Effects of esaxerenone on blood pressure, urinary albumin excretion, serum levels of NT-proBNP, and quality of life in patients with primary aldosteronism.

Primary aldosteronism (PA) is typically managed with mineralocorticoid receptor antagonists (MRAs) barring adrenalectomy. The efficacy of esaxerenone, a nonsteroidal MRA, were explored in patients with PA. Various parameters such as the urinary albumin to creatinine ratio (UACR) and serum levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were evaluated in 25 PA patients before and 3 and 6 months after esaxerenone treatment. Systolic and diastolic blood pressure (BP), and the estimated glomerular filtration rate decreased after treatment, while serum levels of potassium and active renin increased. Significant reductions were observed in UACR 3 and 6 months after treatment. A significant decrease in NT-proBNP was evident at 6 months but not 3 months after treatment. Correlation analysis indicated that the reductions in BP and UACR at 3 months were independent of estimated daily salt intake. Furthermore, the effect of esaxerenone treatment on lowering UACR and NT-proBNP levels was independent of BP reduction. Responders whose systolic BP decreased 6 months after esaxerenone treatment by more than 10 mmHg compared to pretreatment had higher pretreatment NT-proBNP and similar UACR before and after treatment when compared with nonresponders. Esaxerenone improved mental, physical, and social quality of life (QOL) 6 months after treatment compared to healthy controls and increased over time. No patients discontinued treatment due to severe hyperkalemia or renal dysfunction. In conclusion, esaxerenone is a safe and effective MRA for PA treatment, offering significant benefits in terms of hypertension, albuminuria, NT-proBNP levels, and QOL improvement. Esaxerenone effectively lowers BP, UACR, and serum levels of NT-proBNP independent of dietary salt intake in mild PA patients. ARC active renin concentration, DBP diastolic blood pressure, MR mineralocorticoid receptor, MRA mineralocorticoid receptor antagonist, NT-proBNP N-terminal pro-brain natriuretic peptide, PA primary aldosteronism, QOL quality of life, SBP systolic blood pressure, SF-36 Medical Outcomes Study 36-Item Short-Form Health Survey, UACR urinary albumin to creatinine ratio.

Associations of Diabetic Retinopathy Severity With High Ambulatory Blood Pressure and Suppressed Serum Renin Levels.

CONTEXT: The relationships between serum renin levels, severity of diabetic retinopathy (DR), and 24-hour blood pressure (BP) have not been previously reported. OBJECTIVE: To explore causes for DR and the relationships of 24-hour ambulatory BP, and hormone levels with the severity of DR. METHODS: The diabetic patients were classified as having no DR, simple DR, or severe DR (preproliferative DR plus proliferative DR) based on funduscopic examination, and we measured 24-hour BP, serum active renin (ARC), aldosterone (SAC), adrenocorticotropic hormone, and cortisol levels in each group. RESULTS: Compared to those with no DR or simple DR, patients with severe DR showed significantly higher 24-hour BPs, including daytime and nighttime systolic and diastolic BP levels, independent of diabetic duration and HbA1c levels. The variability of nighttime systolic BP was greater in patients with severe DR than in those with nonsevere DR, although nocturnal BP reduction was similar between the groups. The ambulatory BPs were significantly inversely associated with ARC. The ARC was significantly lower in severe DR patients than in those with no DR or simple DR (3.2 [1.5-13.6] vs 9.8 [4.6-18.0] pg/mL, P < .05), but there were no differences in SAC in patients taking calcium channel blockers and/or α-blockers. No associations were found between DR severity and other hormone levels. CONCLUSION: Severe DR was associated with higher 24-hour BPs and suppressed ARC. These findings suggest that mineralocorticoid receptor overactivation may play a role in higher BP levels and severe DR in diabetic patients.

Pitfalls in the diagnosis and treatment of a hypertensive patient with unilateral primary aldosteronism and contralateral pheochromocytoma: a case report.

