Glycaemic control efficacy of switching from dipeptidyl peptidase-4 inhibitors to oral semaglutide in subjects with type 2 diabetes: A multicentre, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 2 study).

AIM: To assess whether oral semaglutide provides better glycaemic control, compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) continuation, in people with type 2 diabetes. MATERIALS AND METHODS: In this multicentre, open-label, prospective, randomized, parallel-group comparison study, participants receiving DPP-4is were either switched to oral semaglutide (3-14 mg/day) or continued on DPP-4is. The primary endpoint was the change in glycated haemoglobin (HbA1c) over 24 weeks. Secondary endpoints included changes in metabolic parameters and biomarkers, along with the occurrence of adverse events. Factors associated with HbA1c improvement were also explored. RESULTS: In total, 174 eligible participants were enrolled; 17 dropped out of the study. Consequently, 82 participants in the DPP-4i group and 75 participants in the semaglutide group completed the study and were included in the analysis. Improvement in HbA1c at week 24 was significantly greater when switching to semaglutide compared with DPP-4i continuation [-0.65 (95% confidence interval: -0.79, -0.51) vs. +0.05 (95% confidence interval: -0.07, 0.16) (p < .001)]. Body weight, lipid profiles and liver enzymes were significantly improved in the semaglutide group than in the DPP-4i continuation group. Multiple linear regression analysis revealed that baseline HbA1c and homeostasis model assessment 2-R were independently associated with HbA1c improvement after switching to semaglutide. Seven participants in the semaglutide group discontinued medication because of gastrointestinal symptoms. CONCLUSIONS: Although the potential for gastrointestinal symptoms should be carefully considered, switching from DPP-4is to oral semaglutide may be beneficial for glycaemic control and metabolic abnormalities in people with higher HbA1c and insulin resistance.

Fulminant ACTH decrease following diabetic ketoacidosis induced by immune checkpoint inhibitor combination therapy with nivolumab and ipilimumab: A case report.

RATIONALE: The increasing use of immune checkpoint inhibitors (ICIs) for treating malignant tumors result in the concomitant rise of immune-related adverse events (irAEs). This case report may provide useful insight to understanding the etiology of ICI-induced hypophysitis, a severe irAE leading to potentially fatal secondary adrenal insufficiency. PATIENT CONCERNS: An 81-year-old Japanese man was hospitalized for diabetic ketoacidosis following 4 courses of ICI combination therapy with nivolumab and ipilimumab for metastatic renal cell carcinoma. DIAGNOSIS: Insulin secretion was depleted, leading to diagnosis of fulminant type 1 diabetes. Adrenocorticotropic hormone (ACTH) and cortisol levels were very high (60.8 pmol/L and 1575 nmol/L, respectively) upon admission. ACTH and cortisol returned to normal ranges on the 2nd day. On the 8th day, an ACTH loading test showed intact cortisol response (peak value 519 nmol/L). However, on the 14th day, there was a sharp decrease in ACTH and cortisol levels (10.5 pmol/L and 47 nmol/L, respectively) accompanied by fatigue and a drop in blood pressure to 97/63 mm Hg. As secondary adrenal insufficiency was suspected, hydrocortisone replacement was initiated. An ACTH loading test on the 17th day revealed low cortisol peak (peak value 232 nmol/L), indicating sudden disruption of adrenal function. Magnetic resonance imaging showed no abnormal findings and there was no other pituitary hormone deficiency. These findings, along with the patient clinical course, suggest that secondary adrenal insufficiency was caused by acute ACTH producing cell destruction as an irAE associated with ICI therapy. INTERVENTIONS: The patient hyperglycemia and ketoacidosis were treated using extracellular fluid and insulin therapy. After development of adrenal insufficiency, hydrocortisone 20 mg was started, and the patient symptoms improved. OUTCOMES: He was continued on insulin therapy, hydrocortisone, and reinitiated nivolumab. LESSONS: This case provides a detailed course of the fulminant onset of ACTH deficiency during ICI administration, emphasizing the importance of close monitoring.

