Anti‐programmed cell death‐1 (PD‐1) antibodies are regarded as a risk factor for insulin‐dependent diabetes mellitus as a side‐effect. While a small number of cases have been reported, evidence remains limited. This is the first report of an Asian patient developing insulin‐dependent diabetes during anti‐PD‐1 therapy. A 55‐year‐old euglycemic woman receiving nivolumab for malignant melanoma showed abrupt onset of ketonuria, and elevated levels of plasma glucose (580 mg/dL) and hemoglobin A1c (7.0%). Over the next 2 weeks, serum C‐peptide levels fell below the limit of detection. Islet autoantibodies were negative, and the patient showed a human leukocyte antigen haplotype associated with type 1 diabetes. Anti‐PD‐1 therapy can cause rapid onset of insulin‐dependent diabetes, possibly because of inappropriate activation of T cells. Human leukocyte antigen haplotypes might be related to the onset of this disease. Physicians should be aware of this serious adverse event and carry out routine blood glucose testing during anti‐PD‐1 therapy.

Non-alcoholic fatty liver disease (NAFLD) is a significant problem because its prevalence is increasing worldwide. Recent animal studies have identified gut microbiota as a potentially important player in the pathogenesis of NAFLD. Previously, we reported that the administration of branched-chain amino acids (BCAAs) reduces hepatic fat accumulation in experimental animal models. This study aimed to clarify how changes in the intestinal microbial flora following the administration of BCAAs affect a high-fat diet (HF)-induced fat accumulation in the liver. We examined whether the administration of BCAAs alters the development of hepatic fat accumulation as well as intestinal microbial flora. The oral administration of BCAAs (3% kcal) induced a significant increase in Ruminococcus flavefaciens (R. flavefaciens) and portal acetic acid levels, and it reduced hepatic fat accumulation in HF-fed rats. In addition, BCAAs reduced the expression of the lipogenesis-related genes FAS and ACC in the liver. Furthermore, we observed that R. flavefaciens is essential for promoting a BCAA-induced reduction in hepatic fat accumulation. These data suggest that BCAA treatment induces the proliferation of intestinal flora including R. flavefaciens and that portal acetic acid synthesized from intestinal flora improves NAFLD by downregulating the expression of FAS and ACC in the liver.

Background and Objectives: This study aimed to investigate the changes in obesity severity, glucose metabolism, and body composition in patients with obesity and type 2 diabetes mellitus treated with glucagon-like peptide 1 receptor agonist (GLP1-RA) semaglutide. Materials and Methods: Body weight (BW), metabolic parameters, and body composition were examined before and 3 months after semaglutide administration. The mass of body fat (FM), fat weight percentage (%FM), mass of skeletal muscle (MM), skeletal MM percentage (%MM), and limb muscles were measured using the bioelectrical impedance method. Results: Semaglutide dramatically reduced the weight, the body mass index (BMI), and the levels of the glucose metabolic markers, including fasting blood glucose and hemoglobin A1c, and accelerated the loss of excess BW. FM, MM, and %FM after semaglutide treatment also decreased. Conversely, semaglutide had no effect on the %MM after 3 months. In limb muscle analyses, right upper and lower leg muscle percentages, left upper and lower leg muscles, and the ratios of the lower/upper muscles were maintained by semaglutide treatment. Conclusions: These results suggest that the GLP1-RA semaglutide effectively reduces body adiposity while maintaining the MM in obese type 2 diabetic patients.