BACKGROUND: Primary aldosteronism (PA) is a common cause of secondary hypertension, whereas pheochromocytoma is a rare cause of it. Thus, concomitant PA and pheochromocytoma is a very rare condition. CASE PRESENTATION: A 52-year-old woman was admitted to our hospital with suspected PA based on the presence of hypertension, spontaneous hypokalemia, and a high aldosterone-to-renin ratio. She had no catecholamine excess symptoms other than hypertension. Abdominal computed tomography (CT) showed a right lipid-rich adrenal mass and a left lipid-poor adrenal mass. PA was diagnosed by the captopril challenge test. The 24-h urinary fractionated metanephrines were slightly elevated. Adrenal vein sampling (AVS) confirmed that the right adrenal gland was responsible for aldosterone hypersecretion. Medical therapy with eplerenone was started because the patient refused surgery. Five years later, she requested surgery for PA. The second AVS confirmed right unilateral hyperaldosteronism, as expected. Repeated abdominal CT showed the enlargement of the left adrenal mass. The 24-h urinary fractionated metanephrines had risen to the diagnostic level. 123I- metaiodobenzylguanidine (MIBG) scintigraphy showed a marked tracer uptake in the left adrenal mass with no metastatic lesion. After preoperative management with α-blockade, laparoscopic left partial adrenalectomy was performed. Immunohistochemical examination of the tumor showed chromogranin A positivity leading to the diagnosis of left pheochromocytoma. CONCLUSIONS: We report an extremely rare case of concomitant unilateral PA and contralateral pheochromocytoma. When diagnosing unilateral PA by AVS, especially in cases with a lipid-poor adrenal mass, clinicians should rule out the possibility of the presence of pheochromocytoma before proceeding to undergo unilateral adrenalectomy. Although there is no standard treatment for this rare condition, it is essential to select personalized treatment from the perspective of conserving the adrenal gland.

Importance of dietary salt restriction for patients with primary aldosteronism during treatment with mineralocorticoid receptor antagonists: The potential importance of post-treatment plasma renin levels.

We measured dietary salt intake in 26 patients with primary aldosteronism treated with mineralocorticoid receptor antagonists and evaluated whether plasma renin levels were affected by dietary salt intake pre-treatment and post 6 months of mineralocorticoid receptor antagonist treatment. The dietary salt intake level was calculated using spot urine sodium and creatinine concentrations, body weight, height, and age. The clinical parameters pre- and post- treatment were compared. The systolic and diastolic blood pressure levels decreased, and the serum potassium and active renin concentration increased significantly. Although the dietary salt intake did not change after treatment, the differences in dietary salt intake and active renin concentration pre- and post- treatment were inversely correlated (r = -0.418, p = 0.03). The 26 patients were divided into two groups with active renin concentration levels ≥5 pg/mL (Group 1) and <5 pg/mL (Group 2) after treatment. The Group parameters did not differ pre- and post- treatment. Group 1 evidenced improvements in systolic and diastolic blood pressures, and the potassium level and active renin concentration over time; Group 2 did not. Group 1 evidenced no significant correlation between the differences in dietary salt intake and active renin concentration levels (r = -0.481, p = 0.11) but Group 2 showed a strong inverse correlation (r = -0.7599, p = 0.01). In conclusion, we found that an active renin concentration level <5 pg/mL post-mineralocorticoid receptor antagonist treatment may indicate that salt sensitivity has not adequately improved, emphasizing the importance of measuring plasma renin levels after such treatment.

The Effectiveness of GLP-1 Receptor Agonist Semaglutide on Body Composition in Elderly Obese Diabetic Patients: A Pilot Study.

BACKGROUND AND OBJECTIVES: This study aimed to investigate the changes in obesity severity, glucose metabolism, and body composition in patients with obesity and type 2 diabetes mellitus treated with glucagon-like peptide 1 receptor agonist (GLP1-RA) semaglutide. MATERIALS AND METHODS: Body weight (BW), metabolic parameters, and body composition were examined before and 3 months after semaglutide administration. The mass of body fat (FM), fat weight percentage (%FM), mass of skeletal muscle (MM), skeletal MM percentage (%MM), and limb muscles were measured using the bioelectrical impedance method. RESULTS: Semaglutide dramatically reduced the weight, the body mass index (BMI), and the levels of the glucose metabolic markers, including fasting blood glucose and hemoglobin A1c, and accelerated the loss of excess BW. FM, MM, and %FM after semaglutide treatment also decreased. Conversely, semaglutide had no effect on the %MM after 3 months. In limb muscle analyses, right upper and lower leg muscle percentages, left upper and lower leg muscles, and the ratios of the lower/upper muscles were maintained by semaglutide treatment. CONCLUSIONS: These results suggest that the GLP1-RA semaglutide effectively reduces body adiposity while maintaining the MM in obese type 2 diabetic patients.