Neuromedin B receptor as a potential therapeutic target for corticotroph adenomas.

PURPOSE: Cushing's disease (CD) results from autonomous adrenocorticotropic hormone (ACTH) secretion by corticotroph adenomas, leading to excessive cortisol production, ultimately affecting morbidity and mortality. Pasireotide is the only FDA approved tumor directed treatment for CD, but it is effective in only about 25% of patients, and is associated with a high rate of hyperglycemia. Neuromedin B (NMB), a member of the bombesin-like peptide family, regulates endocrine secretion and cell proliferation. Here, we assessed NMB and NMB receptor (NMBR) expression in human corticotroph adenomas and the effects of NMBR antagonist PD168368 on murine and human corticotroph tumors. METHODS: To investigate NMB and NMBR expression, real-time qPCR and immunostaining on human pathological specimens of corticotroph, non-functional and somatotroph adenomas were performed. The effects of PD168368 on hormone secretion and cell proliferation were studied in vitro, in vivo and in seven patient-derived corticotroph adenoma cells. NMB and NMBR were expressed in higher extent in human corticotroph adenomas compared with non-functional or somatotroph adenomas. RESULTS: In murine AtT-20 cells, PD168368 reduced proopiomelanocortin (Pomc) mRNA/protein expression and ACTH secretion as well as cell proliferation. In mice with tumor xenografts, tumor growth, ACTH and corticosterone were downregulated by PD168368. In patient-derived adenoma cells, PD168368 reduced POMC mRNA expression in four out of seven cases and ACTH secretion in two out of five cases. A PD168368-mediated cyclin E suppression was also identified in AtT-20 and patient-derived cells. CONCLUSION: NMBR antagonist represents a potential treatment for CD and its effect may be mediated by cyclin E suppression.

Improvement of glycaemic control and treatment satisfaction by switching from liraglutide or dulaglutide to subcutaneous semaglutide in patients with type 2 diabetes: A multicentre, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 1 study).

AIM: To investigate the effects of switching from liraglutide or dulaglutide to once-weekly semaglutide on glycaemic control and treatment satisfaction in patients with type 2 diabetes. MATERIALS AND METHODS: In this multicentre, open-labelled, prospective, randomized, parallel-group comparison study, patients treated with liraglutide 0.9-1.8 mg/day (plan A) or dulaglutide 0.75 mg/week (plan B) were either switched to semaglutide or continued current therapy. The primary endpoint was the mean change in glycated haemoglobin over 24 weeks. The secondary endpoints included the changes of Diabetes Treatment Satisfaction Questionnaire scores, body weight and metabolic indices. RESULTS: In total, 110 patients were enrolled, and 10 were excluded; therefore, 37 patients in plan A and 63 patients in plan B completed the study. Glycated haemoglobin levels were significantly reduced in the semaglutide group in both plans [plan A, 7.8% ± 1.0% to 7.8% ± 0.7% (liraglutide) vs. 7.9% ± 0.7% to 7.3% ± 0.7% (semaglutide), p < .01; plan B, 7.8% ± 1.0% to 7.9% ± 1.2% (dulaglutide) vs. 7.8% ± 0.8% to 7.1% ± 0.6% (semaglutide), p < .01]. Semaglutide also improved Diabetes Treatment Satisfaction Questionnaire scores in both groups (plan A, +0.1 vs. +8.3, p < .01; plan B, -1.2 vs. +3.5, p < .01). Switching from dulaglutide yielded greater reductions in body weight and improved metabolic parameters. CONCLUSIONS: Once-weekly semaglutide administration improved glycaemic control and treatment satisfaction after switching from liraglutide or dulaglutide. These results highlighted a useful treatment option for patients with metabolic abnormalities despite glucagon-like receptor-1 receptor agonist treatment.

Effects of switching from a dipeptidyl peptidase-4 inhibitor to oral semaglutide on glucose metabolism in patients with type 2 diabetes: protocol for a multicentre, prospective, randomised, open-label, parallel-group comparison study (the SWITCH-SEMA 2 study).

