Continuous Subcutaneous Injection Research Articles

Gallic acid ameliorates endometrial hyperplasia through the inhibition of the PI3K/AKT pathway and the down-regulation of cyclin D1 expression

BackgroundGallic acid (GA) is an organic compound with phenolic properties that occurs naturally and can be found in Guizhi Fuling capsules, showcasing a wide range of biological functionalities. PurposeThe objective of this study was to examine the influence of GA on endometrial hyperplasia (EH) and elucidate its underlying mechanism. MethodsInitially, the induction of EH was achieved by administering estradiol to mice via continuous subcutaneous injection for a duration of 21 days. Concurrently, GA treatment was administered, and subsequently, the uterine tissue structure was assessed using hematoxylin and eosin (H&E) staining. Following this, the proliferation of human endometrial cells treated by GA was determined utilizing the CCK-8 method. Furthermore, network pharmacology and single-cell-RNA-seq data were employed to identify the target of GA action. In addition, we will employ immunofluorescence (IF), immunohistochemistry (IHC), flow cytometry, western blot and RT-qPCR methodologies to investigate the impact of GA on the expression level of cyclin D1, PI3K, p-PI3K, AKT, p-AKT. ResultsGA treatment ameliorated histopathological alterations in the uterus and suppress proliferation. Estradiol stimulation can activate the PI3K/AKT pathway, leading to up-regulation of cyclin D1 expression, whereas GA treatment results in down-regulation of its expression. ConclusionsThe expression of cyclin D1 is down-regulated by GA through the inhibition of the PI3K/AKT pathway, effectively mitigating estradiol-induced EH in mice.

Continuous Subcutaneous Infusion Versus Multiple Daily Injections of Insulin for Pregestational Diabetes in Pregnancy: A Systematic Review and Meta-Analysis.

The use of continuous subcutaneous insulin infusion (CSII) therapy in pregnancies affected by pregestational diabetes mellitus (DM) has generated mixed outcome data worthy of further investigation. This systematic review and meta-analysis aims to evaluate clinical outcomes associated with CSII versus multiple daily injections (MDIs) in pregnant persons with pregestational DM. A predefined, systematic, librarian-assisted search of MEDLINE (PubMed), Embase, Cochrane Library, Scopus, ClinicalTrials.gov, and World Health Organization International Clinical Trial Registry Platform (published from 2010 to 2022) yielded 3003 studies describing pregnancy outcomes associated with CSII and/or MDI for pregestational DM. The primary exposure was mode of insulin administration, with cesarean delivery and neonatal hypoglycemia as the primary maternal and neonatal outcomes, respectively. Secondary outcomes included hypertensive disorders of pregnancy, first and third-trimester glycemic control, large-for-gestational age (LGA) neonate, preterm birth, neonatal intensive care unit admission, need for respiratory support, hyperbilirubinemia, 5-minute Apgar <7, shoulder dystocia, and perinatal mortality. We calculated pooled odds ratios (OR) with 95% confidence intervals (CI) using random-effects models. Among 39 eligible studies, 39% of the 5518 pregnancies included were exposed to CSII. Odds of cesarean delivery were higher with CSII (20 studies: 63% vs 56%, odds ratio [OR] 1.3 [95% confidence interval (CI) 1.2-1.5]), but we did not identify a difference in the odds of neonatal hypoglycemia (23 studies: 31% vs 34%, OR 1.1 [95% CI 0.9-1.5]). Among secondary outcomes, only the odds of LGA (20 studies: 47% vs 38%, OR 1.4 [95% CI 1.2-1.6]) were higher in individuals using CSII versus MDI. Use of CSII (vs MDI) for pregestational DM in pregnancy is associated with higher odds of cesarean delivery and delivery of an LGA neonate. Further evaluation of how CSII use may influence neonatal size and delivery route is warranted.

Toxicokinetics of recombinant human fibroblast growth factor 21 for injection in cynomolgus monkey for 3months.

