Metabolomics Panel Associated with Cystic Fibrosis-Related Diabetes toward Biomarker Discovery.

The most prevalent comorbidity among cystic fibrosis (CF) patients is cystic fibrosis-related diabetes (CFRD). CFRD has been linked to one of the worse clinical outcomes and a higher mortality. Improved clinical results have been related to earlier diagnosis and treatment of CFRD. Therefore, the present study aimed to investigate the metabolome of human serum of patients with CFRD. This might aid in identifying novel biomarkers linked with the pathophysiology of CFRD and its diagnosis. The liquid chromatography-high-resolution mass spectrometry (LC-HRMS) metabolomics approach was utilized for serum samples from patients with CF (n = 36) and healthy controls (n = 36). Nine patients in the CF group had CFRD, and 27 were non-CFRD patients (nCFRD). A total of 2328 metabolites were significantly altered in CF compared with the healthy control. Among those, 799 significantly dysregulated metabolites were identified between CFRD and nCFRD. Arachidonic acid (AA), ascorbate, and aldarate metabolism were the most common metabolic pathways dysregulated in CF. l-Homocysteic acid (l-HCA) levels were significantly reduced in CF and CFRD compared to the control and nCFRD, respectively. In addition, gamma-glutamylglycine and l-5-hydroxytryptophan (5-HTP) had the highest discrimination between CFRD and nCFRD with AUC (0.716 and 0.683, respectively). These biomarkers might serve as diagnostic biomarkers and aid in understanding potential metabolic changes linked to CF and CFRD.

Cost consequence analysis of adding semaglutide to treatment regimen for patients with Type II diabetes in Saudi Arabia.

Introduction: Semaglutide, a Glucagon-like Peptide-1 Receptor Agonist (GLP-1 RA), is often prescribed for managing type 2 diabetes, particularly in cases unresponsive to other hypoglycemic agents. Despite its popularity, the real-world efficacy and cost-effectiveness of Semaglutide relative to other treatments remain understudied. Objective: This study aimed to examine the direct medical cost and consequences of adding Semaglutide to the treatment regimen for patients with type 2 diabetes in Saudi Arabia. Methods: We conducted a single-center, retrospective review of Electronic Medical Records (EMRs) for adults with type 2 diabetes. Patients who had been on Semaglutide for at least three months were matched with those receiving alternative hypoglycemic therapies. Exclusions were made for patients with cancer, incomplete EMRs, or lacking prescription data. Investigated outcomes included changes in HbA1C levels and weight, and the direct costs comprised medications, clinic visits, and emergency care. Baseline adjustments were made through inverse probability treatment weighting, and uncertainty was assessed via bootstrapping with 10,000 replications. Results: Out of 350 patients meeting the criteria, 116 were on Semaglutide. Predominantly females (62%), the cohort had an average age of 60 and a disease duration of 22 years. The difference in HbA1C (%) reductions between Semaglutide and non-Semaglutide users over 3,6, and 12 months were 0.154 (95% CI: -0.452-0.483), -0.031(95% CI: -0.754-0.239), -0.16(95% CI: -1.425-0.840), respectively. Semaglutide users did experience modest weight reductions ranging from 0.42 kg to 1.16 kg. The annual additional direct medical cost for Semaglutide was USD 4,086.82 (95% CI: $3,710.85 - $4,294.99). Conclusion: Although Semaglutide induced modest weight reductions, it did not offer significant advantages in lowering HbA1C levels compared to other hypoglycemic treatments. These findings suggest the need for further research involving larger and more diverse cohorts to corroborate these findings.

Plasma Proteomic Signature of Endometrial Cancer in Patients with Diabetes.

