Serum R-Spondin 1 Is a New Surrogate Marker for Obesity and Insulin Resistance

BACKGROUND: Recent in vivo studies indicated that R-spondin 1 (RSPO1) regulates food intake and increases insulin secretion, but its role in humans remains unknown. This study investigated the association between serum levels of RSPO1 and diverse metabolic parameters in humans. METHODS: The study population consisted of 43 subjects with newly diagnosed diabetes mellitus, and 79 non-diabetic participants. Serum levels of RSPO1 were measured using the enzyme-linked immunosorbent assay. The relationships between circulating RSPO1 and diverse metabolic parameters were analyzed. RESULTS: Circulating RSPO1 levels increased to a greater extent in the obese group than in the lean group. Moreover, serum levels of RSPO1 were higher in the insulin-resistant group than in the insulin-sensitive group. Serum levels of RSPO1 were significantly correlated with a range of metabolic parameters including body mass index, fasting C-peptide, homeostasis model assessment of insulin resistance index, and lipid profile. Moreover, levels were significantly associated with insulin resistance and obesity in non-diabetic subjects. CONCLUSION: This study demonstrated the association between serum levels of RSPO1 and a range of metabolic parameters in humans. Serum levels of RSPO1 are significantly related to obesity and insulin resistance, although the precise mechanisms remain unknown.

Genetic Analysis of CLCN7 in an Old Female Patient with Type II Autosomal Dominant Osteopetrosis

BACKGROUND: Type II autosomal dominant osteopetrosis (ADO II) is a rare genetically heterogeneous disorder characterized by osteosclerosis and increased bone mass, predominantly involving spine, pelvis, and skull. It is closely related to functional defect of osteoclasts caused by chloride voltage-gated channel 7 (CLCN7) gene mutations. In this study, we aimed to identify the pathogenic mutation in a Korean patient with ADO II using whole exome sequencing. METHODS: We evaluated the clinical, biochemical, and radiographic analysis of a 68-year-old woman with ADO II. We also performed whole exome sequencing to identify pathogenic mutation of a rare genetic disorder of the skeleton. Moreover, a polymorphism phenotyping program, Polymorphism Phenotyping v2 (PolyPhen-2), was used to assess the effect of the identified mutation on protein function. RESULTS: Whole exome sequencing using peripheral leukocytes revealed a heterozygous c.296A>G missense mutation in the CLCN7 gene. The mutation was also confirmed using Sanger sequencing. The mutation c.296A>G was regarded to have a pathogenic effect by PolyPhen-2 software. CONCLUSION: We detect a heterozygous mutation in CLCN7 gene of a patient with ADO II, which is the first report in Korea. Our present findings suggest that symptoms and signs of ADO II patient having a c.296A>G mutation in CLCN7 may appear at a very late age. The present study would also enrich the database of CLCN7 mutations and improve our understanding of ADO II.

Clinical Implications of Using Post-Challenge Plasma Glucose Levels for Early Diagnosis of Type 2 Diabetes Mellitus in Older Individuals

BACKGROUND: The aim of this study was to explore the differences in the clinical characteristics and diagnostic rates of diabetes mellitus (DM) according to various criteria in different age groups and to evaluate the efficacy of each criterion for screening older patients. METHODS: We studied 515 patients and measured the fasting plasma glucose level (FPG), 2-hour plasma glucose level after the 75 g oral glucose tolerance test (2-hour postload glucose [2-h PG]), and glycosylated hemoglobin (HbA1c) for re-evaluation of hyperglycemia without a history of diabetes. Patients with newly diagnosed DM were grouped by age as younger ( < 65 years) or older (≥65 years). RESULTS: Older patients had significantly lower HbA1c, FPG, and 2-h PG levels and a higher homeostatic level of pancreatic β-cell function compared with younger patients (P < 0.001). The older group had the lowest diagnostic rate when using the FPG level (45.5%) and the highest diagnostic rate when using the 2-h PG level (84.6%). These results were mostly due to the higher frequency of isolated post-challenge hyperglycemia in the older patients than in the younger group (28.8% vs. 9.2%). The use of both the FPG and HbA1c levels significantly enhanced the low diagnostic power when employing only the FPG levels in the older group (71.2% vs. 45.5%). CONCLUSION: In the older patients, the 2-h PG level was the most accurate diagnostic criterion. When we consider the costs and convenience, a combination of the FPG and HbA1c criteria may be recommended as a screening test for DM in older people.