Introduction: Recombinant human fibroblast growth factor 21 (FGF-21) is a potential therapeutic agent for multiple metabolic diseases. However, little is known about the toxicokinetic characteristics of FGF-21. Methods: In the present study, we investigated the toxicokinetics of FGF-21 delivered via subcutaneous injection in vivo. Twenty cynomolgus monkeys were injected subcutaneously with different doses of FGF-21 for 86days. Serum samples were collected at eight different time points (0, 0.5, 1.5, 3, 5, 8, 12, and 24h) on day 1, 37 and 86 for toxicokinetic analysis. The serum concentrations of FGF-21 were measured using a double sandwich Enzyme-linked immunosorbent assay. Blood samples were collected on day 0, 30, 65, and 87 for blood and blood biochemical tests. Necropsy and pathological analysis were performed on d87 and d116 (after recovery for 29days). Results: The average AUC(0-24h) values of low-dose FGF-21 on d1, d37, and d86 were 5253, 25268, and 60445μgh/L, and the average AUC(0-24h) values of high-dose FGF-21 on d1, d37, and d86 were 19964, 78999, and 1952821μgh/L, respectively. Analysis of the blood and blood biochemical indexes showed that prothrombin time and AST content in the high-dose FGF-21 group increased. However, no significant changes in other blood and blood biochemical indexes were observed. The anatomical and pathological results showed that continuous subcutaneous injection of FGF-21 for 86 days did not affect organ weight, the organ coefficient, and histopathology in cynomolgus monkeys. Discussion: Our results have guiding significance for the preclinical research and clinical use of FGF-21.

Retracted: Effect of Continuous Subcutaneous Injection of Insulin Analogues in Pregnant Women with Diabetes Mellitus Complicated with Ketoacidosis.

[This retracts the article DOI: 10.1155/2021/8670474.].

Platelets lipidomics study of blood stasis rat model by using liquid chromatography-tandem mass spectrometry.

This study analyzed a lipidomic profile of platelets from blood stasis rats by liquid chromatography-tandem mass spectrometry. The blood stasis rat was established by low-dose continuous subcutaneous injection of adrenaline, and the evaluation indexes included hemorheology and platelet aggregation. Principal component analysis and partial least-squares discriminant analysis were used to analyze platelet lipidomics, and p-value<0.05, fold change>1.5, and variable importance plot>2 were used to screen potential biomarkers. Then, the biomarkers were optimized by the receiver operating characteristic curve. Compared with the normal rat, the blood stasis model group's whole blood viscosity and platelet aggregation rate were also significantly increased at different shear rates (p<0.05). Twenty-four potential lipid biomarkers showed significant changes in platelets between the two groups. Among them, six long-chain acylcarnitine components and three sphingosine components showed a consistent downward trend, suggesting that these two kinds of components may play an essential role in the process of platelet aggregation. Liquid chromatography-tandem mass spectrometry-based lipidomics studies provide much information to understand the pathology of platelets in blood stasis.

Research Progress of B-Cell Lymphoma/Leukemia-2 Inhibitor Combined with Azacytidine in the Targeted Therapy of Acute Myeloid Leukemia.

Objective To investigate the efficacy and safety of azacytidine and B-cell lymphoma/leukemia-2 inhibitors in the treatment of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods The clinical data of 31 patients with AML/MDS who were clearly diagnosed with AML/MDS were analyzed from 2018.10 to 2021.02, and the total amount of azacyclonol and B-cell lymphoma/leukemia-2 inhibitor was used for single or combined chemotherapy, with a total amount of 75 mg/m2∗7 d, divided into 7-10 days of continuous subcutaneous injection, every 28-30 days for a course of treatment. Overall response rate (ORR), median survival, poor response, and genetic mutations were observed. Results A total of 104 courses of treatment were completed in 31 patients, the median course was 3 (1–12), and 6 patients who did not complete 2 courses of treatment were not counted in the statistics. After 2 courses, ORR was 72.0%, CRES was 2 (8.0%), mCR was 16 (64.0%), disease stable was 5 (20.0%), treatment failures were 2 (8.0%), mortality was 40.0%, and median survival time was >5 months. Single-agent and combined ORR was 64.3% and 81.8%, respectively, with median survival of 7.25 and 9 months; ORR for MDS and AML was 66.7% and 76.9%, respectively, median survival of 8 and 11 months was 66.7% and 80.0% of ORRs at 260 and V60 years, respectively, and median survival of 7 and 11.5 months; MDS-EB-1. The ORR of MDS-EB-2 was 75.0% and 62.5%, respectively, with median survival times of 11.5 and 6.5 months. During 2 courses and 4 courses, the rate of transfusion dependence was 64.0% and 55.5%, respectively. Fifteen cases were detected by second-generation sequencing, and the results were 14 cases of combined gene mutations. Conclusion Azacytidine and B-cell lymphoma/leukemia-2 inhibitors have good efficacy and high safety in the treatment of AML and MDS, and the combined treatment is better than that of monotherapy, but the side effects of combination therapy are large.

