Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2)

Background/Aims@#Germline mutations of the rearranged during transfection (RET) gene cause multiple endocrine neoplasia type 2 (MEN2). About 85% of RET mutations in MEN2 occur in codon Cys634. The RET D631Y mutation has recently been discovered, and we have studied its molecular expression and clinical consequences. @*Methods@#We analyzed the clinical characteristics of a total of 34 D631Y variant MEN2 individuals from seven families. We also constructed wild-type and mutant C630Y, D631Y, and C634R/W expression vectors and investigated their effects on signaling pathways and ability to correct the phenotypes of RET mutant cells. @*Results@#The median ages at diagnosis of pheochromocytoma and medullary thyroid carcinoma (MTC) were higher in patients with RET D631Y variant MEN2 than in those with the C634R/W variant (49:53.5 years vs. 33.5:27 years, respectively), and the penetration of the D631Y mutation with respect to MTC was lower than that of the C634R/W mutation (32.3% vs. 90%). The effects of the mutant vectors on phosphorylation of RET signaling molecules and focus formation were significantly different from those of wild type, but there were no significant differences between the mutants. D631Y scored significantly higher for chemotaxis and wound healing than C630Y, but lower than C634R and C634W. @*Conclusions@#We suggest that the tumorigenic potential conferred by the D631Y mutation is lower than that conferred by the C634R/W mutation, but higher than that conferred by C630Y. Thus, the risk level of the RET D631Y variant appears to be higher than that of C630Y and lower than that of C634R/W.

Comparison of the Effects of Various Antidiabetic Medication on Bone Mineral Density in Patients with Type 2 Diabetes Mellitus

Background@#Prospective comparative studies on the effects of various antidiabetic agents on bone metabolism are limited. This study aimed to assess changes in bone mass and biochemical bone markers in postmenopausal patients with type 2 diabetes mellitus (T2DM). @*Methods@#This prospective, multicenter, open-label, comparative trial included 264 patients with T2DM. Patients who had received a metformin, or sulfonylurea/metformin combination (Group 1); a thiazolidinedione combination (Group 2); a dipeptidyl peptidase-4 inhibitor (gemigliptin) combination (Group 3); or an sodium-glucose cotransporter 2 inhibitor (empagliflozin) combination (Group 4) were prospectively treated for 12 months; bone mineral density (BMD) and bone turnover marker (BTM) changes were evaluated. @*Results@#The femoral neck BMD percentage changes were −0.79%±2.86% (Group 1), −2.50%±3.08% (Group 2), −1.05%±2.74% (Group 3), and −1.24%±2.91% (Group 4) (P<0.05). The total hip BMD percentage changes were −0.57%±1.79% (Group 1), −1.74%±1.48% (Group 2), −0.75%±1.87% (Group 3), and −1.27%±1.72% (Group 4) (P<0.05). Mean serum BTM (C-terminal type 1 collagen telopeptide and procollagen type 1 amino-terminal propeptide) levels measured during the study period did not change over time or differ between groups. @*Conclusion@#Significant bone loss in the femoral neck and total hip was associated with thiazolidinedione combination regimens. However, bone loss was not significantly associated with combination regimens including gemigliptin or empagliflozin. Caution should be exercised during treatment with antidiabetic medications that adversely affect the bone in patients with diabetes at a high risk of bone loss.

Comparison of the Effects of Various Antidiabetic Medication on Bone Mineral Density in Patients with Type 2 Diabetes Mellitus