Changes of Short-Chain Fatty Acids and Their Receptors in an Obese Rat Model After Sleeve Gastrectomy.

BACKGROUND: Short-chain fatty acids (SCFAs) and gut microbiota have health-related effects and are associated with a wide range of disorders. However, the changes of SCFAs and their receptors after sleeve gastrectomy (SG) remain unclear. This study aimed to examine changes of SCFAs and their receptors after SG in an obese rat model. METHODS: Thirty obese Sprague-Dawley rats eating a high-energy diet for 6 weeks were divided into three groups: sham-operated (SO) control, pair-fed (PF) control, and SG group. Six weeks after the surgery, metabolic parameters, SCFA levels in the blood and stool, mRNA and protein expression of SCFA receptors in the ileum and epididymal fat, and gut microbiota were examined. RESULTS: Metabolic parameters in the SG group were significantly improved compared with the SO group. Acetic acid levels in the blood and stool were significantly higher in the SG group than the PF group. The butyric acid level in the stool was also significantly higher in the SG group than in the PF group. In the ileum and epididymal fat, mRNA and protein expression of GPR41 was significantly higher in the SG group than in the other two groups, and mRNA and protein expression of GPR43 was significantly higher in the SG group than in the PF group. Increases in the genera Enterococcus, Lactobacillus, Lactococcus, and Clostridium were observed in the stool after SG. CONCLUSIONS: SG may activate SCFA pathways through a change in gut microbiota.

Re-Assessment of the Oral Salt Loading Test Using a New Chemiluminescent Enzyme Immunoassay Based on a Two-Step Sandwich Method to Measure 24-Hour Urine Aldosterone Excretion.

Since April 2021, the plasma aldosterone concentration has been measured by chemiluminescent enzyme immunoassay (CLEIA) in Japan. In the present study, we developed a new CLEIA using a two-step sandwich method to measure the 24-hour urine aldosterone level. We collected 115 urine samples and measured 24-hour urine aldosterone levels employing radioimmunoassay (RIA), CLEIA, and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results showed that the 24-hour urine aldosterone levels measured using CLEIA and LC-MS/MS were significantly correlated (ρ = 0.992, P < 0.0001). Based on the results of Passing-Bablok regression analysis, the slope was 0.992 and the intercept -19.3. The 24-hour urine aldosterone levels measured using CLEIA and RIA were also significantly correlated (ρ = 0.905, P < 0.0001). However, the aldosterone level measured by CLEIA was lower than that measured by RIA (slope, 0.729; intercept, 120.9). In Japan, a new guideline for primary aldosteronism has been announced, with changes in the aldosterone measurement method. The cutoff values for oral sodium loading test (OSLT) were changed, but clinical verification using real-world urine samples has not been performed. Therefore, we examined the cut-off value of the 24-hour urine aldosterone level after the OSLT. Receiver operating characteristic analysis revealed a cut-off value for primary aldosteronism of 3 µg/day.

Comprehensive lipidomics of lupus-prone mice using LC-MS/MS identifies the reduction of palmitoylethanolamide that suppresses TLR9-mediated inflammation.

