Clinical significance of colonoscopy before laparoscopic bariatric/metabolic surgery in Japanese patients.

PURPOSE: Obesity is known to be associated with colorectal adenoma (CRA) and colorectal cancer (CRC); yet colonoscopy is not considered an essential preoperative evaluation before bariatric/metabolic surgery. The aim of this study was to clarify the clinical significance of preoperative colonoscopy for obese Japanese patients. METHODS: The subjects of this retrospective study were 114 patients who underwent screening colonoscopy before bariatric/metabolic surgery. Multivariate analyses were performed to evaluate the independent predictors of CRA/CRC among the characteristics identified as significant or nearly significant by univariate analyses. RESULTS: Colonoscopy revealed abnormal findings indicating the need for biopsy or polypectomy in 20 of the 114 patients (17.5%), and CRA was diagnosed in 13 patients (11.4%). Three patients (2.6%), who were all ≥ 56 years old, had a CRA ≥ 10 mm in diameter. The multivariate analysis showed that older age and male sex were significant predictors of CRA/CRC, which was identified in 46.2% of the male patients aged ≥ 46 years. CONCLUSION: Our findings suggest that older age and male sex may be risk factors for CRA/CRC in obese Japanese candidates for bariatric/metabolic surgery; thus, preoperative colonoscopy should be considered for these high-risk 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.

Factors Associated with Relapse of Type 2 Diabetes Mellitus after Laparoscopic Sleeve Gastrectomy in Japanese Subjects: A Subgroup Analysis of J-SMART Study.

INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) for morbidly obese patients often results in remission of type 2 diabetes (T2DM), but diabetes relapses in some of those patients. The frequency of T2DM relapse in Asians and the factors involved have not been adequately investigated. METHODS: The J-SMART study was conducted on 322 Japanese subjects with body mass index (BMI) ≥32 kg/m2 who underwent LSG at 10 accredited centers in Japan between 2011 and 2014. Of these, 82 T2DM subjects with diabetes in complete or partial remission at 1 year after LSG and followed postoperatively for 5 years were included in the subgroup analysis and classified into two groups: diabetes remission-maintained and diabetes relapse. RESULTS: The mean age of all included subjects was 49.2 years, median BMI was 41.5 kg/m2, and median HbA1c was 6.7%. Compared with the diabetes remission-maintained group, the diabetes relapse group at 5 years after LSG had significantly higher preoperative HbA1c, number of antidiabetic medications, and high-density lipoprotein cholesterol level; and lower BMI and homeostasis model assessment-beta cell function (HOMA-ß). As many as 83.0% of the subjects were able to achieve HbA1c <7% at 5 years after LSG, but 26.8% of the subjects had diabetes relapse. Preoperative HbA1c significantly contributed to diabetes relapse (odds ratio 1.54, p = 0.049). In addition, the diabetes relapse group tended to have lower percentage total weight loss (%TWL) at 1 year after LSG and higher percentage weight regain (%WR) from postoperative nadir weight, compared with the diabetes remission-maintained group. The hazard ratio for diabetes relapse was 3.14-fold higher in subjects with %TWL ≥20% and %WR ≥25%, and 5.46-fold higher in those with %TWL <20% and %WR ≥25%, compared with %TWL ≥20% and %WR <25%. CONCLUSION: While LSG provides a high remission rate for T2DM, relapse is not uncommon. Preoperative HbA1c, poor weight loss, and excess weight regain after LSG contribute to diabetes relapse, suggesting the importance of treatment strategies focusing on these factors.

Characteristics of Childhood Onset and Post-Puberty Onset Obesity and Weight Regain after Laparoscopic Sleeve Gastrectomy in Japanese Subjects: A Subgroup Analysis of J-SMART.

