Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Publishing type：Research paper (scientific journal)  

Background & aim: Metabolic abnormalities in type 2 diabetes affect the production and the clearance of plasma lipoproteins. Although the improvement of low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol levels are important targets in diabetes, it is not established how changes occur in the production and clearance of plasma lipoproteins in the treatment of diabetes. Serum non-cholesterol sterols are introduced as practical markers to assess endogenous cholesterol synthesis and intestinal cholesterol absorption. This study aimed to investigate the effects of insulin therapy on cholesterol synthesis and absorption markers in patients with type 2 diabetes. Methods: This was a single-center, prospective, 2-week, longitudinal pilot study. Patients with type 2 diabetes who were admitted to start insulin therapy without using lipid-lowering agents were recruited. On the day of hospitalization, the patients discontinued all oral hypoglycemic agents and started with basal-bolus insulin therapy. Cholesterol synthesis (lathosterol) and absorption (campesterol, sitosterol, and cholestanol) markers were assessed at baseline and after 2 weeks of insulin treatment. Results: In eighteen subjects, the mean age of the patients was 56 ± 10 years (mean ± SD). At baseline, body mass index was 24.3 ± 5.0 kg/m2, and HbA1c was 11.6 ± 1.7%. After 2 weeks of insulin therapy, total cholesterol (from 205 ± 48 to 184 ± 43 mg/dL, p = 0.004), lathosterol (from 2.6 ± 1.3 to 2.0 ± 0.7 μg/mL, p = 0.001), campesterol (from 4.3 ± 2.7 to 3.0 ± 2.1 μg/mL, p < 0.0001), and sitosterol (from 2.4 ± 1.6 to 1.7 ± 1.4 μg/mL, p < 0.0001) were significantly decreased, and cholestanol (from 2.5 ± 1.0 to 2.3 ± 0.8 μg/mL, p = 0.05) tended to decrease. Conclusion: This study showed that insulin therapy reduces cholesterol synthesis and absorption markers in patients with type 2 diabetes hospitalized within 2 weeks. The decrease in cholesterol synthesis and absorption seems to be useful for improving lipid metabolism and reducing the risk of atherosclerosis. Further randomized controlled studies are required to confirm the efficacy of insulin therapy for cholesterol synthesis and absorption markers.

DOI： 10.1016/j.nutos.2023.03.001

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BACKGROUND: Tumor-produced high molecular weight insulin-like growth factor-II (big insulin-like growth factor-II) is considered to cause non-islet cell tumor hypoglycemia. This paper presents a case of surgically resected retroperitoneal liposarcoma that produced big insulin-like growth factor-II. CASE PRESENTATION: Here, we report the case of a 62-year-old woman who presented with an abdominal mass and hypoglycemia. Non-islet cell tumor hypoglycemia due to retroperitoneal liposarcoma was suspected. After complete resection of the tumor, the patient's hypoglycemia improved and big insulin-like growth factor-II disappeared in the molecular weight analysis of serum insulin-like growth factor-II by western blotting. The patient had no tumor recurrence or reappearance of hypoglycemia 16 months after the operation without any adjuvant therapy. CONCLUSIONS: Although insulin-like growth factor-II-producing tumors are generally large and difficult to operate on, surgical resection is currently the most effective and only treatment; thus, it is essential to attempt resection aggressively.

DOI： 10.1186/s40792-023-01589-9

PubMed

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Background

Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by a tumor-producing high molecular weight form of insulin-like growth factor 2 (IGF2) known as big IGF2. The only curative treatment for this condition is surgical resection of the responsible tumors. However, this may not be feasible in cases with multiple metastases at diagnosis of NICTH, and no standard treatment strategy for multiple tumors has been established. The effects of pharmacological therapies including somatostatin analogs are often inefficient and remain difficult to predict.

Case description

A 68-year-old man was admitted to our hospital due to impaired consciousness and severe hypoglycemia. His medical history included diagnosis of a left temporal solitary fibrous tumor (SFT) at the age of 48 years, after which local recurrent and metastatic tumors were repeatedly resected. Four years before admission, multiple intraabdominal and subcutaneous tumors were detected and, being asymptomatic, were managed conservatively. Laboratory exam on admission demonstrated hypoglycemia accompanied with low serum insulin and IGF1 levels. Computed tomography (CT) scan revealed multiple intraabdominal and subcutaneous tumors increasing in size. Serum big IGF2 was detected on immunoblot analysis, and he was diagnosed as NICTH. In addition, tumor uptake was observed on ⁶⁸Ga-labelled 1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid-d-Phe¹-Tyr³-octreotide positron emission tomography/CT (DOTATOC-PET/CT). Since larger tumor is more suspicious about responsible producibility of big IGF2, we planned to resect large ones preferentially and reduce the amounts of residual tumors. Debulking surgery was performed by removing eleven intraabdominal tumors; the hypoglycemia was then completely corrected. Histological analyses revealed the resected tumors to be metastases of SFT having somatostatin receptor 2 expression. In immunoblot analysis, the resected tumors were found to be positive for big IGF2; serum big IGF2 was undetectable after surgery.

Conclusion

We present a case of NICTH with multiple metastatic SFTs. We strategically performed debulking surgery, which led to remission of hypoglycemia. This result demonstrates a pioneering practical solution for NICTH cases with multiple tumors. In addition, in cases of SFTs presenting with NICTH, positivity of DOTATOC-PET/CT as well as single-dose administration of octreotide may be predictive of the efficacy of somatostatin-based therapy.

DOI： 10.3389/fendo.2023.1071899

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There is no standard formula for estimating the starting daily dose (SDD) of basal-bolus insulin therapy (BBT). We aimed to develop a formula for estimating SDD and evaluate its efficacy and safety in patients with type 2 diabetes hospitalized for BBT. In the first study (n = 104), we retrospectively analyzed the relationship between peak daily dose (PDD) during hospitalization and clinical parameters. The PDD was significantly associated with fasting plasma glucose (FPG) (R = 0.449, P < 0.0001) and HbA1c levels (R = 0.384, P < 0.0001) but not body weight, body mass index, body surface area, or serum C-peptide levels. Based on the results, we developed a formula for estimating SDD using FPG levels: SDD (U/day) = 0.08 × FPG (mg/dL). In the second study (n = 405), we assessed efficacy and safety of the formula by evaluating the M-value from the daily glucose profile and assessing the frequency of hypoglycemia (blood glucose level < 70 mg/dL). When BBT was initiated using the FPG level-based formula, the M-values decreased from 61.0 ± 52.8 to 12.8 ± 10.8 (P < 0.0001), and hypoglycemia was observed in only 3/405 cases (0.74%) under the SDD. The FPG level-based formula is useful for estimating SDD in BBT and is safe for clinical use.

DOI： 10.1038/s41598-023-28138-6

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Language：Japanese   Publisher：日本医科大学医学会  

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The aim of this retrospective multicenter study was to clarify the antifibrotic effect and long-term outcome of sodium glucose cotransporter 2 inhibitors (SGLT2-Is) in patients with nonalcoholic fatty liver disease (NAFLD) complicated by type 2 diabetes mellitus (T2DM). Of the 1262 consecutive patients with T2DM who recently received SGLT2-Is, 202 patients with NAFLD had been receiving SGLT2-Is for more than 48 weeks and were subjected to this analysis. Furthermore, 109 patients who had been on SGLT2-I therapy for more than 3 years at the time of analysis were assessed for the long-term effects of SGLT2-Is. Significant decreases in body weight, liver transaminases, plasma glucose, hemoglobin A1c, and Fibrosis-4 (FIB-4) index were found at week 48. Overall, the median value of FIB-4 index decreased from 1.42 at baseline to 1.25 at week 48 (p < 0.001). In the low-risk group (FIB-4 index < 1.3), there was no significant change in the FIB-4 index. In the intermediate-risk (≥1.3 and <2.67) and high-risk (≥2.67) groups, the median levels significantly decreased from 1.77 and 3.33 at baseline to 1.58 and 2.75 at week 48, respectively (p < 0.001 for both). Improvements in body weight, glucose control, liver transaminases, and FIB-4 index were found at 3 years of SGLT2-I treatment. In the intermediate-risk and high-risk groups (≥1.3 FIB-4 index), the FIB-4 index maintained a significant reduction from baseline throughout the 3 years of treatment. Conclusion: This study showed that SGLT2-Is offered a favorable effect on improvement in FIB-4 index as a surrogate marker of liver fibrosis in patient with NAFLD complicated by T2DM, especially those with intermediate and high risks of advanced fibrosis, and this antifibrotic effect is sustained for the long term.