INTRODUCTION: Incretin-based therapies exert antihyperglycaemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent fashion. The first-in-class oral glucagon-like peptide-1 receptor agonist semaglutide has potent effects on glycaemic and weight control, but little evidence has been published for the superiority of semaglutide for glycaemic control in patients after switching from a dipeptidyl peptidase-4 (DPP-4) inhibitor. Therefore, we aim to verify the efficacy of oral semaglutide in patients with T2D being treated with a DPP-4 inhibitor. METHODS AND ANALYSIS: This study is a multicentre, prospective, randomised, open-label, parallel-group trial. In total, 172 participants with T2D who have been treated with a DPP-4 inhibitor for more than 12 weeks and who have a glycated haemoglobin (HbA1c) level of 7.0%-9.9% will be randomised to continue using their existing DPP-4 inhibitor or switch to oral semaglutide for 24 weeks. Biochemical analyses and physical assessment will be performed, and adverse events will be recorded at baseline and at the end of the study. The primary endpoint will be the effect of oral semaglutide on the change in HbA1c. The secondary endpoints will be the mean changes in body weight, abdominal circumference, systolic and diastolic blood pressure (BP), pulse rate, the relationship between improvement of metabolic parameters including HbA1c and patient background characteristics, side effects and other laboratory parameters. ETHICS AND DISSEMINATION: This will be the first study to compare the effects of switching from a DPP-4 inhibitor to oral semaglutide on glycaemic control in patients with T2D. The results will be disseminated in peer-reviewed journals and at scientific conferences. Hokkaido University Certified Review Board (CRB no.1180001) has approved the protocol (no. 020-013). TRIAL REGISTRATION NUMBER: UMIN000045270 in the University Hospital Medical Information Network; jRCT1011210032 in the Japan Registry of Clinical Trials.

Lymphocytic panhypophysitis and anti-rabphilin-3A antibody with pulmonary sarcoidosis.

PURPOSE: To explore the clinical significance of anti-rabphillin-3A antibody for the differential diagnosis of lymphocytic panhypophysitis. METHODS AND RESULTS: A 58-year-old Japanese man developed uveitis of unknown cause in 2017. In 2019, he became aware of polyuria. In August 2020, he noticed transient diplopia and was diagnosed with right abducens nerve palsy. At the same time, he complained of fatigue and loss of appetite. Head magnetic resonance imaging demonstrated enlargement of the pituitary stalk and pituitary gland, corresponding to hypophysitis. Hormone stimulation tests showed blunted responses with respect to all anterior pituitary hormones. Central diabetes insipidus was diagnosed on the basis of a hypertonic saline loading test. Taking these findings together, a diagnosis of panhypopituitarism was made. Computed tomography showed enlargement of hilar lymph nodes. Biopsies of the hilar lymph nodes revealed non-caseating epithelioid cell granulomas that were consistent with sarcoidosis. Biopsy of the anterior pituitary revealed mild lymphocyte infiltration in the absence of IgG4-positive cells, non-caseating granulomas, or neoplasia. Western blotting revealed the presence of anti-rabphilin-3A antibody, supporting a diagnosis of lymphocytic panhypophysitis. Because the patient had no visual impairment or severe uveitis, we continued physiological hormone replacement therapy and topical steroid therapy for the uveitis. CONCLUSION: To the best of our knowledge, this is the first case of anti-rabphilin 3A antibody positive lymphocytic panhypophysitis comorbid with sarcoidosis, diagnosed by both pituitary and hilar lymph node biopsy. The utility of anti-rabphilin-3A antibody for the differential diagnosis of hypophysitis like this case should be clarified with further case studies.

Favorable effects of burosumab on tumor-induced osteomalacia caused by an undetectable tumor: A case report.

