Addition of routine blood biomarkers to TIMI risk score improves predictive performance of 1-year mortality in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Several biomarkers have been proposed as independent predictors of poor outcomes in ST-segment elevation myocardial infarction (STEMI). We investigated whether adding information obtained from routine blood tests including hypoxic liver injury (HLI), dysglycemia, anemia, and high neutrophil to lymphocyte ratio (NLR) could improve the prognostic performance of the TIMI risk score for the prediction of 1-year mortality. METHODS: A total of 1057 patients with STEMI undergoing primary percutaneous coronary intervention (PCI) between 2007 and 2014 were retrospectively enrolled from 4-regional hospitals. HLI and dysglycemia were defined as serum transaminase > twice the normal upper limit and glucose < 90 or > 250 mg/dL, respectively. The effect of adding biomarkers to the TIMI risk score on its discriminative ability was assessed using c-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: The 1-year mortality rate was 7.1%. The best cutoff value of NLR for the prediction of 1-year mortality was 4.3 (sensitivity, 67%; specificity, 65%). HLI (HR 2.019; 95% CI 1.104-3.695), dysglycemia (HR 2.535; 95% CI 1.324-3.923), anemia (HR 2.071; 95% CI 1.093-3.923), and high NLR (HR 3.651; 95% CI 1.927-6.918) were independent predictors of 1-year mortality. When these 4 parameters were added to the TIMI risk score, the c-statistic significantly improved from 0.841 to 0.876 (p < 0.001), and the NRI and IDI were estimated at 0.203 (95% CI 0.130-0.275; p < 0.001) and 0.089 (95% CI 0.060-0.119; p < 0.001), respectively. CONCLUSIONS: The addition of HLI, dysglycemia, anemia, and high NLR to the TIMI risk score may be useful for very early risk stratification in patients with STEMI receiving primary PCI.

Identification and characterization of D410E, a novel mutation in the loop 3 domain of CASR, in autosomal dominant hypocalcemia and a therapeutic approach using a novel calcilytic, AXT914.

OBJECTIVE: Activating mutations of the calcium-sensing receptor (CASR) gene are associated with autosomal dominant hypocalcemia (ADH) characterized by benign hypocalcemia, inappropriately low (PTH) levels and mostly hypercalciuria. Herein, we report a novel activating mutation in the CASR gene in a Korean family with ADH. METHOD: The CASR gene was sequenced in the patient with ADH. The identified mutations were also evaluated in the patient's family members by PCR-based sequencing. For functional studies, we examined phosphorylation of ERK1/2. In addition, intracellular Ca(2+) mobilization and the effects of the calcilytic, AXT914 were measured using fluorophore Fura-2 dye. RESULT: Direct sequencing analysis of the CASR gene showed that the proband and her daughter possess a novel mutation c.1230T>A, resulting in a D410E missense mutation on exon 4 of the CASR gene. Escalation of the extracellular Ca(2+) concentration resulted in stronger phosphorylation of ERK1/2 and higher levels of intracellular Ca(2+) in HEK293 cells expressing mutant CASR, compared with wild-type CASR. The increase in intracellular Ca(2+) signalling via CASR was successively blunted by treatment with AXT914. CONCLUSIONS: Over 60 activating mutations in the CASR gene have been identified to cause ADH so far. Here, we add one more activating mutation that causes ADH. The novel activating mutation (D410E) occurred in the loop 3 region of CASR, where its function was believed to be of little importance; therefore, this mutation may be of interest. Further clinical study will be needed to validate the effectiveness of calcilytics in treatment of ADH in vivo.

Genetic and clinical characteristics of korean patients with isolated hypoparathyroidism: from the Korean hypopara registry study.