DOI： 10.1002/hep4.2069

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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PURPOSE: 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). DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

DOI： 10.1007/s11102-022-01231-1

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

Pheochromocytomas can present with various symptoms. Nonspecific manifestations of pheochromocytoma include intestinal pseudo-obstruction and weight loss. Here, we present a case of pheochromocytoma in which prolonged intestinal pseudo-obstruction due to excess catecholamines was one of the factors leading to the development of a liver abscess. An 18-year-old male patient with a history of status epilepticus and severe intellectual disability was transferred to our hospital for a thorough examination of fever and constipation that had lasted for 2 months. When admitted to our hospital, he had fever, and his body mass index was 9.5 kg/m². Upon comprehensive examination of the patient’s fever, the blood culture was found positive for Bacteroides. Computed tomography showed findings of intestinal pseudo-obstruction and a low density region in the liver that indicated a liver abscess. Imaging studies also revealed a right adrenal mass and endocrinological test showed elevated plasma norepinephrine and urine normetanephrine levels. In addition, the right adrenal mass showed uptake on ¹²³I-metaiodobenzylguanidine scintigraphy. These findings led to a definite diagnosis of pheochromocytoma. The patient was eventually diagnosed with a pheochromocytoma coexisting with a liver abscess. After treating the liver abscess with antibiotics and ultrasound-guided drainage, an adrenalectomy was performed. The pathological findings were consistent with pheochromocytoma. Postoperatively, the catecholamine excess normalized and intestinal pseudo-obstruction and weight loss improved. We suspected that prolonged intestinal pseudo-obstruction resulted in bacterial translocation and development of a liver abscess. To the best of our knowledge, this is the first report of a pheochromocytoma associated with a liver abscess. Moreover, the clinical presentation of this patient was unusual for pheochromocytoma, as the patient did not have typical symptoms such as hypertension or tachycardia, but rather presented with constipation, intestinal pseudo-obstruction, and weight loss. This case provides valuable insight regarding the impact of catecholamine excess on the intestinal tract and body weight.

DOI： 10.1177/20420188221139652

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/20420188221139652

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Background: Perioperative hyperglycemia is a risk factor for postoperative complications in the general population. However, it has not been clarified whether perioperative hyperglycemia increases postoperative complications in patients with type-2 diabetes mellitus (T2D). Therefore, we aimed to analyze the relationship between perioperative glycemic status and postoperative complications in non-intensive care unit (non-ICU) hospitalized patients with T2D. Materials and Methods: Medical records of 1217 patients with T2D who were admitted to the non-ICU in our hospital were analyzed retrospectively. Relationships between clinical characteristics including perioperative glycemic status and postoperative complications were assessed using univariate and multivariate analyses. Perioperative glycemic status was evaluated by calculating the mean, standard deviation (SD), and coefficient of variation (CV) of blood glucose (BG) measurements in preoperative and postoperative periods for three contiguous days before and after surgery, respectively. Postoperative complications were defined as infections, delayed wound healing, postoperative bleeding, and/or thrombosis. Results: Postoperative complications occurred in 139 patients (11.4%). These patients showed a lower BG immediately before surgery (P = 0.04) and a higher mean postoperative BG (P = 0.009) than those without postoperative complications. There were no differences in the other perioperative BG parameters including BG variability and the frequency of hypoglycemia. The multivariate analysis showed that BG immediately before surgery (adjusted odds ratio (95% confidence interval [CI]), 0.91 (0.85-0.98), P = 0.01) and mean postoperative BG (1.11 (1.05-1.18), P < 0.001) were independently associated with postoperative complications. Conclusion: Perioperative glycemic status, that is, a low BG immediately before surgery and a high mean postoperative BG, are associated with the increased incidence of postoperative complications in non-ICU patients with T2D.

DOI： 10.1177/20420188221099349

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本動脈硬化学会  

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：一般社団法人 日本内分泌学会  

DOI： 10.1507/endocrine.97.s.hpt_32

CiNii Research

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Other Link： https://search.jamas.or.jp/link/ui/2022074895

Language：Japanese   Publisher：日本内科学会-関東地方会  

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経鼻的生検術を行った自己免疫性下垂体炎3症例を提示し、生検術の方法と注意点について報告した。視床下部下垂体に限局した病変で、診断が絞れないケース対して下垂体部の生検術を行う場合には術中髄液漏のリスクを考慮して、トルコ鞍を後方まで十分に削除し、下垂体硬膜を大きく切開した後、後葉の方向から行っている。各種検査で診断を絞ることができなかった症例1(79歳男性)と症例2(64歳女性)は、生検にてそれぞれ頭蓋咽頭腫、リンパ球汎下垂体炎と診断された。症例3(56歳男性)はIgG4関連下垂体炎が最も疑われたが、MRI所見が非典型的であり、生検にて下垂体腺腫を合併したIgG4関連下垂体炎と診断された。正常組織を一部摘出する生検術は最小限の侵襲で行う必要があり、下垂体および周辺の解剖を理解して正確な生検術を行い、下垂体機能を悪化させないことも極めて重要である。

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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 < 0.01). Non-invasive liver fibrosis markers and scoring systems, including fibrosis-4 index, NAFLD fibrosis score, hyaluronic acid, and Wisteria floribunda agglutinin positive Mac-2-binding protein, demonstrated that the diagnostic performance for max-CIMT ≥ 1.2 mm was similar to that of biopsy-based fibrosis staging. In conclusion, advanced fibrosis is significantly and independently associated with high-risk CIMT. Non-invasive fibrosis markers and scoring systems could help estimate the risk of atherosclerosis progression in patients with NAFLD.

DOI： 10.1038/s41598-021-95581-8

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞Point ◎低血糖を契機に発見される内分泌疾患には,インスリノーマ,下垂体機能低下症,副腎皮質機能低下症などがある.◎上記が否定された場合には,大分子量IGF-IIを産生する膵外腫瘍などの非膵島細胞腫瘍性低血糖症(NICTH)の可能性もある.◎専門医への紹介を検討する際には,低血糖発作時に採血した血液中でのインスリンやその拮抗ホルモンの測定結果があることが望ましい.

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01440&link_issn=&doc_id=20210804040009&doc_link_id=10.11477%2Fmf.1402227751&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1402227751&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：(有)科学評論社  

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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.

DOI： 10.1507/endocrj.EJ20-0335

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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.

DOI： 10.2169/internalmedicine.5328-20

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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.

DOI： 10.12998/wjcc.v9.i1.163

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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.

DOI： 10.1530/EJE-20-0706

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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 < 0.0001). ΔQTc was positively correlated with the changes in fasting plasma glucose (ΔFPG, r = 0.55, p = 0.0008) and glycated albumin (r = 0.38, p = 0.026) following insulin therapy, but not with the final dose of insulin (r = -0.20, p = 0.26). The multiple regression analyses revealed that ΔFPG was independently associated with ΔQTc. 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.

DOI： 10.1177/20420188211010057

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DOI： 10.2169/internalmedicine.E003-21

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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 < 0.001 for both). After propensity score matching (44 patients each in the SGLT2-I and non-SGLT2-I groups), no significant difference in HbA1c decrease was observed between the two groups. However, compared with the non-SGLT2-I group, the SGLT2-I group showed a significant decrease in body weight (p < 0.001), alanine aminotransferase (p = 0.02), uric acid (p < 0.001), and Fibrosis-4 (FIB-4) index (p = 0.01) at week 48. The improvement in FIB-4 index, defined as a ⩾10% decline from baseline at week 48, was 56.8% (25/44) in the SGLT2-I group and 20.5% (9/44) in the non-SGLT2-I group (p < 0.001). 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.

DOI： 10.1177/20420188211000243

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Language：Japanese   Publisher：(公財)成長科学協会  

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© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd A 38-year-old woman with type 1 diabetes, whose fasting plasma glucose levels were >500 mg/dL under 176 U/day of subcutaneous insulin injection, was admitted to Nippon Medical School Hospital, Tokyo, Japan. When insulin was administered intravenously, she was able to maintain favorable glycemic control even under 24 U/day of regular insulin, showing that she was accompanied by subcutaneous insulin resistance. To choose an optimal insulin regimen, we carried out subcutaneous insulin challenge tests without or with heparin mixture, and found a cocktail of insulin lispro and heparin could reduce blood glucose levels markedly. As a consequence, she achieved favorable blood glucose control by continuous subcutaneous insulin infusion of the cocktail. In summary, the insulin and heparin challenge tests are useful for choosing an optimal insulin regimen in cases of subcutaneous insulin resistance.

DOI： 10.1111/jdi.13266

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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© 2020 The Author(s). 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.

