Comparison of clinical efficacy and safety of weekly glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide in Japanese patients with type 2 diabetes: Randomized, parallel-group, multicentre, open-label trial (COMING study).

AIM: To compare the clinical usefulness of once-weekly glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide at the doses approved for use in Japanese patients with type 2 diabetes. METHODS: In total, 120 patients with glycated haemoglobin (HbA1c) ≥7% were randomly assigned to dulaglutide (n = 59) or semaglutide group (n = 61), and 107 participants (dulaglutide/semaglutide = 53/54) completed the 24-week trial. The primary endpoint was the difference of HbA1c level between the two groups at 24 weeks. RESULTS: HbA1c level at 24 weeks was significantly lower in the semaglutide group (7.9 ± 0.5%-6.7 ± 0.5%) compared with the dulaglutide group (8.1 ± 0.6%-7.4 ± 0.8%) (p < .0001). Reduction in body mass index and visceral fat area were also more significant in the semaglutide group (p < .05, respectively). The achievement rate of HbA1c <7% was higher in the semaglutide group (p < .0001). The parameters such as low-density lipoprotein cholesterol, alanine aminotransferase and γ-glutamyl transpeptidase were decreased in the semaglutide group. Surprisingly, only semaglutide group significantly improved the apolipoprotein B/A1 ratio, which is considered a useful myocardial infarction risk index. Using computed tomography, the liver to spleen ratio was significantly elevated only in the semaglutide group. In contrast, gastrointestinal symptoms were observed in 13.2% of dulaglutide and 46.3% of semaglutide group (p < .01). The Diabetes Treatment-Related Quality of Life scores related to pain and gastrointestinal symptoms were also superior in the dulaglutide group. CONCLUSIONS: This prospective trial showed that semaglutide has more pronounced glucose- and body mass index-lowering effects and reduces liver fat percentage and visceral fat area and that dulaglutide has less gastrointestinal symptoms and superior Diabetes Treatment-Related Quality of Life scores related to pain and gastrointestinal symptoms.

Ectopic PTH-producing parathyroid cyst inside the thymus: a case report.

BACKGROUND: The hallmark of hyperparathyroidism is hypersecretion of parathyroid hormone (PTH) which results in hypercalcemia and hypophosphatemia. While hypercalcemia due to malignancy is often brought about by PTH-related protein in adults, PTH-producing tumors are quite rare in clinical practice. Additionally, from the point of embryology, it is very difficult to examine ectopic PTH-producing tissue such as ectopic parathyroid glands. Furthermore, clear histopathological criteria are not present. CASE PRESENTATION: A 57-year-old woman was referred to our hospital for hypercalcemia. Her parathyroid hormone (PTH) level was elevated, but there were no enlarged parathyroid glands. Although 99mTc-MIBI confirmed a localized and slightly hyperfunctioning parathyroid tissue in the anterior mediastinum, it was not typical as hyperfunctioning parathyroid. We finally diagnosed her as ectopic PTH-producing cyst-like tumor with venous sampling of PTH. She underwent anterosuperior mediastinal ectopic PTH-producing cyst-like tumor resection. It is noted that intact-PTH concentration of the fluid in the cyst was very high (19,960,000 pg/mL). Based on histopathological findings, we finally diagnosed her as ectopic PTH-producing parathyroid cyst inside the thymus. After resection of anterosuperior mediastinal thymus including ectopic PTH-producing parathyroid cyst, calcium and intact-PTH levels were decreased, and this patient was discharged without any sequelae. CONCLUSIONS: We should know the possibility of superior mediastinal ectopic PTH-producing parathyroid cyst inside the thymus among subjects with ectopic PTH-producing parathyroid glands. Particularly when the cyst is present in the superior mediastinum, it is necessary to do careful diagnosis based on not only positive but also negative findings in 99mTc-MIBI. It is noted that the patient's bloody fluid in the cyst contained 19,960,000 pg/mL of intact-PTH, and its overflow into blood stream resulted in hyperparathyroidism and hypercalcemia. Moreover, in such cases, the diagnosis is usually confirmed after through histological examination of ectopic PTH-producing parathyroid glands. We think that it is very meaningful to let clinicians know this case.

IgG4-related lung disease with multifocal pulmonary consolidations near the pleura: A case report.

