-
Liver International : Official Journal... Jul 2024We examined the impact of a co-diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) on patient outcomes.
BACKGROUND AND AIMS
We examined the impact of a co-diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) on patient outcomes.
METHODS
Using TriNetX, a global federated research network (n = 114 million), we undertook two retrospective cohort studies, using time-to-event analysis. Analysis 1 compared MASLD with T2D to MASLD alone; analysis 2 compared T2D with MASLD to T2D alone. Propensity score matching using greedy nearest neighbour (calliper .1) balanced the cohorts (1:1) for significant covariates. Primary outcomes were cardiovascular, liver, diabetes-related, and cancer events over 5 years.
RESULTS
Analysis 1 (n = 95 275): a co-diagnosis of T2D significantly increased the risk of ischaemic heart disease (IHD) (HR 1.39; CI: 1.34, 1.44), ischaemic stroke (HR 1.45; CI: 1.35, 1.56), heart failure (HR 1.42; CI: 1.36, 1.49), atrial fibrillation (HR 1.09; CI: 1.03, 1.16), hepatocellular carcinoma (HR 1.96; CI: 1.69, 2.27), pancreatic cancer (HR 1.25; CI: 1.06, 1.48) and liver-related complications over 5 years from MASLD diagnosis. Analysis 2 (n = 15 208): a co-diagnosis of MASLD significantly increased risk of all-cause mortality (HR 1.11; CI: 1.02, 1.22), IHD (HR 1.181; CI: 1.08, 1.29), hepatocellular (HR 50.31; CI: 6.94, 364.72), pancreatic (HR 1.78; CI: 1.12, 2.84), breast (HR 1.43; CI: 1.09, 1.88) and renal cancer (HR 2.01; CI: 1.24, 3.26), and diabetic neuropathy (HR 1.17; CI: 1.09, 1.27) over 5 years from metformin initiation.
CONCLUSIONS
T2D significantly potentiates the risk of cardiovascular, malignancy and liver-related outcomes in people with MASLD. The effect of MASLD on people with T2D, although less dramatic, still potentiated risk of death, IHD, malignancy and peripheral neuropathy.
PubMed: 38949295
DOI: 10.1111/liv.16016 -
Theranostics 2024Myofibroblasts (MYFs) are generally considered the principal culprits in excessive extracellular matrix deposition and scar formation in the pathogenesis of lung...
Myofibroblasts (MYFs) are generally considered the principal culprits in excessive extracellular matrix deposition and scar formation in the pathogenesis of lung fibrosis. Lipofibroblasts (LIFs), on the other hand, are defined by their lipid-storing capacity and are predominantly found in the alveolar regions of the lung. They have been proposed to play a protective role in lung fibrosis. We previously reported that a LIF to MYF reversible differentiation switch occurred during fibrosis formation and resolution. In this study, we tested whether WI-38 cells, a human embryonic lung fibroblast cell line, could be used to study fibroblast differentiation towards the LIF or MYF phenotype and whether this could be relevant for idiopathic pulmonary fibrosis (IPF). Using WI-38 cells, Fibroblast (FIB) to MYF differentiation was triggered using TGF-β1 treatment and FIB to LIF differentiation using Metformin treatment. We also analyzed the MYF to LIF and LIF to MYF differentiation by pre-treating the WI-38 cells with TGF-β1 or Metformin respectively. We used IF, qPCR and bulk RNA-Seq to analyze the phenotypic and transcriptomic changes in the cells. We correlated our transcriptome data from WI-38 cells (obtained via bulk RNA sequencing) with the transcriptomic signature of LIFs and MYFs derived from the IPF cell atlas as well as with our own single-cell transcriptomic data from IPF patients-derived lung fibroblasts (LF-IPF) cultured . We also carried out alveolosphere assays to evaluate the ability of the proposed LIF and MYF cells to support the growth of alveolar epithelial type 2 cells. : WI-38 cells and LF-IPF display similar phenotypical and gene expression responses to TGF-β1 and Metformin treatment. Bulk RNA-Seq analysis of WI-38 cells and LF-IPF treated with TGF-β1, or Metformin indicate similar transcriptomic changes. We also show the partial conservation of the LIF and MYF signature extracted from the Habermann scRNA-seq dataset in WI-38 cells treated with Metformin or TGF-β1, respectively. Alveolosphere assays indicate that LIFs enhance organoid growth, while MYFs inhibit organoid growth. Finally, we provide evidence supporting the MYF to LIF and LIF to MYF reversible switch using WI-38 cells. WI-38 cells represent a versatile and reliable model to study the intricate dynamics of fibroblast differentiation towards the MYF or LIF phenotype associated with lung fibrosis formation and resolution, providing valuable insights to drive future research.