DOI： 10.1186/s12902-020-0529-2

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Language：Japanese   Publisher：(一社)日本病態栄養学会  

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© The Japan Endocrine Society. 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 (<median = low or group L, n = 18; ≥median = moderate or group M, n = 18). Clinical manifestations, body mass index, severity of hypopituitarism and tumor size, volume, and extension were analyzed retrospectively. Compared with group M, group L patients were significantly older and more gonadotropin and ACTH deficient. A lower peak GH release during a GHRP-2 test was associated with a higher number of anterior pituitary hormone deficiencies across all 76 patients. Postoperatively, seven in group M and no patient in group L were assessed as having no longer severe AGHD, respectively. Preoperative peak GH concentrations assessed during a GHRP-2 test reflected the severity of hypopituitarism and the recovery of postoperative GH secretion.

DOI： 10.1507/endocrj.EJ19-0288

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© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd 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.

DOI： 10.1111/jdi.13312

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Purpose: 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.

DOI： 10.2147/DMSO.S283591

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MEDICAL ASSOC NIPPON MEDICAL SCH  

© 2019, Medical Association of Nippon Medical School. All rights reserved. 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.

DOI： 10.1272/jnms.JNMS.2019_86-505

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成人成長ホルモン(GH)分泌不全症患者において、肝生検をしなくても非アルコール性脂肪肝(NASH)の合併および重症度、特に線維化の程度を予測できるバイオマーカーおよび複数の因子による適切なスコアリングシステムの評価を試みた。2005〜2016年度に加療歴がある下垂体機能障害・汎下垂体機能低下症症例の中で、成人GH分泌不全症を伴い、NASHの疑いで肝生検を行った42例の中から他の慢性肝疾患やアルコール性肝障害が除外された39症例において、臨床的・組織学的な検討を行った。肝線維化予測マーカーであるNAFIC score(フェリチン、インスリン、4型コラーゲン)、FIB-4 index(年齢、AST、血小板、ALT)、NAFLD fibrosis score(年齢、BMI、DM、AST、ALT、血小板、アルブミン)を比較したところ、FIB-4 index(P=0.09)、NAFIC score(P=0.07)がNASHの存在を比較的予測できることが明らかになった。次に単純性脂肪肝(NAFL)とNASHにおける臨床的パラメーターの違いについて検討を行ったところ、NASHにおいて有意に年齢が若く、血小板が多く、PRL値が高く、空腹時IRIが高かった。また頭蓋咽頭腫ではNASHが多い傾向があった。IGF-I値はNASHで高い傾向があった。

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© 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd Aims/Introduction: A prolonged QT interval plays a causal role in life-threatening arrhythmia, and becomes a risk factor for sudden cardiac death. Here, we assessed the association between microvascular complications and the QT interval in patients with type 2 diabetes. Materials and Methods: Patients with type 2 diabetes (n = 219) admitted to Nippon Medical School Hospital (Tokyo, Japan) for glycemic control were enrolled. QT interval was measured manually in lead II on the electrocardiogram, and corrected for heart rate using Bazett's formula (QTc). Diabetic neuropathy, retinopathy and nephropathy were assessed by neuropathic symptoms or Achilles tendon reflex, ophthalmoscopy and urinary albumin excretion, respectively. Results: In univariate analyses, female sex (P = 0.025), duration of type 2 diabetes (P = 0.041), body mass index (P = 0.0008), systolic blood pressure (P = 0.0011) and receiving insulin therapy (P < 0.0001) were positively associated with QTc. Patients with each of the three microvascular complications had longer QTc than those without: neuropathy (P = 0.0005), retinopathy (P = 0.0019) and nephropathy (P = 0.0001). As retinopathy or nephropathy progressed, QTc became longer (P < 0.001 and P < 0.001 for trend in retinopathy and nephropathy, respectively). Furthermore, QTc was prolonged with the multiplicity of the microvascular complications (P < 0.001 for trend). Multiple regression analyses showed that neuropathy, nephropathy and the multiplicity of the microvascular complications were independently associated with QTc. Conclusions: Patients with type 2 diabetes with severe microvascular complications might be at high risk for life-threatening arrhythmia associated with QT interval prolongation.

DOI： 10.1111/jdi.12772

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© 2018 The Japanese Society of Internal Medicine. Solitary fibrous tumor (SFT) is a rare subtype of soft tissue sarcoma (STS). We herein describe a case of late onset of non-islet cell tumor hypoglycemia (NICTH) that was managed via multidisciplinary treatment in a patient with SFT. A 67-year-old man previously diagnosed with SFT 4 years prior to this presentation and treated with several rounds of surgery, presented with massive tumors. Eighteen months following his prescribed chemotherapy, the patient developed hypoglycemia. He was diagnosed with NICTH, after confirming the presence of high molecular weight insulin-like growth factor-2. This case suggests that paraneoplastic syndrome can occur even in cases of rare cancers, such as STS.

DOI： 10.2169/internalmedicine.0231-17

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© The Japan Endocrine Society. 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.

DOI： 10.1507/endocrj.EJ16-0297

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© The Japan Endocrine Society. Non-islet cell tumor hypoglycemia (NICTH) is one of the causes of spontaneous hypoglycemia. The pathogenesis of NICTH is thought to be an excessive production by tumors of big insulin-like growth factor (IGF)-II. This study investigated the levels of glucose-regulatory hormones in patients with NICTH with high serum levels of big IGF-II (big IGF-II group) and compared these with profiles of patients with spontaneous hypoglycemia with normal IGF-II (normal IGF-II group). Circulating IRI, CPR, ACTH, cortisol, GH, and IGF-I levels measured during hypoglycemic episodes were examined retrospectively in 37 patients with big IGF-II producing NICTH and 6 hypoglycemic patients with normal IGF-II. The hormone profile data of 15 patients with NICTH from published case reports were reviewed and included in the analyses. Mean plasma glucose levels (36 vs. 29 mg/dL), serum IRI (0.53 vs. 0.37 μIU/mL), CPR (0.15 vs. 0.20 ng/mL), IGF-I SDS (-3.55 vs. -3.18 SD) and ACTH levels (27.3 vs. 33.8 pg/mL) were not significantly different between the big and normal IGF-II groups. However, mean serum GH (0.85 vs. 9.62 ng/mL) and plasma cortisol levels (16.2 vs. 34.5 μg/dL) were significantly lower in the big IGF-II group than in the normal IGF-II group (both p<0.05). In conclusion, although the magnitude of the decrease in insulin and IGF-I levels did not differ between spontaneous hypoglycemic patients caused by other etiologies, patients with NICTH tended to have low basal GH levels during hypoglycemic episodes. These differences in hormone profile may be helpful for selecting patients who require analysis of IGF-II.

DOI： 10.1507/endocrj.EJ17-0072

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© 2016, Spandidos Publications. All rights reserved. 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.

DOI： 10.3892/ol.2016.4665

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© 2016 The Japanese Society of Internal Medicine. 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.

DOI： 10.2169/internalmedicine.55.5848

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© 2015 The Japanese Society of Internal Medicine. We report a 72-year-old Japanese woman with severe hypoglycemia. The laboratory data, which revealed the suppression of serum insulin, suggested the existence of non-islet cell tumor hypoglycemia (NICTH). Abdominal computed tomography demonstrated the presence of a huge uterine tumor. The patient was treated with a continuous infusion of glucose, but died of sepsis on day 46. An autopsy revealed the pathological diagnosis to be a carcinosarcoma of the uterus. Interestingly, an immunohistochemical study discovered the expression of insulin-like growth factor (IGF)-II in both the carcinoma and sarcoma cells. In addition, an immunoblot analysis of blood samples revealed the presence of circulating big IGF-II. Therefore, this is a novel case of NICTH that was caused by a uterine carcinosarcoma.

DOI： 10.2169/internalmedicine.54.4945

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Copyright © 2015 by the Endocrine Society. Context: 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. Case Report: 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. Conclusions: 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.