Background@#Prospective comparative studies on the effects of various antidiabetic agents on bone metabolism are limited. This study aimed to assess changes in bone mass and biochemical bone markers in postmenopausal patients with type 2 diabetes mellitus (T2DM). @*Methods@#This prospective, multicenter, open-label, comparative trial included 264 patients with T2DM. Patients who had received a metformin, or sulfonylurea/metformin combination (Group 1); a thiazolidinedione combination (Group 2); a dipeptidyl peptidase-4 inhibitor (gemigliptin) combination (Group 3); or an sodium-glucose cotransporter 2 inhibitor (empagliflozin) combination (Group 4) were prospectively treated for 12 months; bone mineral density (BMD) and bone turnover marker (BTM) changes were evaluated. @*Results@#The femoral neck BMD percentage changes were −0.79%±2.86% (Group 1), −2.50%±3.08% (Group 2), −1.05%±2.74% (Group 3), and −1.24%±2.91% (Group 4) (P<0.05). The total hip BMD percentage changes were −0.57%±1.79% (Group 1), −1.74%±1.48% (Group 2), −0.75%±1.87% (Group 3), and −1.27%±1.72% (Group 4) (P<0.05). Mean serum BTM (C-terminal type 1 collagen telopeptide and procollagen type 1 amino-terminal propeptide) levels measured during the study period did not change over time or differ between groups. @*Conclusion@#Significant bone loss in the femoral neck and total hip was associated with thiazolidinedione combination regimens. However, bone loss was not significantly associated with combination regimens including gemigliptin or empagliflozin. Caution should be exercised during treatment with antidiabetic medications that adversely affect the bone in patients with diabetes at a high risk of bone loss.

Body Fat Is Related to Sedentary Behavior and Light Physical Activity but Not to Moderate-Vigorous Physical Activity in Type 2 Diabetes Mellitus

Background@#Sedentary behavior (SB) has emerged as a new risk factor for cardiovascular accidents. We investigated whether physical activity levels or SB were related to percent body fat (%BF) in type 2 diabetes mellitus (T2DM). @*Methods@#In this cross sectional study, we measured the duration of SB, light physical activity (LPA), moderate to vigorous physical activity (MVPA), total energy expenditure, and step counts using a wireless activity tracker (Fitbit HR; FB) for 7 days in freeliving conditions, along with %BF using a bio impedance analyzer (Inbody; Biospace) in 120 smartphone users with T2DM. Subjects were divided into exercise (Exe, n=68) and non-exercise (nonExe, n=52) groups based on self-reports of whether the recommended exercises (30 min/day, 3 days/week for 3 months) were performed. SBt, LPAt, MVPAt were transformed from SB, LPA, MVPA for normally distributed variables. @*Results@#Participants were: female, 59.2%; age, 59.3±8.4 years; body mass index, 25.5±3.4 kg/m2; glycosylated hemoglobin (HbA1c), 7.6%±1.2%; %BF, 30.4%±7.1%. They performed SB for 15.7±3.7 hr/day, LPA for 4.4±1.7 hr/day, and MVPA for 0.9±0.8 hr/day. The %BF was related to SBt and LPAt, but not to MVPA after adjustments for age, gender, and HbA1c. VPA was significantly higher in the Exe group than in the nonExe group, but SB, LPA, and moderate physical activity were not different. Predicted %BF was 89.494 to 0.105 (age), –13.047 (gender), –0.507 (HbA1c), –7.655 (LPAt) (F[4, 64]=62.929, P<0.001), with an R2 of 0.785 in multiple linear regression analysis. @*Conclusion@#Reduced body fat in elderly diabetic patients might be associated with reduced inactivity and increased LPA.

Blood Tests for the Diagnosis of Adrenal Diseases / 대한내과학회지

No abstract available.

Functional Identification of Compound Heterozygous Mutations in the CYP17A1 Gene Resulting in Combined 17α-Hydroxylase/17,20-Lyase Deficiency

BACKGROUND: We previously reported a patient with congenital adrenal hyperplasia (CAH) with compound heterozygous mutations in the cytochrome P450 17A1 (CYP17A1) gene. One allele had a p.His373Leu and the other a new p.Glu383fsX36 mutation. The aim of this study was to investigate the functional properties of a new allele present in a compound heterozygote of CYP17A1. METHODS: To understand how p.His373Leu and p.Glu383fsX36 affect P450c17 enzymatic activity, wild type and mutant CYP17A1 cDNAs were cloned into flag-tagged pcDNA3 vector and introduced into human embryonic kidney cells 293T (HEK293T) cells. Protein expression levels of CYP17A1 were then analyzed. And the activities of 17α-hydroxylase and 17,20-lyase of CYP17A1 were evaluated by measuring the conversion of progesterone to 17α-hydroxyprogesterone and of 17α-hydroxypregnenolone to dehydroepiandrosterone, respectively. In addition a computer model was used to create the three-dimensional structure of the mutant CYP17A1 enzymes. RESULTS: Production of the p.His373Leu mutant protein was significantly lower than that of the wild type protein, and the p.Glu383fsX36 protein was hardly produced. Similarly the enzymatic activity derived from the p.His373Leu mutant vector was significantly lower than that obtained from the wild type vector, and little activity was obtained from the p.Glu383fsX36 vector. Three-dimensional modeling of the enzyme showed that p.His373 was located in region important for heme-binding and proper folding. Neither the p.His373Leu nor the p.Glu383fsX36 mutant protein formed a heme-binding structure. CONCLUSION: Enzyme activity measured in both mutants disappeared completely in both 17α-hydroxylase and 17,20-lyase. This result accounts for the clinical manifestations of the patient with the compound heterozygous CYP17A1 mutations.