Aldosterone synthase (CYP11B2) is involved in the final steps of aldosterone biosynthesis and expressed exclusively in the adrenal zona glomerulosa cells. Using an electrophoretic mobility shift assay, we demonstrate that COUP-TFI binds to the –129/–114 element (Ad5) of human CYP11B2 promoter. Transient transfection in H295R adrenal cells demonstrated that COUP-TFI enhanced CYP11B2 reporter activity. However, the reporter construct with mutated Ad5 sequences showed reduced basal and COUP-TFI-enhanced activity, suggesting that binding of COUP-TFI to Ad5 is important for CYP11B2 transactivation. To elucidate molecular mechanisms of COUP-TFI-mediated activity, we subsequently screened for COUP-TFI-interacting proteins from a human adrenal cDNA library using a yeast two-hybrid system and identified Ubc9 and PIAS1, which have small ubiquitin-related modifier-1 (SUMO-1) conjugase and ligase activities, respectively. The coimmunoprecipitation assays confirmed that COUP-TFI forms a complex with Ubc9 and PIAS1 in mammalian cells. Immunohistochemistry showed that Ubc9 and PIAS1 are markedly expressed in rat adrenal glomerulosa cells. Coexpression of Ubc9 and PIAS1 synergistically enhanced the COUP-TFI-mediated CYP11B2 reporter activity, indicating that both proteins function as coactivators of COUP-TFI. However, sumoylation-defective mutants, Ubc9 (C93S) and PIAS1 (C351S), continued to function as coactivators of COUP-TFI, indicating that sumoylation activity are separable from coactivator ability. In addition, chromatin immunoprecipitation assays demonstrated that ectopically expressed COUP-TFI, Ubc9, and PIAS1 were recruited to an endogenous CYP11B2 promoter. Moreover, reduction of Ubc9 or PIAS1 protein levels by small interfering RNA inhibited the CYP11B2 transactivation by COUP-TFI. Our data support a physiological role of Ubc9 and PIAS1 as transcriptional coactivators in COUP-TFI-mediated CYP11B2 transcription.

The role of aldosterone has been implicated in the metabolic syndrome and cardiovascular diseases. The biological actions of aldosterone are mediated through mineralocorticoid receptor (MR). Nuclear receptor-mediated gene expression is regulated by dynamic and coordinated recruitment of coactivators and corepressors. To identify new coregulators of the MR, full-length MR was used as bait in yeast two-hybrid screening. We isolated NF-YC, one of the subunits of heterotrimeric transcription factor NF-Y. Specific interaction between MR and NF-YC was confirmed by yeast two-hybrid, mammalian two-hybrid, coimmunoprecipitation assays, and fluorescence subcellular imaging. Transient transfection experiments in COS-7 cells demonstrated that NF-YC repressed MR transactivation in a hormone-sensitive manner. Moreover, reduction of NF-YC protein levels by small interfering RNA potentiated hormonal activation of endogenous target genes in stably MR-expressing cells, indicating that NF-YC functions as an agonist-dependent MR corepressor. The corepressor function of NF-YC is selective for MR, because overexpression of NF-YC did not affect transcriptional activity mediated by androgen, progesterone, or glucocorticoid receptors. Chromatin immunoprecipitation experiments showed that endogenous MR and steroid receptor coactivator-1 were recruited to an endogenous ENaC gene promoter in a largely aldosterone-dependent manner, and endogenous NF-YC was sequentially recruited to the same element. Immunohistochemistry showed that endogenous MR and NF-YC were colocalized within the mouse kidney. Although aldosterone induces interaction of the N and C termini of MR, NF-YC inhibited the N/C interaction. These findings indicate that NF-YC functions as a new corepressor of agonist-bound MR via alteration of aldosterone-induced MR conformation.

Predominantly or exclusively dopamine-secreting pheochromocytoma and paraganglioma are very rare. We report a 64-year-old woman with an adrenal incidentaloma. She was normotensive and had no symptoms of catecholamine excess. The 24-hour urine catecholamine level showed normal norepinephrine (122.9 μg/day), normal epinephrine (24.3 μg/day), and markedly elevated dopamine (148 212.4 μg/day). ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy revealed tumor uptake. After α-blockade as preoperative management, she successfully underwent laparoscopic left adrenalectomy and was finally diagnosed with an exclusively dopamine-secreting pheochromocytoma. The tumor was histologically comprised of small polygonal cells with high cellularity and was immunohistochemically positive for all 3 catecholamine-synthesizing enzymes: tyrosine hydroxylase (very weak), dopamine β-hydroxylase (heterogeneous), and phenylethanolamine N-methyltransferase (very weak). Electron microscopy revealed very few catecholamine-containing small vesicles with a few organelles, which reflected immature cells. No biochemical or imaging evidence of recurrence or metastasis were evident 1 year after the surgery. We conducted a literature search in the PubMed database. A total of 33 cases were collected. Our case had the second-highest 24-hour urinary dopamine excretion and was the first in which immunostaining for catecholamine synthase and electron microscopy were performed together. Histological findings in our case give a possible hypothesis that the mechanism underlying a dopamine-secreting pheochromocytoma is associated with immature catecholamine vesicles in which dopamine β-hydroxylase is localized, thus resulting in inhibited conversion from dopamine to norepinephrine. We also discuss the reasons for the lack of catecholamine excess symptoms, whether preoperative management of α-blockade is needed, and the association between the prognosis and genetic mutation, with an extensive literature review.