Gene Expression of Somatostatin Receptor (Subtype 2 & 5), Gi2 alpha and Pit-1 in GH-secreting Pituitary Adenomas / 대한내분비학회지

BACKGROUND: Mutation of Gs protein subunit (gsp oncogene), detected in about 30~40% of growth hormone (GH)-secreting pituitary tumors, is associated with an increased long-acting somatostatin analog octreotide sensitivity. However, the mRNA expression of somatostatin receptor (sst) was not changed in the GH-secreting pituitary tumor, regardless of whether they were gsp oncogene positive or negative. This suggests that the expression of genes coding for Gi2 alpha , Pit-1 and the other factors involved in the regulation of secretory activity in somatotrophs is likely to be altered in gsp oncogene positive tumors. We observed the impact of the gsp oncogene on the expression of the genes coding for Gi2 alpha, Pit-1 and sst (2&5) in GH-secreting pituitary tumors. METHODS: The GH response to octreotide was examined in 13 acromegalic patients before transsphenoidal adenomectomy. Genomic DNA and RNA were extracted from fresh frozen tumor tissues. PCR was performed to amplify and sequence the region between codon 184 and 251 that includes exons 8 and 9 of the Gs gene. Sst2, sst5, Gi2 alpha and Pit-1 mRNA levels were measured by semi-quantitative RT-PCR. RESULTS: Sst2 and sst5 mRNA transcripts were detected in all tumors (7 gsp +, 6 gsp-). The amount of sst transcripts varied considerably varied between the tumors. There were no significant differences in sex, age, tumor size, grade or basal GH levels. Pit-1 and sst2 mRNA levels were not different. In contrast, Gi2 alpha mRNA levels were significantly higher in gsp (+) while sst5 mRNA levels were higher in gsp (-). CONCLUSION: These data suggests that gsp oncogene may increase Gi2 alpha levels but decrease sst5 mRNA levels. However, Pit-1 and sst2 mRNA expression may not be affected by gsp oncogene. The increased expression of the Gi2 alpha gene might be an inhibitory compensatory response to the action of gsp oncogene.

Gene Expression of the Somatostatin Receptors, Gi2 alpha and Pit-1 alpha in GH3 Cells Permanently Transfected with a Mutant Gs alpha Gene / 대한내분비학회지

BACKGROUND: Cyclic AMP stimulates the expression of the somatostatin (SRIF) receptor (sst1-5) and human growth hormone (GH)-secreting pituitary tumors with the gsp oncogene which increases intracellular cAMP levels, and shows a good inhibitory response of the GH to SRIF. Taken together, we hypothesized that the gsp oncogene may increase the SRIF receptor expression or and factors related to the postreceptor signal transduction of the SRIF, in order to enhance its responsiveness to SRIF. To test this hypothesis, we investigated if the gsp oncogene could increase the sst1, sst2, Gi2 alpha, and pit-1 alpha gene expression in GH3 cells. METHODS: GH3 cells were permanently transfected with the plasmid expressing Gs alpha gene, where the arginine of codon 201 was replaced with histidine. Intracellular cAMP levels and GH concentrations were measured by radioimmunoassays. Gene expressions of the sst1, sst2, Gi2 alpha, and pit-1 alpha were determined by RT-PCR. RESULTS: Intracellular cAMP levels and medium GH release were increased by 1.7 and 2.7-fold in GH3 cells expressing the gsp oncogene, respectively. In GH3 cells expressing the gsp oncogene, the sst1 mRNA levels were decreased, whereas those of the sst2, Gi2 alpha and pit-1 alpha mRNA were increased. A 4-h forskolin (10 M) stimulation remarkably increased the sst1 and sst2 mRNA levels in GH3 cells expressing wild and mutant Gs alpha . However, forskolin did not affect the Gi2 alpha and pit-1 alpha mRNA levels. In contrast, SRIF (1 M, 2 h) decreased the sst2 mRNA levels only in GH3 cells expressing the gsp oncogene. CONCLUSION: These results suggest that higher expressions of sst2, Gi2 alpha, and pit-1 alpha, induced by the gsp oncogene may be a mechanism by which gsp-positive pituitary tumors show a greater response to SRIF. The discrepancy between these and in vivo results should be explored further.