Serum Soluble Epidermal Growth Factor Receptor Level Increase in Patients Newly Diagnosed with Type 2 Diabetes Mellitus

We analyzed circulating soluble epidermal growth factor receptor (sEGFR) levels in humans. Serum sEGFR levels were higher in subjects with newly diagnosed type 2 diabetes mellitus compared with controls. Serum sEGFR was positively correlated with glycosylated hemoglobin and serum glucose and negatively correlated with serum insulin and C-peptide levels.

The Eosinophil Count Tends to Be Negatively Associated with Levels of Serum Glucose in Patients with Adrenal Cushing Syndrome

BACKGROUND: Cushing syndrome is characterized by glucose intolerance, cardiovascular disease, and an enhanced systemic inflammatory response caused by chronic exposure to excess cortisol. Eosinopenia is frequently observed in patients with adrenal Cushing syndrome, but the relationship between the eosinophil count in peripheral blood and indicators of glucose level in patients with adrenal Cushing syndrome has not been determined. METHODS: A retrospective study was undertaken of the clinical and laboratory findings of 40 patients diagnosed with adrenal Cushing syndrome at Chungnam National University Hospital from January 2006 to December 2016. Clinical characteristics, complete blood cell counts with white blood cell differential, measures of their endocrine function, description of imaging studies, and pathologic findings were obtained from their medical records. RESULTS: Eosinophil composition and count were restored by surgical treatment of all of the patients with adrenal Cushing disease. The eosinophil count was inversely correlated with serum and urine cortisol, glycated hemoglobin, and inflammatory markers in the patients with adrenal Cushing syndrome. CONCLUSION: Smaller eosinophil populations in patients with adrenal Cushing syndrome tend to be correlated with higher levels of blood sugar and glycated hemoglobin. This study suggests that peripheral blood eosinophil composition or count may be associated with serum glucose levels in patients with adrenal Cushing syndrome.

Treatment with Gefitinib, an Epidermal Growth Factor Receptor Inhibitor, Decreases Serum Cholesterol in Patients with Lung Cancer

BACKGROUND: Statins are used to treat hypercholesterolemia; however, major cardiovascular events are decreased only 30% by statin treatment. Treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been reported to decrease serum glucose levels and improved insulin sensitivity in mice and humans, but there was no study in serum cholesterol levels. This study examined the effect of gefitinib, an EGFR tyrosine kinase inhibitor, on cholesterol metabolism in humans. METHODS: We retrospectively reviewed the medical records of 299 patients with primary lung cancer treated with gefitinib for ≥1 month and 72 patients with other treatments. Serum cholesterol, serum triglycerides, and body mass index were measured before and after treatment. The changes in serum cholesterol, serum triglycerides, and body mass index were compared between the gefitinib treatment group and the control group and were also analyzed according to the presence or absence of EGFR mutations. RESULTS: Serum cholesterol levels decreased significantly from 178.9 to 164.4 mg/dL after 1-month of gefitinib treatment. A total of 54 of the 299 patients underwent examination for the presence of the EGFR mutations. Serum cholesterol was significantly decreased in the group with the activating EGFR mutation (Δ=21.3 mg/dL) compared to that of those without the EGFR mutation (Δ=-3.1 mg/dL) after treatment with gefitinib. In contrast, there was no significantly difference between the two groups in control patients. CONCLUSION: Treatment with gefitinib decreased serum cholesterol in lung cancer patients, particularly in those with activating mutations in EGFR. These data suggest that EGFR tyrosine kinase inhibitors provide a novel and attractive strategy for the treatment of hypercholesterolemia.

An Obese Pregnant Woman with Type 2 Diabetes Whose One-Day Insulin Requirements Were 1,000 IU

Insulin resistance in patients with diabetes mellitus may be aggravated by various causes, including infection, obesity, and medications known to affect insulin sensitivity. During pregnancy, insulin resistance can be the result of hormones secreted by the placenta. Blood glucose control during pregnancy is important in preventing obstetric complications including miscarriage, congenital malformations, and macrosomia. We report a case of severe insulin resistance in an obese diabetic pregnant woman whose one-day insulin requirements were up to 1,000 IU.