DOI： 10.1210/jc.2014-4534

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Untreated acromegaly is associated with a twofold to fourfold increased mortality risk compared to the population. Recently, new therapeutic modalities have been developed and may contribute to an improvement in treatment outcomes in patients with acromegaly. In the current study we determined the clinical features and recent therapeutic outcomes in patients with acromegaly. The initial symptoms, selected therapeutic modalities, and outcomes in 125 patients with acromegaly (M/F, 49/76, 19-86 years) who were admitted to our institution between 2001 and 2010 were analyzed using medical charts. The basal GH levels and IGF-I SD scores in the patients ranged from 0.17 to 90.21 μg/L and 1.9-13.6, respectively. Acral enlargement (face, hands, and feet) without overt complications was essential to the diagnosis in 49 % of the patients. In these cases, it required 5 years to establish the diagnosis of acromegaly after symptom onset. Twenty (16 %) and 13 (10 %) patients had diabetes mellitus and hypertension 6 years prior to the diagnosis of acromegaly, respectively. In 35 patients with microadenomas, the rate of controlled cases following transsphenoidal surgery was 93 %. In 90 patients with macroadenomas, the remission rate was 79 % with multidisciplinary treatment. In cases in which the tumor extended beyond the lateral tangent of the internal carotid artery (Knosp grade ≥3), the remission rate was 33-56 %. Improvements in surgical techniques and medical therapies may contribute to increased rates of controlled cases in patients with acromegaly, although advanced lateral extension of the tumor remains a critical determinant of the therapeutic outcome. © 2013 Springer Science+Business Media New York.

DOI： 10.1007/s11102-013-0472-6

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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.

DOI： 10.2176/nmc.ra.2014-0088

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© 2014 by The Japan Neurosurgical Society. 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 individu- alized 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.

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11β-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<0.05). 11β-HSD1 mRNA levels in cells treated with GH in the presence of 1 μM linsitinib were not different from those in absence of linsitinib (35.9% vs. 33.9%). The increase in IGF-I mRNA levels with GH and 1 μM linsitinib was not different from that in the absence of linsitinib (359% vs. 347%). H6PDH mRNA levels were significantly decreased in cells treated with IGF-I for 8 and 24 h (55.6% and 33.7%, P<0.05). In the presence of 1 μM linsitinib, there was no repression of H6PDH mRNA (111.4%). H6PDH mRNA levels were significantly decreased in cells treated with GH in the absence of linsitinib for 24 h (55.9%, P<0.05), but not for 8 h (89.5%). The presence of 1 μM linsitinib also prevented repression of H6PDH mRNA by GH over 24 h (107.8%). These results suggest that GH directly represses 11β-HSD1 mRNA rather than acting via the IGF-I receptor, and that GH represses H6PDH through locally produced IGF-I. © The Japan Endocrine Society.

DOI： 10.1507/endocrj.EJ13-0528

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Hypoglycemia is a rare paraneoplastic manifestation of patients with neoplasms. Hypoglycemia can be induced by several causes, including an aberrant increase of hypoglycemic agents and adrenal insufficiency. Sorafenib is the first agent to demonstrate a survival benefit in the treatment of advanced hepatocellular carcinoma (HCC). This small molecule inhibits serine/threonine kinase RAF in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature and decreases tumor growth and angiogenesis. In this paper, we report a case of HCC who was treated with sorafenib and showed severe hypoglycemia. This hypoglycemia might be induced by two causes, both adrenal insufficiency as an adverse effect of sorafenib and activation of the insulin-like growth factor (IGF) signal by excessive secretion of incompletely processed precursors of IGF-II. Although the IGF signal is suggested to be involved in aberrant growth of HCC in some cases, there is no other report showing the influence of sorafenib on HCC with active IGF signal. Unfortunately, the effect of sorafenib was limited in the present case. However, emerging drugs that directly inhibit the IGF signal can be expected to be highly effective in the treatment of HCC with hypoglycemia. © 2012 S. Karger AG, Basel.

DOI： 10.1159/000346462

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A 41-year-old man was diagnosed with a solitary fibrous tumor (SFT) of the pleura in the posterior mediastinum. Despite two surgeries for excision, the SFT recurred and progressed with direct invasion of the chest wall and bone metastases. He was hospitalized because of cerebral infarction and presented with recurrent severe hypoglycemia fourteen years later. High-molecular-weight (HMW) insulin-like growth factor II (IGF-II) was identified in the serum and tumor using Western blotting and immunohistochemistry. These findings suggested that the cause of the recurrent severe hypoglycemia was SFT production of HMW IGF-II, a mediator of non-islet cell tumor-induced hypoglycemia (NICTH). © 2012 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.51.7906

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J01205&link_issn=&doc_id=20110311240027&doc_link_id=%2Fag6niria%2F2011%2F0069s2%2F028%2F0150-0154%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag6niria%2F2011%2F0069s2%2F028%2F0150-0154%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ENDOCRINE SOC  

In Japan, the growth hormone (GH) assay has been standardized since April 2005 through use of a uniform recombinant human GH (rhGH) standard. Since then, GH values measured using the rhGH standard have been approximately 40% lower than previous values measured using kit standards based on the WHO standards for hGH of pituitary origin. However, the Japanese criteria for evaluating treatment outcomes for acromegaly have remained the same: a nadir GH during a 75 g OGTT <1 μg/L is considered cured, 1≤GH<2.5μg/L is considered inadequately controlled, and ≥2.5 μg/L is considered poorly controlled, instead of these levels were lowered to 60%, i.e. from 1 to 0.6 μg/L for cured and from 2.5 to 1.5μg/L for inadequately controlled (termed as "newly proposed criteria" in this study). We investigated the effects of standardization of the GH assay on the evaluation of post-surgical disease activity in 50 patients with acromegaly (M/F 19/31, 21-72 yr.). Post-surgical nadir GH levels during OGTT were positively correlated with the IGF-I SD score 3 months after TSS. Five of 6 patients whose post-surgical nadir GH levels ranged between 0.6 and 1 μg/L had normal serum IGF-I levels 3 months after TSS. Rates of improvement in glucose metabolism did not differ when patients were classified based on the present criteria vs. the newly proposed criteria. In conclusion, the current Japanese remission criteria for acromegaly still accurately reflect post-surgical disease activity in most patients, though long-term observation is still required. © The Japan Endocrine Society.

DOI： 10.1507/endocrj.K11E-099

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Language：English   Publisher：WILEY  

DOI： 10.1111/j.1440-1827.2010.02563.x

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J01205&link_issn=&doc_id=20100722300042&doc_link_id=%2Fag6niria%2F2010%2F0068s7%2F043%2F0189-0191%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag6niria%2F2010%2F0068s7%2F043%2F0189-0191%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ENDOCRINE SOC  

Hypoglycemia is reported to be one of the manifestations of a patient with hypothalamic sarcoid infiltrates due to impaired counter-regulation of glucose. But, without hypothalamic lesion, patients with sarcoidosis would not be expected to have hypoglycemia. We recently identified a patient with an isolated sarcoidosis of the spleen who had experienced frequent fasting hypoglycemia which completely disappeared after splenectomy. During hypoglycemia, serum insulin was undetectable. Endocrinological examination revealed no abnormality. The objective was to investigate whether the patient's hypoglycemia was due to ectopic secretion of an insulin-mimetic factor by the splenic sarcoidosis. Serum insulin-like growth factor-I (IGF-I) and IGF-II were measured by RIA. Serum visfatin and free IGF-I were by ELISA. A high molecular weight form of IGF-II, termed "big" IGF-II, was identified by Western blotting. Tissue IGF-I was quantified by real time RT-PCR after RNA extraction. Before operation, total and free serum IGF-I, serum IGF-II and serum visfatin were within reference range. Big IGF-II was not detected in patient's serum extract. After operation, hypoglycemia did not recur and serum insulin returned to normal, while serum IGF-I decreased by half the preoperative level. RT-PCR revealed that mRNA level of IGF-I in the sarcoidosis tissue was about 1.8-fold greater than that in the normal spleen tissue. These data suggest that ectopic secretion of IGF-I by the splenic sarcoidosis and its direct access to the liver via the portal vein might cause fasting hypoglycemia mainly by suppressing hepatic gluconeogenesis.

DOI： 10.1507/endocrj.K09E-370

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Language：English   Publisher：JAPAN ENDOCRINE SOC  

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Gender affects the GH secretory pattern both in normal subjects and in patients with acromegaly by an uncertain mechanism. Here, we report the influence of gender on the relationship between serum GH and IGF-I levels and the GH response to dynamic tests in patients with acromegaly. Seventy-four patients with untreated acromegaly (M/F 27/47, age range 22-86 yr.) were studied. The serum GH levels did not differ between male and female (6.1 vs. 8.7 ng/mL; p=0.26), while serum IGF-I levels, IGF-I SDS and the IGF-I/GH ratio were lower in female than those in male (679 vs. 769 ng/mL; p<0.02, 7.3 vs. 9.2 SDS; p<0.02 and 79.6 vs. 141.5; p<0.05). When the subjects were divided into two groups: age ≤50 yr, and age >50 yr, serum IGF-I levels and IGF-I/GH ratios were lower in female than those in male in patients ≤50 yrs (650 vs. 1002 ng/mL; p<0.05 and 59.8 vs. 142.9; p<0.05), but not in patients >50 yrs (684 vs. 680 ng/mL; p=0.39 and 98.7 vs. 118.4; p=0.40). The GH responses to OGTT, TRH, octreotide, and bromocriptine tests were similar in male and female. In conclusion, IGF-I/GH ratio was significantly lower in female than that in male particularly in younger patients with acromegaly. These data suggest that gender, presumably sex steroids in female, may partially modulate the relationship between circulating IGF-I and GH levels in patients with acromegaly.