Lipid mediators are known to play crucial roles not only in the onset of the inflammatory response but also in the induction of resolution of inflammation. Here, we report that palmitoylethanolamide (PEA), an endogenous N-acylethanolamine, can suppress the inflammation induced by Toll-like receptor (TLR) signaling both in vitro and in vivo. PEA was found to be significantly reduced in the serum and spleen of lupus-prone MRL/lpr mice analyzed by lipidomics. PEA suppressed pro-inflammatory cytokine production in a mouse macrophage cell line stimulated with TLR ligands such as lipopolysaccharide, peptidoglycan, poly (I:C), imiquimod, and CpG-ODN. PEA also inhibited both mRNA and protein levels of IL-6 in bone marrow-derived dendritic cells (BMDCs) and B cells stimulated with CpG-ODN. Augmentation of cell surface CD86 and CD40 on BMDCs and B cells, IgM production, and cell proliferation of B cells in response to CpG-ODN were attenuated by PEA. Moreover, PEA treatment significantly reduced mortality and serum IL-6 levels in mice injected with CpG-ODN plus D-galactosamine. Taken together, PEA ameliorates inflammation induced by TLR signaling, which could be a novel therapeutic target for inflammatory disorders.

Glucagon-Like Peptide-1 Receptor Agonist Semaglutide Improves Eating Behavior and Glycemic Control in Japanese Obese Type 2 Diabetic Patients.

We evaluated time-course changes and the relationship between eating behavior and glycemic profile during the treatment of 34 obese type 2 diabetic patients with the glucagon-like peptide-1 receptor agonist (GLP1-RA) semaglutide. Changes in dietary habits were evaluated using the Japan Society for the Study of Obesity questionnaire. Semaglutide improved body weight and hemoglobin A1C (HbA1c) 3 and 6 months after treatment. In addition, semaglutide led to marked improvements in the total scores for eating behavior items on the questionnaire. In particular, changes in the scores regarding the sensation of hunger, food preference, eating style, regularity of eating habits and emotional eating behavior were significantly improved during semaglutide treatment. By contrast, there were no significant changes in the scores for the recognition of weight and constitution and external eating behavior. Furthermore, changes in the scores regarding the sensation of hunger and food preference were correlated with changes in HbA1c after semaglutide treatment. Multivariable regression analyses showed that the change in the sensation of hunger was related to HbA1c during treatment. In conclusion, the GLP1-RA semaglutide regulates eating behavior, and, in particular, the sensation of hunger is closely related to the improvement in HbA1c by semaglutide in obese patients with type 2 diabetes.

Adrenal Vein Sampling With Gadolinium Contrast Medium in a Patient With Florid Primary Aldosteronism and Iodine Allergy.

We describe a 35-year-old woman who was allergic to iodine contrast medium and was diagnosed with primary aldosteronism (PA) based on functional confirmatory tests. She was suspected to have unilateral PA because of marked hypertension, spontaneous hypokalemia, high plasma aldosterone, reduced plasma renin activity, and a right hypodense adrenal tumor. She wanted to become pregnant and requested adrenalectomy instead of medical treatment with mineralocorticoid receptor antagonists. Localization of PA by adrenal vein sampling (AVS) was necessary, but angiography with iodine contrast medium was not possible because of her allergy. AVS was performed using gadolinium contrast agent (gadoterate meglumine) instead of iodine, in combination with computed tomography angiography (CTA). In AVS, before and after adrenocorticotropin (ACTH) loading, 12 blood samples were drawn from the right adrenal vein, left adrenal central vein, left adrenal common duct, left and right renal veins, and the lower inferior vena cava with only 5 mL of gadolinium medium. There were no complications during AVS. Examination revealed an elevated aldosterone/cortisol ratio on the right side, lateralized ratio of 7.4, and contralateral ratio of 0.76; the patient was diagnosed with right unilateral PA. She underwent right adrenalectomy and showed improvements in aldosterone level from 312.4 pg/mL to 83.0 pg/mL, potassium from 3.0 mEq/L to 3.9 mEq/L, and systolic blood pressure from 138 mm Hg to 117 mm Hg. In PA patients with iodine allergy, AVS can be performed safely and precisely using gadolinium contrast combined with CTA.

Dopamine-Secreting Pheochromocytoma and Paraganglioma.

