Influence of Metabolic Syndrome on Small, Dense LDL, and Subclinical Atherosclerosis in Older Subjects.

Aging is known as one of the important risk factors for coronary artery disease (CAD). We explore whether an association of metabolic syndrome (Met-S) increases subclinical atherosclerosis among elderly diabetic subjects estimating the plaque score (PS) of the carotid artery. A total of 187 subjects were enrolled. Middle-aged and older groups were divided into two groups. T-test and Chi-square test were also employed. Simple regression analysis for the PS was performed with respective risk factors as independent variables. After selection of independent variables, multiple regression analysis was performed to estimated the association of PS and dependent variable of the study. There were significant differences in body mass index (BMI) (p < .001), HbA1c (p < .01), TG (p < .05), and PS (p < .001) . Multiple regression analysis in middle-aged subjects showed that the determinant of PS were age (p < .001), BMI (p = .006), Met-S (p = .004), and hs-CRP (p = .019). Multiple regression analysis in older subjects showed that neither age nor Met-S was included as significant determinant of PS. An association of Met-S is an important factor for progression of subclinical atherosclerosis, but it cannot be a significant determinant of PS if the subjects are limited within older group.

A case of α-chain variant hemoglobin (Hb Chad) with falsely high HbA1c levels measured by immunoassay.

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.

Prominent Hyperproinsulinemia in a Middle Age Patient.

INTRODUCTION: Insulin is synthesized in the ß-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 ß-cell defect that is augmented by the increased demand placed on the ß-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.

Long-term follow-up of insulin autoimmune syndrome in an elderly patient.

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.

Role of growth hormone signaling pathways in the development of atherosclerosis.

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.

Higher circulating orosomucoid and lower early-phase insulin secretion in midlife Japanese with slower glucose disposal during oral glucose tolerance tests.

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<0.05), whereas the Matsuda index, the homeostasis model assessment of insulin resistance, adipose insulin resistance (the product of fasting free fatty acid and insulin) and area under the insulin curve did not differ. Although there was no difference in fat mass index, trunk/leg fat ratio and adiponectin, orosomucoid was higher in group C as compared to group A (p<0.05). CONCLUSIONS: Lower early-phase insulin secretion and low-grade inflammation were associated with slower glucose disposal during an oral glucose tolerance test in midlife Japanese. The rate of glucose disposal was not related to adiposity and insulin resistance.

Higher circulating adiponectin and lower orosomucoid were associated with postload glucose ≤70 mg/dL, a possible inverse marker for dysglycemia, in young Japanese women.

Objective: To 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 methods: 75 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 ß-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. Results: Of 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 p<0.001). Multivariate logistic regression analyses revealed that adiponectin (OR: 1.14, 95% CI 1.03 to 1.26, p=0.009) and orosomucoid (0.96, 0.93 to 0.97, p=0.008) were associated with postload low glycemia independently of adipose IR and insulinogenic index. Conclusions: Higher 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.

Association of serum orosomucoid with 30-min plasma glucose and glucose excursion during oral glucose tolerance tests in non-obese young Japanese women.

OBJECTIVE: Inflammatory markers are elevated in insulin resistance (IR) and diabetes. We tested whether serum orosomucoid (ORM) is associated with postload glucose, ß-cell dysfunction and IR inferred from plasma insulin kinetics during a 75 g oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: 75 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. RESULTS: Of 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 ß: 0.517) and AUCg (standardized ß: 0.495) explained 92.8% of ORM variations. CONCLUSIONS: Elevated 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.

Age-related changes of proinsulin processing in diabetic and non-diabetic Japanese individuals.

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 (<64 years and >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 < 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). CONCLUSIONS: 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.

Different Associations of Trunk and Lower-Body Fat Mass Distribution with Cardiometabolic Risk Factors between Healthy Middle-Aged Men and Women.

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.

An Excess of CYP24A1, Lack of CaSR, and a Novel lncRNA Near the PTH Gene Characterize an Ectopic PTH-Producing Tumor.

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).

A case of idiopathic normal pressure hydrocephalus in an elder diabetic patient.

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.

High glycated albumin (GA) levels and the GA/HbA1c ratio in patients with insulin autoimmune syndrome.

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.

Case of anal fistula with Fournier's gangrene in an obese type 2 diabetes mellitus patient.