INTRODUCTION: The psychosocial background of subjects with severe obesity developed from childhood onset obesity (CO) and their outcomes after bariatric surgery have not been fully investigated. METHODS: 305 subjects were enrolled in the J-SMART study, which examined the effects of laparoscopic sleeve gastrectomy (LSG) in Japan, and categorized into two groups: CO defined as onset up to 13 years of age (CO group) and post-puberty onset obesity defined as onset after 13 years of age (PPO group). The subjects were followed up for at least 2 years and up to 5 years after LSG. Changes in physical parameters and remission of obesity-related comorbidities were assessed at 2 years after LSG. Weight regain (WR) was also assessed by evaluating the nadir weight after LSG and maximum weight thereafter during follow-up period. RESULTS: The mean postoperative follow-up period was 3.0 ± 1.1 years. 40.0% of the subjects had CO and these subjects had higher BMI and HOMA-ß and lower age, HbA1c, HDL cholesterol, and visceral/subcutaneous fat area ratio compared to those with PPO. The CO group was also characterized by having higher rates of mental retardation, developmental disorders, and obesity in either parent and lower rate of marriage compared to the PPO group. Two years after LSG, there were no differences in total weight loss and remission rates of diabetes, dyslipidemia, and sleep apnea syndrome between the two groups, although remission rate of hypertension was higher in the CO group. The CO group also had a higher rate of WR after LSG than the PPO group, with CO, BMI, mental disorder, and binge eating contributing to WR. CONCLUSION: This study suggests that CO might be associated with genetic and psychosocial factors. CO and PPO probably differ in pathogenesis and may require different treatment strategies.

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.

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.

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.

Predictors of early withdrawal from follow-up visits after laparoscopic sleeve gastrectomy in a Japanese institution.

PURPOSE: Postoperative weight loss is related to postoperative adherence to follow-up after bariatric/metabolic surgery, but many patients stop attending follow-up visits early. The aim of this study was to clarify predictors of early withdrawal from follow-up after laparoscopic sleeve gastrectomy (LSG) in a Japanese institution. METHODS: One hundred and fifty-three patients who underwent LSG were retrospectively included in this study. Multivariate analysis was performed to evaluate independent predictors of withdrawal from follow-up visits within 12 months after LSG among significant or nearly significant factors in the univariate analyses. The discrimination power of significant factors was estimated using area under the receiver operating characteristic curve (AUC). RESULTS: Within 12 months after LSG, 25 of the 153 patients withdrew from follow-up visits. The multivariate analysis showed that age was the only significant predictor of withdrawal. The AUC for age was 0.685, and the cut-off value was < 40 years. The younger patients (< 40 years old) had a significantly higher rate of withdrawal compared with the older patients (≥ 40 years) (27.0% vs. 8.9%). CONCLUSION: Older Japanese patients (≥ 40 years old) may be better candidates for LSG. We consider it significant to continue to emphasize the importance of follow-up visits in younger patients after LSG.

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.

Background characteristics and diabetes remission after laparoscopic sleeve gastrectomy in Japanese patients with type 2 diabetes stratified by BMI: subgroup analysis of J-SMART.

AIM: The J-SMART study was the first national survey of Japanese patients undergoing laparoscopic sleeve gastrectomy (LSG). We performed a subgroup analysis of J-SMART focusing on the differences in patient background and diabetes remission between patients with BMI 32-34.9 kg/m2 and those with higher BMI. METHODS: In this multi-institutional retrospective study at 10 certified bariatric institutions, 203 Japanese with type 2 diabetes (T2D) and BMI of 32 kg/m2 or higher were analyzed (mean age: 49.2 years, BMI: 43.8 kg/m2, HbA1c: 7.6%). Patients were stratified into five groups according to preoperative BMI. RESULTS: Background characteristics in BMI 32.0-34.9 group were higher adjusted HbA1c, higher visceral/subcutaneous fat area ratio, higher prevalence of diabetic retinopathy, higher frequency of insulin use and lower serum C-peptide. Although 2-year percent total weight loss (21.7%) and diabetes complete remission (CR) rate (52.4%) were lower in BMI 32.0-34.9 group, diabetes improvement rate was 81.0%, and the decrease in HbA1c and number of antidiabetic drugs were comparable or greater than those with higher BMI. Higher BMI and no insulin use were significant independent predictors of diabetes CR. No significant independent predictor was identified for diabetes improvement. CONCLUSION: The patients with 32-34.9 kg/m2 were characterized by more severe visceral obesity, T2D and the complications, and lower intrinsic insulin secretion capacity. LSG should be considered as a treatment option for patients with BMI 32-34.9 kg/m2, to improve diabetes control.

