Efficacy and safety of intragastric expandable oral capsules in adults with overweight or obesity: A randomized, double-blind, placebo-controlled trial.

AIM: This trial assessed the efficacy and safety of 2.24 g intragastric expandable capsules twice per day versus placebo for weight management in adults with overweight or obesity. METHODS: This double-blind, placebo-controlled study included adults with a body mass index of at least 24 kg/m2 and no more than 40 kg/m2 . In total, 280 participants were recruited from six hospitals in China and were assigned in a 1:1 ratio to receive 2.24 g oral intragastric expandable capsules or placebo for 24 weeks. Coprimary endpoints were the percentage change in body weight from baseline and the rate of weight reduction of ≥5%, assessed using both the full analysis set and per protocol set. RESULTS: At baseline, the mean body weight was 81.8 kg, and the mean body mass index was 29.4 kg/m2 . The mean body weight change at week 24 was -4.9% with intragastric expandable capsules versus -1.9% with placebo [estimated treatment difference (ETD) -3.0%, 95% confidence interval (CI) -4.1 to -1.9; p < .001] using the full analysis set and -6.1% versus -2.5% (ETD -3.6%, 95% CI -5.0 to -2.3; p < .001), respectively, using the per protocol set. The percentage of participants who had weight loss exceeding 5% was 45.0% in the intragastric expandable capsule group versus 19.7% in the placebo group (ETD 25.3%, 95% CI 14.7-35.9; p < .001) in the full analysis set and 55.9% versus 26.2% (ETD 29.6%, 95% CI 17.1-42.2; p < .001), respectively, in the per protocol set. Waist circumference significantly decreased at week 24 (intragastric expandable capsules vs. placebo: -5.6 ± 8.3 cm vs. -2.9 ± 4.8 cm; p = .003). The most common adverse events associated with the use of intragastric expandable capsules were gastrointestinal disorders (intragastric expandable capsule vs. placebo, 25.0% vs. 21.9%), and most were mild and transient. CONCLUSIONS: In this 24-week trial including participants with overweight or obesity, 2.24 g of intragastric expandable capsules twice daily led to a clinically meaningful reduction in body weight compared with placebo.

Loss of Muscle Mass in Delayed Diagnosis of Renal Cysts and Diabetes Syndrome: A Case Report.

Renal cysts and diabetes syndrome (RCAD) is a rare disease caused by abnormalities in the HNF1B gene, which often leads to dysfunction in the renal, genital tracts, and pancreas. In this report, we present a rare case of a 27-year-old female with muscle mass loss who experienced a delayed diagnosis of RCAD. The patient had been misdiagnosed as "type 1 diabetes" for a long period. Her main clinical manifestations included muscle loss, renal magnesium loss, and an incomplete longitudinal uterus. Ultimately, the diagnosis of RCAD syndrome was confirmed through genetic testing. Reduction of muscle mass, although rarely reported, can progress to sarcopenia. Therefore, early intervention should be strongly emphasized. Furthermore, in future research, it is crucial to explore the mechanisms and relationships underlying these patients and their unusual manifestations.

Corrigendum: Case report: Primary aldosteronism and subclinical cushing syndrome in a 49-year-old woman with hypertension plus hypokalaemia.

[This corrects the article DOI: 10.3389/fcvm.2022.911333.].

Case Report: Primary Aldosteronism and Subclinical Cushing Syndrome in a 49-Year-Old Woman With Hypertension Plus Hypokalaemia.

Background: Coexisting primary aldosteronism (PA) and subclinical Cushing's syndrome (SCS) caused by bilateral adrenocortical adenomas have occasionally been reported. Precise diagnosis and treatment of the disease pose a challenge to clinicians due to its atypical clinical manifestations and laboratory findings. Case Summary: A 49-year-old woman was admitted to our hospital due to fatigue, increased nocturia and refractory hypertension. The patient had a history of severe left hydronephrosis 6 months prior. Laboratory examinations showed hypokalaemia (2.58 mmol/L) and high urine potassium (71 mmol/24 h). Adrenal computed tomography (CT) showed bilateral adrenal masses. Undetectable ACTH and unsuppressed plasma cortisol levels by dexamethasone indicated ACTH-independent Cushing's syndrome. Although the upright aldosterone-to-renin ratio (ARR) was 3.06 which did not exceed 3.7, elevated plasma aldosterone concentrations (PAC) with unsuppressed PAC after the captopril test still suggested PA. Adrenal venous sampling (AVS) without adrenocorticotropic hormone further revealed hypersecretion of aldosterone from the right side and no dominant side of cortisol secretion. A laparoscopic right adrenal tumor resection was performed. The pathological diagnosis was adrenocortical adenoma. After the operation, the supine and standing PAC were normalized; while the plasma cortisol levels postoperatively were still high and plasma renin was activated. The patient's postoperative serum potassium and 24-h urine potassium returned to normal without any pharmacological treatment. In addition, the patient's blood pressure was controlled normally with irbesartan alone. Conclusion: Patients with refractory hypertension should be screened for the cause of secondary hypertension. AVS should be performed in patients in which PA is highly suspected to determine whether there is the option of surgical treatment. Moreover, patients with PA should be screened for hypercortisolism, which can contribute to a proper understanding of the AVS result.