Association between Growth Differentiation Factor 15 (GDF15) and Cardiovascular Risk in Patients with Newly Diagnosed Type 2 Diabetes Mellitus

We investigated an association between serum Growth Differentiation Factor 15 (GDF15) level and cardiovascular risk in patients with newly diagnosed type 2 diabetes mellitus (T2D). A total of 107 participants were screened for T2D and divided into a T2D group and a control group (without diabetes). We used the Framingham risk score (FRS) and the New Pooled Cohort Equation score to estimate the 10-year risk of atherosclerotic cardiovascular disease. Serum GDF15 levels were measured using an enzyme-linked immunosorbent assay. Correlation analyses were performed to evaluate the associations between GDF15 level and cardiovascular risk scores. The mean serum GDF15 level was elevated in the T2D group compared to the control group (P < 0.001). A positive correlation was evident between serum GDF15 level and age (r = 0.418, P = 0.001), the FRS (r = 0.457, P < 0.001), and the Pooled Cohort Equation score (r = 0.539, P < 0.001). After adjusting for age, LDL-C level, and body mass index (BMI), the serum GDF15 level was positively correlated with the FRS and the New Pooled Cohort Equation score. The serum GDF15 level is independently associated with cardiovascular risk scores of newly diagnosed T2D patients. This suggests that the level of GDF15 may be a useful predictive biomarker of cardiovascular risk in newly diagnosed T2D patients.

Morphological and Functional Changes in the Thyroid Follicles of the Aged Murine and Humans

BACKGROUND: Although both thyroid histology and serum concentrations of hormones are known to change with age, only a few reports exist on the relationship between the age-related structural and functional changes of the thyroid follicles in both mice and humans. Our objectives were to investigate age-related histological changes of the thyroid follicles and to determine whether these morphological changes were associated with the functional activity of the follicles. METHODS: The thyroid glands of mice at 18 weeks and at 6, 15, and 30 months of age were histologically examined, and the serum levels of thyroid hormones were measured in 11-week-old and 20-month-old mice. Samples of human thyroid tissue from 10 women over 70 years old and 10 women between 30 and 50 years of age were analyzed in conjunction with serum thyroid hormone level. RESULTS: The histological and functional changes observed in the thyroid follicles of aged mice and women were as follows: variable sizing and enlargement of the follicles; increased irregularity of follicles; Sanderson’s polsters in the wall of large follicles; a large thyroglobulin (Tg) globule or numerous small fragmented Tg globules in follicular lumens; oncocytic change in follicular cells; and markedly dilated follicles empty of colloid. Serum T3 levels in 20-month-old mice and humans were unremarkable. CONCLUSIONS: Thyroid follicles of aged mice and women show characteristic morphological changes, such as cystic atrophy, empty colloid, and Tg globules.

Effect of Atorvastatin on Growth Differentiation Factor-15 in Patients with Type 2 Diabetes Mellitus and Dyslipidemia

BACKGROUND: Elevated serum levels of growth differentiation factor-15 (GDF-15) are associated with type 2 diabetes. Therefore, the effects of atorvastatin on metabolic parameters and GDF-15 levels in patients with type 2 diabetes and dyslipidemia were evaluated. METHODS: In this prospective randomized trial from February 2013 to March 2014, 50 consecutive type 2 diabetic patients with a low density lipoprotein cholesterol (LDL-C) levels > or =100 mg/dL were enrolled. The patients were divided into two groups based on the amount of atorvastatin prescribed, 10 mg/day (n=23) or 40 mg/day (n=27). The effect of atorvastatin on metabolic parameters, including lipid profiles and GDF-15 levels, at baseline and after 8 weeks of treatment were compared. RESULTS: The baseline metabolic parameters and GDF-15 levels were not significantly different between the two groups. After 8 weeks of treatment, the total cholesterol (TC) and LDL-C levels were significantly decreased in both groups. The mean changes in TC and LDL-C levels were more significant in the 40 mg atorvastatin group. The GDF-15 level was decreased in the 10 mg atorvastatin group, from 1,460.6+/-874.8 to 1,451.0+/-770.8 pg/mL, and was increased in the 40 mg atorvastatin group, from 1,271.6+/-801.0 to 1,341.4+/-855.2 pg/mL. However, the change in the GDF-15 level was not statistically significant in the 10 or 40 mg atorvastatin group (P=0.665 and P=0.745, respectively). CONCLUSION: The GDF-15 levels were not significantly changed after an 8-week treatment with atorvastatin in type 2 diabetic patients.