Endoscopic intragastric balloon therapy for 15 years in Japan: Results of nationwide surveys.

INTRODUCTION: Endoscopic intragastric balloon (IGB) placement has been performed in Japan since 2004. The nationwide surveys were repeatedly carried out to confirm the effectiveness and safety of IGB in Japan. We herein present the accumulated results. METHODS: Twenty-six Japanese endoscopists personally imported products of the BioEnterics Intragastric Balloon (BIB)/Orbera system after completing the training courses in Japan. Mail surveys were posted to them every 2 years from 2010. This study included the accumulated data of the six surveys, and excluded data from non-Japanese patients and the Orbera365 data. RESULTS: Between 2004 and 2019, 399 obese Japanese patients underwent IGB treatment using the BIB/Orbera system. The incidence rates of early removal of IGB within 1 week and complications due to IGB were 4.8% and 6.1%, respectively. The average percent excess weight loss (%EWL) and percent total weight loss (%TWL) at IGB removal were 46.6% and 11.5%, and successful weight loss, defined as %EWL ≥ 25% or %TWL ≥ 10%, was achieved in 65.6% or 54.5% of the patients, respectively. Multivariate analyses revealed that older age and larger saline filling volume were independent predictors of successful weight loss. At 1 year after IGB removal, successful weight loss defined by the %EWL and %TWL was maintained in 44.7% and 34.1% of the patients, respectively. CONCLUSION: IGB therapy using the BIB/Orbera system has been safely and effectively performed in Japan. The successful weight loss may be associated with older age and larger saline filling volume.

Background characteristics and postoperative outcomes of insufficient weight loss after laparoscopic sleeve gastrectomy in Japanese patients.

AIM: Laparoscopic sleeve gastrectomy (LSG) is becoming popular in Japan, but insufficient weight loss is often observed in patients after LSG. We investigated the effect of LSG on obesity-related comorbidities and identified the background characteristics of Japanese patients with insufficient weight loss after LSG. METHODS: In this multi-institutional retrospective study at 10 certified bariatric institutions, 322 Japanese patients who underwent LSG with a follow-up period of more than 2 years were analyzed. Anthropometry, obesity-related comorbidities and psychosocial background data were collected. Weight loss was expressed as 2-year percent total weight loss (%TWL). RESULTS: Mean age, body weight, body mass index (BMI) and glycated hemoglobin were 46.9 years, 119.2 kg, 43.7 kg/m2 and 7.1%, respectively. Prevalence of mental disorders was 26.3%. Mean BMI declined to 30.3 kg/m2 at 2 years and %TWL was 29.9%. Improvements in the markers and prevalence of obesity-related comorbidities were observed. Remission rates of diabetes, dyslipidemia and hypertension were 75.6%, 59.7% and 41.8%, respectively. %TWL at the respective cut-off level of diabetes remission was 20.8%. Lower remission rates of diabetes in patients with %TWL <20%, and less calorie restriction and higher prevalence of mental disorders (46.9%) in patients with %TWL <15% were observed. Frequencies of %TWL <15% and <20% were 6.5% and 18.5%, respectively. CONCLUSION: %TWL 20% was a candidate cut-off point of insufficient weight loss for diabetes remission after LSG, and mental disorders might be relevant to intractable obesity in Japanese patients.

Analysis of amino acid profiles of blood over time and biomarkers associated with non-alcoholic steatohepatitis in STAM mice.

The changes in free amino acid (AA) levels in blood during the progression from non-alcoholic steatohepatitis (NASH) to hepatocellular carcinoma (HCC) are unclear. We investigated serum AA levels, along with biochemical and histological events, in a mouse model of NASH. We induced NASH in male C57BL/6J mice with a streptozotocin injection and high-fat diet after 4 weeks of age (STAM group). We chronologically (6, 8, 10, 12, and 16 weeks, n=4-12 mice/group) evaluated the progression from steatohepatitis to HCC by biochemical and histological analyses. The serum AA levels were determined using an AA analyzer. Serum aspartate aminotransferase and alanine aminotransferase levels were higher in the STAM group than in the normal group (non-NASH-induced mice). Histological analysis revealed that STAM mice had fatty liver, NASH, and fibrosis at 6, 8, and 10 weeks, respectively. Moreover, the mice exhibited fibrosis and HCC at 16 weeks. The serum branched-chain AA levels were higher in the STAM group than in the normal group, especially at 8 and 10 weeks. The Fischer ratio decreased at 16 weeks in the STAM group, with increasing aromatic AA levels. These results suggested that this model sequentially depicts the development of fatty liver, NASH, cirrhosis, HCC, and AA metabolism disorders within a short experimental period. Additionally, serum amyloid A was suggested to be a useful inflammation biomarker associated with NASH. We believe that the STAM model will be useful for studying AA metabolism and/or pharmacological effects in NASH.

