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An 84‐year‐old man was admitted to our hospital. His blood glucose level was 20 mg/dL. Since laboratory tests showed high titers of insulin antibodies, insulin autoimmune syndrome (IAS) was diagnosed. In order to avoid hypoglycemia, steroids can be effective in the long‐term management of IAS in elderly patients., Prednisolone can be effectively used in long‐term management of hypoglycemia in elderly patients with Insulin Autoimmune Syndrome. Scatchard analysis for insulin autoantibodies revealed that an affinity constant and binding capacity of the autoantibodies were also improved.

Introduction:Insulin is synthesized in the β-cells from preproinsulin. Preproinsulin becomes proinsulin after leaving the signal peptide. Proinsulin is separated into C-peptide and insulin by 2 enzymes. Hyperproinsulinemia is suspected to be a pancreatic β-cell defect that is augmented by the increased demand placed on the β-cell by hyperglycemia.Case presentation:A 39-year-old Japanese man visited to Shin-suma hospital in May 2013. Liver dysfunction, dyslipidemia, and hyperuricemia had been found in medical checkups in his workplace. Therefore, he visited Shin-suma hospital in order to receive intensive examination. Diet and exercise therapy were initiated. In November 2013, intact proinsulin and proinsulin per insulin (PI/I) ratio were evaluated as part of an ongoing study. His intact proinsulin level and PI/I ratio were markedly elevated. A 75 g oral OGTT revealed that his glucose tolerance was impaired. His glycosylated hemoglobin was 6.9%. He was diagnosed as having type 2 diabetes mellitus. Although, diet and exercise therapy continued, his hyperproinslinemia and diabetes mellitus remained. Therefore, aloguliptin was started in order to recover insulin secretion in November 2014. Thereafter, pioglitazone was added to improve insulin resistance. Finally, luseogliflozin was commenced to expect glucose-lowering effects. His HbA1c was stabilized. To the best of our knowledge, there have been few reports of patients with hyperproinsulinemia.Conclusion:When the physicians face treatment resistance in diabetes mellitus, we emphasize that evaluation of proinsulin should be considered as one of the methods.

Variant hemoglobin is often detected during the diagnosis and treatment of diabetes mellitus. We here describe a case of α2-chain variant hemoglobin (Hb Chad) that was identified as a result of differences in HbA1cs values determined by different assays. HbA1c measured by immunoassay was thus falsely high, whereas that measured by high-performance liquid chromatography (HPLC) was slightly low. Sequencing analysis revealed a heterozygous GAG (glutamic acid) → AAG (lysine) mutation at amino acid position 23 of the α2-globin gene. This residue is located at the surface of the α-chain in the crystal structure of hemoglobin. The high HbA1c value determined by immunoassay might have been the result of increased antigenicity of the variant hemoglobin, whereas the low value measured by HPLC reflected differential fractionation of the variant relative to the wild-type protein. Hb Chad has been reported in only three cases to date, and HbA1c was measured for the first time. This is the first case where falsely high HbA1c measured by immunoassay due to increased antigenicity in α-chain variant hemoglobin. This case highlights the importance of comparison with other parameters related to plasma glucose such as glycated albumin if an HbA1c abnormality is suspected. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00529-y.

OBJECTIVE: We examined whether serum orosomucoid, an acute phase protein as with C-reactive protein, in addition to insulin resistance and beta-cell dysfunction, was involved in glucose disposal during oral glucose tolerance tests. RESEARCH DESIGN AND METHODS: 124 midlife Japanese (65 women, 66% with normal glucose tolerance) received dual-energy X-ray absorptiometry and 75 g oral glucose tolerance tests with multiple postload glucose and insulin measurements. Subjects were divided based on the relationship between postload and fasting glucose. Obesity measures, insulin resistance, insulin secretion, serum orosomucoid and adiponectin were cross-sectionally analyzed by analysis of variance and then Bonferroni’s multiple comparison procedure. RESULTS: In 10 subjects (group A) and 19 subjects (group B), postload glucose fell below fasting glucose at 1 h and 2 h, respectively. In the remaining 95 subjects (group C), postload glucose never fell below fasting glucose. The insulinogenic index was lower and area under the glucose curve was higher in groups B and C as compared to group A (both p

AIM The present study was carried out to examine whether the insulin secretory mechanism deteriorates during the aging process using the new intact proinsulin assay system in non-diabetic and diabetic individuals. METHODS A total of 172 participants were separated into four groups according to their age ( 65 years) and an association of type 2 diabetes; that is, 46 older diabetics (mean age 74.5 ± 6.2 years, glycated hemoglobin [National Glycohemoglobin Standardization Program] 7.5 ± 1.3%), 27 older non-diabetics (mean age 76.9 ± 7.5 years), 48 middle-aged diabetics (mean age 50.8 ± 10.4, glycated hemoglobin 7.8 ± 1.5%) and 51 middle aged non-diabetics (mean age 46.6 ± 13.0 years) participants were enrolled. RESULTS The proinsulin/insulin (PI/I) ratio of the diabetic group was higher than that of the non-diabetic group in the older group (0.19 ± 0.12 vs 0.11 ± 0.06, P = 0.002). In the middle-aged groups, the PI/I ratio of the diabetic group was higher than that of the non-diabetic group (0.16 ± 0.15 vs 0.09 ± 0.09, P = 0.003). Simple regression analysis showed that male sex (95% CI 0.02-0.01, P = 0.004), age (95% CI 0.00-0.002, P = 0.03), lower body mass index (95% CI -0.06 to 0.00, P = 0.02) and the presence of diabetes mellitus (95% CI 0.04-0.012, P