The Significance of Plasma ADH in Differential Diagnosis of Central Diabetes Insipidus / 대한내분비학회지

BACKGROUND: Although the water restriction test(WRT) has been used as a standard test for the differential diagnosis of diabetes insipidus(DI), the measurement of plasma ADH concentration is also known to be useful method for differential diagnosis. Recent studies have shown that some patients with idiopathic central DI(CDI) were found to have a lesion on follow-up imaging studies. There have been no report in Korea on plasma ADH measurement for the differential diagnosis of DI, nor on follow-up imaging study of the idiopathic CDI. METHODS: We retrospectively reviewed the clinical and laboratory findings of 26 patients(12 men, 14 women, age 9-65 years) with CDI, including pituitary MRI or CT scan, who had been diagnosed with WRT and had undergone plasma ADH concentration measurement. RESULTS: 1) Clinical features of the patients with complete CDI did not differ from those of patients with partial CDI. 2) Maximal urine osmolality of complete CDI and partial CDI were 168+/-69mOsm/kg and 431+/-141mOsm/kg, respectively, and the percentage increase in the urinary osmolality after ADH injection was 209+/-149% and 29+/-17%, respectively. 3) Among the 26 patients, 10 patients had their plasma ADH measured. Nine patients in this group were diagnosed as CDI by WRT and plasma ADH concentration of the 9 was compatible for CDI. The plasma ADH level was also inappropriately low in one patient who had been diagnosed with primary polydipsia by WRT, the patient was diagnosed as partial CDI. 4) The findings of follow-up MRI revealed isolated thickening of the pituitary stalk in two cases of idiopathic CDI diagnosed initially with MRI. CONCLUSION: This study suggests that the measurement of plasma ADH can ensure a better differential diagnosis between partial CDI and primary polydipsia, and that the patients with idiopathic CDI should be examined regularly with MRI brain scan, including the pituitary gland.

The Combined Pituitary Stimulation Test in Patients Suffered from Massive Postpartum Hemorrhage / 대한내분비학회지

BACKGROUND: ackground: Sheehan's syndrome secondary to severe postpartum hemorrhage is one of the major causes of pituitary insufficiency in Korea. Most of these patients do not manifest symptoms or signs of gross endocrinopathies. Earlier detection of pituitary insufficiency is of clinical importance. The combined pituitary stimulation test that uses the four hypothalamic releasing hormones is a rapid, safe, and effective way to evaluate anterior pituitary function. However, the criteria for a normal response has not been established in Korea. METHODS: Combined anterior pituitary stimulation tests were performed on fourteen healthy women who had no history of endocrine disease. Combined tests of anterior pituitary reserve were done no forty-five patients who suffered from massive postpartum hemorrhage which required transfusing, along with subsequent shock or changing consciousness and in thirty-nine patients who experienced mild postpartum hemorrhage. RESULTS: 1) In the severe hemorrhage group, thirty-three of forty-five women (73.3%) showed blunted responses in more than one of the anterior pituitary hormones in the combined pituitary stimulation tests. However, in the mild hemorrhage group, only eighteen of thirty-nine women (46.2%) demonstrated blunted responses of more than one of the anterior pituitary hormones. 2) In the severe hemorrhage group, the TSH response was blunted in twenty-five patients (55.6%), prolactin in eleven patients (24.4%), ACTH in ten patients (22.2%), LH in ten patients (22.2%), GH in nine patients (20%), and FSH in five patients (11.1%). 3) The results of combined pituitary stimulation tests in the normal control group were different from the results of other studies. CONCLUSION: It is recommended that the women who experienced a severe postpartum hemorrhage should be evaluated by using the combined pituitary stimulation test. Moreover, criteria for a normal response to the combined pituitary stimulation test should be established in Korea.