Improvement of non-alcoholic fatty liver disease after laparoscopic sleeve gastrectomy in Japanese obese patients.

PURPOSE: The purpose of this study was to evaluate changes in non-alcoholic fatty liver disease (NAFLD) after laparoscopic sleeve gastrectomy (LSG) using computed tomography (CT) images. METHODS: We analyzed data from 57 patients who underwent LSG and had CTs performed before and after surgery. The patients included 34 women and 23 men (with an average age of 43 years); their mean preoperative weight and body mass index were 120 kg and 46 kg/m2, respectively. Obesity-related health disorders included type 2 diabetes mellitus (T2DM) in 33 patients, hypertension in 33 and dyslipidemia in 32. We diagnosed NAFLD in cases with liver to spleen ratios (L/S ratio) <0.9 on non-contrast CT images. We evaluated changes in body weights, BMIs, comorbidities, metabolic parameters, L/S ratios, and liver volumes after surgery. RESULTS: The mean interval between CT scans before and after surgery was 26 months. The total weight loss and % excess weight loss were 35 kg and 72%, respectively. The remission rates for T2DM, hypertension, and dyslipidemia were 85%, 76% and 84%, respectively. After LSG, the L/S ratio increased in all the patients, while all except for one had L/S ratio >0.9. We diagnosed 33 out of 57 patients (58%) as having NAFLD before the operation. After the operation, the L/S ratios and liver volumes were not statistically different between the patients with previous NAFLD and those without it. CONCLUSION: Laparoscopic sleeve gastrectomy is an effective treatment for obesity-related health disorders including NAFLD in Japanese obese patients.

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.

Effects of Sleeve Gastrectomy on Blood Pressure and the Renal Renin-Angiotensin System in Rats with Diet-Induced Obesity.

OBJECTIVE: Sleeve gastrectomy (SG) has been reported to decrease blood pressure (BP), although the reason has not been revealed. The present study aimed to establish the reason why SG decreases BP. METHODS: Male Sprague-Dawley rats were subjected to surgical (sham operation or SG) and dietary interventions (fed a normal diet or high-fat diet ad libitum or fed by pair-feeding [PF]). Systolic BP (SBP), urinary sodium excretion, and endocrine parameters were examined 4 weeks after surgery. RESULTS: Both SG and PF rats had reduced body weight compared with SO rats fed normal diet or high-fat diet ad libitum. SG rats exhibited a reduction in SBP compared with PF, which was associated with a reduction in renal renin, angiotensin II, and catechol-O-methyltransferase levels (P < 0.01 for each). SG increased plasma cholecystokinin (CCK) levels compared with PF (P < 0.0001 for each), whereas glucagon-like peptide 1 and peptide YY were not changed in fasting. Exogenous administration of CCK reduced renal catechol-O-methyltransferase (P = 0.0233), renin (P < 0.0001), and angiotensin II (P < 0.0001) levels and SBP (P = 0.0053). CONCLUSIONS: SG reduced SBP, at least in part, through suppression of sympathetic nerve action by elevation of CCK, which was followed by suppression of the intrarenal renin-angiotensin system.

Interleukin-10 treatment attenuates sinus node dysfunction caused by streptozotocin-induced hyperglycaemia in mice.

