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Isolated adrenocorticotropic hormone deficiency is a rare disease; however, since immune check point inhibitors (ICIs) have become widely used, many more cases have been reported. In this study, we compared the human leukocyte antigen (HLA) signatures between ICI-induced isolated adrenocorticotropic hormone deficiency (IAD) and idiopathic IAD (IIAD).Clinical features and HLA frequencies were compared among 13 patients with ICI-induced IAD, 8 patients with IIAD, and healthy controls. HLA frequencies of healthy controls were adopted from a HLA database of Japanese population.Age and body mass index were higher, while the rate of weight loss was lower, in patients with ICI-induced IAD than in those with IIAD. No HLA alleles had a significantly higher frequency in patients with ICI-induced IAD than in healthy controls, whereas the frequencies of HLA-DRB1*09:01, HLA-DQA1*03:02, and DQB1*03:03 were significantly higher in patients with IIAD than in healthy controls.ICI-induced IAD and IIAD were different in terms of HLA frequencies. There were no specific HLAs related to ICI-induced IAD, whereas several HLAs in strong linkage disequilibrium were associated with IIAD. This might suggest that the two diseases have different pathological mechanisms. HLAs unique to IIAD may be helpful in predicting its pathophysiology.

Analysis of insulin and related glucoregulatory hormone secretion following high-molecular-weight insulin-like growth factor II (HMW-IGF-II)–releasing tumor excision has never been reported. In a man with chronic hypoglycemia—plasma glucose (PG), 2.1 mmol/L with undetectable serum insulin, less than 7.2 pmol/L on admission—the cause of the hypoglycemia was HMW-IGF-II in the serum secreted by an intrathoracic benign pleural solitary fibrous tumor (size: 15 × 17 × 12 cm). Removal of the tumor nullified serum HMW-IGF-II and hypoglycemia. Postoperative glucose metabolism was evaluated day 272 by 75 g oral glucose tolerance test (OGTT) and on days 5, 202, and 990 by fasted sampling. Glycated hemoglobin A1c (HbA1c) was 37 to 41 mmol/mol, fasting PG was 5.3 to 5.4 mmol/L, and 2-hour PG at 75 g OGTT was 6.9 mmol/L, indicating that he was at the prediabetes stage. Homeostasis Model Assessment 2 of Insulin Resistance and Homeostasis Model Assessment 2 of β-Cell levels were within the normal range but the Stumvoll first phase was lowered. Insulin sensitivity and secretion were compared to age-, sex-, and body mass index–matched controls with normal glucose metabolism. Long-term HMW-IGF-II exposure of pancreatic islet β cells caused the functional impairment, that is, suppressed glucose-stimulated insulin secretion (GSIS), leading to nondiabetic hyperglycemia. This fact suggests long-term HMW-IGF-II exposure of the islet β cell specifically dampens GSIS.

Background Hypoglycemia due to non-insulin-producing tumors is referred to as non-islet cell tumor hypoglycemia (NICTH). As NICTH is a rare lesion, the natural course of NICTH is not well understood. We report a case of NICTH that was observed 30 years before the onset of hypoglycemia. Case summary A 50-year-old man was diagnosed with an abnormal right chest shadow during a routine X-ray examination, but no further examination was undertaken because the lesion appeared benign. Thirty years after the tumor discovery, the patient was admitted to the hospital with symptoms of severe hypoglycemia, which was diagnosed as NICTH based on a complete examination. The tumor was resected and found to be a solitary fibrous mass (15.6 cm × 13.7 cm × 10.4 cm); thereafter, the patient's blood glucose levels normalized and he completely recovered. Conclusion NICTH can have an acute onset, even if the tumor has been present and asymptomatic over a long time period.