A case of prophylthiouracil associated ANCA positive acute glomerulonephritis / 대한내과학회지

Vasculitis is a rare complication of antithyroid drugs. Recently it was reported in association with ANCA. In most cases, the ANCA was specific for myeloperoxidase. The glomerulonephritis was key clinical manifestation in majority of cases. When antithyroid drugs were discontinued, clinical disease generally improved and ANCA titers were tended to fall. We experienced a 44 year old woman who presented with gross hematuria and generalized edema, after she had been treated with prophylthiouracil for 6 week for thyrotoxicosis. Renal biopsy was done, which showed mesangial proliferative glomerulonephritis. Indirect immunoflurorescence staining showed highly positive perinuclear pattern of ANCA in her serum. Prophylthiouracil associated ANCA positive glomerulonephritis was suspected. After cessation of prophylthiouracil and administration of prednisolone, renal function recovered gradually and ANCA titers were reduced. We hereby report a case of prophylthiouracil associated ANCA positive glomerulonephritis with a brief review of literature.

Severe Nausea after Delivery

No abstract available.

Effect of Acute Hyperglycemia - and Isoproterenol - induced Hypothalamic Somatostatin Release on the Thyroid Hormone Releasing Hormone - induced Thyroid Stimulating Hormone Secretion / 대한내분비학회지

BACKGROUND: Acute hyperglycemia stimulates somatostatin (SRIH) release from the hypothalamus, and which in turn suppress growth hormone (GH) secretion and thyroid stimulating hormone (TSH) from the anterior pituitary gland. Beta-adrenergic pathway is known to stimulate the hypothalamus SRIH release. Recently, We demonstrated that isoproterenol, a beta-adrenergic agonist, had an additional suppressive effect on the suppression by glucose of GHRH-stimulated GH response. Therefore, the present study aimed to determine whether isoproterenol has an additional suppressive effect on the suppression by glucose of TRH-stimulated TSH response. METHODS: Seven healthy young men, aged 24 to 27 years, were studied. Four different TRH stimulation tests were carried out. (Test 1) TRH (Hoechst AG, Germany), 200 microgram bolus, was given intravenously at 0 minute. (Test 2) Glucose, 100 g, was given orally 30 min before TRH administration. (Test 3) Isoproterenol(Isuprel, Sanofi Winthrop, USA), 0.012 pg/kg, was infused continuously for 120 min after TRH administration. (Test 4) After pretreatment with glucose as Test 2, isoproterenol and TRH were administered as Test 3. RESULTS: Oral glucose ingestion significantly suppressed the TRH-stimulated TSH secretion. Isoproterenol infusion significantly suppressed the TRH-stimulated TSH secretion. Glucose-induced suppression of the TSH response was significantly greater than that by isoproterenol. 1soproterenol infusion after glucose pretreatment did not show any additional suppressive effect on the glucose-induced suppression of TSH response to TRH. CONCLUSION: The results suggest that isoproterenol infusion in addition to glucose pretreatment before the TRH stimulation test is not necessary for the development of stronger stimulation test for the hypothalamic somatostatin secretion.

Polymorphisms of PPARgamma2 gene in patients with type 2 diabetes mellitus and obesity / 대한내과학회지

BACKGROUND: Peroxisome proliferator activated receptor-gamma (PPAR-gamma) is a nuclear receptor that regulate adipocyte differentiation and modulate intracellular insulin-signaling events. As such, PPARgamma is a candidate gene for several human disorders including obesity and type 2 diabetes mellitus. The objective of our study was to examine the relationship between genetic variation of PPARgamma2 and diabetes and obesity in Korean subjects. METHODS: We studied 99 subjects with type 2 diabetes mellitus, 128 obesity patients and 97 controls. Screening for mutation at codon 12 and 115 of PPARgamma2 were carried out by PCR-RFLP analyses. Statistical significance was evaluated by Chi-square test. RESULTS: The allele frequency of the Pro12Ala PPARgamma2 variant were 0.05 in controls, 0.06 in type 2 diabetes group, and 0.07 in obesity group (p=0.47). Pro115Gln variant were only proline homozygote in all groups. Genotype frequencies were also similar and conformed to expectations of the Hardy-Weinberg rule. The presence of PPARgamma2 gene variant was no associated with concentrations of total cholesterol, triglyceride, HDL-cholesterol, and also with fasting glucose. CONCLUSION: We concluded that the Pro12Ala and Pro115Gln PPARgamma2 missense mutation may not be associated with type 2 diabetes mellitus and obesity in Korean patients.