The clinical entity idiopathic normal pressure hydrocephalus (iNPH) is characterized by dementia, urinary incontinence, gait ataxia. An 80-year old man with a past history of Type 2 diabetes mellitus admitted to our hospital. Combination of twice Aspart and Aspart premixed30/70 insulin were used. Although, he was unable to inject insulin by himself recently. On physical examination, he walked in a mildly wide based manner. According to his family, urinary incontinence was existed. Laboratory data were as follows: Postrandial blood glucose 243 mg/dl and glycated hemoglobin 8.0% (NGSP). Brain magnetic resonance imaging (MRI) scans showed thinning of the corpus callosum with enlargement of the lateral ventricles on a colonal image. Evan's ratio was 0.29. The revised version of Hasegawa's Dementia scale (HDS-R) was 10. The patient showed no evidence a related antecedent event, such as head trauma, intracerebral hemorrhage and meningitis. Thus, he was diagnosed as having possible Idiopathic normal pressure hydrocephalus (iNPH). The following several psychological tests and walking test were applied. Before and after the tap, he was evaluated using the HDS-R, Mini mental state examination (MMSE), Timed Up and Go test (TUG). Insulin was replaced by glargine, and Sitagliptin was added. On the 31 day, the patient underwent Ventriculo-perioneal shunt. Laboratoly data and memory impairment were also improved. 8 month's later, HbA1c was 7.5%. iNPH occurs in the elderly and is characterized by a clinical triad of gait disturbance, urinary incontinence and dementia. In the present case, thinning of the corpus callosum with enlargement of the lateral ventricles was detected by MRI. 49% of iNPH patients had Diabetes mellitus. However, we were unable to detect a relationship iNPH and Diabetes mellitus. Cognitive impairment may interfere with the insulin therapy. In the present case, failure of insulin self-injection was the first clinical sign to appear. We were able to reduce dose of insulin. We conclude that iNPH is a treatable disorder, especially when treatment is started early in the course of the disease.

Insulin autoimmune syndrome (IAS) involves not only fasting hypoglycemia, but also postprandial hyperglycemia. In the present study, we hypothesized that glycated albumin (GA) levels and the GA/HbA1c ratio, which reflect fluctuations in plasma glucose levels, are elevated in IAS patients. Four IAS patients were enrolled in the present study. Thirty-two non-diabetic subjects matched for gender, age, and BMI were used as the control group. The fasting plasma glucose levels in the IAS patients were significantly lower than in the control group. However, the oral glucose tolerance test (OGTT) revealed impaired glucose tolerance or diabetes mellitus in all the IAS patients, and thus the OGTT 2-h plasma glucose levels were significantly higher than in the control group. The GA levels and the GA/HbA1c ratio in the IAS patients were significantly higher than in the control group, despite no significant difference in the HbA1c levels between the two groups. In one case in which IAS spontaneously went into remission, there was a significant correlation between anti-insulin antibodies and GA, but not HbA1c. Improvement in glucose fluctuations was observed by continuous glucose monitoring in another patient along with improvement in the clinical symptoms. Furthermore, anti-insulin antibodies, GA, and the GA/HbA1c ratio decreased, but HbA1c did not change significantly in three IAS patients along with the improvement in clinical symptoms. These results suggest that GA and the GA/HbA1c ratio are useful indicators for determining the level of disease activity in IAS patients.

Objective The direct actions of growth hormone (GH) in the development of atherosclerosis are unclear. The goal of this study was to characterize GH-induced changes in expression of signaling pathway elements and other proteins that may be related to atherosclerosis. Methods Human umbilical vein endothelial cells (HUVEC) and THP-1, a human acute monocytic leukemia cell line, were stimulated by exposure to 10−9 M or 10−8 M human GH with or without pretreatment with a mitogen-activated protein kinase kinase (MEK) 1 inhibitor. Levels of transcripts encoding vascular cell adhesion molecule (VCAM) -1, E-selectin, monocyte chemotactic protein (MCP-1), interleukin (IL) -6, and IL-8 were investigated by reverse transcription (RT) -PCR. For the quantitative adhesion assay, THP-1 cells or human primary monocytes were fluorescently labeled with 3’-O-acetyl-2′,7′-bis(carboxyethyl) -4 diacetoxymethyl ester (BCECF/AM). HUVEC treated with human GH were co-incubated with BCECF-labeled THP-1 cells. One hour later, the number of BCECF-labeled THP-1 cells was assessed. An equivalent experiment was performed using BCECF-labeled primary monocytes, and the number of monocytes adhering to HUVEC was counted. Results Treatment with hGH increased the levels of E-selectin- and VCAM-1-encoding mRNAs in HUVEC. This effect was attenuated by pretreatment with a MEK1 inhibitor. Furthermore, hGH treatment increased adhesion of BCECF-labeled THP-1 cells or primary monocytes to HUVEC, and this effect was attenuated by pretreatment with a MEK1 inhibitor. Conclusions VCAM-1 and E-selectin expression was stimulated by GH via the mitogen-activated protein kinase pathway, resulting in augmented adhesion of THP-1 cells and monocytes to HUVEC. These data suggested that GH directly stimulates the development of atherosclerosis.

A considerable number of people with a normal body mass index (BMI) are at an increased risk of metabolic syndrome due to excessive body fat accumulation (fat mass percentage greater than or equal to 30%). It is important to screen these normal weight obese (NWO) individuals in adolescent and young adults because they are likely to be overlooked due to their normal BMI. The aim of this study is to evaluate the body composition and metabolic characteristics of NWO in a young Japanese female cohort with different physical activity levels. We discovered that (1) a considerable proportion of sedentary young women with normal BMI could be classified as NWO, displaying a cluster of obesity-related phenotypic characteristics including central/abdominal adiposity, hyperleptinemia, enhanced fasting insulin secretion, and hyper-inflammation and hypercoagulative status; (2)endurance trained women had 98% less likelihood of being NWO. Our investigation strongly suggests that active physical exercise should be implemented in sedentary young women in order to avoid the development of NWO.