Mutation of the NF1 Gene and the Associated Clinical Features in Family Members with Neurofibromatosis Type 1 / 대한내과학회지

With an incidence of 1 per 2,500-3,000 individuals, neurofibromatosis type 1 (NF1) is the most common autosomal dominant disorder in humans. NF1 is caused by germline mutations of the NF1 gene, but to date genotype-phenotype analyses have indicated no clear relationship between specific gene mutations and the clinical features of this disease, even among family members with the same mutation. The present study describes a case of two siblings with NF1 with the same genetic mutation but different clinical manifestations. The first patient was a female with iris Lisch nodules, an adrenal incidentaloma, Graves' disease, and skin manifestations, while the second patient, the first patient's younger brother, exhibited only skin neurofibromas and freckling. Further study is needed to reveal the molecular processes underlying gene expression and phenotypes. A better understanding of the genetics associated with NF1 will allow clinicians to detect complications earlier and provide better genetic counseling to NF1 families.

A novel PRKAR1A mutation resulting in a splicing variant in a case of Carney complex

No abstract available.

Protective Effect of Heme Oxygenase-1 on High Glucose-Induced Pancreatic beta-Cell Injury

BACKGROUND: Glucose toxicity that is caused by chronic exposure to a high glucose concentration leads to islet dysfunction and induces apoptosis in pancreatic beta-cells. Heme oxygenase-1 (HO-1) has been identified as an anti-apoptotic and cytoprotective gene. The purpose of this study is to investigate whether HO-1 up-regulation when using metalloprotophyrin (cobalt protoporphyrin, CoPP) could protect pancreatic beta-cells from high glucose-induced apoptosis. METHODS: Reverse transcription-polymerase chain reaction was performed to analyze the CoPP-induced mRNA expression of HO-1. Cell viability of INS-1 cells cultured in the presence of CoPP was examined by acridine orange/propidium iodide staining. The generation of intracellular reactive oxygen species (ROS) was measured using flow cytometry. Glucose stimulated insulin secretion (GSIS) was determined following incubation with CoPP in different glucose concentrations. RESULTS: CoPP increased HO-1 mRNA expression in both a dose- and time-dependent manner. Overexpression of HO-1 inhibited caspase-3, and the number of dead cells in the presence of CoPP was significantly decreased when exposed to high glucose conditions (HG). CoPP also decreased the generation of intracellular ROS by 50% during 72 hours of culture with HG. However, decreased GSIS was not recovered even in the presence of CoPP. CONCLUSION: Our data suggest that CoPP-induced HO-1 up-regulation results in protection from high glucose-induced apoptosis in INS-1 cells; however, glucose stimulated insulin secretion is not restored.

A case of ectopic Cushing's syndrome combined with papillary thyroid carcinoma / 대한내과학회지

Locating a corticotropin-releasing hormone (CRH)- or adrenocorticotropic hormone (ACTH)-secreting tumor is challenging. A 69-year-old woman admitted to our hospital for generalized edema was diagnosed with ectopic Cushing's syndrome. We attempted to find an ectopic tumor and could establish no ectopic focus except a retropharyngeal mass in the neck. We diagnosed the retropharyngeal mass as thyroid papillary carcinoma and examined whether the thyroid papillary carcinoma was the ectopic focus. No relationship between thyroid papillary carcinoma and ectopic Cushing's syndrome has been established. We failed to find another ectopic focus, except for the increased uptake of the retropharyngeal mass on fluorodeoxyglucose positron emission tomography (FDG-PET). Ectopic Cushing's syndrome combined with thyroid papillary carcinoma is very rare, so we report this case along with reviews of related literatures.