Predominantly or exclusively dopamine-secreting pheochromocytoma and paraganglioma are very rare. We report a 64-year-old woman with an adrenal incidentaloma. She was normotensive and had no symptoms of catecholamine excess. The 24-hour urine catecholamine level showed normal norepinephrine (122.9 µg/day), normal epinephrine (24.3 µg/day), and markedly elevated dopamine (148 212.4 µg/day). 123I-metaiodobenzylguanidine (MIBG) scintigraphy revealed tumor uptake. After α-blockade as preoperative management, she successfully underwent laparoscopic left adrenalectomy and was finally diagnosed with an exclusively dopamine-secreting pheochromocytoma. The tumor was histologically comprised of small polygonal cells with high cellularity and was immunohistochemically positive for all 3 catecholamine-synthesizing enzymes: tyrosine hydroxylase (very weak), dopamine ß-hydroxylase (heterogeneous), and phenylethanolamine N-methyltransferase (very weak). Electron microscopy revealed very few catecholamine-containing small vesicles with a few organelles, which reflected immature cells. No biochemical or imaging evidence of recurrence or metastasis were evident 1 year after the surgery. We conducted a literature search in the PubMed database. A total of 33 cases were collected. Our case had the second-highest 24-hour urinary dopamine excretion and was the first in which immunostaining for catecholamine synthase and electron microscopy were performed together. Histological findings in our case give a possible hypothesis that the mechanism underlying a dopamine-secreting pheochromocytoma is associated with immature catecholamine vesicles in which dopamine ß-hydroxylase is localized, thus resulting in inhibited conversion from dopamine to norepinephrine. We also discuss the reasons for the lack of catecholamine excess symptoms, whether preoperative management of α-blockade is needed, and the association between the prognosis and genetic mutation, with an extensive literature review.

Development of a New Chemiluminescent Enzyme Immunoassay Using a Two-Step Sandwich Method for Measuring Aldosterone Concentrations.

In the present study, we developed a new chemiluminescent enzyme immunoassay (CLEIA) using a two-step sandwich method to measure aldosterone concentrations. We investigated serum and plasma aldosterone concentrations in 75 blood samples from 27 patients using a radioimmunoassay (RIA) and the CLEIA (with current and newly improved reagents) as well as liquid chromatography-tandem mass spectrometry (LC-MS/MS). Based on the results of the Passing-Bablok regression analysis, the aldosterone levels measured using CLEIA with the new reagents and those measured by LC-MS/MS were found to be significantly correlated (slope, 0.984; intercept, 0.2). However, aldosterone levels varied depending on the measurement method (i.e., CLEIA with the new reagent, CLEIA with the current reagent, and RIA). Aldosterone levels were lower with the improved CLEIA method than with RIA and CLEIA using the current reagent. Therefore, the cutoff values of the screening test as well as those of the confirmatory test for primary aldosteronism (PA) should be adjusted to follow current clinical practice guidelines for PA. The formula that can be used to obtain the aldosterone level (pg/mL) when using CLEIA with the new reagent is 0.765 × RIA (pg/mL) - 33.7. This formula will enable PA cutoff values to be set for provisional screening and confirmatory tests.

Quality of Life of Primary Aldosteronism Patients by Mineralocorticoid Receptor Antagonists.

CONTEXT: Although primary aldosteronism (PA) reduces quality of life (QOL), there have been no reports on whether treatment with a mineralocorticoid receptor antagonist (MRA) improves QOL in Japanese PA patients. OBJECTIVE: Using the 36-Item Short-Form Health Survey (SF-36), we compared the QOL of PA patients before and after treatment and evaluated whether the effectiveness of MRAs differs by sex and serum potassium level. METHODS: In 50 patients diagnosed with PA (with or without hypokalemia) and treated with an MRA, the SF-36 scores, blood pressure, and clinical features were assessed before, and 3 and 6 months after treatment. Separate analyses were also conducted for males and females. RESULTS: The normative mean SF-36 score of the healthy subjects was 50. The pretreatment Role-Physical (RP) (46.7 ± 1.8, P = .019), General Health (47.1 ± 1.3, P = .042), and Role-Emotional (47.2 ± 1.7, P = .045) SF-36 subscale scores of all PA patients were significantly lower than those of healthy subjects but were improved by MRA treatment. Females with PA had a lower RP score (45.1 ± 2.2, P = .008), which was not improved by MRA treatment (46.1 ± 2.4, P = .036). In addition, PA patients with hypokalemia had a lower Mental Health SF-36 subscale score (43.2 ± 4.4, P = .041), which was improved by treatment with an MRA. CONCLUSION: MRAs improved the QOL of Japanese PA patients, but female PA patients may be more resistant to MRAs.