Isolated hypoparathyroidism (IH) shows heterogeneous phenotypes and can be caused by defects in a variety of genes. The goal of our study was to determine the clinical features and to analyze gene mutations in a large cohort of Korean patients with sporadic or familial IH. We recruited 23 patients. They showed a broad range of onset age and various values of biochemical data. Whole exome sequencing was performed on two affected cases and one unaffected individual in a family. All coding exons and exon-intron borders of GCMB, CASR, and prepro-PTH were sequenced using PCR-amplified DNA. In one family who underwent the whole exome sequencing analysis, approximately 300 single nucleotide changes emerged as candidates for genetic alteration. Among them, we identified a functional mutation in exon 2 of GCMB (C106R) in two affected cases. Besides, heterozygous gain-of-function mutations in the CASR gene were found in other subjects; D410E and P221L. We also found one single nucleotide polymorphism (SNP) in the prepro-PTH gene, five SNPs in the CASR gene, and four SNPs in the GCMB gene. The current study represents a variety of biochemical phenotypes in IH patients with the molecular genetic diagnosis of IH.

Identification and characterization of C106R, a novel mutation in the DNA-binding domain of GCMB, in a family with autosomal-dominant hypoparathyroidism.

OVERVIEW: Glial cells missing B (GCMB) is a transcription factor that is expressed in the parathyroid hormone (PTH)-secreting cells of the parathyroid glands. Several mutations in GCMB have been reported to cause hypoparathyroidism (HP). We identified a family with two individuals in two generations (mother and son), who are affected by autosomal-dominant hypoparathyroidism (AD-HP). A novel heterozygous mutation in exon 2 of GCMB was identified in both affected individuals that changes cysteine at position 106 of the putative DNA-binding domain of GCMB to arginine (C106R). METHODS: We performed mutational analysis of the genes encoding GCMB, pre-pro PTH, GATA3 and CaSR using polymerase chain reaction (PCR)-amplified genomic DNA. The identified GCMB mutant was characterized by functional studies including nuclear localization, electrophoretic mobility shift assays (EMSA) and luciferase reporter assays, and homology modelling was performed to generate a three-dimensional structural model for the DNA-binding domain of GCMB to predict the structural consequences of the identified mutation. RESULTS: The C106R mutant of GCMB failed to interact with the DNA consensus recognition motif, as determined by EMSA. Furthermore, in comparison with wild-type GCMB, the C106R mutant demonstrated reduced transactivation in luciferase reporter assays; however, the mutant GCMB failed to reduce the activity of the wild-type protein. Consistent with the EMSA findings, homology modelling analysis suggested that replacement of cysteine 106 with arginine would interfere with DNA binding. CONCLUSIONS: We have identified a novel GCMB mutation that may explain AD-HP in our family. However, the exact mechanism by which this heterozygous mutation leads to the disease in the described family remains to be elucidated.

Links between Thyroid Disorders and Glucose Homeostasis.

Thyroid disorders and diabetes mellitus often coexist and are closely related. Several studies have shown a higher prevalence of thyroid disorders in patients with diabetes mellitus and vice versa. Thyroid hormone affects glucose homeostasis by impacting pancreatic ß-cell development and glucose metabolism through several organs such as the liver, gastrointestinal tract, pancreas, adipose tissue, skeletal muscles, and the central nervous system. The present review discusses the effect of thyroid hormone on glucose homeostasis. We also review the relationship between thyroid disease and diabetes mellitus: type 1, type 2, and gestational diabetes, as well as guidelines for screening thyroid function with each disorder. Finally, we provide an overview of the effects of antidiabetic drugs on thyroid hormone and thyroid disorders.

Notch1 Has an Important Role in ß-Cell Mass Determination and Development of Diabetes.