ObjectiveTo examine whether serum adiponectin and orosomucoid were associated with postload glucose ≤70 mg/dL during an oral glucose tolerance test (OGTT), termed as postload low glycemia, a possible inverse marker for dysglycemia.Research design and methods75 g OGTTs were performed with multiple postload glucose and insulin measurements over a 30–120 min period in 168 normal-weight Japanese women (18–24 years). Insulin resistance (IR) and β-cell function inferred from serum insulin kinetics during OGTT, fat mass and distribution by dual-energy X-ray absorptiometry (DXA), serum adiponectin and inflammatory markers were compared cross-sectionally between 39 women with and 129 women without postload low glycemia.ResultsOf 168 women, 161 had normal glucose tolerance. Women with as compared with those without postload low glycemia had lower fasting and postload glycemia despite similar fasting and postload insulinemia. They had higher insulinogenic index (p=0.03) and lower adipose IR (a product of fasting free fatty acid and insulin, p=0.01), although DXA-derived general and central adiposity, the Matsuda Index and homeostasis model assessment-IR did not differ. In addition, they had higher adiponectin and lower orosomucoid (both pConclusionsHigher adiponectin and lower orosomucoid were associated with 70 or lower mg/dL of postload glucose, a possible inverse marker for dysglycemia, in young women independently of DXA-derived fat mass and distribution, insulin secretion and IR.

ObjectiveInflammatory markers are elevated in insulin resistance (IR) and diabetes. We tested whether serum orosomucoid (ORM) is associated with postload glucose, β-cell dysfunction and IR inferred from plasma insulin kinetics during a 75 g oral glucose tolerance test (OGTT).Research design and methods75 g OGTTs were performed with multiple postload glucose and insulin measurements over a 30–120 min period in 168 non-obese Japanese women (aged 18–24 years). OGTT responses, serum adiponectin and high-sensitivity C reactive protein (hsCRP) were cross-sectionally analyzed by analysis of variance and then Bonferroni’s multiple comparison procedure. Stepwise multivariate linear regression analyses were used to identify most important determinants of ORM.ResultsOf 168 women, 161 had normal glucose tolerance. Postload glucose levels and the area under the glucose curve (AUCg) increased in a stepwise fashion from the first through the third ORM tertile. In contrast, there was no or modest, if any, association with fat mass index, trunk/leg fat ratio, adiponectin, hsCRP, postload insulinemia, the Matsuda index and homeostasis model assessment IR. In multivariable models, which incorporated the insulinogenic index, the Matsuda index and HOMA-IR, 30 min glucose (standardized β: 0.517) and AUCg (standardized β: 0.495) explained 92.8% of ORM variations.ConclusionsElevated circulating orosomucoid was associated with elevated 30 min glucose and glucose excursion in non-obese young Japanese women independently of adiposity, IR, insulin secretion, adiponectin and other investigated markers of inflammation. Although further research is needed, these results may suggest a clue to identify novel pathways that may have utility in monitoring dysglycemia within normal glucose tolerance.

The aim of this study was to assess whether the gender-specific pattern of fat mass (FM) distribution is related to gender differences in cardiometabolic risk factors. 207 healthy middle-aged Japanese were included in the study. We measured FM in the total body, trunk, and lower-body with dual-energy X-ray absorptiometry (DXA). The percentage of trunk FM (TFM) and lower-body FM (LFM) is noted as %TFM and %LFM, respectively. Other measurements included glucose and insulin during oral glucose tolerance test (OGTT), leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-α(TNF-α), C-reactive protein (CRP), and systemic oxidative stress marker. Arterial properties were indicated by cardio-ankle vascular index (CAVI) and intima-media thickness (IMT) of the common carotid artery. The results showed that %TFM is higher whereas %LFM is lower in men than in women and men have a more atherogenic cardiometabolic profile. In both genders, %TFM (%LFM) is related to an unfavorable (favorable) cardiometabolic profile. In particular, the relation between %LFM and OGTT-derived insulin sensitivity index is stronger in women than in men. These findings suggested that in relatively healthy adults, android and gynoid pattern of FM distribution contributes to gender differences in cardiometabolic risk factors.

The present study was carried out to examine whether the insulin secretory mechanism deteriorates during the aging process using the new intact proinsulin assay system in non-diabetic and diabetic individuals.A total of 172 participants were separated into four groups according to their age (64 years and65 years) and an association of type 2 diabetes; that is, 46 older diabetics (mean age 74.5 ± 6.2 years, glycated hemoglobin [National Glycohemoglobin Standardization Program] 7.5 ± 1.3%), 27 older non-diabetics (mean age 76.9 ± 7.5 years), 48 middle-aged diabetics (mean age 50.8 ± 10.4, glycated hemoglobin 7.8 ± 1.5%) and 51 middle aged non-diabetics (mean age 46.6 ± 13.0 years) participants were enrolled.The proinsulin/insulin (PI/I) ratio of the diabetic group was higher than that of the non-diabetic group in the older group (0.19 ± 0.12 vs 0.11 ± 0.06, P = 0.002). In the middle-aged groups, the PI/I ratio of the diabetic group was higher than that of the non-diabetic group (0.16 ± 0.15 vs 0.09 ± 0.09, P = 0.003). Simple regression analysis showed that male sex (95% CI 0.02-0.01, P = 0.004), age (95% CI 0.00-0.002, P = 0.03), lower body mass index (95% CI -0.06 to 0.00, P = 0.02) and the presence of diabetes mellitus (95% CI 0.04-0.012, P 0.0001) were significantly associated with the increase in the PI/I ratio. Multivariate regression analysis showed that male sex and age were the independent factors determining the increase in the PI/I ratio in the non-diabetic group. After adjusted for body mass index, the PI/I ratio correlated significantly with age only in the non-diabetic group (r = 0.5, P = 0.004).The proinsulin processing system might deteriorate not only in diabetics, but also in non-diabetic Japanese individuals with age. Also, sex-related hormones can be protective for the proinsulin processing system. Geriatr Gerontol Int 2018; 18: 1046-1050.