The incidence and mortality of endometrial cancer (EC) have increased in recent years. There is mounting evidence that diabetes may play a role in the greater incidence of EC. The molecular mechanisms of the interaction between type 2 diabetes and EC are not yet clearly understood yet. The present study was undertaken to investigate the plasma proteomics of EC patients with diabetes in comparison to those of EC patients without diabetes. Plasma samples were obtained from age-matched patients (EC diabetic and EC nondiabetic). Untargeted proteomic analysis was carried out using a two-dimensional differential gel electrophoresis coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Of the 33 proteins identified, which significantly differed in the plasma abundance between groups, 17 were upregulated and 16 were downregulated. The majority of the altered proteins are involved in the acute phase reaction, cholesterol metabolism, scavenging of heme from plasma, and plasma lipoprotein assembly and mobilization. α-2-macroglobulin, Ras association domain-containing protein 3, apolipoprotein A-I, α-1B-glycoprotein, and zinc-α-2-glycoprotein were significantly upregulated. The significantly downregulated proteins included haptoglobin, apolipoprotein A-IV, hemopexin, and α-1-antichymotrypsin. The differential expression of proteins found in patients who had EC and diabetes indicated severe disease and a poor prognosis. The protein interaction analysis showed dysregulation of cholesterol metabolism and heme scavenging pathways in these patients.

Lipids Alterations Associated with Metformin in Healthy Subjects: An Investigation Using Mass Spectrometry Shotgun Approach.

Metformin is an orally effective insulin-sensitizing drug widely prescribed for treating type 2 diabetes mellitus (T2DM). Metformin has been reported to alter lipid metabolism. However, the molecular mechanisms behind its impact on lipid metabolism remain partially explored and understood. In the current study, mass spectrometry-based lipid profiling was used to investigate the lipidomic changes in the serum of 26 healthy individuals after a single-dose intake of metformin. Samples were analyzed at five-time points: preadministration, before the maximum concentration of metformin (Cmax), Cmax, after Cmax, and 36 h post-administration. A total of 762 molecules were significantly altered between the five-time points. Based on a comparison between baseline level and Cmax, metformin significantly increased and decreased the level of 33 and 192 lipids, respectively (FDR ≤ 0.05 and fold change cutoff of 1.5). The altered lipids are mainly involved in arachidonic acid metabolism, steroid hormone biosynthesis, and glycerophospholipid metabolism. Furthermore, several lipids acted in an opposed or similar manner to metformin levels and included fatty acyls, sterol lipids, glycerolipids, and glycerophospholipids. The significantly altered lipid species pointed to fundamental lipid signaling pathways that could be linked to the pleiotropic effects of metformin in T2DM, insulin resistance, polycystic ovary syndrome, cancer, and cardiovascular diseases.

Proteomic Analysis of Endometrial Cancer Tissues from Patients with Type 2 Diabetes Mellitus.

Endometrial cancer (EC) is the most common form of gynecological cancer. Type 2 diabetes mellitus is associated with an increased risk of EC. Currently, no proteomic studies have investigated the role of diabetes in endometrial cancers from clinical samples. The present study aims to elucidate the molecular link between diabetes and EC using a proteomic approach. Endometrial tissue samples were obtained from age-matched patients (EC Diabetic and EC Non-Diabetic) during surgery. Untargeted proteomic analysis of the endometrial tissues was carried out using a two-dimensional difference in gel electrophoresis (2D-DIGE) coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF). A total of 53 proteins were identified, with a significant difference in abundance (analysis of variance (ANOVA) test, p ≤ 0.05; fold-change ≥ 1.5) between the two groups, among which 30 were upregulated and 23 downregulated in the EC Diabetic group compared to EC Non-Diabetic. The significantly upregulated proteins included peroxiredoxin-1, vinculin, endoplasmin, annexin A5, calreticulin, and serotransferrin. The significantly downregulated proteins were myosin regulatory light polypeptide 9, Retinol dehydrogenase 12, protein WWC3, intraflagellar transport protein 88 homolog, superoxide dismutase [Cu-Zn], and retinal dehydrogenase 1. The network pathway was related to connective tissue disorder, developmental disorder, and hereditary disorder, with the identified proteins centered around dysregulation of ERK1/2 and F Actin signaling pathways. Cancer-associated protein alterations such as upregulation of peroxiredoxin-1, annexin 5, and iNOS, and downregulation of RDH12, retinaldehyde dehydrogenase 1, SOD1, and MYL 9, were found in the EC tissues of the diabetic group. Differential expression of proteins linked to cancer metastasis, such as the upregulation of vinculin and endoplasmin and downregulation of WWC3 and IFT88, was seen in the patients with diabetes. Calreticulin and alpha-enolase, which might have a role in the interplay between diabetes and EC, need further investigation.

A Metabolic Pattern in Healthy Subjects Given a Single Dose of Metformin: A Metabolomics Approach.

