Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with increasing prevalence worldwide. Angiopoietin-like protein 8 (ANGPTL8), a member of the angiopoietin-like protein family, is involved in glucose metabolism, lipid metabolism, and energy homeostasis and believed to be associated with T2DM. Expression levels of ANGPTL8 are often significantly altered in metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus. Studies have shown that ANGPTL8, together with other members of this protein family, such as angiopoietin-like protein 3 (ANGPTL3) and angiopoietin-like protein 4 (ANGPTL4), regulates the activity of lipoprotein lipase (LPL), thereby participating in the regulation of triglyceride related lipoproteins (TRLs). In addition, members of the angiopoietin-like protein family are varyingly expressed among different tissues and respond differently under diverse nutritional and metabolic status. These findings may provide new options for the diagnosis and treatment of diabetes, metabolic syndromes and other diseases. In this review, the interaction between ANGPTL8 and ANGPTL3 or ANGPTL4, and the differential expression of ANGPTL8 responding to different nutritional and metabolic status during the regulation of LPL activity were reviewed.
The destruction of thyroid follicular cells by iodine-131 treatment for Graves’ hyperthyroidism to a large extent depends on the amount of intrathyroidal activity absorbed (IAA). A thyroid weighing 50 g should receive an iodine-131 therapeutic dosage of between 110 MBq and 350 MBq for the effective treatment of Graves’ hyperthyroidism. An IAA received of more than 350 MBq to the thyroid will bestow an unnecessary high iodine-131 therapeutic dosage. The objective of the study was to determine if the IAA would remain between 110 MBq and 350 MBq if the calculated administered activity (CAA) has been used with the highest radioactive iodine uptake (RAIU) value. A retrospective analysis was made of the 6- and 24-hr iodine-131 RAIU results of Graves’ hyperthyroid patients (n = 124). Male (n = 18) and female (n = 106) patients from different racial groups and ranging from 15 to 75 years of age were included in the study. Overall, the CAA using the 6-hr RAIU value was higher. The CAA by the 6-hr RAIU values was used with the 24-hr RAIU values to calculate the IAA. 53.3% (n = 66) of the study group would have received IAA higher than 350 MBq when the CAA by the 6-hr RAIU values was used with the 24-hr RAIU values to calculate the IAA. These results suggested that the 24-hr RAIU value was most valuable for the calculation of an administered activity so that IAA of between 110 and 350 MBq can be achieved.
In this study, we aim to explore the anti-tumor effect of liraglutide (Lira), an anti-diabetic medicine, on pancreatic cancer cell PANC-1 co-cultured with or without pancreatic stellate cells (PSCs). The chemical count kit-8 and Annexin V-FITC apoptosis detection were conducted to investigate the effect of Lira on cell viability and proliferation of PANC-1 with or without PSCs co-culture. Then, the wound healing and transwell experiments were performed to explore the influence of Lira on PANC-1 cells’ migration and invasion capabilities. To identify the potential action mechanism of Lira on PANC-1, the expression of E-cadherin and N-cadherin and the intracellular calcium content in PANC-1, after Lira administration, were detected. The results indicated that Lira in 100 and 1,000 nmol/L, effectively decreased the cell viability and dose-dependently promoted cell apoptosis of PANC-1 co-cultured with or without PSCs. Lira significantly reduced the migration and invasion of PANC-1 and also reduced the inducing effect of PSCs to PANC-1. Lira effectively induced the expression of E-cadherin and suppressed the expression of N-cadherin with a dose-dependent manner. Otherwise, Lira significantly reduced the abnormal high content of calcium in PANC-1 and also weakened the elevation of calcium in PANC-1 induced by cell-cell interaction. The current study firstly indicated that Lira suppressed the cell proliferation, migration and invasion of PANC-1 with or without PSCs co-culture. This effect was partially due to the calcium modulation of Lira and its influence on Ca2+-binding proteins, such as E-cadherin and N-cadherin.
