Takumi Kitamoto

Comparison of Cardiovascular Complications in Patients with and without KCNJ5 Gene Mutations Harboring Aldosterone-producing Adenomas

AIM Our objective was to evaluate the incidence of cardiovascular complications before and after unilateral adrenalectomy in patients with and without KCNJ5 gene mutations harboring aldosterone-producing adenoma (APA). METHODS A total of 108 APA patients were evaluated in the present study. We compared the clinical characteristics and laboratory findings according to the cardiovascular complications in the patients with or without KCNJ5 gene mutations harboring APA after excluding five APA patients with ATPase or CACNA1D gene mutations. RESULTS There were 75 and 28 APA patients with somatic mutations of KCNJ5 (p.G151R, p.L168R, p.E145Q, p.T158A or 157del) and no mutations, respectively. There were no double mutations in any of the subjects. The KCNJ5-mutated and wild type groups demonstrated similar advances in left ventricular hypertrophy prior to surgery, although the mutated group was significantly younger, with higher plasma and urine aldosterone levels, than the wild type group (48.2 vs. 55.8 (years old); p＜0.001, 436.0 vs. 247 (pg/mL); p＜0.001, 22.2 vs. 12.6 (μg/day); p=0.008). Both groups displayed postoperative improvements in hyperaldosteronism and hypertension. Moreover, the LV mass index (LVMI) significantly improved after surgery in the mutated group (p＜0.001), but not in the wild type group (p=0.256). A multiple linear regression analysis showed that an improvement in the LVMI was independently associated with KCNJ5 mutations and the plasma aldosterone level in that order (p=0.034, 0.050, respectively). CONCLUSION The present findings clearly demonstrated that KCNJ5 mutations are common among Japanese APA patients (frequency: 69.4%). In this study, the KCNJ5-mutated group demonstrated significant postoperative improvements in LVMI, possibly due to strong autonomous aldosterone production. Hence, it is necessary to precisely diagnose younger APA patients possessing a strong capacity for aldosterone production due to KCNJ5 gene mutations, as such cases may be easily complicated by cardiovascular events.

Clinicopathological study of SDHB mutation-related pheochromocytoma and sympathetic paraganglioma

Pheochromocytoma (PCC) and paraganglioma (PGL) are genetically and phenotypically heterogeneous catecholamine-producing neoplasms. They can occur sporadically or as a part of hereditary disease. Approximately 30% of PCC/PGL are believed to be caused by germline mutations (Welander et al. 2011). Of these, succinate dehydrogenase subunit B (SDHB) gene mutation is considered a high-risk factor for malignancy. Loss of heterozygosity at the SDHB locus (1p36)wasobserved inall tumorswithSDHBmutation, and Gimenez-Roqueplo et al. (2003) strongly suggested that SDHB is a tumor suppressorgene. Subsequently, loss of SDHB protein immunoreactivity in SDHB-mutated PCC/PGL (SDHB–PCC/PGL) was reported with 100% sensitivity and 84% specificity (van Nederveen et al. 2009). Thus, SDHB immunohistochemistry can be used to screen SDHB– PCC/PGL using paraffin-embedded pathological materials. SDHB mutation is the only established factor that indicates future metastasis. Therefore, it is important to analyze the histological characteristics of SDHB–PCC/PGL. It is generally accepted that it is difficult to distinguish histological differences between benign and malignant PCC/PGL. The current consensus is that a long-term follow-up is required after the surgery to screen for recurrence or metastasis in all PCC/PGL patients, regardless whether hereditary or sporadic in origin. Kimura et al. (2014) proposed a histological grading system called the Grading of Adrenal PCC and PGL (GAPP) classification for predicting metastasis. GAPP is composed of six factors: histological pattern, cellularity, presence or absence of comedo-type necrosis, vascular or capsular invasion, Ki67labeling index (%), and elevated catecholamine type. Each factor was assigned a point and the number of points was summated. Tumor scores of 0–2, 3–6, and 7–10 were classified into well differentiated (WD), moderately