RATIONALE: Tumor-induced osteomalacia (TIO) is curable by tumor resection, but detection of the tumor can be challenging. Overproduction of fibroblast growth factor 23 (FGF23) by the tumor causes hypophosphatemia and consequently induces inappropriate bone turnover. Conventionally oral phosphate supplementation was the only treatment for TIO, but had risks of hypercalciuria and nephrocalcinosis. Burosumab, a human monoclonal anti-FGF23 antibody, was recently post-marketed in Japan against for FGF23-related hypophosphatemia. Herein, we present a case of TIO with undetectable tumor that was successfully treated with burosumab. PATIENT CONCERNS: A 47-year-old woman was forced to use a wheelchair because of pain in both feet. DIAGNOSIS: Laboratory findings showed hypophosphatemia, elevated bone markers, and high serum FGF23 without renal tubular defects. Imaging studies revealed bone atrophy in the feet, decreased bone density, and multiple pseudofractures in the talar, sacral, and L5 vertebral regions. After excluding drug-induced and hereditary osteomalacia, we diagnosed her as TIO. INTERVENTIONS: Comprehensive imaging studies and stepwise venous sampling failed to localize the tumor, and we started to administer subcutaneous burosumab. OUTCOMES: After administration of burosumab, her serum phosphate was normalized without phosphate supplementation within 2 months. Improvement of pseudofractures, relief of pain evaluated by a visual analog scale, and normalization of bone biomarkers were observed. The patient was able to stand by herself after 6 months administration of burosumab. LESSONS: This is the first report in clinical practice to demonstrate favorable effects of burosumab, including not only normalization of serum phosphate but also improvements of pseudofractures and subjective pain, in a patient with TIO and undetectable tumor.

Acromegaly Cases Exhibiting Increased Growth Hormone Levels during Oral Glucose Loading with Preadministration of Dipeptidyl Peptidase-4 Inhibitor.

Objective Glucose-dependent insulinotropic polypeptide (GIP) is speculated to worsen growth hormone (GH) hypersecretion in acromegaly and to be a cause of paradoxical increases in GH (PI-GH) during 75-g oral glucose tolerance testing (75-g OGTT). Dipeptidyl peptidase-4 inhibitors (DPP4is), which increase the circulating concentration of active GIP, are frequently administered to diabetic patients, including those with acromegaly. We aimed to determine whether or not the administration of a DPP4i increases GH concentration, especially in patients demonstrating PI-GH during a DPP4i-OGTT, in which a DPP4i was administered immediately before 75-g OGTT. Methods This prospective cross-sectional study was carried out on acromegalic patients admitted to Hokkaido University hospital between June 2011 and May 2018. The participants underwent both 75-g OGTT and DPP4i-OGTT. For those who underwent surgery, immunohistochemical staining and quantitative polymerase chain reaction (PCR) for the GIP receptor (GIPR) were performed on the resected pituitary adenomas. Results Twenty-five percent of the participants had PI-GH confirmed (3 of 12 cases). Two of the three participants who demonstrated PI-GH exhibited higher circulating GH concentrations during DPP4i-OGTT than during OGTT. The increase in plasma glucose was reduced during DPP4i-OGTT compared to during 75-g OGTT, suggesting that the increase in GH during DPP4i-OGTT was due not to high glucose concentrations but instead increased GIP caused by the administration of DPP4i. The adenoma from one participant with PI-GH displayed positive immunostaining for GIPR and a higher GIPR messenger ribonucleic acid (mRNA) expression than the others. Conclusion DPP4i may enhance the GH secretion response during glucose loading, especially in individuals with PI-GH.

Two Distinctive POMC Promoters Modify Gene Expression in Cushing Disease.

CONTEXT: Mechanisms underlying pituitary corticotroph adenoma adrenocorticotropin (ACTH) production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes. OBJECTIVE: We characterized the 5' ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production. METHODS: We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent corticotroph adenomas (SCAs) that immunostain for but do not secrete ACTH. RESULTS: We identified a novel regulatory region located near the intron 2/exon 3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCAs, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the ubiquitin-specific protease 8 (USP8) mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing disease. CONCLUSION: We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.

Dipeptidyl peptidase-4 inhibitor might exacerbate Graves' disease: A multicenter observational case-control study.

