Empagliflozin Contributes to Polyuria via Regulation of Sodium Transporters and Water Channels in Diabetic Rat Kidneys

Besides lowering glucose, empagliflozin, a selective sodium-glucose cotransporter-2 (SGLT2) inhibitor, have been known to provide cardiovascular and renal protection due to effects on diuresis and natriuresis. However, the natriuretic effect of SGLT2 inhibitors has been reported to be transient, and long-term data related to diuretic change are sparse. This study was performed to assess the renal effects of a 12-week treatment with empagliflozin (3 mg/kg) in diabetic OLETF rats by comparing it with other antihyperglycemic agents including lixisenatide (10 μg/kg), a glucagon-like peptide receptor-1 agonist, and voglibose (0.6 mg/kg), an α-glucosidase inhibitor. At 12 weeks of treatment, empagliflozin-treated diabetic rats produced still high urine volume and glycosuria, and showed significantly higher electrolyte-free water clearance than lixisenatide or voglibose-treated diabetic rats without significant change of serum sodium level and fractional excretion of sodium. In empagliflozin-treated rats, renal expression of Na+-Cl- cotransporter was unaltered, and expressions of Na+/H+ exchanger isoform 3, Na+-K+-2Cl- cotransporter, and epithelial Na+ channel were decreased compared with control diabetic rats. Empagliflozin increased an expression of aquaporin (AQP)7 but did not affect AQP3 and AQP1 protein expressions in diabetic kidneys. Despite the increased expression in vasopressin V2 receptor, protein and mRNA levels of AQP2 in empagliflozin-treated diabetic kidneys were significantly decreased compared to control diabetic kidneys. In addition, empagliflozin resulted in the increased phosphorylation of AQP2 at S261 through the increased cyclin-dependent kinases 1 and 5 and protein phosphatase 2B. These results suggest that empagliflozin may contribute in part to polyuria via its regulation of sodium channels and AQP2 in diabetic kidneys

Nogo-A regulates myogenesis via interacting with Filamin-C

Among the three isoforms encoded by Rtn4, Nogo-A has been intensely investigated as a central nervous system inhibitor. Although Nogo-A expression is increased in muscles of patients with amyotrophic lateral sclerosis, its role in muscle homeostasis and regeneration is not well elucidated. In this study, we discovered a significant increase in Nogo-A expression in various muscle-related pathological conditions. Nogo−/− mice displayed dystrophic muscle structure, dysregulated muscle regeneration following injury, and altered gene expression involving lipid storage and muscle cell differentiation. We hypothesized that increased Nogo-A levels might regulate muscle regeneration. Differentiating myoblasts exhibited Nogo-A upregulation and silencing Nogo-A abrogated myoblast differentiation. Nogo-A interacted with filamin-C, suggesting a role for Nogo-A in cytoskeletal arrangement during myogenesis. In conclusion, Nogo-A maintains muscle homeostasis and integrity, and pathologically altered Nogo-A expression mediates muscle regeneration, suggesting Nogo-A as a novel target for the treatment of myopathies in clinical settings. © 2021, The Author(s).1

Sonicated Extract of Enterococcus faecalis Induces Irreversible Cell Cycle Arrest in Phytohemagglutinin-Activated Human Lymphocytes

The purpose of this study was to examine whether the sonicated extract of Enterococcus faecalis (SEF) alters the cell cycle transition of lymphocytes and thus regulates the fate of the arrested cells. Human lymphocytes were activated by phytohemagglutinin in the presence or absence of SEF, and cell cycle was assessed by flow cytometry. Seventy-two hours after activation with phytohemagglutinin, cells were activated from G0/G1 to S (6.1%) and G2/M (3.8%) phases of the cell cycle. In contrast, pretreatment with SEF resulted in 90.5% of cells remaining in G0/G1, and cell cycle progression to the S and G2/M phases was consequently inhibited. Caspase assay demonstrated that SEF-treated cells exhibited significantly increased apoptosis (56.7%) compared with phytohemagglutinin alone (28.1%). We propose that if this irreversible cell cycle arrest induced by E. faecalis occurs in vivo, it may result in local immunosuppression and contribute to the pathogenesis of endodontic failure. Our findings that E. faecalis can inhibit lymphocyte responses may be of particular relevance to the pathogenesis of endodontic failure. Although the immunologic mechanism involved in the pathogenesis of persistent periapical lesion is not clearly defined, it is reasonable to predict that the altered immune reaction may be linked to the immunosuppressive potential of E. faecalis or other oral bacteria.This research was supported by a grant (number 03-2002-100) from Seoul National University Hospital