Non-islet cell tumor hypoglycemia (NICTH) is a very rare symptom of severe hypoglycemia associated with extrapancreatic tumors. It is considered to be caused by insulin-like growth factor (IGF)-II. There have been no autopsy cases of colorectal carcinoma with NICTH confirmed with both serum high molecular weight and tumoral IGF-II. We report the case of a 46-year-old woman with advanced sigmoid colon cancer and liver metastases. She underwent open sigmoidectomy, and histologically, the lesion was a differentiated-type tubular adenocarcinoma. Postoperative chemotherapy was initiated. However, she experienced repeated hypoglycemia attacks 10 months after the operation, while the liver metastases increased. We examined the cause of hypoglycemia, and finally diagnosed her with NICTH associated with high molecular weight IGF-II production, which was proven by Western immunoblot of the serum. She died 12 months after surgery and was examined by autopsy. Liver metastases showed a transition from adenocarcinoma to carcinoma with neuroendocrine differentiation. Immunohistochemistry showed that both metastatic carcinoma of the liver and primary colonic adenocarcinoma were positive for IGF-II. Neuroendocrine differentiation in liver metastases proven by an autopsy may have contributed to tumor growth, which may have exacerbated the symptoms.

Nonalcoholic fatty liver disease (NAFLD) is related to subclinical atherosclerosis. However, whether the severity of the disease (or which histopathological component) is associated with subclinical atherosclerosis remains controversial. This study aimed to investigate the association between the histopathological severity of NAFLD and carotid intima-media thickness (CIMT) in Japanese patients with liver biopsy-proven NAFLD. Maximum-CIMT (max-CIMT) was measured as an index of carotid atherosclerosis in 195 biopsy-proven NAFLD patients. A significant association was observed between the severity of fibrosis (but not steatosis, inflammation, and ballooning) and max-CIMT. Older age, male gender, hypertension, and advanced fibrosis were independently linked to max-CIMT ≥ 1.2 mm. The prevalence of max-CIMT ≥ 1.2 mm was significantly higher in the advanced fibrosis group than in the non-advanced fibrosis group (75.4% versus 44.0%; p

Background: A prolonged QT interval plays a causal role in fatal arrhythmia and is known to be a risk factor for sudden cardiac death. Although diabetic patients with microvascular complications tend to have a longer QT interval, the therapeutic effect of diabetes on the QT interval remains unclear. Here, we assessed the changes in QT interval in patients with type 2 diabetes (T2D) who received multiple daily insulin injections. Materials and methods: Patients with T2D ( n = 34) who were admitted to our hospital and initiated multiple daily insulin injections for glycemic control were enrolled in this study. Clinical measurements, including electrocardiogram, were taken on admission and discharge. The QT interval was measured manually in lead II on the electrocardiogram, and corrected QT interval (QTc) was calculated using Bazett’s formula. The change in QTc (ΔQTc) during hospitalization (median, 15 days) and clinical parameters affecting ΔQTc were investigated. Results: QTc was shortened from 439 ± 24 to 427 ± 26 ms during hospitalization ( p Conclusions: Multiple daily insulin injections can ameliorate QT interval by lowering the blood glucose levels in T2D, suggesting that glycemic control is important for preventing patients with T2D from sudden cardiac death.

Pituitary tumors are discovered either incidentally by imaging studies (incidentalomas) or via evaluation of certain clinical symptoms (symptomatic tumors). In this study, we first surveyed patients with incidentalomas who underwent surgery. Cases included 62.3% non-functioning adenomas (NFPAs), 14.5% functioning adenomas, and 13.8% Rathke's cleft cysts. Next, we compared the clinical features and surgical outcomes of 145 patients whose preoperative diagnosis was NFPA (incidentalomas [n = 79] vs. symptomatic tumors [n = 66]). The patients with incidentalomas were older (59.9 vs. 55.3 years, p < 0.05) and had smaller tumors compared with the patients with symptomatic tumors (mean maximum diameter: 23.1 vs. 27.5 mm, p < 0.01). The main reason for undergoing imaging studies was headache (n = 25) in the incidentaloma group and visual disturbance (n = 46) in the symptomatic tumor group. The incidence of preoperative pituitary hormone deficiencies was lower in the incidentaloma than symptomatic tumor group (growth hormone deficiency: 37.7% vs. 66.7%, p < 0.01; gonadotropin deficiency: 19.0% vs. 39.4%, p < 0.01; adrenocorticotropic hormone deficiency: 3.8% vs. 18.2%, p < 0.01; thyroid stimulating hormone deficiency: 6.3% vs. 12.1%, p = 0.25). Postoperative pituitary function was better preserved in the incidentaloma than symptomatic tumor group (no deficiency: 58.2% vs. 28.8%, p < 0.01). The difference in postoperative complications between groups was not statistically significant (incidentalomas vs. symptomatic tumors: 21.5% vs. 19.7%, p = 0.84). In conclusion, incidentalomas were detected while smaller size and lower incidence of hormone deficiency than symptomatic tumors, and the pituitary hormones were also preserved after surgery. It is important to observe incidentalomas carefully and to judge whether to operate appropriately before they become symptomatic tumors.