Dipeptidyl peptidase-4 (DPP-4), namely CD26, is expressed on the surface of immune cells, suggesting that inhibition of DPP-4 might affect the immune system. The current multicenter observational case-control study was carried out to investigate the effects of DPP-4 inhibitor (DPP-4i) administration on Graves' disease (GD) activity. This study comprised patients with GD and type 2 diabetes, who were administered an oral hypoglycemic agent including DPP-4i. Exacerbation of GD was defined as an increase of antithyroid drug dose by 6 months after oral hypoglycemic agent administration. A total of 80 patients were enrolled and divided into an exacerbation group or a non-exacerbation group. The frequency of DPP-4i administration was significantly higher in the exacerbation group (88%) than that in the non-exacerbation group (31%). In multivariate logistic regression analysis, there was a significant association between DPP-4i administration and GD exacerbation (odds ratio 7.39). The current study suggests that DPP-4i administration is associated with GD exacerbation.

Severe infection including disseminated herpes zoster triggered by subclinical Cushing's disease: a case report.

BACKGROUND: Subclinical Cushing's disease (SCD) is defined by corticotroph adenoma-induced mild hypercortisolism without typical physical features of Cushing's disease. Infection is an important complication associated with mortality in Cushing's disease, while no reports on infection in SCD are available. To make clinicians aware of the risk of infection in SCD, we report a case of SCD with disseminated herpes zoster (DHZ) with the mortal outcome. CASE PRESENTATION: An 83-year-old Japanese woman was diagnosed with SCD, treated with cabergoline in the outpatient. She was hospitalized for acute pyelonephritis, and her fever gradually resolved with antibiotics. However, herpes zoster appeared on her chest, and the eruptions rapidly spread over the body. She suddenly went into cardiopulmonary arrest and died. Autopsy demonstrated adrenocorticotropic hormone-positive pituitary adenoma, renal abscess, and DHZ. CONCLUSIONS: As immunosuppression caused by SCD may be one of the triggers of severe infection, the patients with SCD should be assessed not only for the metabolic but also for the immunodeficient status.

Successful management of a patient with active Cushing's disease complicated with coronavirus disease 2019 (COVID-19) pneumonia.

We provide the details of the successful management of a patient with active Cushing's disease complicated with coronavirus disease 2019 (COVID-19) pneumonia. The patient was a 27-year-old Japanese female healthcare worker who was scheduled to undergo pituitary surgery for Cushing's disease. She had been in close contact with an undiagnosed patient infected with COVID-19 and then developed COVID-19 pneumonia. Despite a lack of known risk factors associated with severe COVID-19 infection, the patient's dyspnea worsened and her respiratory condition deteriorated, as indicated by the need for 7 L/min oxygen supply by mask to maintain her oxygen saturation at >90%. Medical treatment was initiated to control hypercortisolism by the 'block and replace' regimen using steroidogenesis inhibitors and hydrocortisone. The COVID-19 pneumonia improved with multi-modal treatment including antiviral therapy. One month later, after a negative severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) test result and with appropriate protection against virus transmission to medical staff in the operating room and daily medical care nurses, trans-sphenoidal surgery was performed by our highly experienced pituitary surgeon. One month after the surgery, the patient's basal ACTH and cortisol levels and urinary free cortisol were all under the detection limit. Surgical remission was expected. Since hypercortisolism due to active Cushing's disease may worsen a COVID-19 infection, multi-disciplinary management that includes appropriate and prompt treatment strategies is mandatory in such cases.

Silent pituitary adenoma and metabolic disorders: obesity, abnormal glucose tolerance, hypertension and dyslipidemia.