We recently conducted an open-label phase I/II study to evaluate the efficacy and safety of preoperative and chronic treatment with metyrosine (an inhibitor of catecholamine synthesis) in pheochromocytoma/paraganglioma (PPGL) in Japan. We compared creatinine-corrected metanephrine fractions in spot urine and 24-hour urine samples (the current standard for the screening and diagnosis of PPGLs) from 16 patients to assess the therapeutic effect of metyrosine. Percent changes from baseline in urinary metanephrine (uMN) or normetanephrine (uNMN) were compared between spot and 24-hour urine samples. Mean percent changes in uMN or uNMN in spot and 24-hour urine were –26.36% and –29.27%, respectively. The difference in the percent change from baseline between uMN or uNMN in spot and 24-hour urine was small (–2.90%). The correlation coefficient was 0.87 for percent changes from baseline between uMN or uNMN measured in spot and 24-hour urine. The area under the receiver operator characteristic (ROC) curve of uMN or uNMN measured in spot urine vs. 24-hour urine (reference standard) to assess the efficacy of metyrosine treatment was 0.93. Correlations and ROCs between 24-hour urinary vanillylmandelic acid, adrenaline, and noradrenaline and 24-hour uMN or uNMN were similar to those between spot uMN or uNMN and 24-hour uMN or uNMN. No large difference was observed between spot and 24-hour urine for the assessment of metyrosine treatment by quantifying uMN or uNMN in Japanese patients with PPGLs. These results suggest that spot urine samples may be useful in assessing the therapeutic effect of metyrosine.
Diabetes and malnutrition sometimes overlap. Little is known about the relationship between malnutrition and subclinical atherosclerosis in patients with type 2 diabetes. This cross-sectional study investigated this relationship in patients with type 2 diabetes. We evaluated the relationships between malnutrition assessed by controlling nutritional status (CONUT) score and subclinical atherosclerosis assessed by carotid intima-media thickness (IMT) and carotid plaque scores in 461 consecutive patients with type 2 diabetes. Nutritional assessment indicated that 38% of patients were malnourished (CONUT ≥3). Carotid IMT and carotid plaque scores were significantly higher in patients with malnutrition. Multivariate linear regression analyses revealed that a high CONUT score (CONUT ≥3) was correlated with mean IMT (β = 0.196, p = 0.043) and max IMT (β = 0.243, p = 0.011) in patients taking statins and was also correlated with mean IMT (β = 0.287, p = 0.004), max IMT (β = 0.308, p = 0.002), and plaque score (β = 0.190, p = 0.044) in patients not taking statins after adjusting for age, sex, duration of diabetes, body mass index, hemoglobin A1c, creatine, smoking, and hypertension. Our results demonstrate a relationship between malnutrition and subclinical atherosclerosis in patients with type 2 diabetes.
Ancillary studies for primary nodal lymphomas have been well documented; however, studies of primary thyroid lymphoma (PTL) are limited. Here, we aimed to clarify the clinicopathological, flow cytometric, gene rearrangement, and karyotypic characteristics of PTL by investigation of a large series at a single institute. We performed flow cytometric, IgH rearrangement, and karyotypic analyses of 110 PTL tissues surgically resected at Kuma Hospital between January 2012 and April 2017. All PTLs were of B-cell origin, including mucosa-associated lymphoid tissue lymphoma (MALTL; 89 patients, 80.9%), diffuse large B-cell lymphoma (DLBCL; 18 patients, 16.4%), and follicular lymphoma (FL; three patients, 2.7%). In 96 (87.3%) patients, anti-thyroid antibodies were positive. For flow cytometry using aspirated and resected materials, light chain restriction was observed in 73.7% and 69.2% of examined cases, respectively. Heavy chain JH DNA rearrangement was observed in 65.4% of PTLs (58.1% of MALTL cases, 100% of DLBCL cases, and 100% of FL cases). Chromosomal abnormalities were detected in 49.0% of PTLs, and translocation was most frequently detected (24.0%), followed by addition (20.8%) and trisomy (18.8%). The most frequent (9.4%) karyotype was t(3;14)(q27;q32). Both FLs harbored t(14;18)(q32;q21), and the karyotype was not detected in patients with MALTL and DLBCL. The negative rate for all three examinations was 3.8%. We concluded that thyroid MALTL was cytogenetically different from that in other organs. Our results suggested that pre-operative flow cytometry analysis using aspirated materials was as reliable as that using resected materials.
The purpose of this study is to evaluate the impact of insulin secretion-sensitivity index-2 (ISSI-2) in the identification of the role of pancreatic iron deposition on beta-cell function in thalassemia major. Tissue iron stores were measured with magnetic resonance imaging (MRI) in the liver (R2), pancreas (R2*), and heart (T2*). ISSI-2 was assessed as a novel oral glucose tolerance test-based measure of beta-cell function. Also, the Stumvoll index showing the insulin sensitivity and Stumvoll index estimating first and second phase insulin secretion were calculated. Fourteen of the 51 Thalassemia Major patients, aged 8–34 (mean 21.1 ± 7.2) years-old, had either an impaired glucose tolerance test (n = 9, 17.6%) or diabetes mellitus (n = 5, 9.8%)—referred to as the glucose dysregulation (GD) group. The median serum ferritin and the mean liver R2 and cardiac T2* values were not significantly different between the GD and normal glucose tolerance (NGT, n = 37) groups whereas pancreas R2* was significantly higher in the GD group compared to the NGT group (p = 0.004). Patients with GD showed significantly lower ISSI-2 index (p < 0.001) as well as the Stumvoll index and Stumvoll first and second phase indices compared to those with NGT (p < 0.001). All patients with GD displayed a pancreas R2* >50 Hz and ISSI-2 <2. In conclusion, Pancreas R2* MRI combined with ISSI-2 index may be valuable parameters to identify patients at the highest risk for developing glucose dysregulation.