Naoya Emoto,1,2 Akimi Soga,1 Izumi Fukuda,1 Kyoko Tanimura-Inagaki,1 Taro Harada,1 Hajime M Koyano,3 Rei Goto,4 Hitoshi Sugihara1 1Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; 2Diabetes & Thyroid Clinic, Sakura Chuo Hospital, Chiba, Japan; 3Division of Endocrinology and Diabetes, Juntendo University Urayasu Hospital, Chiba, Japan; 4Graduate School of Business Administration, Keio University, Kanagawa, JapanCorrespondence: Naoya EmotoDiabetes & Thyroid Clinic, Sakura Chuo Hospital, 20-4, Sakaecho, Sakura City, Chiba 285-0014, JapanTel +81-43-486-1311Fax +81-43-486-1314Email emotonaoya1954@gmail.comPurpose: The risk preferences of patients with diabetes have profound effects on the progression of complications. The present study aimed to clarify whether the preferences of patients with diabetes and retinopathy are deliberately risk-seeking or irrational and whether this propensity is specific to those with retinopathy or is also found in patients without retinopathy compared with those without diabetes.Patients and Methods: A total of 394 patients with diabetes (264 without retinopathy and 130 with retinopathy) and 198 patients without diabetes agreed to participate in this survey. The questions were modified versions of those from the Japan Household Survey on Consumer Preferences and Satisfaction, which sought to determine the participants’ personal socioeconomic status and risk preferences. In the questionnaires, responses were analyzed by determining the participants’ willingness to pay for a lottery ticket and for an insurance policy. Irrational responses were defined as violations of two axioms of the Expected Utility Theory: completeness and transitivity.Results: The incidence of irrational responses increased with age and was associated with educational level. The incidence of irrational responses was significantly higher in patients with retinopathy than in those without retinopathy after adjusting for age and educational level. There was no significant difference in the incidence of irrational responses between patients with diabetes but without retinopathy and those without diabetes.Conclusion: The risk-seeking behavior of patients with diabetes and retinopathy was not deliberate but was irrational under uncertainty. Medical professionals should be aware of their patients’ propensity to make irrational decisions, which is an important risk factor for the progression of retinopathy in patients with diabetes regardless of age and educational level.Keywords: behavioral economics, expected utility theory, educational level, cognitive function

Objective In insulin-like growth factor II (IGF-II) producing non-islet cell tumor hypoglycemia (NICTH), high molecular weight forms of IGF-II (big IGF-II) are produced as a cause of spontaneous hypoglycemia. MicroRNA (miRNA)-483 family, encoded in an intron lesion of IGF2 gene, is suggested to be co-expressed with IGF-II. Here, we tested whether serum miR-483-5p and -3p levels are associated with the presence of big IGF-II in NICTH. Design Serum samples from patients who were suspected to have IGF-II producing NICTH (n = 42) were tested. MiR-483-5p and -3p levels were evaluated using quantitative PCR. IGF-II level was analyzed using ELISA. The presence of big IGF-II was identified by Western blotting. Results Big IGF-II was detected in the sera of 32 patients. MiR-483-5p (P = 0.0015) and -3p (P = 0.027) levels were significantly higher in sera with big IGF-II (n = 32) than in those without (n = 10), whereas serum IGF-II level (P = 0.055) was not significantly different between the groups. The median serum concentration of miR-483-5p was ~10 times higher than that of miR-483-3p. Although a strong correlation was observed between the two miRNAs (r = 0.844, P < 0.0001), but neither of which was correlated with serum IGF-II level. The areas under the receiver operating characteristic curves of miR-483-5p (0.853) and -3p (0.722) were higher than that of IGF-II (0.694) for detecting the presence of big IGF-II. Conclusion The associations of serum miR-483-5p and -3p levels with the presence of big IGF-II suggest the diagnostic potential of these miRNAs for IGF-II producing NICTH.

