect of paraneoplastic autoimmune condition.

The pathogenesis of anti-pituitary-specific transcription factor-1 (PIT-1) hypophysitis was gradually revealed as cases emerged. Our comprehensive analysis, including all reported cases, identified a new instance of anti-PIT-1 hypophysitis postimmune checkpoint inhibitor therapy. All 9 patients exhibited extremely low growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) levels; 2 had a slightly atrophic pituitary gland; 4 had thymoma, and 5 had malignant neoplasms of diffuse large B-cell lymphoma (DLBCL) and other origins. Patients with thymoma showed multiple autoimmune diseases. HLA-A*24:02 and/or A*02:06 were present in six and DR53 in 5 cases analyzed. High anti-PIT-1 antibody titers and ectopic PIT-1 expression in the cytosol and nucleus of the tumor tissues were observed in patients with thymoma or DLBCL, whereas it was exclusively observed in the nuclei of a bladder cancer patient. These findings provide new insights into the pathophysiology of paraneoplastic autoimmune hypophysitis.

Paraneoplastic isolated adrenocorticotropic hormone deficiency revealed after immune checkpoint inhibitors therapy: new insights into anti-corticotroph antibody.

Introduction: A recently discovered facet of paraneoplastic adrenocorticotropic hormone (ACTH) deficiency exists in two forms: a paraneoplastic spontaneous isolated ACTH deficiency (IAD) and an immune checkpoint inhibitor (ICI)-related hypophysitis. Autoantibodies against corticotrophs, such as circulating anti-proopiomelanocortin (POMC) antibodies are considered disease markers. However, the number of identified cases was limited, implying that the characteristics of these autoantibodies are not fully understood. Methods: We investigate circulating autoimmune autoantibodies in detail through a novel case of IAD that developed as a paraneoplastic autoimmune ACTH deficiency. Results: The patient developed IAD after 25 weeks of ICI therapy for metastasis of large-cell neuroendocrine carcinoma at 69 years of age. Ectopic ACTH expression and infiltration of CD3+, CD4+, CD8+, and CD20+ lymphocytes were observed in the tumor tissues and circulating anti-POMC antibodies were detected specifically in the patient's serum. Moreover, detailed analyses of immunofluorescence staining using patient serum revealed that the recognition site of the autoantibody was ACTH25-39, which had not been identified in previous cases of paraneoplastic autoimmune ACTH deficiency. Conclusion: This case involved a combination of paraneoplastic spontaneously acquired IAD and ICI-related hypophysitis occupying the middle ground. Moreover, our study reveals new aspects of anti-POMC antibodies in patients with paraneoplastic ACTH deficiency. This report expands our understanding of the immunological landscape and provides new insights for the identification of antibodies associated with paraneoplastic autoimmune ACTH deficiency.

A gut microbial metabolite of linoleic acid ameliorates liver fibrosis by inhibiting TGF-ß signaling in hepatic stellate cells.

The antidiabetic drug pioglitazone ameliorates insulin resistance by activating the transcription factor PPARγ. In addition to its blood glucose-lowering action, pioglitazone exerts pleiotropic effects including amelioration of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). The mechanism by which pioglitazone achieves this latter effect has remained unclear, however. We here show that pioglitazone administration increases the amount of linoleic acid (LA) metabolites in adipose tissue of KK-Ay mice. These metabolites are produced by lactic acid bacteria in the gut, and pioglitazone also increased the fraction of Lactobacillus in the gut microbiota. Administration of the LA metabolite HYA (10-hydroxy-cis-12-octadecenoic acid) to C57BL/6 J mice fed a high-fat diet improved liver histology including steatosis, inflammatory cell infiltration, and fibrosis. Gene ontology analysis of RNA-sequencing data for the liver revealed that the top category for genes downregulated by HYA treatment was related to extracellular matrix, and the expression of individual genes related to fibrosis was confirmed to be attenuated by HYA treatment. Mechanistically, HYA suppressed TGF-ß-induced Smad3 phosphorylation and fibrosis-related gene expression in human hepatic stellate cells (LX-2). Our results implicate LA metabolites in the mechanism by which pioglitazone ameliorates liver fibrosis, and they suggest that HYA is a potential therapeutic for NAFLD/NASH.