A non-functioning pituitary macroadenoma detected incidentally with PET-CT / 대한내과학회지

Whole-body positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (18F-FDG) is a tomographic imaging technique that uses a radiolabeled analog of glucose, 18F-FDG, to image relative glucose uptake rates in various tissues. Since the glucose uptake is increased in many malignancies, 18F-FDG PET is a sensitive method for detecting, staging, and monitoring the effects of therapy on many malignancies. However, it is uncommon to discover an asymptomatic non-functioning pituitary tumor unexpectedly as a hypermetabolic lesion in PET studies. Here, we report a pituitary tumor that was detected incidentally by FDG-PET and ultimately turned out to be a non-functioning pituitary macroadenoma.

Average Daily Risk Range-Index of Glycemic Variability-Related Factor in Type 2 Diabetic Inpatients / 당뇨병

BACKGROUND: It is known that chronic sustained hyperglycemia and its consequent oxidative stress causes diabetic complication in type 2 diabetes. It has been further proven that glycemic variability causes oxidative stress. The aim of this study is to measure the average daily risk range (ADDR)-index of glycemic variability, and to evaluate relevant variables. METHODS: We measured the blood glucose level of type 2 diabetic patients who were treated with multiple daily injections from January to July, 2008. The blood glucose levels were checked four times a day for 14 days and were conversed according to the ADRR formula. The degree of glycemic variability was categorized into non-fluctuation and fluctuation groups. We collected patient data on age, sex, duration of diabetes, body mass index, HOMA(IR), HOMA(betacell) and HbA1c. RESULTS: A total of 97 patients were enrolled in this study. The mean age, duration of diabetes, HbA1c and mean ADRR were 57.6 +/- 13.4, 11.5 +/- 8.5 years, 10.7 +/- 2.5%, and 26.6 +/- 9.8, respectively. We classified 18.5% of the patients to the non-fluctuation group, and 81.5% to the fluctuation group. ADRR was significantly correlated with duration of diabetes, fasting and postprandial glucose, fructosamine, HbA1c and BMI and HOMAbetacell. In addition, this study confirmed that BMI, HOMAbetacell and HbA1c were ADRR-related independent variables. CONCLUSION: ADRR can be used as an index for blood glucose fluctuation in type 2 diabetic patients. Measuring ADRR in patients with low BMI and a long duration of diabetes is helpful to improve the effectiveness of their care.

Idiopathic hypoparathyroidism: A rare cause of reversible heart failure / 대한내과학회지

A 65-year-old woman presented with acute pulmonary edema, generalized tetany, and paresthesia. She had severe hypocalcemia, a low intact parathyroid hormone level, and her echocardiogram revealed left ventricular dysfunction. She had no history of heart failure or thyroid surgery. The heart failure improved after calcium replacement and conventional heart failure management. She was diagnosed with hypocalcemia-induced heart failure caused by idiopathic hypoparathyroidism. Despite the crucial role of calcium in myocardial contractility, hypocalcemia is rarely reported as a cause of heart failure. In conclusion, plasma calcium should be measured in the initial workup of all patients with heart failure, and corrected if hypocalcemia is seen. Idiopathic hypoparathyroidism is a rare cause of reversible heart failure that should be considered in the etiologic assessment.

Treatment of Type 1 Diabetes through Genetically Engineered K-cell Transplantation in a Mouse Model / 당뇨병