Thyrotropin-releasing Hormone(TRH) Receptor Gene Expression in GH3 Cells Permanently Transfected with a Mutant Gs alpha Gene / 대한내분비학회지

BACKGROUND: Gs alpha gene mutation, that constitutively increases intracellular cAMP, is found in some acromegalic patients. It was demonstrated that increased intracellular cAMP levels suppress the expression of rat TRH receptor (TRH-R) mRNA. We previously demonstrated that transient expression of a mutant Gs alpha gene suppress the rat TRH-R gene expression in the cultured rat growth hormone-secreting tumor cell line (GH3), whereas TRH-R gene expression in adenomas with Gs alpha gene mutation (gsp oncogene) did not differ from that in tumors without the mutation. The discrepancy suggests the possibilities that the effect of permanent expression of mutant Gs alpha gene on TRH-R gene expression is different from that of transient expression of the mutant gene and hypothalamic hormones including TRH regulate the gene expression. METHODS: We investigated whether permanent expression of the mutant-type Gs alpha does not suppress the TRH receptor gene expression in GH3 cells, and whether TRH suppresses the gene expression by using reverse transcription-polymerase chain reaction (RT-PCR) and in vitro transcription. RESULTS: Permanent expression of a mutant-type Gs alpha increased basal cAMP levels up to 1.7-fold relative to the controls, whereas the wild-type cell line did not show increased cAMP levels. Permanent expression of a mutant-type Gs alpha increased TRH receptor mRNA level up to 2.8 fold compared with the controls. Treatment of the permanently transfected GH3 cells with TRH suppressed TRH-R gene expression more prominently compared to the wild type GH3 cells. CONCLUSION: These results suggest that permanent expression of mutant Gs alpha enhances the expression of TRH-R in GH-secreting pituitary tumors with gsp oncogene, but the gene expression may also be regulated by other factors including TRH.

Cytotoxic T Lymphocyte Antigen-4 (CTla-4) Polymorphism in Korean Autoimmune Thyroid Disease / 대한내분비학회지

BACKGROUND: The cause of autoimmune thyroid diseases (AITD), including Graves disease and Hashimotos thyroiditis, is largely unknown. To identify the genes responsible, most attention has been focussed on the HLA regions in the early studies. However, these studies have repeatedly shown a weak association between AITD and the HLA-DR3 in Caucasians. To understand and find out the mechanisms underlying the development of AITD, a search for non-HLA linked susceptibility genes is important. A recent study from American population have indicated an association between a polymorphism of CILA-4 gene and Graves disease. To clarify the relationship of the CTLA-4 polymorphism and AITD, the allele frequency of CTLA-4 gene from the patients with Graves disease and with Hashimotos thyroiditis in Korean papulation were analysed. METHODS: The CTLA-4 exon 1 polymorphism (49, A/G) was analysed by PCR-based, RFLP (Restriction Fragment Length Polymorphism) from 92 women and 37 men with Graves disease and 50 women and 9 men with Hashimotos thyroiditis diagnosed. Also, 287 healthy controls including 155 women and 132 men with no clinical evidence or family history of thyroid disease were enrolled. RESULTS: 1) In the group of Graves disease, there was significantly more patients with alanine homozygote (GG) than in control group (P<0.0005, RR=1.40). However, there was not significant with threonine homozygote (AA) between two groups (P=0.052). In the group of Hashimotos thyroiditis, no significant differences were found between all homozygotes and heterozygote. 2) In the group of Graves disease, there were significantly more patients with alanine homozygote (GG) (P<0.0001, RR=1.85) and significantly fewer patients with threonine homozygote (AA) than in the group of Hashimoto's thyroiditis (P<0.005, RR 0.25). CONCLUSION: Regardless of sex difference, alanine homozygote (GG) at exon 1 (codon 17) of CTLA-4 is associated with Graves disease in Korean population, which suggests genetic susceptibility is some role in the pathogenesis of Graves disease.