A silent pituitary adenoma (SPA) is characterized by the expression of pituitary hormones, detected by immunohistochemical staining, in the absence of clinical signs or symptoms of hormonal excess. Compared with functional pituitary adenomas, little is known regarding the involvement of SPAs in metabolic disorders. This study aimed to examine the correlations between SPAs and metabolic disorders, including obesity, abnormal glucose tolerance, hypertension and dyslipidemia. Seventy-four patients with nonfunctional pituitary adenomas who underwent a pituitary adenomectomy in Hokkaido University Hospital from 2008 to 2016 were retrospectively examined. Pituitary adenomas were immunohistochemically classified into pituitary hormone positive or negative groups. Twenty whole hormone-negative pituitary adenomas were excluded because we couldn't identify pituitary transcription factors which is necessary for the diagnosis of a null cell adenoma. The preoperative rates of obesity, abnormal glucose tolerance, hypertension and dyslipidemia were compared between each group. Twenty-seven GH positive adenomas (50.0%), 32 gonadotroph positive adenomas (59.3%), 28 TSH positive adenomas (51.9%) and 21 ACTH positive adenomas (38.9%) were identified. Evaluation of the preoperative clinical data showed 25 cases of obesity (46.2%), 16 cases of abnormal glucose tolerance (29.6%), 29 cases of hypertension (53.7%) and 35 cases of dyslipidemia (64.8%). The rate of hypertension was significantly lower in the GH positive group (37.0%) than the GH negative group (70.4%) (p = 0.0140). In the GH negative group, postoperative systolic and diastolic blood pressure levels were significantly lower than preoperative values. GH positive SPAs may affect the homeostasis of blood pressure.

Beneficial effects of switching to denosumab from bisphosphonates or selective estrogen receptor modulators in postmenopausal women with type 2 diabetes and osteopenia/osteoporosis.

AIMS/INTRODUCTION: Patients with type 2 diabetes mellitus have a higher bone fracture risk than patients without diabetes. Although denosumab (Dmab) is a potent bone resorption inhibitor, its efficacy in patients with type 2 diabetes mellitus has not been elucidated. In this study, we investigated the effects of switching to Dmab from bisphosphonates (BP) or a selective estrogen receptor modulator (SERM) in postmenopausal type 2 diabetes mellitus patients. MATERIALS AND METHODS: This was a three medical institutions, prospective, observational study for postmenopausal patients with type 2 diabetes mellitus whose T-score of femoral neck or lumbar spine bone mineral density was under -1.0 standard deviation, even after >6 months of BP or SERM administration. After obtaining consent, participants were treated for osteopenia/osteoporosis by either continuing BP (BP-BP group)/SERM (SERM-SERM group), or by switching to Dmab (BP-Dmab or SERM-Dmab groups). Changes in bone mineral density and bone metabolism marker levels were evaluated after 6 months. RESULTS: A total of 48 patients were included in this study, and each group comprised 12 patients. No significant difference existed in baseline characteristics among the groups. The average age and glycated hemoglobin were 71 ± 8 years and 7.2 ± 0.9%, respectively. In the SERM-Dmab group, lumbar spine bone mineral density was significantly increased by 5.0% compared with the SERM-SERM group (P < 0.04). Serum bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b were significantly decreased in the BP-Dmab and SERM-Dmab groups compared with the BP-BP and SERM-SERM groups, respectively. CONCLUSIONS: Switching to Dmab from BP or SERM is beneficial to prevent osteoporosis progression in postmenopausal patients with type 2 diabetes mellitus patients.

Impact of sodium-glucose cotransporter 2 inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease with normoalbuminuria.

BACKGROUND: We compared the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease (CKD) classified by degree of albuminuria. METHODS: A retrospective review of the clinical records of Japanese participants with type 2 diabetes (age > 20 years; SGLT2 inhibitor treatment > 2 years; estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) was conducted. Based on the urinary albumin-to-creatinine ratio (UACR) or urinary protein-to-creatinine ratio (UPCR) at the start of SGLT2 inhibitor administration, participants were categorized into three groups: normoalbuminuria (A1; UACR < 30 mg/g Cr or UPCR < 0.15 g/g Cr), microalbuminuria (A2; UACR 30 to < 300 mg/g Cr or UPCR 0.15 to < 0.50 g/g Cr), and macroalbuminuria (A3; UACR ≥ 300 mg/g Cr or UPCR ≥ 0.50 g/g Cr). The study outcome was a comparison of the rates of change in renal function evaluated by eGFR at 2 years after starting SGLT2 inhibitor among the three groups. RESULTS: A total of 87 participants (40 females, 47 males) were categorized into three groups: A1 (n = 46), A2 (n = 25), and A3 (n = 16). eGFR was similarly decreased at 2 years before starting SGLT2 inhibitor in all three groups. However, the decline in eGFR was ameliorated at 2 years after starting SGLT2 inhibitor, and eGFR was rather increased in the A1 and A2 groups. Interestingly, the rate of change in eGFR at 2 years after starting SGLT2 inhibitor in the A1 group was significantly higher than that in the A3 group. CONCLUSIONS: These results demonstrate that more favorable effects of SGLT2 inhibitors on renal function were observed in participants with type 2 diabetes and CKD with normoalbuminuria compared with those with macroalbuminuria.Trial registration UMIN-CTR: UMIN000035263. Registered 15 December 2018.