DOI： 10.1507/endocrj.K09E-342

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Turner syndrome (TS) is associated with a number of complications including thyroid disease. In this study, the prevalence of thyroid disease was evaluated in Japanese women with TS. The medical charts of 65 TS women (age 30±9 years old, range: 15-61), treated with estrogen replacement therapy or with antiosteoporotic pharmaceuticals at our outpatient clinic, were reviewed. History of thyroid disease, titer of thyroid autoantibodies and thyroid function were recorded. Thyroid autoantibodies were undetectable in 28 of 65 women (43%), and thyroid function was normal in all these women. Of the 37 women with thyroid autoantibodies (57%), 3 had Graves' disease and 20 women were hypothyroidism and diagnosed as Hashimoto's thyroiditis. The remaining 14 women with euthyroidism were also considered to be so-called probable cases of Hashimoto's thyroiditis. In 20 women with hypothyroidism, 14 (70%) received replacement therapy with levothyroxine. The replacement with levothyroxine started between age 17 and 60 (median: 31 years old), These data showed that more than half of Japanese women with TS in adulthood had thyroid autoantibodies. In women with TS, monitoring of thyroid hormone is important to detect hypothyroidism earlier and start adequate replacement therapy.

DOI： 10.1507/endocrj.K09E-141

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOSCIENTIFICA LTD  

Objective: The purpose of this study was to investigate the influence of age on GH and IGF1 axis, and complications in patients with acromegaly. Subjects and methods: From the medical records, we retrospectively analyzed clinical features and complications in 87 newly diagnosed patients with active acromegaly (34 males, 53 females; aged 18-82 years) who were admitted to Tokyo Women's Medical University between 1999 and 2006. We divided the patients into three groups according to age: ≤ 30 years old (young group), 31-60 years old (middle-aged group), and ≥ 61 years old (elderly group). Results: The median GH levels in young, middle-aged, and elderly groups were 18.5, 8.8, and 6.7 μg/l respectively, and the IGF1 levels were 810, 717, and 740 μg/l respectively. The values were not significantly different among the groups. However, the serum IGF1 SDS were significantly higher in the elderly group (10.2) than those in young and middle-aged groups (6.6 and 6.2 respectively, P<0.001). The age difference in the higher IGF1 SDS was remarkable in female patients. In the elderly group, glucose intolerance and hypertension were found in 94 and 53% of the patients respectively and the incidences were higher than those in the other groups. Conclusion: This study suggests that the relatively high IGF1 secretions in elderly patients might be involved in the progression of clinical complications in acromegalic patients. Therefore, awareness of the early symptoms and examination of serum GH and IGF1 are important for patients with acromegaly. © 2008 European Society of Endocrinology.

DOI： 10.1530/EJE-08-0243

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GH therapy was approved in 2006 for treatment of adult growth hormone deficiency (GHD) in Japan. Until then, GH was used only to treat short stature in children with GHD and the treatment was stopped when the final height was reached. In the present study, we investigated metabolic co-morbidities experienced by adults with childhood-onset (CO) GHD after the cessation of GH. Forty-two patients with COGHD (M/F 22/20, age at follow up when the retrospective analysis was carried out: 18-52 yr) treated with GH in childhood were studied. We reviewed the medical records of these patients to determine the metabolic co-morbidities that developed after cessation of GH. The median age was 19 yrs (range: 14-38) at cessation of GH, and the following co-morbidities were observed: hypertriglyceridemia in 15 (41%) patients, non-alcoholic fatty liver disease (NAFLD) in 11 (29%) patients, hypercholesterolemia in 10 (26%) patients, diabetes mellitus (DM) in 4 (10%) patients, and hypertension in 1 (2.4%) patient. The median BMI when these complications became overt was 23.5 kg/m2 for those with hypertriglyceridemia, 26.0 kg/m2 for those with NAFLD, 20.9 kg/m2 for those with hypercholesterolemia, and 27.2 kg/m2 for those with DM. More than two co-morbidities were experienced by 32% of men and 30% of women. In conclusion, adults with COGHD after the cessation of GH have multiple metabolic co-morbidities. Lifelong GH replacement might be important for improving the overall metabolic profiles in these patients.

DOI： 10.1507/endocrj.K08E-079

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It has been reported that patients with acromegaly may have an increased risk of developing several types of cancers, such as colorectal, breast and prostate tumors. However, some reports do not support these findings and therefore the prevalence of cancers in patients with acromegaly remains controversial. In this study, we determined the prevalence of benign and malignant neoplasms in patients with acromegaly. A retrospective chart analysis was performed on 140 patients with active acromegaly who had attended our outpatient clinic (M/F 54/86, age 55 ± 25 yr, range 21-86). Colon cancer was found in 10 patients, thyroid cancer in 5, breast cancer in 4 and gastric cancer in 2. When compared with the local population, the standardized incidence ratios (SIRs) for thyroid cancer in patients with acromegaly were 61.74 (95% confidence interval (CI): 0.51-114.63) for females and 272.4 (95% CI: 29.12-876.71) for males. The SIRs for colon cancer in the acromegalic patients were 17.4 (95% CI: 4.74-44.55) for females and 19.0 (95% CI: 5.18-48.64) for male patients in comparison with the local population. Of the benign tumors, multinodular goiter and colonic, gastric and gallbladder polyps were observed in 57% (47/83), 39% (31/80), 21% (8/39), and 15% (10/65) of the patients, respectively. This study suggested that patients with acromegaly have an increased risk of colon cancer and polyps. Moreover, it is speculated that the risk for thyroid cancer is increased in male patients. It is therefore recommended that patients with acromegaly should undergo screening colonoscopy and ultrasonography of the thyroid.

DOI： 10.1507/endocrj.K07E-010

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Language：Japanese   Publisher：東京女子医科大学総合研究所  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

In some patients with non-islet-cell tumor hypoglycemia (NICTH), a high molecular weight form of IGF-II (big IGF-II) derived from tumors is present in the circulation and might be associated with recurrent hypoglycemia. In this study, in order to survey the clinical characteristics of patients with IGF-II producing NICTH, we analyzed the medical records of 78 patients with NICTH (M/F 44/34, age 62 ± 1.8, range; 9-86 years.) whose serum contained a large amount of big IGF-II. Hepatocellular carcinoma and gastric carcinoma were the most common causes of NICTH. The diameters of the tumors were more than 10 cm in 70% of the patients. Basal immunoreactive insulin (IRI) levels were less than 3 μU/dl in 79% of the patients. Hypoglycemic attack was the onset of disease in 31 of 65 cases (48%), but the tumor was revealed prior to the occurrence of hypoglycemia in 34 cases (52%). Twenty-five of 47 (53%) patients had decreased serum potassium levels. These data suggested that hypoinsulinemic hypoglycemia associated with the presence of a large tumor supports the diagnosis of IGF-II producing NICTH. Hypokalemia was associated with hypoglycemia in some patients. The BMI (21.4 ± 0.6 kg/m2) and serum total protein levels (6.6 ± 0.1 g/dl) were preserved at the occurrence of first hypoglycemic attack suggesting that malnutrition might not be the main cause of hypoglycemia in most patients. © 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.ghir.2006.05.003

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Language：English   Publisher：東京女子医科大学総合研究所  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ENDOCRINE SOCIETY  

The purpose of this study carried out at a single institute in Japan was to investigate the clinical characteristics and complications of patients with adult growth hormone deficiency (GHD). Clinical and biochemical data of 110 patients (50 males, 60 females; mean age 42 ± 17 yr) with adult GHD who attended Tokyo Women's Medical University between 1990 and 1999 were analyzed retrospectively from medical records. This retrospective analysis demonstrated that 109 patients had multiple pituitary hormone deficiencies, with 98 patients having a deficiency of more than three hormones. Sixty-one patients had childhood onset GHD (COGHD) while the remaining 49 patients had adulthood onset GHD (AOGHD). Body mass index (BMI) ranged from 16.9 to 35.9 with a mean of 23.9 ± 4.1 (kg/m2), with BMI being ≥25 kg/m2 in 38 patients (31% of COGHD and 38% of AOGHD). Forty-one percent of the patients had hypercholesterolemia, 41% had hypertriglyceridemia, 47% had decreased levels of HDL cholesterol and 48% had increased levels of LDL cholesterol. Intima-media thickness (IMT) of the carotid arteries was investigated in 33 patients, with abnormal findings including increased IMT or plaque being observed in 4 of 18 COGHD patients and 4 of 15 AOGHD patients. Diabetes mellitus and impaired glucose tolerance was found in 4 COGHD patients and 16 AOGHD patients. Insulin resistance was assessed in 36 patients by the homeostasis model insulin resistance index (HOMA-R) and ranged from 0.65 to 10.58 with a mean of 2.80 ± 0.37. This mean value of HOMA-R was significantly greater than that measured in normal subjects (1.58 ± 0.05: P<0.05). These data suggest that abnormal lipid and glucose metabolism, and atherosclerotic changes occur frequently in adult patients with GHD. Insulin resistance may play a role in glucose and lipid metabolism disorders associated with GHD.