α-Tocopherol suppresses hepatic steatosis by increasing CPT-1 expression in a mouse model of diet-induced nonalcoholic fatty liver disease.

AIM: Antioxidant therapy for with vitamin E appears to be effective for the treatment of nonalcoholic fatty liver disease　(NAFLD). However, the mechanism of action and optimal therapeutic dosage is unclear. The present study was undertaken to examine whether the effects of α-tocopherol (α-Toc) on NAFLD are dose-dependent in a diet-induced obese model. METHODS: Male mice were fed standard chow, high-fat (HF) diet, HF diet with low-dose, or with high dose of α-Toc supplementation. Histological findings, triglyceride content, and the levels of protein expression related to fatty acid synthesis/oxidation such as carnitine palmitoyltransferase I (CPT-1) of liver were evaluated. In addition, 2-tetradecylglycidic acid (TDGA), a CPT-1 inhibitor, was administered to mice fed HF diet with low-dose of α-Toc. Finally, HepG2 cells in fat-loaded environment were treated with 0-50 µM α-Toc. RESULTS: Treatment of low-dose of α-Toc decreased HF-induced hepatic fat accumulation, but this finding was not observed in treatment of high dose of α-Toc. HF-induced reduction of CPT-1 was attenuated with low-dose of α-Toc but not with high dose of α-Toc. TDGA suppressed the improvement of histological findings in liver induced by low-dose of α-Toc treatment. CPT-1 expression in HepG2 cells increased in response to low-dose of α-Toc, but not in high dose. CONCLUSIONS: Dual action of α-Toc on CPT-1 protein levels was observed. The effect of vitamin E on NAFLD may be not be dose-dependent.

Supplementation of branched-chain amino acids decreases fat accumulation in the liver through intestinal microbiota-mediated production of acetic acid.

Non-alcoholic fatty liver disease (NAFLD) is a significant problem because its prevalence is increasing worldwide. Recent animal studies have identified gut microbiota as a potentially important player in the pathogenesis of NAFLD. Previously, we reported that the administration of branched-chain amino acids (BCAAs) reduces hepatic fat accumulation in experimental animal models. This study aimed to clarify how changes in the intestinal microbial flora following the administration of BCAAs affect a high-fat diet (HF)-induced fat accumulation in the liver. We examined whether the administration of BCAAs alters the development of hepatic fat accumulation as well as intestinal microbial flora. The oral administration of BCAAs (3% kcal) induced a significant increase in Ruminococcus flavefaciens (R. flavefaciens) and portal acetic acid levels, and it reduced hepatic fat accumulation in HF-fed rats. In addition, BCAAs reduced the expression of the lipogenesis-related genes FAS and ACC in the liver. Furthermore, we observed that R. flavefaciens is essential for promoting a BCAA-induced reduction in hepatic fat accumulation. These data suggest that BCAA treatment induces the proliferation of intestinal flora including R. flavefaciens and that portal acetic acid synthesized from intestinal flora improves NAFLD by downregulating the expression of FAS and ACC in the liver.

Oral Salt Loading Test is Associated With 24-Hour Blood Pressure and Organ Damage in Primary Aldosteronism Patients.

OBJECTIVE: In the present study, we investigated the most useful confirmatory test for reflecting the severity of primary aldosteronism (PA), by evaluating 24-hour blood pressure (BP), urine albumin, left ventricular mass (LVM), and intima media thickness (IMT). METHODS: This study included 113 patients (80 PA and 33 non-PA hypertensive patients) who were admitted to Oita University Hospital and evaluated using ambulatory blood pressure monitoring (ABPM). First, casual blood pressure (BP) and ABPM parameters were compared between PA and non-PA patients. Second, patients were divided into PA-positive and PA-negative groups based on confirmatory tests, including the saline infusion test (SIT), captopril challenge test (CCT), and oral salt loading test (OSLT), and casual BP and ABPM parameters were compared between the 2 groups. In addition, urine albumin excretion, LVM, and maximum IMT as markers of organ damage were compared between the 2 groups. RESULTS: The ABPM parameters but not casual BP, were higher in PA patients than in non-PA patients. Nocturnal and 24-hour systolic BP (SBP) in OSLT-positive patients were significantly higher than in OSLT-negative patients. ABPM parameters in other confirmatory tests were not different between the PA-positive and PA-negative groups. Urine albumin excretion in OSLT-positive patients was significantly higher than in the OSLT-negative patients. However, in other confirmatory tests, organ damage markers were not different between the 2 groups. CONCLUSION: The OSLT is potentially useful not only for the diagnosis of PA but also for assessment of 24-hour SBP and organ damage, as indicated by urine albumin excretion.