Central Obesity Is Associated with Variations in TSH and ACTH Levels among Euthyroid Obese Individuals.

Introduction: The interactions of central obesity and body composition with thyroid hormones and the hypothalamus-pituitary-adrenal (HPA) axis are unclear; both central obesity and body composition have an impact on energy homeostasis. Our study aimed to investigate the association between body composition and pituitary hormones, including the HPA axis and pituitary-thyroid axis, in a Chinese population of euthyroid overweight and obese individuals. Methods: This was a cross-sectional study. Overweight and obese patients who regularly visited the multidisciplinary team (MDT) for obesity at Peking University First Hospital were enrolled in the study. Thyroid function, morning serum ACTH and cortisol levels, thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), body composition, and metabolic indicators, including liver function and the lipid profile, were measured at the first visit. Statistical analysis was performed using SPSS version 21.0 (IBM, USA). Results: In total, 441 patients with overweight or obesity were enrolled (male/female, 123/318). Patients were assigned to four groups according to the thyroid-stimulating hormone (TSH) level stratified by quartiles, and increased body mass index (BMI) was revealed in the highest TSH quartile group (p=0.002). Hip circumference (HC) of patients in the highest TSH quartile group was significantly increased (p=0.021). Morning ACTH levels and fasting insulin levels were significantly elevated in patients in the highest TSH quartile group (p=0.027 for fasting insulin, p < 0.001 for ACTH). In the female subgroup, patients in the highest TSH quartile group showed increases in BMI (p=0.010), waist circumference (WC) (p=0.007), muscle mass of the lower extremities (p=0.020), fasting C-peptide (p=0.031), and ACTH (p=0.002). In the male subgroup, patients in the highest TSH quartile group exhibited higher BMI (p=0.017), HC (p=0.036), and ACTH (p=0.003). Among patients in the highest ACTH quartile group, there was an elevated proportion of males (p=0.003), and FT3 (p=0.005), fasting insulin (p=0.037), and cortisol (p < 0.001) levels were increased. Weight (p < 0.001), BMI (p < 0.001), WC (p < 0.001), HC (p < 0.001), muscle mass of the upper extremities (p=0.003), muscle mass of the lower extremities (p=0.005), and total muscle mass (p=0.003) were elevated in patients in the highest ACTH quartile group. HC was found to be an independent factor after adjustment for other confounders and was positively associated with the TSH level (p=0.004 for the regression model, B = 0.152, p=0.004). Conclusions: BMI is positively correlated with TSH and ACTH levels in both male and female obese individuals. The ACTH level was positively associated with male sex and increased BMI and muscle mass. Hip circumference was an independent factor that was positively related to TSH levels.

Body Composition and Metabolic Improvement in Patients Followed Up by a Multidisciplinary Team for Obesity in China.

BACKGROUND: This study evaluated the effectiveness of the multidisciplinary team (including a specialist, a dietitian, a physical exercise trainer, a surgeon for bariatric surgery, an acupuncturist, and several health educators) for obesity management and the body composition change and improvements in metabolic biomarkers during a 2-year follow-up. MATERIALS AND METHODS: A total of 119 patients participated in the multidisciplinary team for obesity. Patients were followed up at 3 months, 6 months, 1 year, 18 months, and 2 years after their first visit. Individuals were divided into the high-protein diet (HPD) and standard-protein diet (SPD) group according to their results on a diet questionnaire that they filled out during follow-up. RESULTS: After 1.2 years, the mean body weight of the participants dropped from 89.7 kg to 80.9 kg (p < 0.001). The body adiposity index was reduced from 33.9 to 32.0 (p < 0.001), while the fat-free mass index from 17.0 to 15.2 (p = 0.043). Fasting glucose and HbA1c were also lower after treatment (p = 0.002 and 0.038 for FPG and HbA1c, respectively). Fasting insulin and HOMA-IR were reduced (p = 0.002 and <0.001 for fasting insulin and HOMA-IR, respectively). HDL-c increased along with weight loss (1.06 mmol/L vs. 1.19 mmol/L, p < 0.001), and transaminase levels significantly dropped (p = 0.001 and 0.021 for ALT and AST, respectively). During treatment, mean protein intake was 29.9% in the HPD group and 19.5% in the SPD group (p < 0.001). Weight loss, reduction of visceral fat area, maintenance of lean body mass, body adiposity index, and fat-free mass index showed no statistical significance between the HPD and SPD groups, as well as glucose metabolic variables. CONCLUSIONS: A multidisciplinary team for obesity management could significantly reduce body weight and improve metabolic indicators, including HDL-c, transaminase, and insulin resistance. A high-protein diet does not produce better weight control or body composition compared with a standard calorie-restricted diet.