BACKGROUND: K-cells function as targets for insulin gene therapy. In a previous study, we constructed EBV-based plasmids expressing rat preproinsulin controlled by glucose-dependent insulinotropic polypeptide promoters. In the present study, we attempted to correct hyperglycemia in vivo using genetically engineered K-cells in a mouse model of type 1 diabetes. METHODS: K-cells expressing insulin were transplanted under the kidney capsules of STZ-induced diabetic mice. The blood glucose levels and body weights of the experimental animals were measured daily. After four weeks, the mice were injected intra-peritoneally with 2 g/kg glucose following a 6 hr fast. Blood glucose levels were measured immediately following glucose injections. All animals were sacrificed at the end of the glucose tolerance study, and pancreas and graft-bearing kidney tissue samples were stained with antibodies against insulin, glucagon, and C-peptide. RESULTS: The body weights of K-cell-transplanted diabetic mice increased after transplantation, whereas those of untreated diabetic control mice continued to decline. The blood glucose levels of K-cell-transplanted diabetic mice decreased gradually during the two weeks following transplantation. After intra-peritoneal injection of glucose into K-cell-transplanted diabetic mice, blood glucose levels increased at 30 minutes, and were restored to the normal range between 60 and 90 minutes, while untreated control diabetic mice continued to experience hyperglycemia. Kidney capsules containing transplanted K-cells were removed, and sections were stained with anti-insulin antibodies. We detected insulin-positive cells in the kidney capsules of K-cell-transplanted diabetic mice, but not in untreated control mice. CONCLUSION: We detected glucose-dependent insulin secretion in genetically engineered K-cells in a mouse model of type 1 diabetes. Our results suggest that genetically modified insulin producing K-cells may act as surrogate beta-cells to effectively treat type 1 diabetes.

Transdifferentiation of Enteroendocrine K-cells into Insulin-expressing Cells / 당뇨병

BACKGROUND: Despite a recent breakthough in human islet transplantation for treating type 1 diabetes mellitus, the limited availability of donor pancreases remains a major obstacle. Endocrine cells within the gut epithelium (enteroendocrine cells) and pancreatic beta cells share similar pathways of differentiation during embryonic development. In particular, K-cells that secrete glucose-dependent insulinotropic polypeptide (GIP) have been shown to express many of the key proteins found in beta cells. Therefore, we hypothesize that K-cells can be transdifferentiated into beta cells because both cells have remarkable similarities in their embryonic development and cellular phenotypes. METHODS: K-cells were purified from heterogeneous STC-1 cells originating from an endocrine tumor of a mouse intestine. In addition, a K-cell subclone expressing stable Nkx6.1, called "Kn4-cells," was successfully obtained. In vitro differentiation of K-cells or Kn4-cells into beta cells was completed after exendin-4 treatment and serum deprivation. The expressions of insulin mRNA and protein were examined by RT-PCR and immunocytochemistry. The interacellular insulin content was also measured. RESULTS: K-cells were found to express glucokinase and GIP as assessed by RT-PCR and Western blot analysis. RT-PCR showed that K-cells also expressed Pdx-1, NeuroD1/Beta2, and MafA, but not Nkx6.1. After exendin-4 treatment and serum deprivation, insulin mRNA and insulin or C-peptide were clearly detected in Kn4-cells. The intracellular insulin content was also increased significantly in these cells. CONCLUSION: K-cells are an attractive potential source of insulin-producing cells for treatment of type 1 diabetes mellitus. However, more experiments are necessary to optimize a strategy for converting K-cells into beta cells.

Incidence of Diabetic Foot and Associated Risk Factors in Type 2 Diabetic Patients: A Five-year Observational Study / 당뇨병

BACKGROUND: The frequency of lower extremity amputation due to diabetic foot has been increasing in type 2 diabetic patients. The aim of this study was to observe the incidence, clinical aspects and associated risk factors for diabetic foot. METHODS: We evaluated the incidence of diabetic foot through a five-year observation of type 2 diabetic patients who presented to St. vincent's Hospital between January and December 2003. To identify the risk factors for diabetic foot, we evaluated mean glycosylated hemoglobin A1c (HbA1c) every six months and assessed renal function based on the existence of proteinuria and estimated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) equation. Patients were also evaluated for retinopathy, peripheral neuropathy and autonomic neuropathy using Ewing's method. RESULTS: From an initial pool of 613 patients, the observational study of 508 patients (82.9%) was completed. The mean age, duration of diabetes and HbA1c were 50.3 +/- 10.6 yrs, 7.2 +/- 6.5 yrs and 8.8 +/- 2.1%, respectively. Diabetic foot occurred in 32 patients (6.3%). The incidence of diabetic foot increased when diabetic retinopathy (OR = 6.707, 2.314~19.439), peripheral neuropathy (OR = 2.949, 1.075~8.090), and autonomic neuropathy (OR = 3.967, 1.476~10.660) were present and when the MDRD GFR (OR = 5.089, 1.712~15.130) decreased. Mean HbA1c (OR = 12.013, 1.470~98.179) was found to be an independent risk factor for diabetic foot. CONCLUSION: The present study confirmed the importance of intensive glycemic control and the role of autonomic dysfunction in the development of diabetic foot. In addition, diabetic retinopathy and impaired renal function proved to be factors associated with the occurrence of diabetic foot. Therefore, intensive glycemic control, as well as periodic examination of renal function, are essential for the prevention of diabetic foot.