Relationships between computed tomography-assessed density, abdominal fat volume, and glucose metabolism after sleeve gastrectomy in Japanese patients with obesity.

In this study, we investigated the relationships between body weight (BW), computed tomography (CT)-assessed abdominal adipose tissue, and the glycemic metabolic profile in obese Japanese patients following laparoscopic sleeve gastrectomy (LSG). This study analyzed adipose tissue compartments using CT methods before and 1 year after LSG. Thirty obese patients were studied, and variables measured included visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), density of VAT (VAT-D), and density of SAT (SAT-D). We also examined the parameters in patients according to whether they had type-2 diabetes (T2DM). LSG induced significant losses in BW, SAT, and VAT after LSG. Additionally, SAT-D and VAT-D both increased and fasting plasma glucose (FPG) and HbA1c, but not C-peptide, decreased after surgery. ΔSAT and ΔVAT were positively related, and ΔSAT-D and ΔVAT-D were negatively related to ΔBW and/or FPG. Furthermore, a multivariate regression model showed that total BW loss (TBWL) was closely related to ΔSAT (ß = 0.84; p < 0.001) and ΔVAT-D (ß = -0.45; p < 0.05) and improvement of FPG was related to ΔVAT (ß = 0.61; p < 0.05) after LSG. Finally, ΔFPG was correlated with ΔVAT in 16 T2DM patients (r = 0.58; p < 0.05) but not in non-T2DM patients. TBWL was related to ΔSAT and ΔVAT-D, and improvement of FPG was related to ΔVAT in obese Japanese patients after LSG.

Synonymous but Not Silent: A Synonymous VHL Variant in Exon 2 Confers Susceptibility to Familial Pheochromocytoma and von Hippel-Lindau Disease.

CONTEXT: von Hippel-Lindau (VHL) disease, comprising renal cancer, hemangioblastoma, and/or pheochromocytoma (PHEO), is caused by missense or truncating variants of the VHL tumor-suppressor gene, which is involved in degradation of hypoxia-inducible factors (HIFs). However, the role of synonymous VHL variants in the disease is unclear. OBJECTIVE: We evaluated a synonymous VHL variant in patients with familial PHEO or VHL disease without a detectable pathogenic VHL mutation. DESIGN: We performed genetic and transcriptional analyses of leukocytes and/or tumors from affected and unaffected individuals and evaluated VHL splicing in existing cancer databases. RESULTS: We identified a synonymous VHL variant (c.414A>G, p.Pro138Pro) as the driver event in five independent individuals/families with PHEOs or VHL syndrome. This variant promotes exon 2 skipping and hence, abolishes expression of the full-length VHL transcript. Exon 2 spans the HIF-binding domain required for HIF degradation by VHL. Accordingly, PHEOs carrying this variant display HIF hyperactivation typical of VHL loss. Moreover, other exon 2 VHL variants from the The Cancer Genome Atlas pan-cancer datasets are biased toward expression of a VHL transcript that excludes this exon, supporting a broader impact of this spliced variant. CONCLUSION: A recurrent synonymous VHL variant (c.414A>G, p.Pro138Pro) confers susceptibility to PHEO and VHL disease through splice disruption, leading to VHL dysfunction. This finding indicates that certain synonymous VHL variants may be clinically relevant and should be considered in genetic testing and surveillance settings. The observation that other coding VHL variants can exclude exon 2 suggests that dysregulated splicing may be an underappreciated mechanism in VHL-mediated tumorigenesis.