Oral Glucose-Responsive Nanocarrier System for Management of Diabetes

Background: The regulation of postprandial blood glucose concentration in a diabetic person is a toilsome task by the conventional approaches. The continuous monitoring and subcutaneous injection of insulin are always imperative for diabetes management. To overcome the hurdle associated with the conventional system, a glucose-responsive nanoparticle (NP)-based approach was developed for oral insulin administration. The objective of the work is the formulation and characterization of a nanocarrier-based bio-responsive, self-regulated oral insulin drug delivery system. Methods: The mannose ligand-conjugated NPs were prepared by the inotropic gelation method in which insulin and glucose oxidase enclosed alginate nanocarrier cross-linked by tripolyphosphate. The prepared NPs were filled into the enteric-coated capsule and their release profile was determined at different pH and glucose concentrations. NPs were characterized by size distribution, % drug entrapment, enzyme activity, and in vivo and in vitro drug release studies. Results: The average size, surface potential, % drug entrapment of optimized NPs were 245.52 ± 3.37 nm, 22.12 ± 2.13, and 76.15±1.3%, respectively. The release of insulin from optimized NPs (GOx-ALG-MCNPs) (98.56±0.06%) occurs only at higher sugar concentrations (? 400 mg/dL) and prevents the release at low sugar concentrations (&lt; 100 mg/dL). The enteric capsule shell protected the formulation to the gastric environment upon oral administration and directed them into the intestine. Mucoadhesion characteristics of NPs prolonged intestinal retention to make them available for cellular uptake. Glucose sensitivity and glucose-dependent effect on different pH environments study revealed that NPs released the drug only at higher concentrations of sugar solution while inhibiting the release at normal and lower sugar concentrations. Besides, compared to other prepared formulations, the GOx-ALG-MCNPs displayed controlled insulin release in response to glucose concentration. Conclusions: An important finding of GOx-ALG-MCNPs is auto-regulating, glucose-responsive behavior imparting a significantly controlled lowering of blood glucose in an animal model. The findings reveal that the developed glucose-responsive NPs may prove to be a potential strategy for oral insulin delivery. J Endocrinol Metab. 2022;12(4-5):146-160 doi: https://doi.org/10.14740/jem747

Continuous Intravenous versus Subcutaneous Administration of Insulin for Glycemic Variability in Acute Ischemic Stroke.

BackgroundContinuous intravenous infusion (IV) or subcutaneous injection (SC) of insulin was widely applied to control hyperglycemia after ischemic stroke. However, the impact of different administration modes on glycemic variability was unknown.MethodsConsecutive stroke patients treated with intravenous thrombolysis were screened. Subjects who received insulin treatment were included and entered into the IV or SC group according to the respective administration mode. Blood glucose was closely monitored within the first 72 hours, and the target range of glucose was from 7.7 to 10.0 mmol/L for all patients. The variabilities of glucose, assessed using standard deviation of the mean, variable coefficient and range from the maximum to the minimum value, were compared between the two groups.ResultsA total of 130 patients were enrolled with 66 in the IV groups and 64 in the SC group. Compared with the SC group, the IV group had higher glycemic variability evaluated as either standard deviation (2.7 ± 0.7 mmol/L vs 2.2 ± 0.9 mmol/L, p = 0.002), variable coefficient (0.26 ± 0.06 vs 0.23 ± 0.08, p = 0.011) or range (10.0 ± 3.6 mmol/L vs 8.1 ± 3.1 mmol/L, p = 0.001). Multivariate logistic regression analyses found that continuous intravenous infusion was associated with higher level of the standard deviation (adjusted OR 3.01, 95% CI 1.29–7.28, p = 0.011), variable coefficient (adjusted OR 5.97, 95% CI 2.55–13.96, p < 0.001) and range (adjusted OR 6.08, 95% CI 2.63–14.05, p < 0.001).ConclusionContinuous intravenous infusion of insulin was associated with higher glycemic variability than subcutaneous injection in acute stroke patients receiving thrombolysis.