Background Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome that secretes incompletely processed high molecular weight insulin growth factor 2 (big-IGF2), which results in stimulation of the insulin receptor and subsequently induces hypoglycemia. Gastrointestinal stromal tumor (GIST) is a common intestinal mesenchymal neoplasm of the gastrointestinal tract. The most frequent site of GIST is the stomach; NICTH induced by IGF2-producing stomach GISTs is rare. Case presentation An 84-year-old man was admitted to the hospital due to impaired consciousness (JCS II-10) in the morning. At the time of admission, his serum glucose was 44 mg/dL; his consciousness was restored with 20 ml of 50% glucose. To avoid hypoglycemia, a continuous intravenous infusion of glucose as well as dietary intervention was required. At the time of hypoglycemia, the levels of insulin and C-peptide were suppressed. Additionally, IGF1 levels were below the normal range. Abdominal computed tomography revealed that he had a large lobulated mass (116 × 70 × 72 mm) around the gastric corpus. Pathological analysis of biopsy specimens identified disarray of spindle cells and positivity for c-kit as well as strong positivity for DOG-1. Further analysis revealed high levels of Ki-67 (Mib-1 index: 15.5%) and mitotic index (7/50HPF); the tumor was diagnosed as high-risk GIST, and complete surgical resection was performed. Hypoglycemia resolved immediately after tumor resection. The resected tumor specimen was positive for IGF2 staining, and big-IGF2 (11–18 kDa) was detected in preoperative serum and tumor samples; the patient was diagnosed with NICTH due to an IGF2-producing tumor. Conclusions NICTH is rare in GIST of the stomach; however, the large GIST could produce big-IGF2 and subsequently cause severe hypoglycemia, requiring prompt evaluation and complete tumor resection.

Background: To date, precise pathological studies and the improvement of imaging studies have made it clear that a part of idiopathic diabetes insipidus (DI) could be lymphocytic infundibulo-neurohypophysitis (LINH) caused by autoimmune abnormality. Recently, anti-rabphilin (RPH) 3A antibody was identified and expecting as a useful diagnostic marker of LINH*. Objective: Here, we present the clinical course of 6 patients with central DI (CDI) who were thought to be due to LINH and compared with results of serum anti- RPH3A antibody in each. Patients and methods: Clinical characteristics of 6 patients with CDI regarded as due to LINH (M/F; 3/3, age range; 26–67 years old) were investigated. Clinical course, anterior pituitary functions, MRI findings, complications and results of serum anti-RPH3A antibody were retrospectively analyzed by medical charts. Pituitary biopsy was conducted in 2 patients. Results: On the T1-weighted MR image, one patient (# 3: 67 F) had only a lacking of high signal intensity in the posterior lobe. Thickening of pituitary stalk was seen in other 5 patients. Anti-RPH3A antibody was studied in those 5 patients and positive in 3 and negative in 2. Anterior pituitary function was preserved in 2 patients with positive anti-RPH3A antibody. One patient (#1: 26 F) was diagnosed as LINH by changes in MRI findings over time and the other patient (#5: 41 M) by pituitary biopsy. Impaired anterior pituitary function was observed in 2 of 6 patients. One patient (# 2: 32 F) suffered from CDI since late pregnancy. She had a history of massive bleeding at delivery. Postpartum evaluation revealed that besides CDI, she had TSH, ACTH and GH deficiency. Anti-RPH3A antibody was positive in this patient. A mild low GH response (not severe GHD) to GHRP-2 test was seen in another patient (#4: 37 M). Pituitary biopsy of this patient revealed that infiltration of lymphocytes distributed not only posterior but also anterior pituitary. Anti-RPH3A antibody was negative in this patient. As a complication, Type 2 DM in 2 patients, Graves’ disease and cerebral infarction in one each were observed. Conclusion: Anti-RPH3A antibody was useful as a non-invasive diagnostic marker for LINH. However, among patients who were inferred to have LINH, the clinical course, a degree of extension and severity of inflammation in the pituitary region varied from case to case, suggesting that the clinical features of LINH might be diverse. *: JCEM 100: E 946, 2015