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The aim of this study was to define the preoperative diagnosis of thyroid follicular carcinoma by the vascular pattern and velocimetric parameters using high resolution pulsed and power Doppler ultrasonography (US). We compared the vascular pattern and the velocimetric parameters, such as peak systolic velocity (Vmax), end-diastolic velocity (Vmin), pulsatility index (PI), or resistance index (RI) between follicular adenoma (FA, n = 25) and follicular carcinoma (FC, n = 10) and analysed them by means of receiver characteristics curves (ROC). Of 10 patients with FC, 8 (80%) patients presented a moderate increase of intranodular vascularization using power Doppler US. In contrast, the majority (84%, 21 out of 25 cases) of FA cases showed only a peripheral rim of color flow even by power Doppler US. These color flow imagings by power Doppler US were suggested to be a reliable tool for the differential diagnosis of thyroid follicular tumor with a sensitivity of 87.5% and a specificity of 92%. In velocimetric analyses, the Vmax/Vmin ratios, PI, and RI were significantly higher in the patients with FC than those with FA (p<0.001, p<0.005, and p<0.001, respectively). By means of ROC, FC could be diagnosed with a cutoff value of ratio of PI (>1.35), RI (>0.78), and Vmax/Vmin (>3.79). The diagnostic efficiency evaluated by ROC curves were 0.898 for PI, 0.876 for RI, and 0.888 for Vmax/Vmin, respectively. In conclusion, the evaluation of the vascular pattern and the velocimetric parameters using pulsed and power Doppler ultrasound may provide important information that is useful in making correct differential diagnosis of malignant or benign thyroid follicular tumor preoperatively.

DOI： 10.1507/endocrj.52.207

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Patients with growth hormone deficiency (GHD) often have obesity, hyperlipidemia, fatty liver and diabetes mellitus which are similar to metabolic syndrome. Recently, it has been reported that non-alcoholic fatty liver disease (NAFLD), especially with non-alcoholic steatohepatits (NASH) are associated with metabolic syndrome. Therefore, it is interesting to know the relationship between GHD and NASH/NAFLD. In the present study, we investigated NASH/NAFLD in patients with childhood-onset adult GHD. A retrospective chart analysis was performed on 38 patients (M/F 19/19, age 35 ± 11, range 18-62) with childhood-onset GHD who visited our outpatient clinic. Clinical course, symptoms and laboratory data were reviewed in these patients. The average body mass index (BMI) and the value of HOMA-R of the patients were 24.9 ± 3.8 kg/m2 and 3.09 ± 2.9, respectively. Liver dysfunction was found in 17 patients. We performed abdominal ultrasonography on 7 of 17 patients with liver dysfunction, and observed fatty liver change in all patients. The majority of these patients had impaired glucose tolerance and dyslipidemia by the time of diagnosis of NAFLD. Moreover, microscopic examination of liver biopsy specimens from one patient revealed NASH with fibrosis. In conclusion, patients with GHD are at risk of excessive weight gain, impaired glucose tolerance, and dyslipidemia with subsequent development of NAFLD. As NAFLD is related to the occurrence of NASH and cirrhosis, this novel evidence that GHD may be accompanied by progressive NAFLD has important implications for follow-up and management of patients with GHD. Copyright© 2005 by The Japanese Society for Pediatric Endocrinology.

DOI： 10.1297/cpe.14.S24_85

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

Atherosclerosis and insulin resistance are common complications of adult growth hormone deficiency (GHD) and acromegaly. Circulating adiponectin, an adipocyte-derived protein, has both anti-atherogenic and insulin-sensitising effects. In this study, we measured serum adiponectin levels in patients with either adult GHD or acromegaly to clarify the impact of GH secretory states on the regulation of serum adiponectin levels. Serum adiponectin level was measured by radioimmunoassay in 32 patients with adult GHD, 49 patients with acromegaly and 25 normal subjects. The relationships between adiponectin and insulin sensitivity index assessed as quantitative insulin sensitivity check index (QUICKI), BMI, and serum GH and IGF-I levels were then investigated. The values of QUICKI were significantly lower in patients with acromegaly or adult GHD compared to normal subjects (0.33 ± 0.03, P < 0.01, 0.35 ± 0.04, P < 0.05 and 0.36 ± 0.01, respectively). While patients with adult GHD had significantly lower serum adiponectin levels than patients with acromegaly (6.5 ± 3.9, 9.2 ± 5.0, P < 0.01) these levels were not significantly different from those found in normal subjects (7.8 ± 4.3 μg/ml). There was an inverse correlation between serum adiponectin levels and BMI in both patient groups (GHD r = -0.39, P < 0.05; Acromegaly r = -0.35, P < 0.05). However, serum adiponectin levels correlated positively with QUICKI (Rs = 0.37, P < 0.05) only in patients with adult GHD. In patients with acromegaly, the levels of circulating adiponectin showed an inverse correlation with serum IGF-I levels (Rs = -0.34, P < 0.05), but not with basal GH levels. These results demonstrate that adiponectin levels are significantly lower in patients with adult GHD than in patients with acromegaly. Adiponectin levels are similar in patients with GHD and healthy controls, whereas in patients with acromegaly, insulin resistance appears to be not closely related to adiponectin levels compared with BMI. The different relationship between adiponectin and QUICKI observed in the adult GHD and acromegaly groups presumably reflects differences in the mechanisms of insulin resistance under states of GH deficiency or excess. © 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.ghir.2004.06.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

We report an 80-year-old man who presented with non-islet cell tumor hypoglycemia (NICTH) in association with hepatic recurrence of gastric cancer. His serum potassium was reduced from 3.9 to 3.1 mmol/l 5 weeks after gastrectomy, and he subsequently developed hypoglycemic coma. He was diagnosed as having NICTH because of the presence of serum big IGF-II and positive staining for IGF-II in gastric cancer cells obtained at surgery. A computed tomography showed multiple liver metastases. His hypoglycemia was refractory to steroid therapy. This case suggested that NICTH could develop in association with hepatic metastases of gastric cancer. Unexpected hypokalemia may be a manifestation of occult NICTH.

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We studied the efficacy and safety of oral 1-deamino-8-D-arginine-vasopressin (DDAVP) tablets in 9 patients, aged 17-36 years, with central diabetes insipidus (DI). The tablet contained 100 μg of desmopressin acetate. Maximum plasma concentration was obtained at 90 min after a single oral administration of 100 μg DDAVP with a mean plasma level of 14. 7 ± 5.4 (range: 5.3-50.9) pg/ml. The onset of action was observed 2 h after oral administration, while the maximum effect was obtained at 4 h. Mean urine volume in patients decreased significantly from 402 ± 52 to 26 ± 3 ml/hr and urine osmolality increased from 91 ± 8 to 732 ± 21 mosm/kg at 4 h after the intake of oral DDAVP. Plasma osmolality level and serum sodium concentration remained unchanged throughout the study. Long-term treatment for 5 years with oral DDAVP resulted in control of diuresis in 8 of the 9 patients. The average oral DDAVP dose required to obtain this control was 19 ± 2 (range: 15-30) times more than that of prior intranasal treatment. No adverse effects were observed during this follow-up period. These results indicate that oral DDAVP is a safe therapeutic agent that may be a good alternative treatment of central DI, particularly in patients who have chronic rhinitis and visual disturbances.