High-sensitivity C-reactive protein (hs-CRP) performs important roles on the onset of metabolic syndrome and cardiovascular diseases (CVD), but little is known about association between hs-CRP and obesity-related metabolic abnormalities in young people without classical CVD risk factors. It thus motivated us to investigate association among hs-CRP, body fat mass (FM) distribution, and other cardiometabolic risk factors in young healthy women. Our approach is based on biological experiments, statistical analysis, and semantic search. Research outcomes in this study resulted in two novel discoveries. Discovery 1: There are four primary determinants for hs-CRP, i.e., central/abdominal FM (a.k.a. trunk FM) accumulation, leptin, high density lipoprotein cholesterol (HDL-C), and plasminogen activator inhibitior-1 (PAI-1). Discovery 2: Chronic inflammation may involve in adipocyte-cytokine interaction underlying the metabolic derangement in healthy young women.

Summary Background Limited evidence suggests that multifactorial interventions for control of glucose, blood pressure, and lipids reduce macrovascular complications and mortality in patients with type 2 diabetes. However, safe and effective treatment targets for these risk factors have not been determined for such interventions. Methods In this multicentre, open-label, randomised, parallel-group trial, undertaken at 81 clinical sites in Japan, we randomly assigned (1:1) patients with type 2 diabetes aged 45–69 years with hypertension, dyslipidaemia, or both, and an HbA 1c of 6·9% (52·0 mmol/mol) or higher, to receive conventional therapy for glucose, blood pressure, and lipid control (targets: HbA 1c 1c 1c , and history of cardiovascular disease. Neither patients nor investigators were masked to group assignment. The primary outcome was occurrence of any of a composite of myocardial infarction, stroke, revascularisation (coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting), and all-cause mortality. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00300976. Findings Between June 16, 2006, and March 31, 2009, 2542 eligible patients were randomly assigned to intensive therapy or conventional therapy (1271 in each group) and followed up for a median of 8·5 years (IQR 7·3–9·0). Two patients in the intensive therapy group were found to be ineligible after randomisation and were excluded from the analyses. During the intervention period, mean HbA 1c , systolic blood pressure, diastolic blood pressure, and LDL cholesterol concentrations were significantly lower in the intensive therapy group than in the conventional therapy group (6·8% [51·0 mmol/mol] vs 7·2% [55·2 mmol/mol]; 123 mm Hg vs 129 mm Hg; 71 mm Hg vs 74 mm Hg; and 85 mg/dL vs 104 mg/dL, respectively; all p vs 283 [22%] in the conventional therapy group, p vs 129 [10%], p=0·0001), the frequencies of major adverse events did not differ between groups. Interpretation Our results do not fully support the efficacy of further intensified multifactorial intervention compared with current standard care for the prevention of a composite of coronary events, cerebrovascular events, and all-cause mortality. Nevertheless, our findings suggest a potential benefit of an intensified intervention for the prevention of cerebrovascular events in patients with type 2 diabetes. Funding Ministry of Health, Labour and Welfare of Japan, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Kissei Pharmaceutical, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanwa Kagaku Kenkyusho, Shionogi, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda.

Papillary thyroid carcinoma (PTC) is the most frequent thyroid carcinoma. PTC cell lines have been of considerable value in studying aspects of thyroid cancer, such as gene expression, cell proliferation, and differentiation. Here we report three novel PTC lines established from three patients with different backgrounds. Case 1 was a 38-year-old woman with PTC in the right thyroid lobe, with no metastasis. The cell line was established from the resection sample and named D-PTC. The cell line consisted of epithelial cells with few lysosomes and showed a pavement structure and follicular formation at confluency. There was a little pilling up. The secretion of free thyroxin (fT4) and thyroglobulin (Tg) was increased by TSH, or GH and IGF-I treatment. Case 2 was a 22-year-old woman with PTC initially in the right thyroid lobe, but 4 years after the right lobe resection, PTC metastasis was observed in left lobe. The cell line was established from a sample of the second resection and named UD-PTC. This cell line consisted of small epithelial cells with evident lysosomes and exhibited floating cell clusters. The secretion of fT4 and Tg was slightly increased by TSH, or GH and IGF-I treatment. Case 3 was an 85-year-old man with PTC and with acromegaly. Metastasis was observed at cervical lymph nodes. The cell line was derived from the metastasis region and named A-PTC. This cell line consisted of small epithelial cells and many lysosomes. The cells frequently showed pilling up. The secretion of fT4 and Tg was significantly increased by GH and IGF-I treatment. We have established three PTC cell lines with substantial variation in their phenotype. The cell lines may be useful for thyroid cancer research.

Aim It is known that plasma low-density lipoprotein cholesterol (LDL-C) levels tend to decrease with age. Thus, most elderly diabetic patients often show normal LDL-C levels. Therefore, the present study was carried out to examine whether elderly diabetic patients show “the atherogenic phenotype” even if their LDL-C is not elevated. Methods The study participants consisted of 236 patients. They were separated into four groups according to their age (below 64 years and above 65 years) and an association of type 2 diabetes. A total of 88 middle-aged diabetic, 34 middle-aged non-diabetic, 64 elderly diabetic and 50 elderly non-diabetic participants were enrolled. LDL-C, small dense LDL-C (sLDL-C) were investigated. ANOVA were used for comparison of LDL-C, sLDL-C and the sLDL-C/LDL-C ratio between the four groups. Multivariate regression analysis was carried out in order to find the independent factors associated with the sLDL-C/LDL-C ratio. Results Among the four groups, the LDL-C of the elderly diabetic group showed lower LDL-C levels compared with that of middle-aged diabetic group, although the difference was not significant (128.6 ± 38.7 vs 138.4 ± 35.8 mg/dL). In contrast, sLDL-C and the sLDL-C/LDL-C ratio in the elderly diabetic group were both higher than those of the elderly non-diabetic group (47.0 ± 24.2 mg/dL and 0.36 ± 0.14 mg/dL, vs 21.4 ± 16.7 mg/dL and 0.19 ± 0.11 mg/dL, P