Efficacy and Safety of Biphasic Insulin Aspart 30/70 in Type 2 Diabetes Suboptimally Controlled on Oral Antidiabetic Therapy in Korea: A Multicenter, Open-Label, Single-Arm Study

BackgroundThe purpose of this study was to evaluate change in glycosylated hemoglobin (HbA1c), side effects, and quality of life (QOL) after a 16-week treatment period with Biphasic insulin aspart 30/70 (BIasp30) in patients with type 2 diabetes mellitus (T2DM) who had been suboptimally controlled with oral antidiabetic drugs (OADs).MethodsThe study consisted of a 4-week titration period when concurrent OAD(s) were replaced with BIasp30 and followed by a 12-week maintenance period. All patients completed the Diabetes Treatment Satisfaction Questionnaire at the beginning and the end of the trial. Hypoglycemic episodes were recorded by the patient throughout the trial.ResultsSixty patients were included, of whom 55 patients (92%) completed the full 16-week treatment period. Seven-point blood glucose was significantly improved as compared with the baseline, except for the postlunch blood glucose level. HbA1c at the end of period was significantly improved from 9.2% to 8.2% (P<0.001). Eleven percent (n=6) of patients achieved HbA1c values ≤6.5% and 22% (n=12) of patients achieved <7.0%. There were 3.4 episodes/patients-year of minor hypoglycemia and 0.05 episodes/patients-year of major hypoglycemia. QOL showed significant changes only in the acceptability of high blood glucose category (P=0.003).ConclusionTreatment with once or twice daily BIasp30 may be an option for the patients with T2DM suboptimally controlled with OADs in Korea. However, considering the low number of patients achieving the HbA1c target and the high postlunch blood glucose levels, additional management with another modality may be required for optimal control

Severe Hypoglycemia Is a Serious Complication and Becoming an Economic Burden in Diabetes

BackgroundThe prevalence of hypoglycemia is increasing due to the growing incidence of diabetes and the latest strict guidelines for glycated hemoglobin (HbA1c) levels under 7%. This study examined the clinical characteristics, causal factors, and medical costs of severely hypoglycemic patients in an emergency room (ER) of Uijeongbu St. Mary's Hospital.MethodsThe study consisted of a retrospective analysis of the characteristics, risk factors, and medical costs of 320 severely hypoglycemic patients with diabetes who presented to an ER of Uijeongbu St. Mary's Hospital from January 1, 2006 to December 31, 2009.ResultsMost hypoglycemic patients (87.5%, 280/320) were over 60 years old with a mean age of 69.5±10.9 years and a mean HbA1c level of 6.95±1.46%. Mean serum glucose as noted in the ER was 37.9±34.5 mg/dL. Renal function was decreased, serum creatinine was 2.0±2.1 mg/dL and estimated glomerular filtration rate (eGFR) was 48.0±33.6 mL/min/1.73 m2. In addition, hypoglycemic patients typically were taking sulfonylureas or insulin and a variety of other medications, and had a long history of diabetes.ConclusionSevere hypoglycemia is frequent in older diabetic patients, subjects with low HbA1c levels, and nephropathic patients. Therefore, personalized attention is warranted, especially in long-term diabetics with multiple comorbidities who may not have been properly educated or may need re-education for hypoglycemia