Effect of cilostazol on the neuropathies of streptozotocin-induced diabetic rats

OBJECTIVES: This study examined the effect of cilostazol, a potent phosphodiesterase inhibitor, on the progression of neuropathies associated with streptozotocin-induced diabetes mellitus in Sprague-Dawley rats. METHODS: Eight weeks after streptozotocin treatment, a pelleted diet containing 0.03% cilostazol (15 mg/kg body weight) was given for four weeks. Body weight, blood glucose level, motor nerve conduction velocity (MNCV), myelinated fiber density and size distribution of sciatic nerves were compared between age-matched normal rats (Group 1), control diabetic rats (Group 2) and cilostazol-treated diabetic rats (Group 3). RESULTS: Body weight was significantly reduced and blood glucose level was significantly increased in diabetic rats (Group 2 and 3) compared to normal rats. MNCV and cAMP content of sciatic nerves were significantly reduced in diabetic rats 12 weeks after streptozotocin treatment. Myelinated fiber size and density were also significantly reduced, and thickening of the capillary walls and duplication of the basement membranes of the endoneural vessels were observed in the diabetic rats. Whereas both body weight and blood glucose level of Group 3 did not differ significantly from those of Group 2, cilostazol treatment significantly increased MNCV and cAMP content of sciatic nerves in Group 3 but not to the levels observed in Group 1. MNCV positively correlated with cAMP content of sciatic nerves (r = 0.86; p < 0.001). Cilostazol treatment not only restored myelinated fiber density and size distribution but reversed some of the vascular abnormalities. CONCLUSION: These findings suggest that a reduced cAMP content in motor nerves may be involved in the development of diabetic neuropathy, and that cilostazol may prevent the progression of diabetic neuropathy by restoring functional impairment and morphological changes of peripheral nerves.

The Effect of Slow Release Lanreotide in Korean Acromegalic Ratients / 대한내분비학회지

BACKGROUND: Previous studies have shown that somatostatin analogues such as octreotide are effective in suppressing GH and IGF-I levels in acromegaly. The recent availability of slow release lanreotide could avoid the inconveniences associated with either repeated subcutaneous injections or continuous infusions. We investigated the effects of the SR-lanreotide on clinical, biochemical and safety responses in five patients with acromegaly. And we investigated whether the response of the GH level to acute adrninistration of octreotide predicts the response after 12 weeks of treatment with the SR-lanreotide and whether the identification of gsp oncogene could be used as a therapeutic and prognostic clue in treatment with the SR-lanreotide. METHODS: We studied the effects of SR-lanreotide 30 mg administered intramuscularly biweekly for 12 weeks in five Korean acromegalic patients. Subjective improvements in the clinical symptoms of acromegaly and adverse reactions were recorded. During SR-lanreotide treatment, serum GH, IGF-I and IGFBP-3 concentrations were evaluated just before the next injection of the SR-lanreotide. Before the start of SR-lanreotide therapy the sensitivity of GH secretion to the octreotide was tested by measuring the effect of the acute response to 0.1 mg intravenously on plasma GH levels followed until 6 hours after administration of octreotide. Direct polymerase chain reaction sequencing of the gsp oncogene were performed. We compared the responses to SR-lanreotide in patients harboring gsp-positive and gsp-negative somatotroph adenomas. RESULTS: The treatment with SR-lanreotide for 12 weeks could suppress the GH level by more than 50% in four of five patients and normalize the IGF-I in two patients. No correlation was found between the GH level and IGF-I level at the end of the study. The IGFBP-3 level correlated with the IGF-I level in three of five patients. Although the initial GH response to octreotide tended to correlate with the IGF-I response after SR-lanreotide treatment, the results were statistically insignificant. The patients with gsp-positive tumor tended to show a better response to SR-lanreotide. During treatment, there was a reduction in the percentage of patients complaining of joint pain, fatigue, digital paresthesia, and hyperhydrosis. Changes in soft tissue swelling were documented by decreases in finger circumference. The common adverse events were abdominal discomfort, loose stool, and diarrhea. These events were decreased progressively. No patients discontinued the treatment of SR-lanreotide due to adverse events. CONCLUSION: This study showed that SR-lanreotide is effective in controlling acromegalic symptoms as well as GH and IGF-I hypersecretion. This treatment was well tolerated and more convenient for the patients. Further studies are required for clinical outcome of long-term SR-lanreotide treatment and cost-effective analysis.