BACKGROUND: Notch signaling pathway plays an important role in regulating pancreatic endocrine and exocrine cell fate during pancreas development. Notch signaling is also expressed in adult pancreas. There are few studies on the effect of Notch on adult pancreas. Here, we investigated the role of Notch in islet mass and glucose homeostasis in adult pancreas using Notch1 antisense transgenic (NAS). METHODS: Western blot analysis was performed for the liver of 8-week-old male NAS mice. We also conducted an intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test in 8-week-old male NAS mice and male C57BL/6 mice (control). Morphologic observation of pancreatic islet and ß-cell was conducted in two groups. Insulin secretion capacity in islets was measured by glucose-stimulated insulin secretion (GSIS) and perifusion. RESULTS: NAS mice showed higher glucose levels and lower insulin secretion in IPGTT than the control mice. There was no significant difference in insulin resistance. Total islet and ß-cell masses were decreased in NAS mice. The number of large islets (≥250 µm) decreased while that of small islets (<250 µm) increased. Reduced insulin secretion was observed in GSIS and perifusion. Neurogenin3, neurogenic differentiation, and MAF bZIP transcription factor A levels increased in NAS mice. CONCLUSION: Our study provides that Notch1 inhibition decreased insulin secretion and decreased islet and ß-cell masses. It is thought that Notch1 inhibition suppresses islet proliferation and induces differentiation of small islets. In conclusion, Notch signaling pathway may play an important role in ß-cell mass determination and diabetes.

Graves' Disease Presenting with Complete Atrioventricular Block.

Hyperthyroidism commonly causes tachyarrhythmias such as sinus tachycardia and atrial fibrillation. Impaired atrioventricular conduction is a very rare complication of hyperthyroidism. We report a case of a patient with hyperthyroidism due to Graves' disease presenting with syncope and complete atrioventricular block. Because lack of awareness of atypical presentation in patients with hyperthyroidism may delay diagnosis and treatment, the recognition that hyperthyroidism can be one of the reversible causes of complete atrioventricular block is important.

Prognostic impact of the combination of serum transaminase and alkaline phosphatase determined in the emergency room in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

BACKGROUND: Elevated serum transaminase or alkaline phosphatase (ALP) has been proposed as a novel prognosticator for ST-segment elevation myocardial infarction (STEMI). We evaluated the combined prognostic impact of elevated serum transaminases and ALP on admission in STEMI patients who underwent primary percutaneous coronary intervention (PCI). METHODS: A total of 1176 patients with STEMI undergoing primary PCI were retrospectively enrolled from the INTERSTELLAR registry. Hypoxic liver injury (HLI) was defined as serum transaminase > twice the upper limit of normal. The cut-off value of high ALP was set at the median level (73 IU/L). Patients were divided into four groups according to their serum transaminase and ALP levels. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), defined as the composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, and ischemia-driven revascularization. RESULTS: Median follow-up duration was 25 months (interquartile range, 10-39 months). The rate of MACCE was highest in patients with HLI (+) and high ALP (25.9%), compared to those in the other groups (8.2% in HLI [-] and low ALP, 11.8% in HLI [-] and high ALP, and 15.0% in HLI [+] and low ALP). Each of HLI or high ALP was an independent predictor for MACCE (HR 1.807, 95% CI 1.191-2.741; HR 1.721, 95% CI 1.179-2.512, respectively). Combined HLI and high ALP was associated with the worst prognosis (HR 3.145, 95% CI 1.794-5.514). CONCLUSIONS: Combined HLI and high ALP on admission is associated with poor clinical outcomes in patients with STEMI who have undergone primary PCI.

Factors influencing insulin sensitivity during hyperinsulinemic-euglycemic clamp in healthy Korean male subjects.

Background and objective: The effects of age and related factors on insulin sensitivity have not been definitively evaluated in East Asian populations. We proposed a reference range for the glucose disposal rate (M-value) on hyperinsulinemic-euglycemic study and its association with other parameters. Methods: Healthy, non-diabetic young (n=10) and elderly (n=13) male subjects with normal body mass index were eligible for this study. Subjects who passed the oral glucose tolerance test (OGTT) underwent hyperinsulinemic-euglycemic clamp with high-dose (80 mU/m2·min) insulin infusion. Results: M-values were normalized to body weight (MBW) and fat-free mass (MFFM). Neither M-value was significantly different between age groups (P=0.458 and P=0.900, respectively). An inverse correlation was observed between MFFM and baseline insulin (r=-0.418; P=0.047), baseline C-peptide (r=-0.426; P=0.043) and OGTT 2-hour glucose (r=-0.452; P=0.030). Regarding correlations with other insulin sensitivity indices, M-values were positively associated with the Matsuda index but not with homeostasis model assessment of insulin resistance. Conclusion: Our results suggest that age is not a critical determinant of insulin sensitivity, while fasting insulin and C-peptide levels, OGTT 2-hour glucose level, and Matsuda index are predictable markers of insulin sensitivity in healthy Koreans.

Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats.

Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model.

Genetic Analysis of Multiple Endocrine Neoplasia Type 1 (MEN1) Leads to Misdiagnosis of an Extremely Rare Presentation of Intrasellar Cavernous Hemangioma as MEN1.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder characterized by the simultaneous occurrence of endocrine tumors in target tissues (mainly the pituitary, endocrine pancreas, and parathyroid glands). MEN1 is caused by mutations in the MEN1 gene, which functions as a tumor suppressor and consists of one untranslated exon and nine exons encoding the menin protein. This condition is usually suspected when we encounter patients diagnosed with tumors in multiple endocrine organs, as mentioned above. METHODS: A 65-year-old woman who underwent surgery for a pancreatic tumor (serous cystadenoma) 5 years previously was referred to our hospital due to neurologic symptoms of diplopia and left ptosis. Brain magnetic resonance imaging revealed a 3.4-cm lesion originating from the cavernous sinus wall and extending into the sellar region. It was thought to be a nonfunctioning tumor from the results of the combined pituitary function test. Incidentally, we found that she also had a pancreatic tumor, indicating the necessity of genetic analysis for MEN1. RESULTS: Genomic analysis using peripheral leukocytes revealed a heterozygous c.1621G>A mutation in the MEN1 gene that was previously reported to be either a pathogenic mutation or a simple polymorphism. We pursued a stereotactic approach to the pituitary lesion, and microscopic findings of the tumor revealed it to be an intrasellar cavernous hemangioma, a rare finding in the sellar region and even rarer in relation to oculomotor palsy. The patient recovered well from surgery, but refused further evaluation for the pancreatic lesion. CONCLUSION: There is great emphasis placed on genetic testing in the diagnosis of MEN1, but herein we report a case where it did not assist in diagnosis, hence, further discussion on the role of genetic testing in this disease is needed. Also, in cases of pituitary tumor with cranial nerve palsy, despite its low prevalence, intrasellar cavernous hemangioma could be suspected.

Evaluation of stress in korean patients with diabetes mellitus using the problem areas in diabetes-Korea questionnaire.

BACKGROUND: It is known that diabetes and stress are directly or indirectly related, and that it is important to evaluate stress in patients with diabetes. The relationship between Korean diabetics and diabetes-related stress has never been reported. The objective of this study was to develop a stress questionnaire suitable for use with Korean diabetics and to evaluate its utility. METHODS: This study subjects were 307 Korean diabetics, aged 40 to 74 years old, who visited the Department of Endocrinology and Metabolism at Gachon University Gil Hospital, Yeungnam University Medical Center, and Inha University Hospital in Korea between March 2006 and February 2008. We developed a Korean version of Polonsky's Problem Areas in Diabetes (PAID) stress questionnaire (PAID-K) and used it to assess degrees of stress in our sample of Korean patients. We evaluated the utility of the questionnaire and analyzed the relationships between clinical characteristics of the study subjects and degrees of stress. RESULTS: Cronbach's alpha for PAID-K was 0.95, and PAID-K scores were significantly correlated with Hypoglycemia Fear Survey scores (r=0.44, P<0.05) and State Trait Anxiety Inventory-6 scores (r=0.21, P<0.05). PAID-K scores were significantly higher in patients with longer durations of diabetes, patients using insulin, and female patients (P=0.02, P=0.038, and P=0.001, respectively). The score also tended to increase as HbA1c levels increased, except for very high HbA1c levels (above 11%) (P for trend<0.05). CONCLUSION: We developed the PAID-K questionnaire and demonstrated its utility to evaluate levels of stress in diabetic patients in Korea.