RATIONALE: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic immune-mediated condition that can cause fibroinflammatory lesions in multiple organs. Approximately 35% of IgG4-RD patients have some symptoms in the chest and IgG4-related lung disease (IgG4-RLD) is observed in about 10% of IgG4-RD cases. In addition, it is thought that glucocorticoid therapy is effective for IgG4-RD and IgG4-RLD. It is difficult to diagnose IgG4-RLD complicated with another lung disease. PATIENT CONCERNS: An 85-year-old Japanese man was hospitalized due to pulmonary consolidations just below the pleura in chest computed tomography while being treated with antibiotics. Previously, an upper lobectomy of the right lung was performed for an upper lung mucinous adenocarcinoma, and he was diagnosed with chronic obstructive pulmonary disease. Although he took antibiotics before admission, C-reactive protein levels were elevated. DIAGNOSIS: IgG4 levels were also elevated (IgG4; 733 mg/dL), and lung biopsy histology showed an abundance of IgG4-positive plasma cell infiltration; about 40% of the affected area was occupied by such infiltration. Based on such findings, we finally diagnosed him as IgG4-RLD. INTERVENTIONS: We administered 20 mg/d prednisolone. OUTCOMES: About 2 weeks after administration of prednisolone by intravenous injection, his multifocal pulmonary consolidations just below the pleura were markedly improved and his pulmonary symptoms disappeared. Four weeks after glucocorticoid therapy, IgG4 levels decreased from 831 mg/dL (peak) to 547 mg/dL. LESSONS: We should consider IgG4-RLD, a rare disease, when lesions are detected as pulmonary consolidations near the pleura and are unresponsive to antibiotic therapy. Glucocorticoid therapy, however, is very effective for such IgG4-RLD.

Case Report: A Patient With Neuroleptic Malignant Syndrome, Water Intoxication and Hyponatremia Associated With Severe Cerebral Edema and Coma.

Background: Water intoxication is typically caused by primary or psychogenic polydipsia that potentially may lead to fatal disturbance in brain functions. Neuroleptic malignant syndrome (NMS) is a serious complication induced by administration of antipsychotics and other psychotropic drugs. The combination of inappropriate secretion of antidiuretic hormone (SIDAH), NMS and rhabdomyolysis have been rarely reported. Our patient also developed severe water intoxication. Case presentation: Herein we report a comatose case of NMS complicated with water intoxication, syndrome of SIADH and rhabdomyolysis. This patient had severe cerebral edema and hyponatremia that were improved rapidly by the correction of hyponatremia within a couple of days. Conclusions: Malignant neuroleptic syndrome water intoxication, SIADH and rhabdomyolysis can occur simultaneously. Comatose conditions induced by cerebral edema and hyponatremia can be successfully treated by meticulous fluid management and the correction of hyponatremia.

Formation of large abscess tumor including gallstone in ileum during therapy for hyperosmolar hyperglycemic syndrome: a case report.

Hyperosmolar hyperglycemic status (HHS) is one of the most serious acute metabolic complications of diabetes mellitus (DM) and the patients with type 2 DM are immunocompromised host, especially when glycemic control is poor. Under hyperglycemic conditions, we have to pay much attention even for rare infection. Bouveret's syndrome is a rare type of gallstone ileus together with duodenal obstruction secondary to the passage of a stone through a cholecystoduodenal fistula. Herein, we reported a rare case with formation of large abscess tumor, including necrotic ileum and gallstone after taking therapy for HHS. She was under more rare conditions rather than Bouveret's syndrome, because large abscess tumor was formed not in the duodenal bulb but in the ileum together with necrotic ileitis and abdominal abscess with impacted gallstone. We should bear in mind that T2DM patients are immunocompromised host in particular under untreated or poorly controlled conditions and thereby they could have rare inflammatory diseases such as a large abscess tumor. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00540-3.

Syndrome of inappropriate secretion of thyroid-stimulating hormone in a subject with galactorrhea and menstrual disorder and undergoing infertility treatment: Case report.