Socioeconomic status has profound effects on glycemic control and diabetic complications in patients with type 2 diabetes. Sex differences are one of the most important factors in socioeconomic status and may vary among countries or areas. The study aim was to determine if sex differences are associated with glycemic control and diabetic complications in Tokyo, Japan, one of the most educated countries in the world. This study initially enrolled 3307 patients treated from 2017 to 2019 at the medical school hospital located in Tokyo. All enrolled patients were asked to complete behavioral and socioeconomic surveys. A total of 276 type 2 diabetic patients (175 males, age 64.1 ± 0.88 y, disease duration 15.2 ± 0.78 y, mean ± SE y; 101 females, age 64.0 ± 1.1 y, disease duration 15.6 ± 1.01 y) agreed to participate in the study. The survey questionnaire has been previously reported in detail (Patient Preference and Adherence, 10:2151-2162, 2016). The questionnaire attempted to determine estimations of risk preference regarding things like lottery gambling and accident insurance. After reviewing the patients’ answers, however, it became clear that some were illogical, which suggested that these patients did not understand the context of the questions, the hypothetical economical situations, or even the instructions, probably because of lower literacy skills. Thus, we labeled these patients as the unreasonable (UR) group (n = 81), and the patients who provided appropriate answers, even if extremely risk averse or risk loving, were labeled as the reasonable (R) group (n = 195). The prevalence of UR answers generally increased with age (

Aims/Introduction An increased risk of diabetes mellitus has been reported in primary aldosteronism, but the pathogenesis of glucose intolerance between the primary aldosteronism subtypes remains unclear. This study aimed to evaluate glucose metabolism in oral glucose tolerance test between aldosterone‐producing adenoma and idiopathic hyperaldosteronism, and characterize patients with improved glucose intolerance after primary aldosteronism treatment. Materials and Methods Oral glucose tolerance test was carried out in 116 patients who were diagnosed with primary aldosteronism and received adrenal venous sampling for subtyping. Oral glucose tolerance test was re‐evaluated after starting the treatment of primary aldosteronism for those who had glucose intolerance before the treatment. Results A total of 46.4% and 52.3% of patients with aldosterone‐producing adenoma and idiopathic hyperaldosteronism, respectively, were diagnosed with impaired glucose tolerance or diabetes. The insulinogenic index was significantly lower in aldosterone‐producing adenoma than in idiopathic hyperaldosteronism (P = 0.045), whereas the Matsuda insulin sensitivity index was significantly higher in aldosterone‐producing adenoma than in idiopathic hyperaldosteronism (P = 0.022). After the treatment of primary aldosteronism, glucose intolerance was improved in 66.6% and 45.8% of aldosterone‐producing adenoma and idiopathic hyperaldosteronism, respectively. The presence of obesity and central obesity were significantly lower in patients who improved glucose intolerance after the treatment of primary aldosteronism as compared with those not improved (P = 0.013 and P = 0.033, respectively). Conclusions Insulin secretion impairment and insulin resistance play pathogenic roles for glucose intolerance in aldosterone‐producing adenoma and idiopathic hyperaldosteronism, respectively. In addition, primary aldosteronism treatments can ameliorate glucose intolerance more effectively in patients without obesity and/or central obesity., Insulin secretion impairment and insulin resistance play pathogenic roles for glucose intolerance in aldosterone‐producing adenoma and idiopathic hyperaldosteronism, respectively. Primary aldosteronism treatments can ameliorate glucose intolerance more effectively in idiopathic hyperaldosteronism patients without obesity.

Non-functioning pituitary adenoma (NFPA) is one common cause of adult growth hormone deficiency (AGHD). In Japan, a GH-releasing peptide (GHRP)-2 test is used to evaluate GH secretion. Although the cut-off for peak GH during a GHRP-2 test for severe AGHD is ≤9 ng/mL, severe AGHD may further diminish responses (range, nearly no-response to ≤9 ng/mL). We studied whether the peak GH responses during a GHRP-2 test could be predicted based on clinical characteristics of patients with NFPA. We compared patients with almost no-response during a GHRP-2 test with other patients considered as severe AGHD. Among the 76 patients with NFPA who were admitted to our institution, 36 patients (mean age, 61 years; male/female, n = 23/n = 13) were diagnosed with severe AGHD based on a preoperative GHRP-2 test. Based on the preoperative median peak GH concentration (2.83 ng/mL), patients were divided into two groups (