Metformin is a widely prescribed medication for the treatment of type 2 diabetes mellitus (T2DM). It possesses effective roles in various disorders, including cancer, dyslipidemia, and obesity. However, the underlying mechanisms of metformin's multiple benefits are not fully understood. Herein, a mass spectrometry-based untargeted metabolomics approach was used to investigate the metabolic changes associated with the administration of a single dose of metformin in the plasma of 26 healthy subjects at five-time points; pre-dose, before the maximum concentration of metformin (Cmax), Cmax, after Cmax, and 36 h post-dose. A total of 111 metabolites involved in various biochemical processes were perturbed, with branched-chain amino acid (BCAA) being the most significantly altered pathway. Additionally, the Pearson similarity test revealed that 63 metabolites showed a change in their levels dependent on metformin level. Out of these 63, the level of 36 metabolites was significantly altered by metformin. Significantly altered metformin-dependent metabolites, including hydroxymethyl uracil, propionic acid, glycerophospholipids, and eicosanoids, pointed to fundamental biochemical processes such as lipid network signaling, energy homeostasis, DNA lesion repair mechanisms, and gut microbiota functions that could be linked to the multiple beneficial roles of metformin. Thus, the distinctive metabolic pattern linked to metformin administration can be used as a metabolic signature to predict the potential effect and mechanism of actions of new chemical entities during drug development.

Safety and cost-effectiveness of outpatient thyroidectomy: A retrospective observational study.

OBJECTIVES: To investigate the safety and cost-effectiveness of outpatient thyroidectomy and provide a systematic postoperative protocol for safe discharge. METHODS: In this retrospective review, the medical records of all patients who underwent total, hemi, or completion thyroidectomy from July 2017 to April 2019 at 2 tertiary care hospitals were reviewed. Multivariable analysis was performed on the potential predictors of postoperative complications. Healthcare costs were calculated by the type of admission based on the average costs at the 2 centers. RESULTS: One hundred twenty-two patients were enrolled in this study. The majority of cases were in the outpatient group (n=76, 62.3%). Total thyroidectomy was the most prevalent type of surgery (n=90, 73.7%). There were a total of 20 complications in 18 patients (inpatient=9 versus [vs.] outpatient=9). No cases of cervical hematoma or bilateral vocal cord paralysis were encountered. No significant difference was found between the type of admission (outpatient vs. inpatient) and postsurgical complications (p=0.24). The multivariable regression model retained significance for male gender and American Society of Anesthesiologists Classification III as potential predictors of postoperative complications. Healthcare costs would be reduced by at least 15.5% with the implementation of outpatient surgery. CONCLUSION: Outpatient thyroidectomy is as safe as inpatient thyroidectomy given the proper selection of cases. We project cost containment of over $711 thousand per 1,000 cases for outpatient thyroid surgeries.

Clinical significance of Saussurea Costus in thyroid treatment.

Saussurea costus (S. costus) belongs to family of Asteraceae and is one of the therapeutic plants extensively used as a traditional medicine in Saudi Arabia. Constituents of this plant have the potential to be developed as bioactive molecules. Among Arabs, the prevalence of thyroid disorders ranges from 6.18 % to 47.34% and hypothyroidism has been reported to be the most prevalent. Although there is no natural treatment that can directly replace thyroid hormones, their role as an alternate treatment or as an add-on to available thyroid treatment has been explored. Flavanoids and antioxidant properties of S. costus may be an important mechanism involved in supporting its medicinal use. Current data on the possible role of S. costus in thyroid disorders is lacking and the available evidence is inconclusive. This review deal with the current understanding of use and myth regarding the use of this medicinal plant in thyroid disease.

Celiac autoantibody positivity in relation to clinical characteristics in children with type 1 diabetes.