CO18 Real-World Evidence of the Effect of Continuous Subcutaneous Insulin Infusion Vs Multiple Daily Injections on HBA1C in 25,000 Adults with Type 1 Diabetes: A Quasi-Experimental Study

The use of continuous subcutaneous insulin infusion (CSII) is a widely used therapeutic strategy for achieving near-normal blood glucose for people with type 1 diabetes (T1D). Clinical trials have shown that CSII can improve glycated hemoglobin (HbA1c) compared with multiple daily injections (MDI). However, whether this is the case in the real world remains largely unresolved. Thus, the objective of this study was to estimate the effect of CSII on HbA1c compared with MDI, using real-world population data.

Abstract 5288: Development of lead mutant-p53 reactivating peptides towards clinical application

Abstract p53 is the most extensively studied tumor suppressor. It serves as a major barrier against malignant transformation and the p53 pathway is inactivated in almost all human tumors. A large percentage of tumors inactivate p53 by point mutations in the DNA binding domain (DBD) of the protein. Most mutations destabilize p53 protein folding, causing its partial denaturation at physiological temperature. Thus a high proportion of human tumors overexpress a potential potent tumor suppressor in a non-functional, improperly folded form. Previously, we reported the use of phage display technology to select for peptides that reactivate mutant p53 by stabilizing a wt protein conformation, taking advantage of a unique combination of selection steps (Tal P, at al Oncotarget. 2017 Jan 3;8(1):164-178). We now describe further progress in the development of one lead peptide, pCAP-250, which contains 9 amino acids and a myristic fatty acid at its N-terminus. The pCAP-250 sequence bears 100% homology to RAD9, a known p53 interacting protein. We show physical interaction between pCAP-250 and the p53DBD. Characterization of this interaction by NMR reveals a significant chemical shift of amino acids located in the p53DBD L1 loop and Helix-2, two regions critical for p53 transcriptional activity and interaction with DNA. We also report the optimization of our lead sequence by rational design to yield more potent derivatives with higher efficacy in cancer cell elimination and longer in vivo half-life. RNA-seq analysis shows that our lead peptides induce robust activation of p53 target genes. Furthermore, we report that in addition to p53 activation, pCAP-250 also has a p53-independent anti-cancer activity. Overall, our lead peptides cause specific cell death in a wide spectrum of mutant p53 expressing cell lines, with an IC50 of 0.1-12µM, while having no effect on non-transformed cells at these concentrations. The pharmacokinetic profile of pCAP-250 and its derivatives shows that they are completely stable in human serum and have plasma half-life of 1.5-10h in vivo when administered IV or subcutaneously, presumably due to interaction with albumin through the fatty acid moiety. Remarkably, our lead peptides elicit remarkable regression of very aggressive tumors in several preclinical mouse models of renal, colon, pancreatic and ovarian cancer. In vivo efficacy can be achieved through several routes of administration, including intra-tumor injection as well as systemic subcutaneous continuous slow release and subcutaneous bi-daily injections. Thus, such peptides might serve as novel therapeutic agents for p53-mutated human cancer. Citation Format: Perry Tal, Moshe Oren, Orna Palgi, Varda Rotter, KWANGIL JEONG. Development of lead mutant-p53 reactivating peptides towards clinical application [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5288.

Experience with Blonanserin Patch for Prevention of Nausea and Vomiting during the Initiation of Continuous Subcutaneous Injection of Hydromorphone Hydrochloride in Patients with End-stage Cancer Who are Difficult to Take Internal Medication in Palliative Care Unit

Experience with Blonanserin Patch for Prevention of Nausea and Vomiting during the Initiation of Continuous Subcutaneous Injection of Hydromorphone Hydrochloride in Patients with End-stage Cancer Who are Difficult to Take Internal Medication in Palliative Care Unit

Successful Dose Titration to Cancer Pain by Continuous Subcutaneous Injection of Hydromorphone Hydrochloride: A Retrospective Analysis

Successful Dose Titration to Cancer Pain by Continuous Subcutaneous Injection of Hydromorphone Hydrochloride: A Retrospective Analysis

Effect of Continuous Subcutaneous Injection of Insulin Analogues in Pregnant Women with Diabetes Mellitus Complicated with Ketoacidosis.