[Levels of interlukin-6 and tumor necrosis factor-α in saliva of patients with type 2 diabetes mellitus and oral lichen planus].

OBJECTIVE: To study the relationship between type 2 diabetes mellitus (T2DM) and oral lichen planus (OLP) by detecting the level of salivary tumor necrosis factor (TNF-α) and interlukin-6 (IL-6). METHODS: Subjects were divided into 4 groups: T2DM/OLP group 29 patients, T2DM group 39 patients, OLP group 21 patients, and control group 43 individuals. The salivary interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) were detected by enzyme-linked immuno sorbent assay (ELISA). RESULTS: (1) The level of salivary IL-6 in patients with T2DM/OLP [(12.30 ± 16.03) ng/L] was significantly higher than those in T2DM [(6.29 ± 5.91) ng/L] and OLP groups [(3.64 ± 4.47) ng/L], P<0.05. The level of salivary IL-6 was significantly lower in OLP group [(3.64 ± 4.47) ng/L] than in control group [(7.91 ± 4.05) ng/L], P<0.001. The level of salivary TNF-α in T2DM group [(8.80 ± 8.41) ng/L] was significantly lower than those in OLP [(14.02 ± 9.65) ng/L] and control groups [(15.02 ± 6.13) ng/L], P<0.05. (2) The level of salivary TNF-α is significantly negative correlated with pH value of saliva in T2DM/OLP group(r=-0.593, P<0.01);The level of salivary TNF-α and IL-6 are significantly positive correlated with waistline in control group(r=0.312,P=0.05).(3) The levels of salivary IL-6 and TNF-α were positively related to OLP clinical type, P<0.05. (4)When OLP played an overlying role on T2DM, the level of TNF-α was weakened and that of IL-6 was strengthened. CONCLUSION: When T2DM and OLP are in concurrence,there is a synergistic effect,and the secretion of IL-6 increases markedly; The level of salivary TNF-α is associated with local oral environment.

Abnormal subcellular localization of AQP5 and downregulated AQP5 protein in parotid glands of streptozotocin-induced diabetic rats.

BACKGROUND: The mechanisms underlying diabetic xerostomia have not been clarified in relation with aquaporin-5 (AQP5) subcellular localization in salivary glands. METHODS: Western blotting, real-time PCR, and immunocytochemistry were used to analyse AQP5 protein levels and mRNA expression. AQP5 protein levels were measured in the apical plasma membrane (APM) and detergent-insoluble fraction prepared from streptozotocin-diabetic rat parotid glands. RESULTS: Despite an increase in AQP5 mRNA, AQP5 protein levels were decreased in diabetic parotid glands compared with controls. Immunohistochemical studies indicated that AQP5, under unstimulated conditions, colocalised with flotillin-2 and GM1 with a diffuse pattern in the apical cytoplasm of acinar and duct cells in both control and diabetic rats. Ten minutes after intravenous injection of muscarinic agonist cevimeline, AQP5 was dramatically increased together with flotillin-2 and GM1 in the APM of parotid acinar and duct cells of control but not diabetic rats. Sixty minutes after injection, AQP5 was located in a diffuse pattern in the apical cytoplasm in both rats. Treatment of the parotid tissues with cevimeline for 10min increased the Triton X-100 solubility of AQP5 in control but not diabetic rats. Administration of insulin to diabetic rats tended to restore the cevimeline-induced translocation of AQP5. CONCLUSION: Lack of AQP5 translocation in the salivary gland in response to a muscarinic agonist and downregulation of AQP5 protein might lead to diabetic xerostomia. GENERAL SIGNIFICANCE: Cevimeline is useful to cure diabetic xerostomia under insulin administration.

Water channels and zymogen granules in salivary glands.