Clinical and Steroidogenic Characteristics of Aldosterone-Producing Adenomas With ATPase or CACNA1D Gene Mutations

OBJECT This comparative study clarified the clinical characteristics and in vitro steroidogenic activities of aldosterone-producing adenomas (APAs) harboring ATPase or CACNA1D gene mutations. DESIGN AND PATIENTS Genetic testing was performed on 159 unilateral APAs. Somatic ATPase and CACNA1D gene mutations were analyzed in 42 APA tissues without KCNJ5 gene mutations. RESULTS ATP1A1, ATP2B3, and CACNA1D mutations were detected in one, four, and four patients, respectively. Compared with patients without KCNJ5, ATPase, or CACNA1D mutations (wild type), ATPase mutations tended to have more severe hyperaldosteronism and smaller tumors; those with CACNA1D mutations had clinical characteristics and tumor sizes similar to those with wild-type genes. APAs with ATPase mutations were composed mainly of compact eosinophilic tumor cells, whereas CACNA1D mutations resulted in predominantly clear tumor cells. Aldosterone production in APA cells with ATP2B3 mutations were more responsive to dibutyryl cAMP, whereas those with CACNA1D mutations were more responsive to adrenocorticotropic hormone than the wild-type cells. CONCLUSION APAs with ATPase mutations demonstrated a potentially severe primary aldosteronism phenotype, whereas those with CACNA1D mutations displayed characteristics similar to wild-type APAs. The status of stimulated aldosterone production was also different according to the cell types, suggesting that the regulatory effects of adrenocorticotropic hormone on aldosterone synthesis could possibly vary according to the intracellular signaling involved in hormone production.

Sitagliptin Successfully Ameliorates Glycemic Control in Werner Syndrome With Diabetes

Werner syndrome (WS) is an autosomal recessive disorder caused by a mutation in the WRN gene, and it is considered to be a representative type of progeroid syndrome (1). Patients with WS often exhibit insulin resistance, which is associated with the accumulation of visceral fat and disadipocytokinemia. We and others have previously reported that pioglitazone, a peroxisome proliferator–activated receptor γ ligand, improved glycemic control and insulin sensitivity with normalization of disadipocytokine levels in patients with WS (2,3). Here we describe a diabetic subject with WS that had good glycemic control with pioglitazone initially but worsened because of abdominal obesity and increasing visceral fat area. Sitagliptin, an inhibitor of dipeptidyl peptidase-4, was then administered, which resulted in successful improvement of …

Recent Trends in WRN Gene Mutation Patterns in Individuals with Werner Syndrome

To determine recent trends in mutation patterns in the WRN gene, which cause Werner syndrome (WS), a rare, inheritable progeroid syndrome in Japan.

Outcomes of laparoscopic sleeve gastrectomy in elderly obese Japanese patients

Laparoscopic sleeve gastrectomy (LSG) has proven to be the most effective strategy for the treatment of morbid obesity, however its efficacy and safety in an aging population has not yet been confirmed. In this study, we evaluated the effectiveness and safety of LSG in elderly obese Japanese patients.

Steroidogenic Activity of Aldosterone-Producing Adenoma with and without KCNJ5 Gene Mutations, Comparing with that in Each Adherent Normal Tissue