A 21-year-old man presented with hyperthyroidism and hypokalemia and was treated for thyrotoxic hypokalemic periodic paralysis caused by Graves' disease. Thyroid function soon normalized but hypokalemia persisted. Laboratory data revealed hyperreninemic hyperaldosteronism and metabolic alkalosis consistent with Gitelman Syndrome. The patient was found to have a previously unreported compound heterozygous mutation of T180K and L858H in the SLC12A3 gene, and Gitelman Syndrome was diagnosed. He was started on eplerenone to control serum potassium level. Alternative diagnoses should be considered when electrolyte imbalances persist after disease resolution.

Objective: Pituitary tumors are discovered by imaging studies incidentally (incidentalomas), or based on certain clinical symptoms (symptomatic pituitary tumor). In this study, we investigated differences in clinical features between incidentalomas and symptomatic pituitary tumors. Patient and method: 151 patients who regarded as non-functioning pituitary tumor and underwent transsphenoidal surgery (TSS) between 2011 and 2017 at our institution were studied. Among 151 patients, pituitary tumors were discovered as incidentalomas in 83 (M/F; 45/38) and symptomatic in 68 (M/F; 39/29). Age, sex, BMI, reasons for taking imaging study, tumor maximum diameter, pituitary function and final pathological diagnosis were analyzed and compared between the two groups. Results: Patients with incidentalomas were older than those with symptomatic tumors (59.7±3.0 vs 54.8±3.3 y.o., p=0.03), though gender ratio and BMI did not differ between the two groups. Reasons for taking imaging studies were mainly because of headache that was not considered as a symptom of pituitary mass (n=29), medical checkup (n=17), dizziness (n=15) and trauma (n=8) in incidentalomas, whereas visual disturbance (n=46), acute headache due to pituitary apoplexy (n=9), hyponatremia (n=4) and irregular menstruation (n=2) in symptomatic tumors. The size of incidentalomas were significantly smaller than those of symptomatic tumors (22.8±1.9 vs 27.1±2.0 mm, p=0.003). The incidence of pre-surgical pituitary hormone deficiency in both groups (incidentalomas vs symptomatic tumors) were 37.0% vs 66.1% for GH deficiency (P=0.007), 19.3% vs 39.7% for hypogonadism (P=0.007), 4.8% vs 16.2% for ACTH deficiency (P=0.027) and 7.2% vs 10.3% for TSH deficiency (P=0.57). Post-surgical hypopituitarism was observed more in symptomatic tumors (40.9% vs 70.6%, P=0.003). Pre-surgical diagnosis was either non-functioning adenomas (n=145) or Rathke’s cyst (n=6) in all patients, however after TSS, 3 patients in symptomatic group and one in each group were diagnosed as prolactinoma and pituicytoma, respectively. Conclusion: Incidentalomas were most frequently noticed by imaging for check on headache, whereas symptomatic tumors were by visual disturbance. Compared with incidentalomas, symptomatic tumors were larger, more associated with hypopituitarism that persisted still after TSS. These data suggested that detection of incidentalomas and their appropriate management might contribute better therapeutic outcomes of pituitary adenoma.

A 77-year-old man was treated with a DPP-4 inhibitor for type 2 diabetes. Hypoglycemia occurred frequently, and an examination revealed a tumor with a maximum diameter of 140 mm in both lobes of the liver. Western immunoblotting detected a high-molecular-weight form of insulin-like growth factor-II, and non-islet cell tumor hypoglycemia was diagnosed. Although prednisolone 40 mg was started, hypoglycemia continued to occur frequently. Surgical tumor removal was not indicated, so lenvatinib was initiated. Hypoglycemia improved quickly, and the tumor shrank until it had partially disappeared. His condition continued to improve, and he was discharged.