Validation of Waist-to-Height Ratio for Predicting Metabolic Syndrome in Patients with Prediabetes

BACKGROUND: Metabolic syndrome is associated with type 2 diabetes and cardiovascular disease in patients with prediabetes. The aim of this study was to investigate and compare WHtR (Waist-to-Height Ratio) as a predictor of metabolic syndrome with other anthropometric indices as in Body Mass Index (BMI), Waist Circumference (WC) and Waist to Hip Ratio (WHR) in prediabetes. METHODS: A total of 816 subjects with prediabetes were recruited from a community based Cohort Study. Receiver operating characteristic (ROC) curve was performed to find the optimal cutoff value of WHtR. Area under the curve (AUC) was calculated for each anthropometric index and correlation coefficient between WHtR and various dermographic and clinical factors was calculated. RESULTS: WHtR had a significant correlation with metabolic parameters except for fasting glucose and increased with increasing number of risk factors for metabolic syndrome. AUC of WHtR was significantly higher than that of other anthropometric indices. The optimal cutoff value of WHtR was 0.53 for metabolic syndrome in prediabetes. CONCLUSION: WHtR may be the simple and effective anthropometric index for predicting metabolic syndrome in prediabetic patients.

Plasma Adiponectin Levels in Elderly Patients with Prediabetes

BACKGROUND: The significance of adiponectin levels in elderly individuals with prediabetes has yet to be determined. Thus, the present study was performed to evaluate the relationships between adiponectin levels and anthropometric variables, body composition parameters, insulin sensitivity, and lipid profiles in elderly prediabetic patients. METHODS: The present study included 120 subjects with prediabetes who were >65 years of age and were selected from among 1,993 subjects enrolled in the Korea Rural Genomic Cohort Study. All subjects underwent a 75 g oral glucose tolerance test and tests for measurement of insulin sensitivity. All diagnoses of prediabetes satisfied the criteria of the American Diabetes Association. RESULTS: Plasma adiponectin levels were lower in elderly prediabetic subjects than elderly subjects with normal glucose tolerance (P<0.01) as well as in elderly prediabetic patients with metabolic syndrome (MetS) than in those without MetS (P<0.02). When the subjects were categorized into two groups according to plasma adiponectin levels, the waist-to-hip ratio and 2-hour insulin levels were significantly lower in individuals with high plasma adiponectin levels than in those with low plasma adiponectin levels. Additionally, the plasma adiponectin levels of elderly prediabetic subject were inversely correlated with body mass index (BMI), waist circumference (WC), waist-to-hip ratio, visceral fat, visceral fat ratio, and 2-hour insulin levels. CONCLUSION: The present findings demonstrated that the major factors correlated with adiponectin levels in elderly prediabetic subjects were BMI, WC, waist-to-hip ratio, visceral fat, visceral fat ratio, and 2-hour insulin levels.

Mitochondrial Energy Metabolism and Thyroid Cancers

Primary thyroid cancers including papillary, follicular, poorly differentiated, and anaplastic carcinomas show substantial differences in biological and clinical behaviors. Even in the same pathological type, there is wide variability in the clinical course of disease progression. The molecular carcinogenesis of thyroid cancer has advanced tremendously in the last decade. However, specific inhibition of oncogenic pathways did not provide a significant survival benefit in advanced progressive thyroid cancer that is resistant to radioactive iodine therapy. Accumulating evidence clearly shows that cellular energy metabolism, which is controlled by oncogenes and other tumor-related factors, is a critical factor determining the clinical phenotypes of cancer. However, the role and nature of energy metabolism in thyroid cancer remain unclear. In this article, we discuss the role of cellular energy metabolism, particularly mitochondrial energy metabolism, in thyroid cancer. Determining the molecular nature of metabolic remodeling in thyroid cancer may provide new biomarkers and therapeutic targets that may be useful in the management of refractory thyroid cancers.