DOI： 10.1507/endocrj.50.437

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ENDOCRINE SOCIETY  

In serum, insulin-like growth factors (IGFs) are primarily present as a ∼150 kDa ternary protein complex, which consists of IGFs, IGF binding protein-3 (IGFBP-3), and acid-labile subunit (ALS). Like IGF-I and IGFBP-3, serum levels of ALS depend on growth hormone (GH). To date, the diagnostic relevance of ALS in adult GH deficiency (GHD) has remained uncertain. To clarify the clinical utility of ALS measurement in adults, we measured serum ALS levels in patients with adult GHD or acromegaly. We also measured the levels of serum IGF-I and IGFBP-3 in these patients to compare the utility of ALS with IGF-I and IGFBP-3 as a marker of GH secretion. Serum ALS was measured by radioimmunoassay (RIA) kit, and serum IGF-I and IGFBP-3 were measured by immunoradiometric assay (IRMA) kits in 56 patients with adult GHD (adult-onset (AO)/child-onset (CO), 13/43) and 43 patients with acromegaly. Serum ALS levels were less than 5th percentile in 40 of 56 (71%) patients with adult GHD (32/43 (74%) for CO and 8/13 (62%) for AO), and more than 95th percentile in 38 of 43 (88%) patients with acromegaly, respectively. Serum IGF-I levels were less than -1.96 SD in 43 of 56 (77%) patients with adult GHD (35/43 (81%) for CO and 8/13 (62%) for AO) and more than +1.96 SD in 42 of 43 (98%) patients with acromegaly, respectively. Serum IGFBP-3 levels were less than -1.96 SD in 51 of 56 (91%) patients with adult GHD (42/43 (98%) for CO and 9/13 (69%) for AO) and more than +1.96 SD in 31 of 43 (72%) patients with acromegaly, respectively. These data suggested that measurement of ALS offers no advantage over measurements of serum IGF-I and IGFBP-3. Furthermore, our results indicate that serum IGFBP-3 is the most suitable marker of GH secretion for adult GHD, especially CO, while IGF-I may be the most useful in acromegaly.

DOI： 10.1507/endocrj.49.379

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective. The purpose of this study was to survey the clinical characteristics, complications, and therapeutic outcome in patients with acromegaly. Patients and Methods. The clinical features of 65 patients with acromegaly (31 males, 34 females; mean age: 50±2 yr.) who were admitted to Tokyo Women's Medical University between 1990 and 1999 were analyzed retrospectively from medical records. Results. The retrospective analysis revealed that the diagnosis of acromegaly was preceded by approximately 8.1±1.1 years of signs and symptoms of the disease. Forty-six of the 65 patients (71%) had macroadenomas, 16 (25%) had microadenomas, and the remaining three had empty sella. The rate of biochemical cure or remission was 81% for microadenoma (13/16), 64% for macroadenoma without extrasellar extension (9/14), and 13% for macroadenoma with cavernous sinus extension (2/15). Eighteen (28%) patients had impaired glucose tolerance (IGT) and 32 (49%) had diabetes mellitus (DM). After treatment for acromegaly, glucose metabolism was analyzed again in 38 patients, and it improved in 26 patients with IGT or DM. Twenty-five of 65 patients (38%) had hypertension. Of 26 patients who underwent barium enema or colonoscopy, 10 had colonic polyps and 4 had colon cancer. Conclusion. This study suggests that long-term excessive growth hormone (GH) secretion causes many complications. Therefore, awareness of the early symptoms and signs of acromegaly and long-term careful management of complications, along with therapy to reduce serum GH/insulin-like growth factor (IGF)-I levels, are important for patients with acromegaly.

DOI： 10.2169/internalmedicine.40.987

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ENDOCRINE SOCIETY  

Initial investigations of a 70-year-old woman with clinical Cushing's syndrome, including overnight dexamethasone suppression test, CRH test, and pituitary MRI, suggested the presence of ectopic ACTH production. Thoracic computed tomography (CT) scan revealed a mass measuring 7 mm in the right lung, but it was thought to be an incidental opacity, leaving the source of ectopic ACTH undetermined for several years. During this period, although the size of the lung opacity did not change remarkably, serum cortisol levels became elevated to 43μ/dl, and the patient's symptoms worsened. T1-201 SPECT demonstrated intense accumulation in the right lung. The mass was surgically resected using thoracoscopy to investigate it as the focus of ACTH production. Histological and immunohistochemical examination confirmed that the area of intense T1-201 uptake was an ACTH-producing bronchial carcinoid. Plasma ACTH and cortisol levels decreased immediately after the surgery. In conclusion, this case demonstrated T1-201 scintigraphy as a useful tool in identifying the location of an ACTH-producing bronchial carcinoid.

DOI： 10.1507/endocrj.48.697

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ENDOCRINE SOC  

Malnutrition is one of the risk factors for bone loss in patients with anorexia nervosa (AN). To clarify the effects of nutritional status on bone metabolism, we examined the relationship between serum levels of nutritional indicators [insulin-like growth factor I (IGF-I), IGF-binding protein-2 (IGFBP-2), and IGFBP-3] and markers for bone metabolism [serum osteocalcin and urinary excretion of C-terminal telopeptide of collagen type I (CrossLaps)] in 45 AN out-patients, including 8 severely malnourished patients who required hospitalization and iv hyperalimentation (IVH). Compared to healthy subjects, serum IGF-I and IGFBP-3 were lower, whereas IGFBP-2 was higher in out-patients who had a body mass index (BMI) less than 16.5 kg/m2. In these patients, urinary excretion of CrossLaps, a marker of bone resorption, was higher, whereas serum osteocalcin, a marker of bone formation, was lower than those in control subjects. All of these parameters were normal in patients whose BMI ranged from 16.5-18.5 kg/m2. Serum levels of osteocalcin correlated positively with BMI (r = 0.512; P < 0.0001), IGF-I (r = 0.558; P < 0.0001), and IGFBP-3 (r = 0.369; P < 0.001) in AN out-patients. In the 8 severely malnourished AN patients, serum levels of IGF-I and osteocalcin significantly increased 3 and 7 days, respectively, after the start of a 5-week IVH therapy regimen and reached normal levels within 5 weeks, accompanied by still elevated urinary excretion of CrossLaps. The present study demonstrates that an improvement in nutritional status in AN patients during IVH therapy rapidly increases the serum IGF-I levels, followed by a progressive increase in osteocalcin, suggesting immediate start of bone formation. However, increased bone resorption appears to continue for at least 5 weeks.

DOI： 10.1210/jc.85.1.200

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Serum insulin-like growth factor II (IGF-II) was characterized by radioimmunoassay and Western immunoblot in 44 patients with non-islet cell tumor hypoglycemia (NICTH). 31 of 44 patients with NICTH had big IGF-II in sera. When the presence of IGF-II in tumors from 20 patients was investigated, IGF-II in tumors was detected in 18 patients and these patients had big IGF-II in sera. In two patients whose tumors did not contain IGF-II, big IGF-II in sera was not detected. In six patients with IGF-II in tumors, hypoglycemia disappeared and the big IGF-II decreased after successful removal of the tumors. These data indicate that the big IGF-II could be related to hypoglycemia, and that the increased serum big IGF-II suggests IGF-II-producing NICTH. Serum IGF-II levels in 31 patients with big IGF-II were greater than those in 13 patients without it (Mean ± SEM: 723 ± 54 vs. 326 ± 31 ng/ml), but the elevated IGF-II levels were found in only 13 patients. Serum IGF-I levels were low in all patients with NICTH. In the 13 patients without big IGF-II, serum IGF-II levels were lower than those in the patients with big IGF-II, and serum IGF-I levels were also low. Serum IGF- II/IGF-I ratios in the patients with big IGF-II were elevated and greater than those in the patients without big IGF-II (35.0 ± 2.2 vs. 11.5 ± 2.4). The present data indicate that IGF-II-producing tumors are not rare in NICTH, and serum big IGF-II and IGF-II/IGF-I ratio are useful for screening patients with IGF-II-producing NICTH.