Introduction: The steroidogenic activity in a KCNJ5-gene mutated aldosterone-producing adenoma (APA) was reported to be much stronger than that in an APA of the wild type, while it is still controversial. Objectives: We examined whether the normal adrenal tissue attached to APA also possesses KCNJ5 gene mutations, and also investigated steroidogenic activity of mutated and non-mutated APA tissue cells with that of each normal tissue cell attached to APA in order to clarify the nature of steroidogenic activity. Methods: We selected 12 patients with and without KCNJ5 gene mutation-harboring APA in whom normal adrenal tissue adhered to the APA. We analyzed the presence of KCNJ5 gene mutations by using those tissues. Results: APA tissues of 6 patients possessed KCNJ5 gene mutations, whereas those mutations were not detected in any of the adjacent normal tissue samples as well as another 6 cases of APA. In two APA tissues with or without KCNJ5 gene mutation, we also compared the steroidogenic activity of isolated cells from each APA tissue with that from the normal adherent tissues. The cortisol production of the mutated APA cells was markedly decreased compared with that of the normal cells, suggesting that the aldosterone production pathway becomes dominant and the cortisol production pathway is downregulated in that APA tissue. Furthermore, the ratio of aldosterone to cortisol in the normal adherent tissue was about 1/4th of that of the wild-type APA tissue, while it was about 1/10th in the mutated APA. Conclusion: KCNJ5 gene mutations in the normal tissue adhering to KCNJ5 gene mutation-harboring APA was not observed, suggesting that somatic mutations of the KCNJ5 gene only occur in APA tissue. It is also suggested that KCNJ5 gene mutations dominantly induce the aldosterone production pathway as well as concomitant decline in cortisol production, resulting in highly autonomous aldosterone production.

Fasting C-Peptide Index May be the Strongest Predictor for Detecting Effectiveness of Glycemic Control by GLP-1 Analogue, Liraglutide Therapy for Japanese Type 2 Diabetic Patients

A genome-wide association study (GWAS) and subsequent replication studies in diverse ethnic groups indicate that common Niemann-Pick C1 gene (NPC1) polymorphisms are associated with morbid-adult obesity or diabetes independent of body weight. The objectives for this prospective cross-sectional study were to determine allele frequencies for NPC1 polymorphisms (644A>G, 1926C>G, 2572A>G, and 3797G>A) and association with metabolic disease phenotypes in an ethnically diverse New Mexican obstetric population. Allele frequencies for 1926C>G, 2572A>G, and 3797G>A were significantly different between race/ ethnic groups (non-Hispanic white, Hispanic, and Native American). The results also indicated a significant pairwise linkage-disequilibrium between each of the four NPC1 polymorphisms in race/ethnic groups. Moreover, the derived and major allele for 1926C>G was associated (OR 2.11, 95% CI 1.10-3.96, P = 0.022) with increased risk for maternal prepregnancy overweight (BMI 25.0-29.9kg/m2) while the ancestral and major allele for 2572A>G was associated (OR 4.68, 95% CI 1.23-17.8, P = 0.024) with increased risk for gestational diabetes in non-Hispanic whites, but not Hispanics or Native Americans. In summary, this is the first transferability study to investigate common NPC1 polymorphisms in a multiethnic population and demonstrate a differential association with increased risk for maternal prepregnancy overweight and gestational diabetes. *Corresponding Author: William S. Garver, Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA; Tel: 1-505-272-4790; Fax: 1-505-2726587; E-Mail: wgarver@unm.edu

A Case of Type 1 Diabetes With Nocturnal Hypoglycemia After Desensitization Therapy for Insulin Allergy

Antibodies against exogenously injected insulin are common with insulin treatment but seldom have serious effects on blood glucose (1). In insulin autoimmune syndrome (IAS), however, the insulin antibody causes hypoglycemia (2) in the absence of exogenous insulin treatment. Here, we report a case of type 1 diabetes with insulin antibody, whereby the patient developed nocturnal hypoglycemia after desensitization therapy for an insulin allergy. After receiving insulin therapy for 1 year, a 61-year-old man was admitted to our hospital because of an insulin allergy and poor control of diabetes. He had an itchy eruption at the insulin injection site. At the time of admission, the patient presented with an HbA1c level of 16.2% (154 mmol/mol); anti-GAD antibody 80.0 U/L (<1.5 U/mL); serum C-peptide level 0.01 ng/mL after glucagon injection (fasting 0.67–2.48 ng/mL); and insulin-specific IgE 41.5 UA/mL (<0.34 …