Thus far, only 23 cases of the ectopic production of parathyroid hormone (PTH) have been reported. We have characterized the genome-wide transcription profile of an ectopic PTH-producing tumor originating from a retroperitoneal histiocytoma. We found that the calcium-sensing receptor (CaSR) was barely expressed in the tumor. Lack of CaSR, a crucial braking apparatus in the presence of both intraparathyroid and, probably, serendipitous PTH expression, might contribute strongly to the establishment and maintenance of the ectopic transcriptional activation of the PTH gene in nonparathyroid cells. Along with candidate drivers with a crucial frameshift mutation or copy number variation at specific chromosomal areas obtained from whole exome sequencing, we identified robust tumor-specific cytochrome P450 family 24 subfamily A member 1 (CYP24A1) overproduction, which was not observed in other non–PTH-expressing retroperitoneal histiocytoma and parathyroid adenoma samples. We then found a 2.5-kb noncoding RNA in the PTH 3′-downstream region that was exclusively present in the parathyroid adenoma and our tumor. Such a co-occurrence might act as another driver of ectopic PTH-producing tumorigenesis; both might release the control of PTH gene expression by shutting down the other branches of the safety system (e.g., CaSR and the vitamin D3–vitamin D receptor axis)., We examined a genome-wide transcription profile of an ectopic PTH-producing tumor. Scarcity of CaSR, CYP24A1 overproduction, and an lncRNA near the PTH gene are candidate culprits of PTH ectopy.

Thyroglobulin (Tg) is a macromolecular precursor in thyroid hormone synthesis to which iodine is stably bound. Tg, which is stored in the follicular space, is also a potent negative feedback regulator of follicular function, and this is achieved by suppressing mRNA levels of thyroid-specific genes such as the sodium/iodide symporter (Slc5a5), Tg, and thyroid peroxidase. Dual oxidase 1 (DUOX1) and DUOX2, originally identified in the thyroid, are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases that are necessary to produce the H2O2 required for thyroid hormone biosynthesis. Since follicular Tg regulates the expression of genes that are essential for thyroid hormone synthesis, we hypothesized that Tg might also regulate DUOX expression and H2O2 production.Rat thyroid FRTL-5 cells were treated with Tg, and the mRNA expression of Duox1 and Duox2 and their corresponding maturation factors Duoxa1 and Duoxa2 were evaluated by DNA microarray and real-time PCR. Duox2 promoter activity was examined by luciferase reporter gene assay. Protein levels of DUOX2 were also examined by Western blot analysis. Intracellular H2O2 generation was quantified by a fluorescent dye, 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, and acetyl ester (CM-H2DCFDA).mRNA levels of Duox2 and its activation factor Duoxa2 (but not Duox1 or Duoxa1) were significantly suppressed by Tg in a dose-dependent manner and a time-dependent fashion in rat thyroid FRTL-5 cells. DUOX2 promoter activity was significantly suppressed by Tg in a dose-dependent manner. Protein levels of DUOX2 and H2O2 generation in cells were also reduced by Tg treatment.We show that physiological concentrations of Tg suppressed the expression and function of DUOX2 in thyroid cells. These results suggest that Tg is a strong suppressor of the expression and the activity of DUOX2/DUOXA2, thereby regulating iodide organification and hormone synthesis in the thyroid. The evidence supports a reported model in which accumulated Tg in thyroid follicles plays important roles in autoregulating the function of individual follicles, which produces the basis of follicular heterogeneity.

Aims: Small dense LDL (sdLDL) cholesterol is considered a cardiovascular risk. Our purpose in this study was to evaluate the efficacy of rosuvastatin in reducing sdLDL and large buoyant LDL (lbLDL-C) in hypercholesterolemia. Methods: Fifty-six patients with a mean baseline LDL-cholesterol (LDL-C) concentration of 173.9 ± 40.5 mg/dL were treated with rosuvastatin 2.5 mg/day for 12 weeks. LDL-C, sdLDL-C, and apolipoprotein (apo) B were assessed and l lbLDL-C was calculated (LDL-C minus sdLDL-C). Results: After 12-week treatment with rosuvastatin 2.5mg, sdLDL-C and lbLDL-C were significantly reduced from 62.1 ± 23.8 mg/dL to 34.0 ± 13.4 mg/dL, p

We present a case of a malignant adrenal rest tumor arising from the retroperitoneum with Cushing's syndrome in a 31-year-old female. Her serum cortisol and dehydroepiandrosterone sulfate levels were elevated, while adrenocorticotropic hormone levels were low. Computed tomography scans and magnetic resonance imaging revealed a retroperitoneal tumor with no visible lesions in the adrenal glands and ovaries. From those results and the histopathologic findings following biopsy of an enlarged supraclavicular lymph node, the patient was diagnosed as a malignant adrenal rest tumor of the retroperitoneum. Despite chemotherapy, the patient died of rapid development of multiple metastases. Autopsy revealed a large tumor that extended around the abdominal aorta from the levels of the left kidney to the aortic bifurcation with generalized metastases. Tumor cells were characterized by clear and eosinophilic cytoplasm and atypical nuclei that exhibited frequent and atypical mitoses. Immunohistochemistry regarding steroidogenesis was performed and revealed that the tumor cells were immunopositive for adrenal 4 binding protein/steroidogenic factor-1, cholesterol side-chain cleavage enzyme, 17α-hydroxylase, and 21-hydroxylase. We thus elucidated the adrenocortical steroid production in the tumor cells causing Cushing's syndrome. This case report first demonstrates the steroidogenic capacity in a malignant adrenal rest tumor.