BACKGROUND: Type 1 diabetes is an autoimmune disorder with a high risk of celiac disease (CD). AIM: This study aimed to determine the celiac autoantibody status and the clinical characteristics among children with type 1 diabetes and autoantibody positivity for CD compared to those without serological evidence of CD. MATERIALS AND METHODS: In this cross-sectional study, 240 children with type 1 diabetes underwent serological screening CD. Blood glucose, glycated hemoglobin (HbA1c), hemoglobin, calcium, phosphorous, Vitamin D, alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) were evaluated. The participants were screened for human anti-endomysial antibody and human anti-tissue transglutaminase antibody. RESULTS: Of the 240 children with type 1 diabetes, 66 children were antibody positive for either anti-endomysial or anti-tissue transglutaminase or both autoantibodies for CD. There were 36 (54.5%) female and 30 (45.5%) male children with the mean age of 15.5±2.1 years. The mean duration of diabetes was 6.8±3.8 years. Only 35 (14.6%) children were found to have serological evidence of CD. CONCLUSION: CD is associated with type 1 diabetes. Serological screening for CD autoantibody should be performed routinely in children with type 1 diabetes. There is discrepancy in screening CD with antibodies, so a prospective follow-up of this cohort is needed for endoscopic evaluation and histopathological examination of intestinal biopsy to confirm CD in this population. RELEVANCE FOR PATIENTS: Anti-endomysial and anti-tissue transglutaminase autoantibodies should be included for screening CD among children with type 1 diabetes. Patients should undergo an endoscopy to confirm a diagnosis of CD.

Association of urinary non-albumin protein with the different urinary marker for glomerular and tubular damage in patients with type 2 diabetes.

BACKGROUND/AIM: In recent years, the diagnostic utility of urinary protein levels has been demonstrated for the early detection and progression of kidney disease. This study aimed to evaluate the associations of the non-albumin protein (NAP) with different urinary marker for tubular and glomerular damage in patients with type 2 diabetes (T2D). METHODS: In this observational cross-sectional study, 424 patients with T2D duration > 10 years were classified into two groups according to estimated glomerular filtration rate (eGFR). The ratios of different urinary markers (albumin, NAP, total protein, transferrin, retinol-binding protein (RBP), and neutrophil gelatinase-associated lipocalin (NGAL) to creatinine were analyzed. RESULTS: The levels of urinary biomarkers increased significantly with decrease in eGFR levels. In the group with moderately decreased eGFR, the albumin to-creatinine ratio (ACR), non-albumin protein-to-creatinine ratio (NAPCR), and total protein-to-creatinine ratio (PCR) were independently associated with all urinary markers after being adjusted for risk factors. The area under the receiver operating characteristics (ROC) curve for ACR and PCR had a better diagnostic value than other urinary biomarkers. Comparing ROC curve of NAPCR with other urinary biomarkers, it was significantly better than NGAL/Cr (p = 0.033). CONCLUSIONS: The findings of the present study confirm that ACR and PCR are diagnostic biomarkers in T2D patients with decreased eGFR. NAPCR in these patients diagnostically only outperformed NGAL/Cr.

Risk Stratification of Thyroid Nodules with Bethesda III Category: The Experience of a Territorial Healthcare Hospital.

Background The Bethesda System for Reporting Thyroid Cytolopathology (TBSRTC) is the standardized category-based reporting system for thyroid nodule (TN) aspirations; however, atypia of undetermined significance/follicular lesion of undetermined significance (Bethesda category III, AUS/FLUS) is the most controversial category. The aim of this study was to identify the degree of malignancy risk and the related risk factors in the surgical pathology of the Bethesda Category III thyroid nodules.  Methods A total of 4074 patients (15-90 years, 81.5% of females) were subjected to retrospective analysis, and a total of 463 nodules were classified as Bethesda Class III and included in the analysis. Once all the thyroid cytopathological slides and ultrasound (US) reports were reviewed, they were classified according to the Bethesda System for Reporting Thyroid Cytology, the American College of Radiology (ACR) and the Thyroid Imaging Reporting and Data System (TI-RADS). Results Among the 463 Bethesda class III nodules, 167 nodules were surgically excised, showing an overall malignancy of 27.6% (n = 46/167). Patients having thyroid-stimulating hormone (TSH) levels of >4.5 mIU/L (35%), TN <2 cm (34.6%), solid or nearly solid (28.7%), highly hypoechoic (58.3%), longer than wide (50%), lobulated (45.5%), punctate echogenic (48.6%), ACR TI-RAD 5 (55.2%) and falling under the ATA category of high suspicion (50%), displayed a higher risk of malignancy (ROM). The chi-square test revealed a strong association between the echogenicity, echogenic foci, ACR TI-RAD and American Thyroid Association (ATA) category between the malignant and benign nodules. The papillary thyroid carcinoma (PTC) follicular variant (39%) and PTC classical (27%) were identified, in this study population, as the commonest forms of thyroid cancer. Conclusion The nodules with AUS/FLUS cytology malignancy rate are comparable with the earlier estimations of other countries. The ACR TI-RAD displayed more accurate diagnostic performances in predicting malignancy in the Bethesda III nodules. However, to confirm the accuracy of the molecular marker tests in specific cytological scenarios, more extensive studies are required in the future.

