Up-Titration Strategy After DPP-4 Inhibitor-Based Oral Therapy for Type 2 Diabetes : A Randomized Controlled Trial Shifting to a Single-Dose GLP-1 Enhancer Versus Adding a Variable Basal Insulin Algorithm

Introduction: It is unclear whether adding basal insulin or enhancing incretin signaling with a glucagon-like peptide-1 receptor agonist (GLP-1RA) is more effective as an up-titration strategy after dipeptidyl peptidase-4 inhibitor (DPP-4i)-based oral antidiabetic drug (OAD) therapy. GLP-1RAs can be injected without dose adjustment, unlike basal insulin. Our objective was to examine the efficacy of changing patients inadequately controlled with oral DPP-4i-based OAD therapy to injectable GLP-1RA and discontinuing the DPP4i versus adding basal insulin glargine (IGlar) with the continuation of the oral DPP4i. Methods: Sixty patients with type 2 diabetes (T2DM) and glycated hemoglobin (HbA1c) between 7.0% and 10.0% on DPP-4i-based OAD therapy were randomized to either adding IGlar and remaining on the DPP-4i or liraglutide and discontinuing the DPP-4i for 24 weeks. Patients in the IGlar group started with 0.1 unit/kg and were titrated according to the algorithm. In the liraglutide group, the DPP-4i was replaced with liraglutide 0.9 mg/day, the maximum dose in Japan. We evaluated HbA1c, glycated albumin (GA), and anthropometrics. Results: HbA1c was significantly lower at week 24 (− 1.0 ± 0.9% in the IGlar group and − 0.6 ± 0.8% in the liraglutide group), but the difference between groups was not significant. Changes in GA were similar (− 2.9 ± 3.2% vs. − 2.6 ± 3.2%) in both groups. Body weight (BW) was significantly lower only in the liraglutide group (+ 0.5 ± 2.6 kg vs. − 2.2 ± 2.0 kg). The rate of minor hypoglycemic episodes was similar for both groups. Conclusion: For poorly controlled T2DM on DPP-4i-based OAD therapy, switching to single-dose liraglutide to enhance incretin signaling is as effective as dose-titrated basal IGlar, but significant BW reduction was only seen in the liraglutide group. These results suggest that enhancing incretin signaling with a single-dose injectable GLP-1 RA might be an alternative to dose-titrated basal insulin therapy in patients with T2DM poorly controlled with DPP-4i-based OAD therapy. These findings should be confirmed in a longer and larger trial

Urinary Myoinositol Index: A New and Better Marker for Postmeal Hyperglycemia

We investigated the usefulness of the urinary myoinositol index (UMI) for identifying postmeal hyperglycemia in type 2 diabetics undergoing a meal tolerance test. Fifty-eight patients (18 males, 40 females) were enrolled, fasted overnight and blood collected prior to and 1 and 2 hours following the test meal. Urine was collected 2 hours after the test meal. Plasma 1,5-anhydroglucitol (1,5-AG) was measured enzymatically, and UMI with an improved enzymatic cycling method. Simple and multiple regression analyses were employed to determine correlations between plasma glucose (PG) and three PG markers; HbA1C (Japan Diabetes Society), 1,5-AG and UMI. Study population characteristics were age 67.6±7.9 years, body mass index 24.9±3.8kg/m2 and waist circumference 90.2±10.4cm. Mean concentrations for PG were 130±23mg/dL (fasting), 179±46mg/dL (1h postmeal) and 150±49mg/dL (2h postmeal), HbA1C (6.3±0.6%), 1,5-AG (11.9±5.7μg/mL) and 2h UMI (52.0±35.9mg/gCr). Correlation coefficients were calculated between 1h postmeal PG and HbA1C (r=0.558), 1,5-AG (r=0.256), and 2h UMI (r=0.496), and 2h postmeal PG HbA1C (r=0.605), 1,5-AG (r=0.306), and 2h UMI (r=0.606). Two hour UMI and HbA1C (Japan Diabetes Society) were significant determinants of 2h postmeal PG. As HbA1C reflects PG excursion during the previous 1-3 months, UMI may be a useful marker for monitoring and management of postmeal hyperglycemia in type 2 diabetics

Thyroid storm associated with Graves' disease covered by diabetic ketoacidosis: A case report

<p>Abstract</p> <p>Background</p> <p>Thyroid storm is a condition in which multiple organ dysfunction results from failure of the compensatory mechanisms of the body owing to excessive thyroid hormone activity induced by some factors in patients with thyrotoxicosis. While diabetic ketoacidosis (DKA) is an important trigger for thyroid storm, simultaneous development of DKA and thyroid storm is rare.</p> <p>Case presentation</p> <p>A 59-year-old woman with no history of either diabetes mellitus or thyroid disease presented to our hospital because of developing nausea, vomiting and diarrhea for 2 days. Physical examination showed mild disturbance of consciousness, fever, and tachycardia. There were no other signs of thyrotoxicosis. Laboratory studies revealed elevation of random blood glucose and glycosylated hemoglobin, strongly positive of urine acetone, and metabolic acidosis. Since DKA was diagnosed, we initiated the patient on treatment with administration of insulin and adequate fluid replacement. Although the hyperglycemia and acidosis were immediately relieved, the disturbance of consciousness and tachycardia remained persistent. Levels of FT3 and FT4 were extremely high and TSH was below the detectable limit. TRAb was positive. The thyroid storm score of Burch & Wartofsky was 75/140, and the thyroid storm diagnostic criteria of the Japan Thyroid Association were satisfied. Oral administration of thiamazole, potassium iodide and propranolol resulted in immediate relief of the tachycardia.</p> <p>Discussion</p> <p>We encountered a case of thyroid storm associated with Graves' disease covered by DKA. Thyroid storm and DKA are both potentially fatal, and the prognosis varies depending on whether or not these conditions are detected and treated sufficiently early. The thyroid storm diagnostic criteria prepared in 2008 by the Japan Thyroid Association are very simple as compared to the Burch & Wartofsky scoring system for thyroid storm. The Japanese criteria may be useful in the diagnosis of this condition since they enable clinicians to identify a broad range of cases with thyroid storm. When dealing with cases of DKA or thyroid storm, it seems essential to bear in mind the possibility of the coexistence of these two diseases.</p