The variation of pancreatic beta-cell specific glucokinase gene promoter at the position of -30 bp in Koreans with gestational diabetes mellitus / 대한내과학회지

Glucokinase is expressed only in both liver and pancreatic beta cells and has a key role in the regulation of glucose metabolism in these tissues. A number of gene defects associated with glucokinase gene and the cause of non-insulin-dependent diabetes mellitus are known, and the defects along the -30bp promoter site in particular are thought to be related to diabetes and glucose intolerance. To research on gene study related to diabetes, we looked into the relationship between the variation at -30bp of pancreatic beta cell specific glucokinase gene promoter and gestational diabetes mellitus(GDM) in Korea. METHODS: Forty patients with GDM and 62 normal controls were studied. Genomic DNA was extracted from peripheral leukocyte of patients with GDM and normal controls. The nucleotide variation at -30 bp of pancreatic beta cell specific glucokinase gene promoter was analyzed by PCR-SSCP methods. The sequences of amplified DNA were confirmed with direct sequencing method. The clinical features and the response of insulin secretion to oral glucose were analyzed between patients with GDM according to genotypes. RESULTS: Allelic frequency of position -30 bp of pancreatic beta cell specific glucokinase gene promoter did not differ between patients with GDM and normal subjects. However the frequency of G/A and A/A genotypes seemed to show a higher tendency in patients with GDM compare to the normal subjects. Clinical features, insulin response to oral glucose did not differ according to the type of variation at -30bp of pancreatic beta cell specific glucokinase gene promoter. CONCLUSION: These data suggested that the variation at -30 bp of pancreatic beta cell specific glucokinase gene promoter in patients with GDM are unlikely to be one of the possibilities of the genetic factors in the development of GDM. Therefore more sophisticated studies will be needed to elucidate the role of variation at -30bp of pancreatic beta cell specific glucokinase gene promoter in the insulin secretion to oral glucose.

The variation of pancreatic beta-cell specific glucokinase gene promoter at the position of -30 bp in Koreans with gestational diabetes mellitus / 대한내과학회지

Glucokinase is expressed only in both liver and pancreatic beta cells and has a key role in the regulation of glucose metabolism in these tissues. A number of gene defects associated with glucokinase gene and the cause of non-insulin-dependent diabetes mellitus are known, and the defects along the -30bp promoter site in particular are thought to be related to diabetes and glucose intolerance. To research on gene study related to diabetes, we looked into the relationship between the variation at -30bp of pancreatic beta cell specific glucokinase gene promoter and gestational diabetes mellitus(GDM) in Korea. METHODS: Forty patients with GDM and 62 normal controls were studied. Genomic DNA was extracted from peripheral leukocyte of patients with GDM and normal controls. The nucleotide variation at -30 bp of pancreatic beta cell specific glucokinase gene promoter was analyzed by PCR-SSCP methods. The sequences of amplified DNA were confirmed with direct sequencing method. The clinical features and the response of insulin secretion to oral glucose were analyzed between patients with GDM according to genotypes. RESULTS: Allelic frequency of position -30 bp of pancreatic beta cell specific glucokinase gene promoter did not differ between patients with GDM and normal subjects. However the frequency of G/A and A/A genotypes seemed to show a higher tendency in patients with GDM compare to the normal subjects. Clinical features, insulin response to oral glucose did not differ according to the type of variation at -30bp of pancreatic beta cell specific glucokinase gene promoter. CONCLUSION: These data suggested that the variation at -30 bp of pancreatic beta cell specific glucokinase gene promoter in patients with GDM are unlikely to be one of the possibilities of the genetic factors in the development of GDM. Therefore more sophisticated studies will be needed to elucidate the role of variation at -30bp of pancreatic beta cell specific glucokinase gene promoter in the insulin secretion to oral glucose.