A 64-year-old man was admitted to Shin-suma General Hospital, Kobe, Japan, complaining of a 3-day history of scrotal swelling and high fever. He had type 2 diabetes mellitus. On examination, his body temperature had risen to 38.5 °C. Examination of the scrotum showed abnormal enlargement. Laboratory data were as follows: white cell count 35,400/µL and glycated hemoglobin 9.6%. Anal fistula was found in an endorectal ultrasound. Computed tomography scan showed a relatively high density of subcutaneous tissue and elevated air density. Thus, he was diagnosed with Fournier's gangrene. On the fourth hospital day, the patient underwent debridement of gangrenous tissue. Seton surgery was carried out for anal fistula on the 34th hospital day. He responded to the treatment very well. He was discharged on the 33rd postoperative day. Once Fournier's gangrene has been diagnosed, considering the association of anal fistula and perianal abscess is important.

Atherogenic phenotype remains in elderly diabetic patients.

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 < 0.05). Multivariate regression analysis showed that age, sex, the presence of diabetes mellitus and plasma triglyceride were the independent factors determining the sLDL-C/LDL-C ratio. DISCUSSION: It is concluded from the present data that the atherogenic phenotype remains in elderly diabetic patients even if their LDL-C is not elevated.

Functional analysis of three novel cell lines derived from human papillary thyroid carcinomas with three different clinical courses.

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.

[Trends of evaluation of hypertriglyceridemia -from fasting to postprandial hypertriglyceridemia-].

It has been a matter of debate whether hypertriglyceridemia contributes to the development of atherosclerosis. Several explanations for this were available. For example, although there was close relationship between the incidence of coronary heart disease and the plasma triglyceride level, this significant correlation was no longer detected after multiple regression analysis being performed including total cholesterol and HDL-cholesterol. Furthermore, histological examination revealed that the major component of atherosclerotic lesion is oxidized LDL and that triglyceride is rarely detected from these lesions. On the other hand, according to recent large-scale and long-term observational studies from Western countries as well as from Japan, postprandial hypertriglyceridemia can be one of the significant risk factors for coronary heart disease. Association of an appearance of atherogenic remnant particles in the circulation and smaller sized LDL particles with postprandial hypertriglyceridemia may support the atherogenicity of this pathologic condition.

A case of severe acute necrotizing pancreatitis after administration of sitagliptin.

A 55-year-old Japanese man with a 3-year history of type 2 diabetes mellitus was admitted to our hospital for upper abdominal pain. Control of diabetes mellitus was good with voglibose and metformin, with sitagliptin added to this regimen 8 months prior. His pancreatic enzyme levels were elevated, and abdominal computed tomography (CT) showed diffuse pancreatic swelling with fluid accumulation and ascites of CT grade 3. The patient was diagnosed with severe acute pancreatitis. There were no obvious causes for pancreatitis except the recently administered sitagliptin. Since incretin-related drugs entered the market, the number of incretin-related drugs prescriptions rapidly increased and so did the incidence of pancreatitis. There are several reports suggesting the correlation between incretin-related drugs and pancreatitis, such as a report based on data obtained from the United States Food and Drug Administration (FDA) which revealed a significant correlation between the administration of exenatide or sitagliptin and pancreatitis. However, there also is a report that denied the evidence for such in a large cohort study. The relation between incretin based drugs and pancreatitis is still controversial.

Propylthiouracil increases sodium/iodide symporter gene expression and iodide uptake in rat thyroid cells in the absence of TSH.

BACKGROUND: Propylthiouracil (PTU) and methimazole (MMI) are drugs that are widely used to treat Graves' disease. Although both exert an antithyroid effect primarily by blocking thyroid peroxidase activity, their molecular structure and other actions are different. We hypothesized that PTU and MMI may have differential effects on thyroid-specific gene expression and function. METHODS: The effects of PTU and MMI on thyroid-specific gene expression and function were examined in rat thyroid FRTL-5 cells using DNA microarray, reverse transcriptase (RT)-polymerase chain reaction (PCR), real-time PCR, Western blot, immunohistochemistry, and radioiodine uptake studies. RESULTS: DNA microarray analysis showed a marked increase in sodium/iodide symporter (NIS) gene expression after PTU treatment, whereas MMI had no effect. RT-PCR and real-time PCR analysis revealed that PTU-induced NIS mRNA levels were comparable to those elicited by thyroid-stimulating hormone (TSH). PTU increased 5'-1880-bp and 5'-1052-bp activity of the rat NIS promoter. While PTU treatment also increased NIS protein levels, the size of the induced protein was smaller than that induced by TSH, and the protein localized predominantly in the cytoplasm rather than the plasma membrane. Accumulation of (125)I in FRTL-5 cells was increased by PTU stimulation, but this effect was weaker than that produced by TSH. CONCLUSIONS: We found that PTU induces NIS expression and iodide uptake in rat thyroid FRTL-5 cells in the absence of TSH. Although PTU and MMI share similar antithyroid activity, their effects on other thyroid functions appear to be quite different, which could affect their therapeutic effectiveness.

Regulation of dual oxidase expression and H2O2 production by thyroglobulin.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.