Aims: Diabetes, characterized by hyperglycaemia, causes sinus node dysfunction (SND) in several rodent models. Interleukin (IL)-10, which is a potent anti-inflammatory cytokine, has been reported to decrease in obese and diabetic patients. We tested the hypothesis that administration of IL-10 inhibits the development of SND caused by hyperglycaemia in streptozotocin (STZ)-induced diabetic mice. Methods and results: Six-week old CL57/B6 (WT) mice were divided into the following groups: control, STZ injection, and STZ injection with systemic administration of IL-10. IL-10 knockout mice were similarly treated. STZ-induced hyperglycaemia for 8 weeks significantly depressed serum levels of IL-10, but increased several proinflammatory cytokines in WT mice. STZ-induced hyperglycaemia-reduced resting heart rate (HR), and attenuated HR response to isoproterenol in WT mice. In isolated perfused heart experiments, corrected-sinus node recovery time was prolonged in WT mice with STZ injection. Sinus node tissue isolated from the WT-STZ group showed fibrosis, abundant infiltration of macrophages, increased production of reactive oxygen species (ROS), and depressed hyperpolarization activated cyclic nucleotide-gated potassium channel 4 (HCN4). However, the changes observed in the WT-STZ group were significantly attenuated by IL-10 administration and were further exaggerated in IL-10 knockout mice. In cultured cells, preincubation of IL-10 suppressed hyperglycaemia-induced apoptotic and profibrotic signals, and overproduction of ROS. IL-10 markedly inhibited the high glucose-induced p38 activation, and activated signal transducer and activator of transcription (STAT) 3 phosphorylation. Conclusions: Our results suggest that IL-10 attenuates ROS production, inflammation and fibrosis, and plays an important role in the inhibition of hyperglycaemia-induced SND by suppression of HCN4 downregulation. In addition, IL-10-mediated inhibition of p38 is dependent on STAT3 phosphorylation.

Bioelectrical Impedance Analysis Results for Estimating Body Composition Are Associated with Glucose Metabolism Following Laparoscopic Sleeve Gastrectomy in Obese Japanese Patients.

We investigated the association between body composition and changes in glucose metabolism following laparoscopic sleeve gastrectomy (LSG) in obese Japanese patients. Thirty-two Class III obese patients were assessed before LSG and 3, 6, and 12 months postoperatively. Variables including fat mass (FM), % body fat (%FM), total and skeletal muscle mass (MM), the ratio of lower extremity MM to body weight (BW) (L/W), and the ratio of upper extremity MM to BW (U/W) were measured while using bioelectrical impedance analysis (BIA). LSG significantly decreased BW, FM, and %FM in all time periods observed after surgery with concomitant improvements in metabolic markers. MM was decreased at three months but maintained from 3⁻12 months post-surgery. Importantly, %MM, U/W, and the L/W ratio increased after LSG. Furthermore, change in FM was positively correlated with change in BW 12 months after LSG, whereas changes in %MM were negatively correlated with fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). Finally, multivariable stepwise regression analyses showed that changes in % total MM was an independent determinant of FPG and change in % skeletal MM was a significant independent determinant of HbA1c in Class III obese Japanese patients after LSG.

Glucagon-like peptide-1 reduces pancreatic ß-cell mass through hypothalamic neural pathways in high-fat diet-induced obese rats.

We examined whether glucagon-like peptide-1 (GLP-1) affects ß-cell mass and proliferation through neural pathways, from hepatic afferent nerves to pancreatic efferent nerves via the central nervous system, in high-fat diet (HFD)-induced obese rats. The effects of chronic administration of GLP-1 (7-36) and liraglutide, a GLP-1 receptor agonist, on pancreatic morphological alterations, c-fos expression and brain-derived neurotrophic factor (BDNF) content in the hypothalamus, and glucose metabolism were investigated in HFD-induced obese rats that underwent hepatic afferent vagotomy (VgX) and/or pancreatic efferent sympathectomy (SpX). Chronic GLP-1 (7-36) administration to HFD-induced obese rats elevated c-fos expression and BDNF content in the hypothalamus, followed by a reduction in pancreatic ß-cell hyperplasia and insulin content, thus resulting in improved glucose tolerance. These responses were abolished by VgX and SpX. Moreover, administration of liraglutide similarly activated the hypothalamic neural pathways, thus resulting in a more profound amelioration of glucose tolerance than native GLP-1 (7-36). These data suggest that GLP-1 normalizes the obesity-induced compensatory increase in ß-cell mass and glucose intolerance through a neuronal relay system consisting of hepatic afferent nerves, the hypothalamus, and pancreatic efferent nerves.