Background: Although sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) improve not only glycemic control but also liver inflammation and fatty changes in patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), its sustainability and effect on liver fibrosis have remained unclear. The current study aimed to clarify the effects of 48-week SGLT2-I therapy on liver inflammation, fatty changes, and fibrosis in NAFLD patients with T2DM. Methods: This study evaluated the effects of SGLT2-I on NAFLD, including liver fibrosis assessed via transient elastography, in 56 patients with NAFLD who received SGLT2-I for 48 weeks. Moreover, changes in each clinical parameter between patients receiving SGLT2-I (the SGLT2-I group) and those receiving other oral hypoglycemic agents (OHAs) (the non-SGLT2-I group) were compared, using 1:1 propensity score matching to adjust for baseline factors. Results: The SGLT2-I group exhibited a significant decrease in controlled attenuation parameter (312 dB/m at baseline to 280 dB/m at week 48) and liver stiffness measurement (9.1–6.7 kPa) ( p Conclusion: SGLT2-Is improved not only glycemic control but also liver fatty infiltration and fibrosis in patients with NAFLD and T2DM, suggesting their possible superiority to other OHAs concerning these effects.

The present study reports a case of recurrent malignant pelvic solitary fibrous tumor (SFT) that induced non-islet cell tumor hypoglycemia via high-molecular-weight insulin-like growth factor-II in a 72-year-old male patient. The tumor recurred ~12 years after the complete resection of the original mass. The recurrent tumor, which had directly invaded the left ureter and perirectal fat tissue, could not be completely excised due to its fragility and adhesiveness. At 13 days post-surgery, the patient presented with rectal perforation, and an urgent rectal resection and colostomy was performed. Neither recurrence of the tumor nor hypoglycemic symptoms were observed 9 months after the surgery. High molecular weight insulin-like growth factor-II was detected in the serum and tumor specimens by western blot analysis and immunohistochemistry. The present case report suggests that certain SFTs can relapse even ≥10 years after a presumed complete resection of the primary tumor, and that performing a safe and complete resection of these tumors can be challenging, due to their adhesiveness or physical presentation; therefore, the indications for surgery should be considered with caution.

A 61-year-old woman with multiple metastatic and unresectable gastrointestinal stromal tumors (GISTs) was referred for investigation of refractory hypoglycemia that developed four months before this hospitalization. On admission, her fasting plasma glucose was 38 mg/dL despite 10% glucose infusion. Investigations revealed that her serum C-peptide, insulin and growth hormone levels were suppressed, and big insulin-like growth factor II was observed. She was diagnosed with non-islet cell tumor hypoglycemia, which resolved after glucocorticoid treatment. Clinicians should thus be vigilant to identify hypoglycemia in patients with large metastatic GISTs because glucocorticoid therapy is useful even if the GIST is inoperable.

Tumors producing IGF-2 (IGF-2oma) are a major cause of spontaneous hypoglycemia. The treatment mainstay is surgical resection. Many case reports note resolution of hypoglycemia after IGF-2oma resection; however, outcomes are variable according to tumor type. We report a case of resolving hypoglycemia, observed on continuous glucose monitoring, after resection of an IGF-2-producing solitary fibrous tumor of pleura and review the current literature.A 69-year-old woman presented with impaired consciousness because of hypoglycemia. An IGF-2oma was diagnosed as the cause for hypoglycemia because of decreased serum insulin and IGF-1, the presence of a pleural tumor, and a high-molecular-weight form of serum IGF-2 detected by Western immunoblot. Surgical resection was performed; pathological examination demonstrated a solitary fibrous tumor with low-grade malignancy. Continuous glucose monitoring showed reversal of hypoglycemia after tumor resection. Approximately 2 years after resection, the patient has no signs of tumor recurrence or hypoglycemia.An IGF-2-producing solitary fibrous tumor of pleura in this case caused hypoglycemia. From a search of the literature of 2004-2014, 32 cases of IGF-2oma with hypoglycemia that underwent radical surgery were identified; in 19 (59%) patients, hypoglycemia was reversed, and there was no subsequent recurrence. The remaining 13 (41%) patients experienced tumor recurrence or metastasis an average of 43 months after initial tumor resection. The tumor of the present case was a low-grade malignancy. Regular follow-up with biomarker monitoring of glucose metabolism and assessment of hypoglycemic symptomatology, in conjunction with imaging tests, is important for detecting possible tumor recurrence and metastasis.