DOI： 10.1507/endocrj.45.suppl_s61

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Human insulin-like growth factor-II (IGF-II) gene (IGF2) is maternally imprinted, and only the paternal allele of IGF2 is usually expressed. It has been suggested that IGF-II might be one of the modulators of tumour growth. Recently, loss of imprinting (LOI) of IGF2 has been reported in some embryonal tumours and adult-onset malignant tumours, suggesting that biallelic expression of the gene leads to overexpression of IGF-II peptide and increased mitogenic activity. In this study, we examined allelic gene expression of IGF2 in various adult-onset tumour tissues using the Apa I restriction enzyme fragment length polymorphism (RFLP) in exon 9 of IGF2. Total RNA and genomic DNA were extracted in IGF-II producing tumours of non-islet cell tumour hypoglycemia (NICTH: n = 14), adrenal tumours (pheochromocytoma (PC): n = 1; aldosterone producing adenoma (PA): n = 2: adrenal carcinoma (AC): n = 1). and gastric neurofibroma (GN: n = 1). The DNase treated RNA was transcribed into cDNA using reverse transcriptase (RT), and the cDNA or genomic DNA was amplified by PCR for IGF2. The PCR products were digested with Apa I and the RFLP for Apa I was analyzed. IGF2 expressed in all examined tumour tissues, and 15 of tumours (10 NICTH, one PC, two PA, one AC and one GN) were heterozygous for the Apa I polymorphism. IGF2 was expressed biallelically (LOI) in eleven of informative tumours (seven NICTH, one PC, one PA, one AC and one GN). These data demonstrate that LOI of IGF2 occurs not only in childhood tumours and malignant tumours but also in adult-onset benign tumours.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

The pathophysiological roles of insulin-like growth factor binding protein (IGFBP)-6 have not been elucidated. Recently we measured serum IGFBP-6 by Western immunoblot (WIB) and have found that serum IGFBP-6 levels increased in patients with chronic renal failure (CRF). In the present study, serum IGFBP-6 levels were measured in ten patients with CRF before and 1, 7 and 14 days after renal transplantation to investigate further clinical significance and regulation of serum IGFBP-6. IGFBP-2 and -3 levels, usually elevated in patients with CRF, were also measured after renal transplantation. Serum IGFBP-2 and -6 levels from patients with GRF by Western immunoblot increased to 230 +/- 90% (mean + SD), and 400 +/-: 110% of the reference serum, respectively, and these levels did not change after hemodialysis. Serum IGFBP-6 levels decreased to 47 +/- 20% of the basal level 1 day after renal transplantation, and the IGFBP-6 levels in two patients whose renal function worsened again due to rejection increased to more than 60% of the basal levels on the 14th day. In contrast to IGFBP-6, serum IGFBP-2 levels did not decrease during the 14 days after renal transplantation in all patients. Serum IGFBP-3 levels were significantly higher in CRF than normal sera (5.5 +/- 1.2 versus 3.7 +/- 0.5 mu g/ml, p &lt; 0.01), and the levels decreased to the normal range (2.7 +/- 1.0 mu g/ml) within one day after the transplantation, whereas the levels increased again in one of two patients with poorly-functioning graft. In addition, we demonstrated IGFBP-6 in urine from normal adults. These results indicate that IGFBP-6 might be excreted by the kidneys and serum IGFBP-3 and -6 levels might be related with renal function, and that the regulation of serum IGFBP-2 levels differs from those of IGFBP-2 and -6.

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Insulin-like growth factor-II (IGF-II) has an insulin-like effect in vitro and in vivo. Recently, mutants of IGF-II have been synthesized by the site-directed mutagenesis technique, and the structure determinants for the function of IGF-II have been studied. With the availability of the biosynthetic IGF-II and IGF-II mutants, we have investigated the hypoglycemic effect of IGF-II in normal rats and insulin resistant mice. When the IGF-II mutants with markedly decreased affinities for both insulin and IGF-I receptors were injected in normal rats, the blood glucose levels slightly decreased. However, when IGF-II mutant with slightly decreased affinities for both insulin and IGF-I receptors was injected, the blood glucose decreased to the same extent as with IGF-II. In insulin resistant mice, insulin did not decrease the blood glucose levels, but, the blood glucose levels decreased after IGF-I and IGF-II injection. The hypoglycemic effect of IGF-II was greater than that of IGF-I. The IGF-II mutant without affinity for IGF-II receptor but with affinities for both IGF-I and insulin receptors the same as IGF-II, caused hypoglycemia the same as IGF-I. However, the IGF-II mutant with markedly decreased affinities for both insulin and IGF-I receptors did not decrease blood glucose levels, and the IGF-II mutant with slightly decreased affinities for both insulin and IGF-II receptors slightly decreased blood glucose levels. These data indicate that the hypoglycemic effect of IGF-II is mediated mainly through insulin and/or IGF-I receptor but not IGF-II receptor. Furthermore, the data suggest that IGF-II might also be useful for the treatment of the insulin resistant status.

DOI： 10.1297/cpe.5.supple8_77

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Language：Japanese   Publisher：(公財)成長科学協会  

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A totally thyroidectomized patient with thyroid and parathyroid carcinomas, which had developed after neck irradiation in childhood, became hypercalcemic due to pulmonary metastases. The hypercalcemia was ameliorated by intermittent iv administration of bisphosphonate for 3.5 years, but this gradually became refractory to the bisphosphonate treatment. After right thoracotomy for resection of pulmonary metastases, acute necrotizing pancreatitis developed. The patient was therefore placed on total parenteral nutrition supplemented with T4 and a restricted dose of magnesium. Thyroxine(T4) (30 μg/day, iv) was not sufficient to maintain euthyroidism, but a higher dose (60 μg/day) elicited mild hyperthyroidism to the same extent as that elicited by an oral dose of 100 μg/day. The present case showed that the appropriate iv dose of T4 in this thyroidectomized patient with acute pancreatitis was about 60% of the oral dose. Furthermore, bisphosphonates (pamidronate and alendronate) and magnesium depletion were very effective in controlling the hypercalcemia. (Internal Medicine 34:176-182, 1995). © 1995, The Japanese Society of Internal Medicine. All rights reserved.

DOI： 10.2169/internalmedicine.34.176

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DOI： 10.1297/cpe.3.Supple5_243

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：PLENUM PRESS DIV PLENUM PUBLISHING CORP  

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＜文献概要＞▼本症は成人期の成長ホルモン(GH)欠乏によって引き起こされる疾患であり,原因となる病態は多岐にわたる.▼臨床症状として易疲労感,スタミナや集中力の低下,うつ状態などQOLの低下,体組成の変化,皮膚の乾燥や体毛の柔軟化が認められ,心血管系合併症による死亡率が高いと考えられている.▼一般検査では脂質代謝異常,耐糖能異常,脂肪肝などが認められる.▼診断にはインスリン低血糖刺激試験,アルギニン試験,グルカゴン試験,GHRP-2試験が用いられる.▼GHは,毎日就寝前に自己皮下注射にて補充する.▼GH治療の効果として諸症状の改善が認められているが,生命予後への効果についてはさらなる検討が必要である.

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内分泌疾患のなかには、発症頻度に明らかな性差を認めるもの、同一疾患であっても男性と女性で臨床像が異なるものがある。女性に多い内分泌疾患として、プロラクチノーマ、リンパ球性下垂体前葉炎、Basedow病、橋本病、Cushing症候群などが知られている。プロラクチノーマでは女性のほうが発症頻度は高いものの、男性に比べて腫瘍サイズは小さい傾向がある。リンパ球性下垂体前葉炎は女性において妊娠後期から産褥期にかけて好発する。甲状腺機能異常を呈する原因の多くは自己免疫性甲状腺疾患であり、代表的なBasedow病と橋本病はともに女性に好発する。これらの甲状腺疾患は生殖年齢にも発症するため、妊娠時の対応も重要事項である。コルチゾールの慢性的過剰分泌をきたすCushing症候群も女性に多い疾患であり、Cushing病(下垂体ACTH産生腫瘍)では臨床像に性差があることが報告されている。本稿では、これらの内分泌疾患を中心に概説する。(著者抄録)

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症例は89歳男性。血管造影と血清学的所見から肝細胞癌と診断され、腫瘍切除不能例として保存的に治療中、頻回の低血糖発作が出現、意識障害にて救急搬送。空腹時血糖65mg/dl、血中インスリン(IRI)1.3μU/ml、血中C-ペプチド(CPR)0.46ng/ml、インスリン様成長因子(insulin-like growth factor:IGF)-I17ng/ml、抗インスリン抗体125IU未満、腹部CTで多発する最大径8cmの巨大肝細胞癌を認めた。血清中Westernimmunoblotで大分子量のIGF-IIを確認し、膵外腫瘍由来のIGF-IIによる低血糖症、即ちIGF-II産生NICTH(non-islet cell tumor hypoglycemia)と診断した。CGM(continuous glucose monitoring)観察下でフルカリック3号1103ml(ブドウ糖250g)の持続点滴を開始したが、夜間に低血糖発作が頻発し、プレドニゾロン40mg/日の静脈内投与にて血糖上昇傾向あり、最終的にデカドロン2mg/日内服で低血糖発作は消失した。難治性の低血糖発作をきたす腫瘍切除不能例では、IGF-II産生NICTHの可能性を考慮し、CGMを用いてステロイド療法による積極的な治療を試みるべきである。(著者抄録)

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