Obesity Connected Metabolic Changes in Type 2 Diabetic Patients Treated With Metformin.

Metformin is widely used in the treatment of Type 2 Diabetes Mellitus (T2DM). However, it is known to have beneficial effects in many other conditions, including obesity and cancer. In this study, we aimed to investigate the metabolic effect of metformin in T2DM and its impact on obesity. A mass spectrometry (MS)-based metabolomics approach was used to analyze samples from two cohorts, including healthy lean and obese control, and lean as well as obese T2DM patients on metformin regimen in the last 6 months. The results show a clear group separation and sample clustering between the study groups due to both T2DM and metformin administration. Seventy-one metabolites were dysregulated in diabetic obese patients (30 up-regulated and 41 down-regulated), and their levels were unchanged with metformin administration. However, 30 metabolites were dysregulated (21 were up-regulated and 9 were down-regulated) and then restored to obese control levels by metformin administration in obese diabetic patients. Furthermore, in obese diabetic patients, the level of 10 metabolites was dysregulated only after metformin administration. Most of these dysregulated metabolites were dipeptides, aliphatic amino acids, nucleic acid derivatives, and urea cycle components. The metabolic pattern of 62 metabolites was persistent, and their levels were affected by neither T2DM nor metformin in obesity. Interestingly, 9 metabolites were significantly dysregulated between lean and obese cohorts due to T2DM and metformin regardless of the obesity status. These include arginine, citrulline, guanidoacetic acid, proline, alanine, taurine, 5-hydroxyindoleacetic acid, and 5-hydroxymethyluracil. Understanding the metabolic alterations taking place upon metformin treatment would shed light on possible molecular targets of metformin, especially in conditions like T2DM and obesity.

Long-Term Outcomes of Patients with Papillary Thyroid Cancer Undergoing Remnant Ablation with 30 milliCuries Radioiodine.

BACKGROUND: The study considered the long-term outcome of patients with papillary thyroid carcinoma treated with 30 mCi radioiodine. OBJECTIVE: The aims of this study were to define and compare the remission rates of papillary thyroid carcinoma ablated with 30 mCi (131)I prepared by either thyroid hormone withdrawal (THW) or recombinant human thyrotropin (rhTSH; Thyrogen(®)), and to identify variables predictive of a favorable prognosis. METHOD: An observational study was conducted at an academic medical center and a comparative summary of six studies is presented. Three hundred and seventy patients (THW group, n = 203; rhTSH group, n = 167) were recruited from a prospectively managed registry. The mean follow-up was 9.3 years (range 5.1-15.8 years) in the THW group and 7.1 years (range 5.0-9.7 years) in the rhTSH group. The primary endpoint was the long-term remission rates (no evidence of disease) in the THW group compared with the rhTH group. RESULTS: The response at 12-18 months after 30 mCi remnant ablation was excellent in 79.3% and 76.0% of patients in the THW group and the rhTSH group, respectively (p > 0.05). The long-term remission rates also did not significantly differ between both groups at 95.6% and 97.0%. Although the surveillance period for the THW group exceeded that of the rhTSH group, no significant difference in recurrence-free survival was discerned by the Kaplan-Meier curves. In a multivariate analysis, an excellent response to therapy at 12-18 months correlated significantly with long-term remission rates in the THW group (p = 0.031, odds ratio [OR] = 2.6 [confidence interval (CI) 1.1-6.0]), the rhTSH group (p = 0.03, OR = 5.3 [CI 1.2-23.8]), and the pooled groups (p = 0.001, OR = 3.43 [CI 1.63-7.2]). The pre-ablation thyroglobulin level significantly correlated with remission rates only in the THW group (p = 0.035, OR = 5.5 [CI 1.1-27.1]). CONCLUSIONS: The response to remnant ablation with 30 mCi radioiodine is often excellent, and the long-term remission rates can be expected to be high, independent of the method of delivery (i.e., THW or rhTSH).