Salivary secretion occurs in response to stimulation by neurotransmitters released from autonomic nerve endings. The molecular mechanisms underlying the secretion of water, a main component of saliva, from salivary glands are not known; the plasma membrane is a major barrier to water transport. A 28-kDa integral membrane protein, distributed in highly water-permeable tissues, was identified as a water channel protein, aquaporin (AQP). Thirteen AQPs (AQP0 - AQP12) have been identified in mammals. AQP5 is localized in lipid rafts under unstimulated conditions and translocates to the apical plasma membrane in rat parotid glands upon stimulation by muscarinic agonists. The importance of increases in intracellular calcium concentration [Ca(2+)](i) and the nitric oxide synthase and protein kinase G signaling pathway in the translocation of AQP5 is reviewed in section I. Signals generated by the activation of Ca(2+) mobilizing receptors simultaneously trigger and regulate exocytosis. Zymogen granule exocytosis occurs under the control of essential process, stimulus-secretion coupling, in salivary glands. Ca(2+) signaling is a principal signal in both protein and water secretion from salivary glands induced by cholinergic stimulation. On the other hand, the cyclic adenosine monophosphate (cAMP)/cAMP-dependent protein kinase system has a major role in zymogen granule exocytosis without significant increases in [Ca(2+)](i). In section II, the mechanisms underlying the control of salivary protein secretion and its dysfunction are reviewed.

Aquaporin-5 water channel in lipid rafts of rat parotid glands.

Aquaporin-5 (AQP5), an apical plasma membrane (APM) water channel in salivary glands, lacrimal glands, and airway epithelium, has an important role in fluid secretion. The activation of M3 muscarinic acetylcholine receptors (mAChRs) or alpha1-adrenoceptors on the salivary glands induces salivary fluid secretion. AQP5 localizes in lipid rafts and activation of the M3 mAChRs or alpha1-adrenoceptors induced its translocation together with the lipid rafts to the APM in the interlobular ducts of rat parotid glands. This review focuses on the mechanisms of AQP5 translocation together with lipid rafts to the APM in the interlobular duct cells of parotid glands of normal rats and the impairment of AQP5 translocation in diabetes and senescence.

Identification of AQP5 in lipid rafts and its translocation to apical membranes by activation of M3 mAChRs in interlobular ducts of rat parotid gland.

Aquaporin-5 (AQP5), an apical plasma membrane (APM) water channel in salivary glands, lacrimal glands, and airway epithelium, has an important role in fluid secretion. M(3) muscarinic acetylcholine receptor (mAChR)-induced changes in AQP5 localization in rat parotid glands were investigated with immunofluorescence or immunoelectron microscopy, detergent solubility, and gradient density floatation assays. Confocal microscopy revealed AQP5 localization in intracellular vesicles of interlobular duct cells in rat parotid glands and AQP5 trafficking to the APM 10 min after injection of the mAChR agonist cevimeline. Conversely, 60 min after injection, there was a diffuse pattern of AQP5 staining in the cell cytoplasm. The calcium ionophore A-23187 mimicked the effects of cevimeline. Immunoelectron microscopic studies confirmed that cevimeline induced AQP5 trafficking from intracellular structures to APMs in the interlobular duct cells of rat parotid glands. Lipid raft markers flotillin-2 and GM1 colocalized with AQP5 and moved with AQP5 in response to cevimeline. Under control conditions, the majority of AQP5 localized in the Triton X-100-insoluble fraction and floated to the light-density fraction on discontinuous density gradients. After 10-min incubation of parotid tissue slices with cevimeline or A-23187, AQP5 levels decreased in the Triton X-100-insoluble fraction and increased in the Triton X-100-soluble fraction. Thus AQP5 localizes in the intracellular lipid rafts, and M(3) mAChR activation induces AQP5 trafficking to the APM with lipid rafts via intracellular Ca(2+) signaling and induces AQP5 dissociation from lipid rafts to nonrafts on the APM in the interlobular duct cells of rat parotid glands.

Effect of SNI-2011 on amylase secretion from parotid tissue in rats and in neuronal nitric oxide synthase knockout mice.

The effect of (+/-)cis-2-methylspilo(1,3-oxathiolane-5,3')quinuclidine (SNI-2011) on the secretory pathway of amylase in parotid tissues was investigated. SNI-2011-induced exocytosis was inhibited by a cell-permeable Ca(2+) chelator or inhibitors of calmodulin kinase II, neuronal nitric oxide synthase (nNOS), soluble guanyl cyclase, cyclic GMP-dependent protein kinase (PKG), and myosin light chain kinase, suggesting that these enzymes were coupled with the exocytosis. Stimulation with SNI-2011 of isolated rat parotid acinar cells loaded with 4,5-diaminofluorescein/diacetate (DAF-2/DA) induced a fast increase in DAF fluorescence corresponding to an increase in the NO production. SNI-2011-induced amylase secretion from parotid tissues in nNOS knockout mice has not been observed yet in spite of the expression of muscarinic M(3) receptors and the maintenance of secretory response to isoproterenol in the tissues. These results indicate the implication of the activation of Ca(2+)- and calmodulin-dependent enzymes and NOS-PKG signaling pathway in SNI-2011-induced amylase secretion from parotid acinar cells.