A Novel Expression Profile of Cell Cycle and DNA Repair Proteins in Nonfunctioning Pituitary Adenomas.

The molecular mechanisms underlying the formation of nonfunctioning pituitary adenomas (NFAs) are largely unknown. In this study, we aimed to understand the relationship between NFAs and functional pituitary adenomas and the possible role of proteins involved in cell cycle, senescence, and DNA damage control mechanisms in the etiology of NFA. We analyzed pATM-S1981, pRb-S608, Rb, pE2F1-S364, p16, E2F1, p73, cyclin D1, and CHEK2 protein expression (in a group of 20 patients with acromegaly, 18 patients with Cushing's disease (CD), and 29 NFA patients) by immunohistochemistry and their relevant mRNA expression by qRT-PCR (in a group of 7 patients with acromegaly, 7 patients with CD, and 7 NFA patients). The clinical and histopathological results on the patients were statistically evaluated. pE2F1-S364 protein expression in the CD group was significantly lower than that in the NFA and acromegaly groups (p = 0.025, p = 0.034, respectively). However, the expression of the p16 protein was lower than in the NFA group than in the CD and acromegaly groups (p = 0.030, p = 0.033, respectively), and E2F1 protein expression was significantly higher in the NFA group than in the CD group (p = 0.025). p73 protein expression in patients with acromegaly was significantly higher (p = 0.031) than that in the CD group. CHEK2 mRNA expression in the CD group was significantly higher than that in the acromegaly group (p = 0.012). The selective and tumor-specific associations between E2F1, pE2F1-S364, CHEK2, and p73 mRNA and protein levels indicate their involvement in pituitary adenoma formation in NFA, CD, and acromegaly patients.

Nivolumab-induced hypophysitis causing secondary adrenal insufficiency after transient ACTH elevation.

A 62-year-old man was referred to our department for elevation of plasma ACTH and cortisol levels during nivolumab administration for renal cell carcinoma. Although his ACTH and cortisol levels had been maintained within their reference ranges, they were elevated to 232.7 pg/mL and 21.9 µg/dL, respectively, after eight courses of nivolumab without any subjective symptoms or Cushing's sign. He was hospitalized for endocrinological investigation. ACTH and cortisol returned to their normal ranges (29.18 pg/mL and 11.4 µg/dL, respectively) in the early morning on day 1, but fell down sharply to 3.7 pg/mL and 1.6 µg/dL, respectively, in the early morning on day 2 without subjective symptoms or vital sign changes. Brain magnetic resonance imaging showed no abnormality in his pituitary gland. ACTH response to CRH was apparently normal, but cortisol did not respond to increased ACTH. A rapid ACTH stimulation test showed slightly reduced response of cortisol to exogenous ACTH (1-24). These findings and his clinical course suggested secondary adrenal insufficiency arising from nivolumab-induced hypophysitis. In previous reports, most cases of immune checkpoint inhibitor (ICI)-induced hypophysitis were diagnosed based on adrenal insufficiency symptoms or hyponatremia with low ACTH and cortisol. The ACTH elevation observed in the present case may reflect destruction of the pituitary gland, suggesting that this finding may be important for early detection of ICI-induced hypophysitis. Our case underlines the necessity of close monitoring for subsequent onset of adrenal insufficiency when ACTH elevation is observed during ICI administration.