A Case of spontaneous hemorrhagic pseudocyst of adrenal gland mimicking cystic pheochromocytoma / 대한내과학회지

Cysts of the adrenal glands are uncommon and present difficult problems in differential diagnosis. In autopsy studies, the incidence of adrenal cysts is ranges from 0.064% to 0.18%. Recently, we have experienced a 22-year-old female patient with spontaneous hemorrhagic pseudocyst of adrenal gland without known cause, presenting symptoms of nausea, epigastric discomfort and intermittent pain of right upper abdomen. In clinical presentation, abdominal ultrasonogram and computerized tomogram suggest cystic degeneration of malignant pheochromocytoma, but screening hormonal evaluation was normal. Selective adrenal venous sampling, adrenal scintigram and pathologic examination were not compatible with the functioning adrenal cortical or medullary adenoma/carcinoma, the mass results in spantaneous hemorrhagic necrosis and cystic degeneratio#n of adrenal gland. The authors reported a case of spontaneous hemorrhagic pseudocyst of adrenal gland, which was successfully resected by laparoscopic excision with reviews of the literatures.

Paraoxonase Genotypes of Korean Diabetic Patients with Coronary Artery Disease or Ischemic Stroke / 대한내과학회지

OBJECTIVES: Paraoxonase is a high-density-lipoprotein- associated enzyme capable of hydrolysing lipid peroxides. Thus it might protect lipoproteins from oxidation. It has two isoforms, which arise from a glutamine (A isoform) to arginine (B isoform) interchange at position 192. More recently, Ruiz et al. investigated the relationship between the paraoxonase genetic polymorphism and coronary heart disease in a case-control study of NIDDM in France. We investigated the correlation between the polymorphism of paraoxonase gene and cardiovascular disease in Korean diabetic patients. METHODS: Of 106 patients with NIDDM, 50 had confirmed cardiovascular disease (coronary heart disease or ischemic stroke). The other 56 patients had no history of such disease and ECG abnormality. An additional control group of non-diabetic, healthy subjects (N=55) was selected. The polymorphism of paraoxonase gene was assessed by PCR-RFLP in their blood leukocytes DNA. RESULTS: The healthy control revealed paraoxonase genotype frequencies of 18.1% AA, 36.4% AB and 45.5% BB. The NIDDM group revealed paraoxonase genotype frequencies of 11.3% AA, 39.6% AB, 49.1% BB. The genotype frequencies did not differ between healthy control with diabetic group. The genotype frequencies did not differ between diabetic group with coronary heart disease and diabetic control group (AA ; 8.4% vs 12.5%, AB ; 45.8% vs 37.5%, BB ; 45.8% vs 50.0%). There was also no difference in genotype frequencies between diabetic group with ischemic stroke and diabetic control (AA ; 11.5% vs 12.5%, AB ; 38.5% vs 37.5%, BB ; 50.0% vs 50.0%). In multiple logistic regression analysis with other risk factors, hypertension emerged as the most related factors for cardiovascular disease, but paraoxonase genotype was not associated with the presence of cardiovascular disease. CONCLUSION: In Korean diabetic patients, the polymorphism of paraoxonase gene might not be associated with the presence of coronary heart disease or ischemic stroke.

Usefulness of Fibrinogen B beta 448 Polymorphism as a Marker of Cerebral Infarction in Patients with Diabetes Mellitus / 대한내과학회지

OBJECTIVES: Cerebral infarction as a macrovascular complication in patients with diabetes mellitus is frequent. However, mechanisms for the development of cerebral infarction were not well known until today. The aims of this study were 1) to determine the relationship between the fibrinogen B beta 448 polymorphism and fibrinogen levels in patients with cerebral infarction, and 2) to assess usefulness of fibrinogen B beta 448 polymorphism as a marker of cerebral infarction in patients with diabetes mellitus. METHODS: We studied 60 diabetes mellitus patients, 26 diabetes mellitus patients with cerebral infarction, 17 cerebral infarction patients, and 121 normal controls. Fibrinogen B beta 448 genotype was determined by the PCR-RFLP method using restriction enzyme Mnl I. RESULTS: Fibrinogen levels in each patient group were not significantly different from one another. Fibrinogen B beta 448 genotype frequencies of the patient groups did not significantly differ from those of the normal controls. CONCLUSION: This study didn't show the relationship between the fibrinogen B beta 448 polymorphism and fibrinogen levels in patients with cerebral infarction. Moreover, these data didn't suggest the fibrinogen B beta 448 polymorphism as a marker of cerebral infarction in patients with diabetes mellitus. Further studies are needed to find the other polymorphic sites of fibrinogen gene which can affect the levels of fibrinogen.