A Novel PHEX Gene Mutation in a Patient with Sporadic Hypophosphatemic Rickets

Phosphate regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) is a common cause of X-linked hypophosphatemic (XLH) rickets. Diverse PHEX gene mutations have been reported; however, gene mutations in sporadic rickets are less common than in XLH rickets. Herein, we describe a 50-year-old female patient with sporadic hypophosphatemic rickets harboring a novel splicing-site mutation in the PHEX gene (c.663+1G>A) at the exon 5-intron 5 boundary. The patient had recently suffered from right thigh pain and an aggravated waddling gait. She also presented with very short stature, generalized bone pain, and muscle weakness. Despite low serum phosphate levels, her phosphate reabsorption rate was lower than normal. Additionally, her 1,25-dihydroxyvitamin D3 concentration was lower than normal, although FGF23 level was normal. After treatment with alfacalcidol and elemental phosphate, her rachitic symptoms subsided, and callus formation was observed in the fracture site on the right femur.

GDF15 Is a Novel Biomarker for Impaired Fasting Glucose

BACKGROUND: Growth differentiation factor-15 (GDF15) is a protein that belongs to the transforming growth factor beta superfamily. An elevated serum level of GDF15 was found to be associated with type 2 diabetes mellitus (T2DM). T2DM is an inflammatory disease that progresses from normal glucose tolerance (NGT) to impaired fasting glucose (IFG). Hence, we aimed to validate the relationship between GDF15 and IFG. METHODS: The participants were divided into the following three groups: NGT (n=137), IFG (n=29), and T2DM (n=75). The controls and T2DM outpatients visited the hospital for routine health check-ups. We used fasting blood glucose to detect IFG in nondiabetic patients. We checked the body mass index (BMI), C-reactive protein level, metabolic parameters, and fasting serum GDF15 level. RESULTS: Age, BMI, triglyceride, insulin, glucose, homeostatic model assessment-insulin resistance (HOMA-IR), and GDF15 levels were elevated in the IFG and T2DM groups compared to the NGT group. In the correlation analysis between metabolic parameters and GDF15, age and HOMA-IR had a significant positive correlation with GDF15 levels. GDF15 significantly discriminated between IFG and NGT, independent of age, BMI, and HOMA-IR. The serum levels of GDF15 were more elevated in men than in women. As a biomarker for IFG based on the receiver operating characteristic curve analysis, the cutoff value of GDF15 was 510 pg/mL in males and 400 pg/mL in females. CONCLUSION: GDF15 had a positive correlation with IR independent of age and BMI, and the serum level of GDF15 was increased in the IFG and T2DM groups. GDF15 may be a novel biomarker for detecting IFG in nondiabetic patients.

Epigenetic Regulation of RUNX3 in Thyroid Carcinoma

No abstract available.

Model Development of Papillary Thyroid Carcinoma by BRAFV600E Transgenic Mice / 대한갑상선학회지

BACKGROUND AND OBJECTIVES: The BRAFV600E mutation has been regarded as the leading cause of papillary thyroid cancer (PTC). However, the multi-step carcinogenic process induced by BRAFV600E has been remained to be elucidated in thyroid gland. In this study, to investigate staged development of papillary thyroid carcinoma, we observed the histo-pathological findings of thyroid gland from BRAFV600E transgenic mice with a period of 60 weeks. MATERIALS AND METHODS: We histologically inspected 3, 9, 20, 27, 39, 44, 48 and 60 week old BRAFV600E transgenic mice derived from FVB/N background mice with a bovine thyroglobulin promoter which are providing thyroid specific BRAFV600E expression. RESULTS: Thyroid glands from 3 and 9 week old BRAFV600E transgenic mice were enlarged and showed abnormal histologic feature such as distorted follicular architectures. The 20 and 27 week old BRAFV600E transgenic mice showed irregularly enlarged thyroid gland sprouting out above the carotid arteries. Thyroid gland derived from 39 week old mice showed reduced formation of intact follicular structure and increased solid area. Thyroid glands were entirely replaced by firm tumor mass composed of poorly differentiated cell at 44 weeks. Interestingly, we could observe tracheal invasion, surrounding muscle invasion in thyroid gland from 48 week old mice and detect lung metastasis in 60 week old mice. CONCLUSION: Thyroid specific expression of BRAFV600E induced staged development of thyroid cancer. This finding may support that BRAFV600E have a role in entire carcinogenic process such as tumor initiation, development and progression.