The improvement of formability has been investigated in the multistage deep drawing of beta titanium alloy sheet. The beta titanium alloys have good cold workability in the metal forming. However, a seizure tends to occur during metal forming due to high reactivity with other metals. The occurrence of the seizure becomes remarkable in sever forming operations such as deep drawing and ironing. Especially, it is hard to prevent the occurrence of seizure in multistage deep drawing process. In this study, to improve the formability of titanium alloy sheet, the formability in multistage deep drawing process of beta titanium alloy was investigated. The blank used was the commercial beta titanium alloy Ti-15V-3Cr-3Sn-3Al. To prevent the occurrence of seizure, the blank treated by oxide coating was used. The coated sheet was not in direct contact with the tools of die and punch during deep drawing due to the existence of the oxide layer. The effects of the surface roughness and hardness on the formability in the multistage deep drawing processes were examined. The improvement of surface roughness of drawn cup was also attempted by using heat treatment. A long titanium alloy cup was successfully formed by intermediate annealing at the 3rd stage. The drawn cup by multistage deep drawing could be formed to the 6th stage. It was found that the beta titanium alloy sheet covered with oxide layer has sufficient ability in preventing the seizure in multistage deep drawing processes.

The clinical syndrome of adult growth hormone deficiency (AGHD) was widely recognized in the 1980s. In this review, we first describe the clinical features and diagnosis of AGHD and then state the effects of growth hormone (GH) therapy for these patients. The main characteristics of AGHD are abnormal body composition, dyslipidemia, insulin resistance, and an impaired quality of life (QoL) due to decreased psychological well-being. For diagnosing AGHD, the international consensus guidelines have suggested that an insulin tolerance test (ITT) is the gold standard, but in Japan, the growth hormone releasing peptide-2 (GHRP-2) test is available and is recommended as a convenient and safe GH stimulating test. The cut-off for diagnosing severe AGHD is a peak GH concentration of 9 g/L during the GHRP-2 test. Since 2006, GH therapy has been approved for Japanese patients with severe AGHD. For adults, GH replacement therapy should be initiated at a low dose (3 g/kg body weight/day), followed by individualized dose titration while monitoring patients' clinical status and serum insulin-like growth factor-I (IGF-I) concentrations. A variety of favorable effects of GH replacement have been indicated; however, it has not yet been established fully whether there is a direct effect of GH treatment on reducing mortality.

β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an NADPH-dependent reductase that converts cortisone to cortisol in adipose tissue. We previously reported that GH and IGF-I decrease 11β-HSD1 activity and mRNA levels in adipocytes. Hexose-6-phosphate dehydrogenase (H6PDH) is involved in the production of NADPH, which is a coenzyme for 11β-HSD1. The aim of the present study was to clarify further the mechanism of repression of 11β-HSD1 activity by GH using linsitinib, an IGF-I receptor inhibitor. The suppression of 11β-HSD1 mRNA by IGF-I was attenuated in the presence of 1 μM linsitinib (17.2% vs. 53.3% of basal level, P

The diagnostic steps for primary aldosteronism (PA) include case screening tests, confirmatory tests, and localization. The aim of this study was to identify useful confirmatory tests and their cut-off values for differentiating the subtype of primary aldosteronism, especially in unilateral PA, such as aldosterone-producing adenoma, and bilateral PA, such as idiopathic hyperaldosteronism. Seventy-six patients who underwent all four confirmatory tests, the captopril-challenge test (CCT), furosemide upright test (FUT), saline infusion test (SIT), and ACTH stimulation test (AST), and who were confirmed to have an aldosterone excess by adrenal venous sampling (AVS) were recruited. Subjects were diagnosed as having unilateral aldosterone excess (n=17) or bilateral aldosterone excess (n=59) by AVS. The SIT-positive rate was significantly higher in the unilateral group (94.1%) than in the bilateral group (57.6%). Multivariable logistic regression analysis showed that tumor on computed tomography (CT) and plasma aldosterone concentration (PAC)max/cortisol on the AST were useful for differentiating the subtype of PA. Receiver operating characteristic (ROC) curve analysis for distinguishing the subtype of PA showed that a cut-off value of 18.3 PACmax/cortisol on the AST had a sensitivity of 83% and a specificity of 88%. The area under the ROC curve was 0.918 (95% confidence interval 0.7916-0.9708). These data suggest that abdominal CT and AST are useful for differentiating the subtype of PA and the indication for AVS.