A Case of Multiple endocrine neoplasia type 2a / 대한내분비학회지

Multiple endocrine neoplasia type2a (MEN type2a) is a dominantly inherited cancer syndrome which is characterized by medullary thyroid carcinoma, pheochromocytoma and parathyroid hyperplasia or adenoma. Recent reports show that DNA analysis will be introduced into screening of MEN type2a families. Regular prospective screening and appropriate surgical intervention can reduce the morbidity and mortality due to MEN type2a. We experienced a case of MEN type 2a in a 46-year-old female patient. She had undergone bilateral adrenalectomy due to pheochromocytoma, followed by a total radical thyroidectomy, which revealed medullary thyroid carcinoma of the both thyroid gland and parathyroid hyperplasia.

Characteristics of gsp-Positive Growth Hormone-secreting Pituitary Tumors

A subset of human growth hormone(GH)-secreting pituitary tumors contains the gsp oncogene that encodes an activation mutation of the alpha subunit of Gsalpha, a stimulatory GTP-binding protein. The purpose of this study was to investigate the frequency of the gsp oncogene in GH-secreting pituitary tumors in Korean acromegalic patients and to elucidate the clinical reaction of these patients to endocrine testing. Direct PCR sequencing revealed gsp oncogene mutation in nine of 21 tumors(43%) at amino acid 201 of the Gsalpha protein. A single nucleotide mutation in tumors carrying the gsp oncogene was observed in eight tumors, this replaced an arginine(CGT) in normal protein with cysteine(TGT), and in one, with serine(AGT). Patients in the in whom gsp oncogene mutation occurred were older(54 years vs. 41 years, p=0.01) than those in the normal group. Sex, tumor grade, basal GH and PRL levels, GH response to oral glucose loading, GH fluctuation, and paradoxical response to TRH or GnRH did not differ between the groups : gsp oncogene was found mostly in somatotroph adenomas. Octreotide-induced GH suppression was significantly higher in the mutation group than in the normal group(95% vs. 81%, p=0.03), but the GH response to bromocriptine did not differ between the groups. These results suggest that Gsalpha mutations of GH-secreting tumors occur in Korean acromegalic patients with a similar frequency to that found in Western countries. Patients with gsp oncogene are likely to be older than those without it, and show high levels of octreotide-induced GH suppression.

Significance of beta3- adrenergic Receptor Gene Polymorphism in the Pathogenesis of NIDDM in Koreans / 대한내과학회지

OBJECTIVES: The beta3 adrenergic receptor(beta3 -AR) may play an important role in the regulation of energy expenditure and lipolysis. A mutation of the beta3 - AR gene(Trp64Arg) has been reported to be associated with early onset of non-insulin dependent diabetes mellitus(NIDDM), obesity and syndrome X which are related with insulin resistance. It is well known that Korean NIDDM patients, in contrast to Caucasians, are mainly non-obese and have experienced severe weight loss during the course of disease. We studied the frequency of the mutation in Korean NIDDM patients and non-diabetics control and evaluated the clinical characteristics of Korean obese NIDDM patients. We investigated the frequency of the mutation in NIDDM patients and clinical characteristics of the patients with the mutation in order to elucidate the significance of the mutation in the pathogenesis of NIDDM in Koreans. METHODS: We studied 401 NIDDM patients and 99 controls. The NIDDM patients were divided into two groups, non-obese group and obese group, according to their body mass index at diagnosis of the disease. The Trp64Arg mutation was detected by the PCR/RFLP method using restriction enzyme Mva I. RESULTS: The Trp64Arg allele frequency(16M) of NIDDM did not differ from that(16%) of controls. Although the mutant allele frequency was not different between non-obese and obese group both in NIDDM patients and controls, the frequency of patient with the mutant allele was significantly higher in obese NIDDM patients than in non-obese NIDDM patients(38.5% vs. 26.9%, P=0.04). However, no significant differences were found in clinical and laboratory findings between the NIDDM patients with the mutant allele and those without the mutant allele. CONCLUSION: These data suggest that beta3 -AR mutation might be associated with Korean obese NIDDM, and other factors might also be associated with the development of obesity and insulin resistance in NIDDM patients.