RATIONALE: Syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH) is a rare cause of hyperthyroidism. Thyroid-stimulating hormone (TSH) levels are usually normal or high, and triiodothyronine (FT3) and free thyroxine (FT4) levels are usually high in subjects with SITSH. PATIENT CONCERN: A 37-year-old woman had experienced galactorrhea and menstrual disorder for a couple of years before. She had undergone infertility treatment in 1 year before, hyperthyroidism was detected and she was referred to our institution. DIAGNOSIS: She was suspected of having SITSH and was hospitalized at our institution for further examination. The data on admission were as follows: FT3, 4.62 pg/mL; FT4, 1.86 ng/dL; TSH, 2.55 µIU/mL. Although both FT3 and FT4 levels were high, TSH levels were not suppressed, which is compatible with SITSH. In addition, in brain contrast-enhanced magnetic resonance imaging, nodular lesions were observed in the pituitary gland with a diameter of approximately 10 mm. In the thyrotropin-releasing hormone load test, TSH did not increase at all, which was also compatible with TSH-secreting pituitary adenoma. In the octreotide load test, the TSH levels were suppressed. Based on these findings, we diagnosed this subject as SITSH. INTERVENTIONS: Hardy surgery was performed after the final diagnosis. In TSH staining of the resected pituitary adenoma, many TSH-producing cells were observed. These findings further confirmed the diagnosis of pituitary adenoma producing TSH. OUTCOMES: Approximately 2 months after the operation, TSH, FT3, and FT4 levels were normalized. Approximately 3 months after the operation, she became pregnant without any difficulty. LESSONS: We should consider the possibility of SITSH in subjects with galactorrhea, menstrual disorders, or infertility. In addition, we should recognize that it is very important to repeatedly examine thyroid function in subjects with galactorrhea, menstrual disorder, or infertility.

Case Report: Emphysematous Cystitis and Pyelonephritis Induced by Uterine Prolapse in a Subject With Untreated Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is often accompanied by a lot of complications due to chronic hyperglycemia and inflammation. Emphysematous cystitis and pyelonephritis are rare types of urinary tract infections and are often complicated with DM. Herein, we report a case of emphysematous cystitis and pyelonephritis complicated with untreated DM. In addition, this case was very rare and interesting in that her emphysematous cystitis and pyelonephritis were induced by severe uterine prolapse, obstructive uropathy and urination disorders. Both uterine prolapse and DM should be appropriately treated because both can lead to the development of emphysematous cystitis and pyelonephritis.

Case Report: Various Abnormalities in Lipid and Glucose Metabolism Induced by Capecitabine.

Capecitabine has been used for the treatment of various types of tumors. The rare side effects induced by capecitabine have been reported as hypertriglyceridemia, acute pancreatitis associated with hypertriglyceridemia and hypertriglyceridemia complicated with hyperglycemia. The mechanisms of capecitabine-induced hypertriglyceridemia are unclear. In this report, we present a subject with sigmoid colon cancer and capecitabine-induced dyslipidemia. LDL-cholesterol level was markedly elevated throughout the long period of treatment with capecitabine. In addition, triglyceride level was high and not stable during the treatment period. Her dyslipidemia was ameliorated by the treatment with 5 mg of rosuvastatin, which is one of the HMG-CoA reductase inhibitors.

Primary Epstein-Barr virus infection shortly after primary Cytomegalovirus infection: a case report.

BACKGROUND: Infectious mononucleosis (IM) and mononucleosis-like illnesses are common viral infectious diseases which are often accompanied by a high fever, pharyngitis and lymphadenopathy in adults, although such infection in childhood is generally subclinical. Most cases of IM are caused by the Epstein-Barr virus (EBV) or Cytomegalovirus (CMV). However, it is difficult to diagnose IM only with subjective symptoms, and thus EBV and CMV are nearly indistinguishable in clinical practice. CASE PRESENTATION: A 20-year-old healthy Japanese woman had a 2-day history of high fever and consulted us. She had sex for the first time 6 months earlier. Her virus antibodies showed that she was infected with primary CMV. About 5 months later, she again experienced high fever and lymph node enlargement at the posterior cervical region. Her virus antibodies showed that she was infected with primary EBV at that time. CONCLUSION: Herein, we report a healthy adult Japanese woman with primary EBV infection relatively soon after primary CMV infection. It is very interesting to compare the symptoms and/or clinical data after EBV and CMV infection in the same patient within a short period of time. Our patient was diagnosed based only on subjective symptoms, physical examination and laboratory data, without tests of such virus-related antibodies. Therefore, clinicians should bear in mind that primary EBV infection and/or primary CMV infection is possible when patients have symptoms such as high fever, pharyngitis and lymphadenopathy, even in healthy adults.

Basedow's disease with associated features of Hashimoto's thyroiditis based on histopathological findings.