Objective To investigate the clinical effect of continuous subcutaneous injection of insulin analogues in pregnant women with diabetes mellitus complicated with ketoacidosis. Methods A total of 92 pregnant patients with diabetes mellitus complicated with ketoacidosis from June 2014 to January 2021 were selected. All patients were randomly divided into an observation group and control group according to the method of random number. The control group received intravenous infusion of insulin, and the observation group received continuous subcutaneous infusion of quick-acting insulin analogues. The clinical effects of the two groups were observed. Results The time needed to control blood glucose <13.8 mmol/L, the amount of insulin needed to control blood glucose <13.8 mmol/L, the time needed to correct DKA, and the amount of insulin needed to correct DKA in the observation group were significantly less than those in the control group (P < 0.05). Compared with the control group, the average occurrence times of hypoglycemia, the length of stay, the total amount of insulin in hospital, and the total amount of insulin used during pregnancy in the observation group were significantly less than those in the control group (P < 0.05). The values of SCr, CRP, BUN, arterial blood gas pH, and adiponectin in the two groups were significantly improved as compared with those before treatment, and the improvement in the observation group was significantly better than that in the control group (P < 0.05). After treatment, the fasting blood glucose, 2-hour postprandial blood glucose, carbon dioxide binding capacity, and glycosylated hemoglobin in the experimental group were significantly better than those in the routine group, and the difference was statistically significant (P < 0.05). Conclusion Continuous subcutaneous injection of insulin analogues is effective in the treatment of diabetic patients with ketoacidosis, which can effectively improve blood glucose, carbon dioxide binding capacity, and glycosylated hemoglobin and accelerate the negative conversion of urinary ketone body. It is worth popularizing to reduce the occurrence of hypoglycemia and the dose of insulin and shorten the time of hospitalization.

Continuous subcutaneous insulin infusion alters microRNA expression and glycaemic variability in children with type 1 diabetes

To determine whether continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) therapy from near-diagnosis of type 1 diabetes is associated with reduced glycaemic variability (GV) and altered microRNA (miRNAs) expression. Adolescents (74% male) within 3-months of diabetes diagnosis (n = 27) were randomized to CSII (n = 12) or MDI. HbA1c, 1-5-Anhydroglucitol (1,5-AG), high sensitivity C-peptide and a custom TaqMan qPCR panel of 52 miRNAs were measured at baseline and follow-up (median (LQ-UQ); 535 (519–563) days). There were no significant differences between groups in baseline or follow-up HbA1c or C-peptide, nor baseline miRNAs. Mean ± SD 1,5-AG improved with CSII vs. MDI (3.1 ± 4.1 vs. − 2.2 ± − 7.0 mg/ml respectively, P = 0.029). On follow-up 11 miRNAs associated with diabetes vascular complications had altered expression in CSII-users. Early CSII vs. MDI use is associated with lower GV and less adverse vascular-related miRNAs. Relationships with future complications are of interest.

Accelerating transdermal delivery of insulin by ginsenoside nanoparticles with unique permeability

Diabetes is a metabolic disease caused by insufficient insulin secretion, action or resistance, in which insulin plays an irreplaceable role in the its treatment. However, traditional administration of insulin requires continuous subcutaneous injections, which is accompanied by inevitable pain, local tissue necrosis and hypoglycemia. Herein, a green and safe nanoformulation with unique permeability composed of insulin and ginsenosides is developed for transdermal delivery to reduce above-mentioned side effects. The ginsenosides are self-assembled to form shells to protect insulin from hydrolysis and improve the stability of nanoparticles. The nanoparticles can temporarily permeate into cells in 5 min and promptly excrete from the cell for deeper penetration. The insulin permeation is related to the disorder of stratum corneum lipids caused by ginsenosides. The skin acting as drug depot mantains the nanoparticles released continuously, therefore the body keeps euglycemic for 48 h. Encouraged by its long-lasting and effective transdermal therapy, ginsenosides-based nano-system is expected to deliver other less permeable drugs like proteins and peptides and benefit those who are with chronic diseases that need long-term medication.

Farnesol-Loaded Liposomes Protect the Epidermis and Dermis from PM2.5-Induced Cutaneous Injury.