Aim: We determined the association of lower-body fat mass (LFM) and trunk fat mass (TFM) with cardiometabolic risk factors and adipokines in young, healthy, slim women.Methods: A total of 481 college female students underwent the following: regional body fat distribution as assessed by dual energy X-ray absorptiometry (DXA), a 75g oral glucose tolerance test (OGTT) and fasting blood sampling for measurement of lipids, lipoproteins, apolipoproteins (apo), liver enzymes and adipokines.Results: After adjusting for TFM, LFM was positively associated with HDL cholesterol, adiponectin, pre-heparin lipoprotein lipase and insulin sensitivity, as estimated by the Matsuda index, whereas it was negatively related to triglycerides, apo B, apo B/A1 ratio, small dense LDL, FFA, glucose and insulin at 2h during OGTT, area under the curve of insulin response during OGTT and the white blood cell count. Participants were divided into 9 groups according to tertiles of TFM and LFM. In the middle tertile of TFM, HDL cholesterol and adiponectin increased and triglycerides, apoB/A1 ratio and plasminogen-activator inhibitor-1 decreased from the low to high LFM tertiles. Gamma-glutamyltransferase levels in middle and high LFM tertiles were lower than in the lower LFM tertile.Conclusion: For a given level of trunk fat mass, a higher lower-body fat mass is associated with an advantageous profile of not only blood lipoproteins but also serum adipokines, even in healthy, slim women in early adulthood.

Currently there is no good hepatocyte model for studying growth hormone (GH) function that reflects its normal physiological roles. Here we report the establishment of a functional hepatocyte cell line, SDRL-1, from the liver of young male spontaneous dwarf rats (SDR), with isolated GH deficiency. This line has been maintained in Dulbecco's Modified Eagle Medium (DMEM)/F12 medium supplemented with 10% fetal bovine serum (FBS) with retention of a near diploid karyotype for extended periods of time. When grown as a monolayer sheet, it displayed a pavement-like appearance and contact inhibition. These cells have a poorly developed rough endoplasmic reticulum (r-ER), few mitochondria and glycogen granules, and produce a small amount of albumin and α-fetoprotein, that is enhanced when grown on a collagen gel sponge. Human recombinant GH stimulated JAK2 and STAT5b tyrosine phosphorylation and IGF-I production in a concentration-dependent manner. When the cells were cultured with GH-supplemented medium, the number of mitochondria and glycogen granules increased together with the r-ER and Golgi apparatus. A number of microvilli were observed on the surface of the cultured cells, further suggesting that this cell line is composed of normally functioning hepatocytes. In summary, we established a novel hepatocyte cell line (SDRL-1), that appears to display normal function, which we propose can serve as a good in vitro model for studying GH-target organ interactions.

There are few case reports describing small cell lung carcinoma (SCLC), which secrete parathyroid hormone (PTH)-related protein (PTHrP) and result in hypercalcemia. We have established a novel cell line, derived from a 37-year-old woman with SCLC, which produced PTH, PTH-rP, and a part of proopiomelanocortin (POMC), and led to hypercalcemia. The cell line, named SS-1, was grown as floating cell clusters in DMEM/F12 medium supplemented with 10% fetal bovine serum and had a population doubling time of 72 h. The modal chromosome number was 47 (88%); marker chromosomes were not observed. The SS-1 cell line secreted not only PTHrP but also PTH, and both were decreased by CaCl2 administration. Decreasing the concentration of Ca++ in the growth medium stimulated the secretion of both PTHrP and PTH. The cell line had calcium sensing receptor (Cas-R). Since PTHrP and PTH secretion from the SS-1 cells was related to Ca++ concentration in the growth medium, the cell line might be useful for the study of PTH-rP and PTH regulation as well as for SCLC analysis. In addition, the cells secreted N terminal POMC, the precursor of adrenocorticotropic hormone, in response to stimulation with corticotropin releasing hormone. In summary, we established a novel cell line, SS-1 from SCLC, which produced PTHrP, PTH and N terminal POMC.

Acromegaly is characterized by chronic hypersecretion of growth hormone (GH) and is associated with increased mortality rate because of the potential complications such as cardiovascular disease, respiratory disease, or malignancy, which are probably caused by the long-term exposure of tissues to excess GH, for at least 10 years, before diagnosis and treatment. A 22-year-old man with a 2-month history of fatigue was admitted to our hospital because of chest discomfort, dyspnea, and pitting edema of the lower limbs experienced over a 1-month period. On admission, his height and body weight were 186 cm and 138.5 kg, respectively, with a BMI of 39.8 kg/m(2). He showed acromegalic features and elevated serum GH and IGF-1 levels, which were 11.5 ng/mL and 960 ng/mL, respectively. There was no GH suppression in the 75-g oral glucose tolerance test. Pituitary magnetic resonance imaging (MRI) revealed microadenoma. Chest X-ray revealed cardiomegaly, and echocardiogram showed dilated left ventricular (LV) cavity and diffuse hypokinesis with extremely decreased ejection fraction (EF). He was diagnosed as having acromegaly with congestive heart failure from diastolic cardiomyopathy. After the successful transsphenoidal resection of the pituitary adenoma, the level of GH was normalized. However, the cardiac dysfunction did not show any improvement even after the administration of β-blockers, angiotensin-converting enzyme inhibitor (ACE-I), or diuretics. The patient was re-hospitalized, and he died of cardiac failure at the age of 25 years. Patients with acromegaly have been reported to have about 30% higher mortality rate, and cardiovascular disease accounts for 60% of the deaths. We report a case of a patient with juvenile acromegaly who was diagnosed with severe cardiac failure at the time of diagnosis and failed to recover cardiac function even after the successful resection of the pituitary adenoma. Immediate diagnosis and treatment are required for better control of acromegalic cardiomyopathy.

(-) Hydroxycitric acid (HCA), an active ingredient extracted from the Garcinia cambogia fruit rind, has been commonly used as a dietary supplement for weight management. Given the controversy over HCA related testicular toxicity in animal studies, we investigated changes in serum sex hormones levels as an extension of our previous double-blind placebo-controlled trial in human subjects, in which 44 participants received either G. cambogia extract (1667.3 mg/day equivalent to 1000 mg HCA/day) or placebo for 12 weeks. Compared to the placebo group, administration of the extract did not significantly alter the serum testosterone, estrone, and estradiol levels. Similarly, hematology, serum triacylglycerol and serum clinical pathology parameters did not reveal any significant adverse effects. The results of this preliminary investigation indicate that ingestion of G. cambogia extract at dose levels commonly recommended for human use does not affect serum sex hormone levels and blood parameters.