BACKGROUND: Basedow's disease and Hashimoto's thyroiditis are autoimmune thyroid disorders and usually diagnosed with elevation of serum autoimmune antibodies. Thyrotropin receptor antibodies (TRAb) and/or thyroid-stimulating antibody (TSAb) are usually used for diagnosis of Basedow's disease, and thyroid peroxidase antibodies (TPOAb) and/or thyroglobulin antibodies (TgAb) are for diagnosis of Hashimoto's thyroiditis. However, it is difficult to diagnose a subject as Basedow's disease with associated features of Hashimoto's thyroiditis only with elevation of such autoimmune antibodies. CASE PRESENTATION: A 44-year-old woman with 5-year history of Basedow's disease underwent a total thyroidectomy. She did not have a goiter. TRAb, TSAb, TPOAg and TgAb were all positive before a total thyroidectomy. In histopathological macroscopic examination, diffuse hyperplasia of the thyroid gland was observed. Furthermore, in histopathological microscopic examination, both characteristics of Basedow's disease and Hashimoto's thyroiditis were observed. After a total thyroidectomy, titers of all thyroid-associated autoimmune antibodies were markedly reduced. CONCLUSION: Herein, we report a subject with Basedow's disease without a goiter whose TPOAb and TgAb were relatively high at the onset of Basedow's disease. In addition, interestingly, the histopathological findings of this subject showed direct signs of Basedow's disease and Hashimoto's thyroiditis in the same thyroid gland. Considering from such findings, she seemed to have Basedow's disease with associated features of Hashimoto's thyroiditis. In conclusion, we should bear in mind the possibility of Basedow's disease with associated features of Hashimoto's thyroiditis in subjects with Basedow's disease, particularly when TPOAb and TgAb as well as TRAb and TSAb are positive.

A rare case of large pyosalpinx in an elderly patient with well-controlled type 2 diabetes mellitus: a case report.

BACKGROUND: Pyosalpinx, which is one of the pelvic inflammatory diseases, is usually observed in young women; it is rarely found in older women. Possible causative agents are thought to be Chlamydia trachomatis and Neisseria gonorrhea in addition to some Enterobacteriaceae. On the other hand, type 2 diabetes is a disease with a lot of complications such as hyperglycemia, inflammation, and immune disorders. Therefore, patients with type 2 diabetes mellitus have an increased susceptibility to infection especially when glycemic control is poor. CASE PRESENTATION: We experienced a rare case of large pyosalpinx in an elderly patient with well-controlled type 2 diabetes mellitus. A 72-year-old Japanese woman with a 10-year history of type 2 diabetes mellitus had symptoms of diarrhea and persistent pain in left lower abdomen. She had mild tenderness to palpation in her abdomen. Inflammation markers were markedly elevated. Her abdominal computed tomography and magnetic resonance imaging on admission revealed a tumor in left side of intrapelvis and we diagnosed her as having pyosalpinx. Pathogenic bacteria were not detected. On admission, her glycemic control was relatively good; in addition, her glycated hemoglobin levels were around 6% for over 1 year. Although pathogenic bacteria were not detected, we started antibiotics therapy. Fourteen days after starting the antibiotics her laboratory data were improved. Three months later, the tumor was markedly smaller compared to that on admission. CONCLUSIONS: We should keep in mind that older patients with type 2 diabetes mellitus are immunocompromised hosts and thereby they could have rare pelvic inflammatory disease such as pyosalpinx even when good glycemic control is obtained for a long period of time.

Clinical course of pituitary function and image in IgG4-related hypophysitis.

A 76-year-old man had a hypopituitarism including adrenal insufficiency, hypogonadism and hypothyroidism. Based on various findings including the swelling of the pituitary gland, increase of serum IgG4 level and abundant IgG4-positive plasma cell infiltration in immunostaining of the pituitary gland, we diagnosed this subject as IgG4-related hypophysitis. In general, a high-dose glucocorticoid treatment is effective for IgG4-related disease. His clinical symptom, laboratory data and adrenal insufficiency were almost improved without any therapy. The serum IgG4 level was decreased and pituitary size was normalized with hydrocortisone as physiological replacement. This case report provides the possibility that IgG4 level is decreased spontaneously or with physiological dose of glucocorticoid therapy. LEARNING POINTS: We performed the pituitary gland biopsy and histochemical examination glucocorticoid therapy in a subject with IgG4-related hypophysitis.This case report provides the possibility that IgG4 level is decreased spontaneously or with a physiological dose of glucocorticoid therapy. We reported the clinical course of IgG4-related hypophysitis without a high-dose glucocorticoid treatment, although there were a few reports about the retrospective examination.Although the patient had still higher IgG4 level compared to normal range, his clinical symptom disappeared and his laboratory data were improved.We should keep in mind the possibility of IgG4-related hypophysitis when we examine one of the uncertain causes of a hypopituitarism including adrenal insufficiency, hypogonadism and hypothyroidism.

The mammalian target of rapamycin complex 1 regulates leptin biosynthesis in adipocytes at the level of translation: the role of the 5'-untranslated region in the expression of leptin messenger ribonucleic acid.