Protective effect of sodium-glucose cotransporter 2 inhibitors in patients with rapid renal function decline, stage G3 or G4 chronic kidney disease and type 2 diabetes.

AIMS/INTRODUCTION: The risk of end-stage kidney disease increases in proportion to the decline in the estimated glomerular filtration rate (eGFR). Although protective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the eGFR decline were shown in several large-scale clinical trials, there are no studies investigating patients with a high risk of end-stage kidney disease. We investigated the efficacy and safety of SGLT2i in advanced renal dysfunction patients (stage G3 or G4 of chronic kidney disease) with a rapid decline in eGFR. MATERIALS AND METHODS: This retrospective, longitudinal study enrolled patients with type 2 diabetes who were treated with SGLT2i, and whose eGFR was <60 mL/min/1.73 m2 and had declined >20% over 2 years (%ΔeGFR-2y) before initiating SGLT2i. The primary end-point was the change in eGFR 2 years after initiation (%ΔeGFR+2y) compared with %ΔeGFR-2y. RESULTS: A total of 17 patients among 553 patients treated with SGLT2i for ≥2 years were included in the study. The average age, glycated hemoglobin and eGFR at SGLT2i initiation were 68.5 years, 7.3% and 38.3 mL/min/1.73 m2 , respectively. %ΔeGFR+2y in patients who were treated with SGLT2i was significantly increased compared with the patients not treated with SGLT2i (2.3 and -21.7%, respectively; P < 0.0001). A multiple regression analysis showed that only the proportion of the rate of eGFR decline was the independent factor associated with improvement of %ΔeGFR+2y. There was no increase in serious adverse events including acute kidney injury. CONCLUSIONS: SGLT2i was safe, and prevented further eGFR decline in patients with type 2 diabetes and advanced renal dysfunction.

Breakdown of Autonomously Functioning Thyroid Nodule Accompanied by Acromegaly After Octreotide Treatment.

Patients with acromegaly are at increased risk of developing certain tumors, including goiter and thyroid nodules, and occasionally autonomous thyroid nodules. A 53-year-old woman presented at our hospital with untreated acromegaly. She had typical physical features of acromegaly with pituitary adenoma, and thyrotoxicosis with thyroid-stimulating hormone suppression was also confirmed. Thyroid ultrasonography and scintigraphy showed an autonomously functioning thyroid nodule on her right lobe. Because her thyrotoxicosis was mild, she was initially treated with octreotide for acromegaly. However, 1 month after octreotide administration, she developed neck pain and fever with transient thyrotoxicosis. The blood flow around the nodule then decreased and the excess trapping of isotope detected by scintigraphy was reduced, followed by normalization of insulin-like growth factor-1 levels and thyroid function. This case suggests that octreotide may have unexpected effects on autonomous thyroid nodules. However, further studies are needed to determine the clinical course of autonomously functioning thyroid nodules, including thyroid function and tumor manifestations, during octreotide therapy.

Case of fulminant type 1 diabetes induced by the anti-programmed death-ligand 1 antibody, avelumab.

With the expansive use of immune checkpoint inhibitors, the frequency of immune-related adverse events, including autoimmune type 1 diabetes, has been exponentially increased. The anti-programmed death-ligand 1 antibody, avelumab, has recently been approved for metastatic Merkel cell carcinoma therapy. Here, we report a patient that developed fulminant type 1 diabetes during avelumab treatment. An 81-year-old woman with no history of diabetes received avelumab for metastatic Merkel cell carcinoma. Elevated plasma glucose level (483 mg/dL), hemoglobin A1c level (7.5%) and ketosis were observed after 10 courses of avelumab without any symptoms related to hyperglycemia. As the laboratory tests showed insulin depletion, we diagnosed her with fulminant type 1 diabetes induced by avelumab. This is the first reported case of avelumab-induced type 1 diabetes, illustrating the necessity for close monitoring of glycemic control during avelumab therapy, as well as other immune checkpoint inhibitors.