Small dense low-density lipoprotein (sdLDL) is well known as an atherogenic lipoprotein. We developed a new assay to measure serum concentration of sdLDL-cholesterol (sdLDLC). Using this assay, we reported a unique circadian rhythm of sdLDLC. We determined whether a glucose intake and/or a fat intake affects on serum sdLDLC concentration and determined the modulators of serum sdLDLC concentration.Ten healthy volunteers were recruited to perform both a 75 g oral glucose tolerance test (OGTT) and an oral fat tolerance test (OFTT) to determine the effects of glucose and fat ingestion separately. Blood was measured for sdLDLC concentration and other valuables.Serum concentrations of total cholesterol, LDLC, remnant-like particles-cholesterol (RLPC), and apolipoprotein B significantly decreased during OGTT (p0.05). SdLDLC also decreased and was a minimum at 2 h after glucose ingestion and increased to the baseline by 3 h. The sdLDLC decrease was seen while serum insulin level was high. The change of sdLDLC during OGTT had greater inverse correlationship with that of serum insulin level (r=-0.74, p0.01) than that of plasma glucose level (r=-0.69, p=0.04). After fat ingestion, triglyceride and RLPC increased remarkably (p0.01) but sdLDLC, LDLC, apolipoprotein B, and insulin did not change significantly.Serum concentration of sdLDLC was not affected by a fat intake but by a glucose intake. The change of sdLDLC was associated by that of serum insulin level, suggesting that insulin can be one of the key modulator of serum sdLDLC level as well as LDL metabolism.

It is now well recognized that both Postprandial hyperglycemia and postprandial hyperlipidemia contribute to the development of atherosclerosis. Both an impaired glucose tolerance (IGT) and hyperglycemia after glucose loading have been reported to be risk factors for coronary arterial disease. Postprandial hyperlipidemia, or an increase in remnant lipoproteins in the plasma after a meal has been recognized as atherogenic. It therefore becomes important to establish an international standard test meal for simultaneously assessing both postprandial hyperglycemia and postprandial hyperlipidemia. Test meal A was developed for this purpose by the Working Group for Test Meals under the Committee of Laboratory Testing for Diabetes Mellitus of the Japan Diabetes Society. Test meal A contains total energy of 450 kcal with 51.4% of carbohydrate, 33.3% of fat and 15.3% of protein. Eighteen diabetics, 12 IGTs and 29 subjects with normal glucose tolerance were enrolled for this study. An oral glucose tolerance test was performed one week after loading with the test meal. There was a close correlation between the blood glucose values 120min. after glucose loading and 120min. after test meal loading. A blood glucose value of 200mg/dl 2 hour after glucose loading corresponds to 150mg/dl at the same sampling point after test meal loading, and a blood glucose value of 140mg/dl 2 hour after glucose loading corresponds to 10mg/dl at the same sampling point after the test meal loading. No significant increase in plasma triglyceride was apparent in the hypertriglyceridemic subjects, while the normotriglyceridemic group showed a significant rise in plasma triglyceride after the test meal loading. The results indicate that test meal A can be applied as a pilot model for the simultaneous assessment of both postprandial hyperglycemia and hyperlipidemia in diabetic subjects.

A 56-yr-old man was admitted to our university hospital for severe back pain one month after a resection for lung adenocarcinoma (stage IIIA) without evidence of the adrenal mass. Computed tomography (CT) of the abdomen showed bilateral bleeding of adrenal tumors. Endocrinological laboratory studies showed high plasma ACTH and normal serum cortisol levels with the loss of circadian rhythm. Although plasma ACTH levels increased, there was no cortisol response to administration of human corticotropichormone (hCRH). Core-needle biopsy was performed on the right adrenal tumor and revealed adenocarcinoma cells mimicking a primary lung tumor previously examined. We diagnosed retroperitoneal hemorrhage due to bilateral adrenal gland metastasis from lung adenocarcinoma with adrenal insufficiency. Adrenal metastases most commonly originate from a primary lung tumor, followed by stomach, esophagus and liver/bile ducts. Bilateral adrenal metastases were noted in approximately half of all adrenal metastases patients. Clinically significant adrenal hemorrhage by metastasis is exceedingly rare and non-specific symptoms, such as abdominal, chest or back pain, nausea and vomiting, confusion, weakness, hypotension, shock and high fever, are often observed in these patients. We present a case of massive retroperitoneal hemorrhage and adrenal insufficiency due to adrenal gland metastasis from adenocarcinoma of lung.

Mitochondrial dysfunction has been reported to contribute to insulin resistance (IR) in the elderly and type 2 diabetes. To test this hypothesis, we examined relations of insulin resistance in young men to their mother's body mass index (BMI) and compared with those to their father's BMI, because as a rule, mitochondrial DNA is exclusively maternally inherited and because mitochondria are fundamental in mediating effects on energy dissipation. We measured heights, weights, waist circumference, systolic and diastolic blood pressure (BP), and biochemical variables in sera from 193 male college students aged 18 to 20 years after an overnight fast. Birth weight was available from 184 students. Self-reported heights and weights of their parents were obtained from 148 students. Insulin resistance and insulin secretion were estimated using homeostasis model assessment (HOMA-IR and HOMA-beta, respectively). Mother's BMI was associated with their son's birth weight (r=0.23, P=.008), BMI (r=0.37, P.0001), waist circumference (r=0.42, P.0001), fasting insulin (r=0.19, P=.02), and HOMA-IR (r=0.18, P=.03) but not with fasting glucose, HOMA-beta , and systolic and diastolic BP. In addition, high-density lipoprotein cholesterol and lipoprotein(a) [Lp(a)] were inversely associated with mother's BMI (r=-0.21, P=.01 and r=-0.17, P=.03, respectively). Furthermore, there were significant associations with aspartate (r=0.20, P=.01) and alanine (r=0.28, P=.0008) aminotransferase and gamma-glutamyl transpeptidase (r=0.30, P=.0003), all of which are associated with mitochondrial function. In contrast, none of those variables were associated with father's BMI, except for Lp(a), which showed a significant and inverse association (r=-0.17, P=.05). After adjustment for sons' BMI, waist circumference and 3 hepatic enzymes were associated with mother's BMI, whereas Lp(a) was associated with both mother's and father's BMI. In multiple regression analysis for HOMA-IR as a dependent variable, BMI of their own (beta=.10, P.0001) and of their mothers (beta=.04, P=10) and birth weight (beta=-.27, P=.10) emerged as determinants of HOMA-IR of the students(R2=0.30). Our results are consistent with clinical observations of a greater risk of transmission of type 2 diabetes from the mother than the father and suggest that son's IR may be influenced by maternal effect as well as their adiposity.