A case of Addison's disease due to tuberculosis: pathologic confirmation by laparoscopic biopsy / 대한내과학회지

Addison's disease is a rare disorder that is characterized by primary adrenal hypofunction and the underlying causes are various according to geographic regions. In order to establish an appropriate therapeutic regimen to treat adrenal insufficiency associated with Addison's disease, knowledge of the underlying adrenal abnormality is essential. We report a case of a 37-year-old man who showed biochemical evidence of adrenocortical insufficiency without signs of tuberculosis. Computed tomography showed bilateral adrenal enlargement and definitive diagnosis of adrenal tuberculosis was established by laparoscopic biopsy.

A case of adrenocortical adenoma clinically mimicking pheochromocytoma / 대한내과학회지

The coexpression of cortical and medullary features in a single adrenal cortical cell has been recognized, leading to terms such as cortico-medullary cells. Here, we reported a case of adrenocortical adenoma consisting of cortico-medullary cells that clinically mimicked pheochromocytoma. A 52-year-old woman was admitted to our hospital complaining of an 8-month history of paroxysmal palpitation with refractory hypertension. A 24-hour urine study revealed increased norepinephrine and metanephrine levels. Computed tomography of the abdomen revealed a 1.0x0.9-cm mass in the left adrenal gland. The patient subsequently underwent unilateral laparoscopic adrenalectomy for a presumptive pheochromocytoma. Light microscopic findings of the left adrenal mass indicated an adrenocortical adenoma, but electron microscopy identified lipid vacuoles and smooth endoplasmic reticulum, along with dense core neurosecretory granules, so-called cortico-medullary cells. This is the first report of the detection of cortico-medullary cells in adrenocortical adenoma presenting as pheochromocytoma in Korea.

A Case of Atypical McCune-Albright Syndrome Associated with Hyperthyroidism / 대한내분비학회지

McCune-Albright syndrome (MAS) is a sporadic disease that's characterized by polyostotic fibrous dysplasia, cafe-au-lait pigmentation of the skin, and multiple endocrinopathies, including sexual precocity, hyperthyroidism, acromegaly, and hypercortisolism. Recent evidence has shown that the clinical manifestations are caused by a postzygotic activating missense mutation in the gene coding for the alpha-subunit of Gs protein that stimulates c-AMP formation in the affected tissues. Substitution of the Arg(201) residue in Gsalpha with cysteine or histidine have been identified in many MAS patients and Arg(201) to Gly or Leu mutations have also been recently identified. We identified the Arg(201) to His mutation in the gene encoding Gsalpha in the thyroid tissue from a 36-year-old man who was suffering with polyostotic fibrous dysplasia and hyperthyroidism.

Primary aldosteronism due to unilateral adrenal hyperplasia: report of a case and review of the literature / 대한내과학회지

Unilateral adrenal hyperplasia (UAH) is a rare, surgically correctable subset of primary aldosteronism. It has similar clinical features to aldosterone-producing adenoma (APA), but different pathologic finding. We report a case of UAH in a 51-year-old Korean man. The patient had hypertension. Hypokalemia and suppressed plasma renin activity (PRA) with elevated plasma aldosterone concentration (PAC) was observed. The 1.5 cm-sized nodule in left adrenal gland was scanned by abdominal computed tomography (CT). The selective adrenal venous sampling for determinations of PAC showed an overfunctioning left adrenal gland, and laparoscopic left adrenalectomy was performed. Pathologically, 1.3 cm-sized nodular hyperplasia lesion was observed. Hypokalemia, hypertension, and endocrine data were corrected after surgery, and there was no sign of recurrence for eight months after surgery. Clinical features of UAH are also reviewed.