Pancreas transplantation (PTx) has been performed worldwide for patients with type 1 diabetes accompanied with end-stage renal disease or uncontrollable glycemic fluctuation. Nevertheless, risk factors of posttransplant glucose intolerance, which is responsible for progress of diabetic complications, remains unclear, especially in cases without pancreatic graft function loss. Therefore, this study was conducted to search for predictive factors of future glucose tolerance in PTx recipients without pancreatic graft function loss. Subjects were selected from among 41 Japanese patients with type 1 diabetes who received PTx between 2000 and 2016 in Osaka University Hospital, and 24 subjects free from rejections and thromboses were analyzed. Several examinations to evaluate insulin secretion and insulin sensitivity within 6 months after transplantation (initial examination) were performed. Glucose tolerance was evaluated by 120-minute post-load plasma glucose level during 75-g oral glucose tolerance tests (OGTT), referred to as PGOGTT120, at the initial examination and between 1 year and 2 years posttransplantation (maintenance period). The initial examination factors that were correlated with PGOGTT120 in the maintenance period were PGOGTT120 [r = 0.52 (p = 0.01)], insulinogenic index [r = –0.65 (p < 0.01)], and the ratio of incremental area under the curve of insulin to that of plasma glucose (iAUCR) calculated from data of OGTT [r = –0.65 (p < 0.01)]. Insulinogenic index [β = –0.28 (p = 0.02)] and iAUCR [β = –0.29 (p = 0.02)] were still significantly correlated with PGOGTT120 in the maintenance period after adjustment for PGOGTT120 at the initial examination. In conclusion, insulinogenic index and iAUCR from OGTT performed in the early posttransplantation period were predictive factors of future glucose intolerance.
We report a sporadic case of maturity-onset diabetes of the young type 5 (MODY5) with a whole-gene deletion of the hepatocyte nuclear factor-1beta (HNF1B) gene. A 44-year-old Japanese man who had been diagnosed with early-onset non-autoimmune diabetes mellitus at the age of 23 was examined. He showed multi-systemic symptoms, including a solitary congenital kidney, pancreatic hypoplasia, pancreatic exocrine dysfunction, elevation of the serum levels of liver enzymes, hypomagnesemia, and hyperuricemia. These clinical characteristics, in spite of the absence of a family history of diabetes, prompted us to make the diagnosis of maturity-onset diabetes of the young 5 (MODY 5). One allele deletion of the entire HNF1B gene revealed by multiplex ligation-dependent probe amplification (MLPA) led us to the diagnoses of 17q12 microdeletion syndrome even though there were negative chromosomal analyses with array comparative genomic hybridization (CGH). 17q12 microdeletion syndrome, which is not rare especially in sporadic cases since 17q12 is a typical hot spot for chromosomal deletion, could have complicated the clinical heterogeneity of MODY5.
A 14-year-old girl was referred to our department because of headache and visual impairment following the resection of recurrent cardiac myxoma. Head magnetic resonance imaging (MRI) scan detected an intra- and supra-sellar tumor. Moreover, the patient showed the presence of spotty skin pigmentations on her cheeks and lower lip. Blood examination revealed hypothyrotropinemia, and ultrasonography results revealed multiple thyroid nodules. She was diagnosed with Carney complex (CNC). Her pituitary tumor was suspected as growth hormone (GH)-secreting adenoma, because overgrowth was observed in the patient. However, biochemical examinations, including oral glucose tolerance test, failed to show the characteristic findings of GH-secreting adenoma. In contrast, insulin tolerance test showed GH deficiency. Her visual impairment improved without performing decompression surgery, and the tumor size decreased, as per the MRI findings. Based on clinical course, the patient was diagnosed with pituitary apoplexy in pituitary adenoma, following which she was discharged. At 3 months after discharge, thyrotropin-releasing hormone loading test performed revealed low thyrotropin-stimulating hormone and thyroid hormone levels, and the patient was in a depressed mood. Therefore, l-T4 replacement was initiated, following which her GH secretory capacity gradually improved. Here, we report, to the best of our knowledge, the first case of a patient with pituitary apoplexy in CNC. Such condition must be identified in young patients with recurrent cardiac myxoma, and examinations, such as head MRI, must be performed.