Leptin production by adipose cells in vivo is increased after feeding and decreased by food deprivation. However, molecular mechanisms that control leptin expression in response to food intake remain unknown. Here, we test the hypothesis that leptin expression in adipose cells is regulated by nutrient- and insulin-sensitive mammalian target of rapamycin complex 1 (mTORC1)-mediated pathway. The activity of mTORC1 in 3T3-L1 adipocytes was up-regulated by stable expression of either constitutively active Rheb or dominant-negative AMP-activated protein kinase. In both cases, expression of endogenous leptin was significantly elevated at the level of translation. To investigate the role of leptin 5'-untranslated region (UTR) in the regulation of protein expression, we created bicistronic reporter constructs with and without the 5'-UTR. We found that the presence of leptin 5'-UTR renders mRNA resistant to regulation by mTORC1. It appears, therefore, that mTORC1 controls translation of leptin mRNA via a novel mechanism that does not require the presence of either the 5'-terminal oligopyrimidine tract or the 5'-UTR.

Endoplasmic reticulum stress induces Wfs1 gene expression in pancreatic beta-cells via transcriptional activation.

OBJECTIVE: The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein. Homozygous WFS1 gene mutations cause Wolfram syndrome, characterized by insulin-deficient diabetes mellitus and optic atropy. Pancreatic beta-cells are selectively lost from the patient's islets. ER localization suggests that WFS1 protein has physiological functions in membrane trafficking, secretion, processing and/or regulation of ER calcium homeostasis. Disturbances or overloading of these functions induces ER stress responses, including apoptosis. We speculated that WFS1 protein might be involved in these ER stress responses. DESIGN AND METHODS: Islet expression of the Wfs1 protein was analyzed immunohistochemically. Induction of Wfs1 upon ER stress was examined by Northern and Western blot analyses using three different models: human skin fibroblasts, mouse pancreatic beta-cell-derived MIN6 cells, and Akita mouse-derived Ins2 (96Y/Y) insulinoma cells. The human WFS1 gene promoter-luciferase reporter analysis was also conducted. RESULT: Islet beta-cells were the major site of Wfs1 expression. This expression was also found in delta-cells, but not in alpha-cells. WFS1 expression was transcriptionally up-regulated by ER stress-inducing chemical insults. Treatment of fibroblasts and MIN6 cells with thapsigargin or tunicamycin increased WFS1 mRNA. WFS1 protein also increased in response to thapsigargin treatment in these cells. WFS1 gene expression was also increased in Ins2 (96Y/Y) insulinoma cells. In these cells, ER stress was intrinsically induced by mutant insulin expression. The WFS1 gene promoter-luciferase reporter system revealed that the human WFS1 promoter was activated by chemically induced ER stress in MIN6 cells, and that the promoter was more active in Ins2 (96Y/Y) cells than Ins2 (wild/wild) cells. CONCLUSION: Wfs1 expression, which is localized to beta- and delta-cells in pancreatic islets, increases in response to ER stress, suggesting a functional link between Wfs1 and ER stress.

Unregulated elevation of glutamate dehydrogenase activity induces glutamine-stimulated insulin secretion: identification and characterization of a GLUD1 gene mutation and insulin secretion studies with MIN6 cells overexpressing the mutant glutamate dehydrogenase.

Glutamate dehydrogenase (GDH) is important in normal glucose homeostasis. Mutations of GDH result in hyperinsulinism/hyperammonemia syndrome. Using PCR/single-strand conformation polymorphism analysis of the gene encoding GDH in 12 Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI), we found a mutation (Y266C) in one PHHI patient. This mutation was not found in any of the control or type 2 diabetic subjects. The activity of the mutant GDH (GDH266C), expressed in COS-7 cells, was constitutively elevated, and allosteric regulations by ADP and GTP were severely impaired. The effect of the unregulated increase in GDH activity on insulin secretion was examined by overexpressing GDH266C in an insulinoma cell line, MIN6. Although glutamine alone did not stimulate insulin secretion from control MIN6-lacZ, it remarkably stimulated insulin secretion from MIN6-GDH266C. This finding suggests that constitutively activated GDH enhances oxidation of glutamate, which is intracellularly converted from glutamine to alpha-ketoglutarate, a tricarboxylic acid cycle substrate, which thereby stimulates insulin secretion. Interestingly, insulin secretion is also exaggerated significantly at low glucose concentrations (2 and 5 mmol/l) but not at higher glucose concentrations (8--25 mmol/l). Our results directly illustrate the importance of GDH in the regulation of insulin secretion from pancreatic beta-cells.