Particulate matter with aerodynamic diameter ≤2.5 μm (PM2.5) increases oxidative stress through free radical generation and incomplete volatilization. In addition to affecting the respiratory system, PM2.5 causes aging- and inflammation-related damage to skin. Farnesol (Farn), a natural benzyl semiterpene, possesses anti-inflammatory, antioxidative, and antibacterial properties. However, because of its poor water solubility and cytotoxicity at high concentrations, the biomedical applications of Farn have been limited. This study examined the deleterious effects of PM2.5 on the epidermis and dermis. In addition, Farn-encapsulated liposomes (Lipo-Farn) and gelatin/HA/xanthan gel containing Lipo-Farn were prepared and applied in vivo to repair and alleviate PM2.5-induced damage and inflammation in skin. The prepared Lipo-Farn was 342 ± 90 nm in diameter with an encapsulation rate of 69%; the encapsulation significantly reduced the cytotoxicity of Farn. Lipo-Farn exhibited a slow-release rate of 35% after 192 h of incubation. The half-maximal inhibitory concentration of PM2.5 was approximately 850 μg/mL, and ≥400 μg/mL PM2.5 significantly increased IL-6 production in skin fibroblasts. Severe impairment in the epidermis and hair follicles and moderate impairment in the dermis were found in the groups treated with post-PM2.5 and continuous subcutaneous injection of PM2.5. Acute and chronic inflammation was observed in the skin in both experimental categories in vivo. Treatment with 4 mM Lipo-Farn largely repaired PM2.5-induced injury in the epidermis and dermis, restored injured hair follicles, and alleviated acute and chronic inflammation induced by PM2.5 in rat skin. In addition, treatment with 4 mM pure Farn and 2 mM Lipo-Farn exerted moderate reparative and anti-inflammatory effects on impaired skin. The findings of the current study indicate the therapeutic and protective effects of Lipo-Farn against various injuries caused by PM2.5 in the pilosebaceous units, epidermis, and dermis of skin.

195-OR: A Comparison of Inpatient Glycemic Control Using Continuous Subcutaneous Insulin Infusion vs. Multiple Daily Injections in Persons with Type 1 Diabetes

Background: Continuous subcutaneous insulin infusion (CSII) therapy is increasingly being used in the outpatient setting, but there is little known information about its efficacy in the inpatient setting. This study compares inpatient glycemic control of persons with type 1 diabetes (T1D) using CSII, multiple daily injections (MDI), or both. Method: This retrospective chart review assessed the glycemic control of adult patients with T1D who used CSII, MDI or a combination of both during their hospitalization between January 1, 2017 and December 31, 2019. Those who were pregnant and/or treated with continuous intravenous insulin infusion were excluded. Variables were summarized descriptively using means and frequencies. Continuous variables were compared across groups using the ANOVA or Kruskal-Wallis test, and categorical variables were compared using the Fisher’s Exact test. Results: We analyzed records of 65 patients who were mostly male (53.8%) and white (72%) with a mean age of 51.7 ± 16.0 years. The mean hemoglobin A1c was 7.80 ± 1.08%. Though not statistically significant, both mean blood glucose and proportion of hyperglycemic events (proportion of blood glucose measures &amp;gt; 300 mg/dL) were lowest in the CSII group. Mean blood glucose for CSII, MDI, and both was 172.88 ± 40.14, 195.40 ± 43.90, and 199.50 ± 49.99 mg/dL, respectively (p=0.17). The proportion of hyperglycemic events for CSII, MDI, and both was found to be 0.11 ± 0.11, 0.26 ± 0.20, and 0.27 ± 0.27, respectively (overall p=0.0267, pairwise comparisons not significant). Conclusion: Glycemic control of patients with CSII is not significantly different than patients with MDI or a combination of both in persons with T1D, thus suggesting that patients can remain on CSII therapy while inpatient. Disclosure Y. Ye: None. S. Izard: None. A. Myers: None.

The Effect of Prestudy Insulin Therapy on Safety and Efficacy of Human Regular U-500 Insulin by Pump or Injection: A Posthoc Analysis

ObjectiveWe conducted a posthoc analysis of the VIVID study (Safety and Efficacy of Human Regular U-500 Insulin Administered by Continuous Subcutaneous Insulin Infusion Versus Multiple Daily Injections in Subjects With Type 2 Diabetes Mellitus: A Randomized, Open-Label, Parallel Clinical Trial), comparing 2 delivery methods of human regular U-500 insulin (U-500R), continuous subcutaneous insulin infusion (CSII) versus multiple daily injection (MDI), in type 2 diabetes requiring high insulin, to determine influence of prestudy insulin on glycemic outcomes. MethodsWe compared A1C, total daily insulin dose (TDD), weight, and hypoglycemia by subgroups of prestudy insulin (prestudy U-500R vs non-U-500R) and treatment (CSII vs MDI). ResultsAt baseline, prestudy U-500R had higher TDD, higher body mass index, lower A1C and fasting plasma glucose, and higher rate of hypoglycemia compared to non-U-500R. Active titration of U-500R reduced A1C in both subgroups, with maximum benefit at 8 weeks. At 26 weeks, CSII provided the greatest reduction in A1C in both subgroups, with a greater reduction in non-U-500R. MDI provided an A1C reduction in both subgroups, with the greater reduction in non-U-500R. At 8 weeks, prestudy U-500R reached its lowest A1C; thereafter, A1C rebounded with MDI and remained stable with CSII. In non-U-500R, A1C continued to decrease to study end. In non-U-500R, hypoglycemia increased during active titration, but then decreased in the posttitration maintenance period. In both subgroups, TDD increased from baseline with MDI but not with CSII. Body weight increased in both subgroups but was greater in prestudy U-500R with CSII compared to MDI. ConclusionRegardless of previous insulin, people on high-dose insulin could lower A1C with U-500R, with additional benefit from CSII. These results may provide guidance for use of U-500R in clinical practice.