Scanning SQUID microscope system for geological samples: system integration and initial evaluation

We have developed a high-resolution scanning superconducting quantum interference device (SQUID) microscope for imaging the magnetic field of geological samples at room temperature. In this paper, we provide details about the scanning SQUID microscope system, including the magnetically shielded box (MSB), the XYZ stage, data acquisition by the system, and initial evaluation of the system. The background noise in a two-layered PC permalloy MSB is approximately 40–50 pT. The long-term drift of the system is approximately ≥1 nT, which can be reduced by drift correction for each measurement line. The stroke of the XYZ stage is 100 mm × 100 mm with an accuracy of ~10 µm, which was confirmed by laser interferometry. A SQUID chip has a pick-up area of 200 µm × 200 µm with an inner hole of 30 µm × 30 µm. The sensitivity is 722.6 nT/V. The flux-locked loop has four gains, i.e., ×1, ×10, ×100, and ×500. An analog-to-digital converter allows analog voltage input in the range of about ±7.5 V in 0.6-mV steps. The maximum dynamic range is approximately ±5400 nT, and the minimum digitizable magnetic field is ~0.9 pT. The sensor-to-sample distance is measured with a precision line current, which gives the minimum of ~200 µm. Considering the size of pick-up coil, sensor-to-sample distance, and the accuracy of XYZ stage, spacial resolution of the system is ~200 µm. We developed the software used to measure the sensor-to-sample distance with line scan data, and the software to acquire data and control the XYZ stage for scanning. We also demonstrate the registration of the magnetic image relative to the optical image by using a pair of point sources placed on the corners of a sample holder outside of a thin section placed in the middle of the sample holder. Considering the minimum noise estimate of the current system, the theoretical detection limit of a single magnetic dipole is ~1 × 10-14 Am2. The new instrument is a powerful tool that could be used in various applications in paleomagnetism such as ultrafine-scale magnetostratigraphy and single-crystal paleomagnetism

Plasma Free Amino Acid Profiling of Five Types of Cancer Patients and Its Application for Early Detection

BACKGROUND: Recently, rapid advances have been made in metabolomics-based, easy-to-use early cancer detection methods using blood samples. Among metabolites, profiling of plasma free amino acids (PFAAs) is a promising approach because PFAAs link all organ systems and have important roles in metabolism. Furthermore, PFAA profiles are known to be influenced by specific diseases, including cancers. Therefore, the purpose of the present study was to determine the characteristics of the PFAA profiles in cancer patients and the possibility of using this information for early detection. METHODS AND FINDINGS: Plasma samples were collected from approximately 200 patients from multiple institutes, each diagnosed with one of the following five types of cancer: lung, gastric, colorectal, breast, or prostate cancer. Patients were compared to gender- and age- matched controls also used in this study. The PFAA levels were measured using high-performance liquid chromatography (HPLC)-electrospray ionization (ESI)-mass spectrometry (MS). Univariate analysis revealed significant differences in the PFAA profiles between the controls and the patients with any of the five types of cancer listed above, even those with asymptomatic early-stage disease. Furthermore, multivariate analysis clearly discriminated the cancer patients from the controls in terms of the area under the receiver-operator characteristics curve (AUC of ROC >0.75 for each cancer), regardless of cancer stage. Because this study was designed as case-control study, further investigations, including model construction and validation using cohorts with larger sample sizes, are necessary to determine the usefulness of PFAA profiling. CONCLUSIONS: These findings suggest that PFAA profiling has great potential for improving cancer screening and diagnosis and understanding disease pathogenesis. PFAA profiles can also be used to determine various disease diagnoses from a single blood sample, which involves a relatively simple plasma assay and imposes a lower physical burden on subjects when compared to existing screening methods

FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters

乳がんの再発を起こす原因細胞を解明. 京都大学プレスリリース. 2023-11-16.The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain–containing ion transport regulator 3 (FXYD3), a component of the Na⁺/K⁺ pump. Accordingly, FXYD3⁺ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3⁺ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3⁺ CSCs were sensitive to senolytic Na⁺/K⁺ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3⁺ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na⁺/K⁺ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis

Existence of a Neuropathic Pain Component in Patients with Osteoarthritis of the Knee

∙ The authors have no financial conflicts of interest. © Copyright: Yonsei University College of Medicine 2012 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licens