We investigated whether the electrophoretic patterns and clinical information derived from the five principal fractions of the Beckman Paragon capillary zone electrophoresis (CZE) 2000 system are comparable to the results obtained by the cellulose acetate electrophoresis (CAE: Olympus AES 320) system. Concordance studies between the results obtained by CAE and CZE were performed on sera from pregnant women and from patients with nephrotic syndrome, acute and chronic inflammatory diseases, cirrhosis, monoclonal and polyclonal gammopathy, and bisalbuminemia. In all subjects except for the pregnant women, the results of CAE and CZE agreed 100% in terms of percent composition for albumin, and α1- and α2-globulins. Concordance for γ-globulin was 92-100% in terms of both percent composition and absolute concentration. Three discordant cases according to the results for β-globulin by CAE and CZE were found in patients with monoclonal gammopathy, who also showed discordant results for γ-globulin. An M-protein spike observed in either the β-globulin or γ-globulin fraction was 100% detected by both CAE and CZE analyses. In another six discordant cases for the β-globulin fraction observed in patients with cirrhosis and polyclonal gammopathy, part of the tail of the β-globulin fraction tended to be measured as γ-globulin by CAE. In three of the four bisalbuminemia cases, the double band of albumin observed by CZE was not detected by CAE. The results show that the electrophoretic patterns and clinical information derived from the five principal fractions of the Beckman Paragon CZE 2000 system are comparable to the results obtained by classical CAE.

Low density lipoprotein (LDL) particles are heterogeneous with respect to their size, density and lipid composition. Among LDL particles, the smaller and denser LDL particles [small dense (sd) LDL] are more atherogenic and the sd LDL phenotype is strongly associated with development of coronary heart disease. Here we will review various methods for measurement of sd LDL. Although ultracentrifugation, nuclear magnetic resonance (NMR) spectroscopy and gradient-gel electrophoresis (GGE) are usually employed for the measurement of sd LDL, such methods are either too laborious or expensive for general clinical use. We recently established a simple precipitation method for the quantification of sd LDL. This method is applicable to routine clinical use and allows the rapid measurement of a large number of samples.

Background: The Committee on Standardization of Laboratory Testing Related to Diabetes Mellitus of the Japan Diabetes Society (JDS) previously recommended use of the primary calibrator (JDS Lot 1) prepared by the former Committee for Standardization of Glycohemoglobin for standardizing the measurement of haemoglobin A1c (HbA1c). Owing to the depletion of vials of Lot 1 in March 2001, the present committee certified a new reference material, Lot 2, now distributed by the Health Care Technology Foundation (HECTEF). The standardization programme for HbA1c measurement in Japan is currently based on Lot 2, which has values assigned from within Lot 1; the Lot 1 values were consensus values based on assays by laboratories in the Japanese national quality control programme. In this study, for the purpose of international comparison and standardization, Lot 2 was assayed by the JDS reference laboratories, the National Glycoprotein Standardization Program (NGSP) in the USA, and by reference laboratories approved by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). Method: The HbA1c values of JDS Lot 2 were transferred from those assigned to Lot 1 using KO500, a high-resolution HPLC method, at three laboratories approved by the JDS committee. Subsequently, vials of JDS Lot 2 were shipped to and assayed by the NGSP in the USA and 10 IFCC reference laboratories. Result: The JDS-assigned HbA1c values (from Lot 1) are 4.04 for Level 1, 5.38 for Level 2, 7.32 for Level 3, 9.88 for Level 4, and 12.63 for Level 5, all expressed as a percentage of total haemoglobin. The values obtained by NGSP and the IFCC laboratories gave the following formulas: NGSP value (%) = JDS value (%) + 0.3%; IFCC value (%) = 1.068 x JDS value (%) -1.741%. Conclusion: Although the values obtained by the IFCC laboratories are significantly lower than the values assigned to Lot 2 by the JDS, the relationship is linear. In addition, standardization of HbA1c based on JDS Lot 2 is currently at a satisfactory level in Japan. As a result, the reassignment of values for Lot 2 to agree with the IFCC values should be relatively easy and will be done after all relevant parties agree to the change.

Objective— Recently, we established a simple method for the quantification of small dense LDL cholesterol (C) using heparin-magnesium precipitation. The small dense LDL-C level was identical to cholesterol in the denser LDL fraction with a density of 1.044 to 1.063 g/mL. The aim of this study was to examine clinical significance of this precipitation method for small dense LDL-C. Methods and Results— Small dense LDL-C was measured by a direct homogenous LDL-C assay in the supernatant that remained after heparin-magnesium precipitation with density Conclusion— These results suggest that measurement of small dense LDL-C by the present precipitation method is useful to evaluate atherogenic risk and may be applicable to routine clinical examination.

—Silk sericin extracted from a cocoon was sulfated by chlorosulfonic acid. Sulfation of sericin was confirmed by FT-IR and the reaction efficiency was calculated as 44.9%. 1H-NMR suggested that sulfation mainly occurred at serine residues in the sericin molecule. The sulfated sericin was separated in three fractions by gel-filtration chromatography using Sephacryl S-200. The sulfate group content and amino-acid composition of each fraction were almost identical, while the anticoagulant activity differed for each fraction of sulfated sericin. Higher anticoagulant activity was observed for the higher-molecular-mass fraction. The anticoagulant activity of sulfated sericin was estimated at 1/10 to 1/20 of heparin.