Curcumin in Combination with Aerobic Exercise Improves Follicular Dysfunction via Inhibition of the Hyperandrogen‐Induced IRE1α/XBP1 Endoplasmic Reticulum Stress Pathway in PCOS‐Like Rats

Combining diet with exercise can improve health and performance. Exercise can reduce androgen excess and insulin resistance (IR) in polycystic ovary syndrome (PCOS) patients. Curcumin is also presumed to improve the follicle development disorder. Here, we investigated the effects of a combination therapy of oral intake of curcumin and exercise on hyperandrogen-induced endoplasmic reticulum (ER) stress and ovarian granulosa cell (GC) apoptosis in rats with PCOS. We generated a PCOS model via continuous dehydroepiandrosterone subcutaneous injection into the necks of Sprague Dawley rats for 35 days. PCOS-like rats then received curcumin treatment combined with aerobic (treadmill) exercise for 8 weeks. We found that compared to control rats, the ovarian tissue and ovarian GCs of hyperandrogen-induced PCOS rats showed increased levels of ER stress-related genes and proteins. Hyperandrogen-induced ovarian GC apoptosis, which was mediated by excessive ER stress and unfolded protein response (UPR) activation, could cause follicle development disorders. Both curcumin gavage and aerobic exercise improved ovarian function via inhibiting the hyperandrogen-activated ER stress IRE1α-XBP1 pathway. Dihydrotestosterone- (DHT-) induced ER stress was mitigated by curcumin/irisin or 4μ8C (an ER stress inhibitor) in primary GC culture. In this in vitro model, the strongly expressed follicular development-related genes Ar, Cyp11α1, and Cyp19α1 were also downregulated.

Lactobacillus plantarum Y44 alleviates oxidative stress by regulating gut microbiota and colonic barrier function in Balb/C mice with subcutaneous d-galactose injection.

Probiotics have been proved to ameliorate the symptoms of the host induced by oxidative stress. In this study, the protective effects of Lactobacillus plantarum Y44 on Balb/C mice injured by d-galactose (d-gal)-injection were examined. Six weeks of continuous subcutaneous d-gal injection caused liver and colon injury of the Balb/C mice. L. plantarum Y44 administration significantly reversed the injury by modulating hepatic protein expressions related to the Nrf-2/Keap-1 pathway, and enhancing expressions of colonic tight junction proteins. L. plantarum Y44 administration restored the d-gal injection-induced gut microbiota imbalance by manipulating the ratio of Firmicutes/Bacteroidetes (F/B) and Proteobacteria relative abundance at the phylum level, and manipulating relative abundances of Lactobacillaceae, Muribaculaceae, Ruminococcaceae, Desulfovibrionaceae, and Prevotellaceae at the family level. Moreover, the d-gal injection-induced glycerophospholipid metabolism disorder was ameliorated, evidenced by the decline of phosphatidyl ethanolamine (PE), phosphatidylcholine (PC), phosphatidyl serine (PS), and lysophosphatidyl choline (LysoPC) levels in the serum of the mice after the L. plantarum Y44 administration. Spearman correlation analysis revealed a significant correlation between changes in gut microbiota composition, glycerophospholipid levels, and oxidative stress-related indicators. In summary, L. plantarum Y44 administration ameliorated d-gal injection-induced oxidative stress in Balb/C mice by manipulating gut microbiota and intestinal barrier function, and further influenced the glycerophospholipid metabolism and hepatic Nrf-2/Keap-1 pathway-related protein expressions.