Topics: Humans; Myofibroblasts; Cell Differentiation; Fibroblasts; Cell Line; Idiopathic Pulmonary Fibrosis; Transforming Growth Factor beta1; Lung; Transcriptome; Metformin; Cell Plasticity; Phenotype
PubMed: 38948058
DOI: 10.7150/thno.93519 -
ACS Omega Jun 2024Drug repurposing is a method of investigating new therapeutic applications for previously approved medications. This repurposing approach to "old" medications is now... (Review)
Review
Drug repurposing is a method of investigating new therapeutic applications for previously approved medications. This repurposing approach to "old" medications is now highly efficient, simple to arrange, and cost-effective and poses little risk of failure in treating a variety of disorders, including cancer. Drug repurposing for cancer therapy is currently a key topic of study. It is a way of exploring recent therapeutic applications for already-existing drugs. Theoretically, the repurposing strategy has various advantages over the recognized challenges of creating new molecular entities, including being faster, safer, easier, and less expensive. In the real world, several medications have been repurposed, including aspirin, metformin, and chloroquine. However, doctors and scientists address numerous challenges when repurposing drugs, such as the fact that most drugs are not cost-effective and are resistant to bacteria. So the goal of this review is to gather information regarding repurposing pharmaceuticals to make them more cost-effective and harder for bacteria to resist. Cancer patients are more susceptible to bacterial infections. Due to their weak immune systems, antibiotics help protect them from a variety of infectious diseases. Although antibiotics are not immune boosters, they do benefit the defense system by killing bacteria and slowing the growth of cancer cells. Their use also increases the therapeutic efficacy and helps avoid recurrence. Of late, antibiotics have been repurposed as potent anticancer agents because of the evolutionary relationship between the prokaryotic genome and mitochondrial DNA of eukaryotes. Anticancer antibiotics that prevent cancer cells from growing by interfering with their DNA and blocking growth of promoters, which include anthracyclines, daunorubicin, epirubicin, mitoxantrone, doxorubicin, and idarubicin, are another type of FDA-approved antibiotics used to treat cancer. According to the endosymbiotic hypothesis, prokaryotes and eukaryotes are thought to have an evolutionary relationship. Hence, in this study, we are trying to explore antibiotics that are necessary for treating diseases, including cancer, helping people reduce deaths associated with various infections, and substantially extending people's life expectancy and quality of life.
PubMed: 38947816
DOI: 10.1021/acsomega.4c00617 -
Research Square Jun 2024Background Current effective breast cancer treatment options have severe side effects, highlighting a need for new therapies. Drug repurposing can accelerate...
Background Current effective breast cancer treatment options have severe side effects, highlighting a need for new therapies. Drug repurposing can accelerate improvements to care, as FDA-approved drugs have known safety and pharmacological profiles. Some drugs for other conditions, such as metformin, an antidiabetic, have been tested in clinical trials for repurposing for breast cancer. Here, we exploit the genetics of breast cancer and linked predisposing diseases to propose novel drug repurposing. We hypothesize that if a predisposing disease contributes to breast cancer pathology, identifying the pleiotropic genes related to the risk of cancer could prioritize drug targets, among all drugs treating a predisposing disease. We aim to develop a method to not only prioritize drug repurposing, but also to highlight shared etiology explaining repurposing. Methods We compile breast cancer's predisposing diseases from literature. For each predisposing disease, we use GWAS summary statistics to identify genes in loci showing genetic correlation with breast cancer. Then, we use a network approach to link these shared genes to canonical pathways, and similarly for all drugs treating the predisposing disease, we link their targets to pathways. In this manner, we are able to prioritize a list of drugs based on each predisposing disease, with each drug linked to a set of implicating pathways. Finally, we evaluate our recommendations against drugs currently under investigation for breast cancer. Results We identify 84 loci harboring mutations with positively correlated effects between breast cancer and its predisposing diseases; these contain 194 identified shared genes. Out of the 112 drugs indicated for the predisposing diseases, 76 drugs can be linked to shared genes via pathways (candidate drugs for repurposing). Fifteen out of these candidate drugs are already in advanced clinical trial phases or approved for breast cancer (OR = 9.28, p = 7.99e-03, one-sided Fisher's exact test), highlighting the ability of our approach to identify likely successful candidate drugs for repurposing. Conclusions Our novel approach accelerates drug repurposing for breast cancer by leveraging shared genetics with its known risk factors. The result provides 59 novel candidate drugs alongside biological insights supporting each recommendation.
PubMed: 38947022
DOI: 10.21203/rs.3.rs-4536370/v1 -
MedRxiv : the Preprint Server For... Jun 2024Prediabetes, a high-risk state for developing diabetes, affects more than 1 in 3 adults nationally. However, <5% of people with prediabetes are receiving any treatment...
BACKGROUND
Prediabetes, a high-risk state for developing diabetes, affects more than 1 in 3 adults nationally. However, <5% of people with prediabetes are receiving any treatment for prediabetes. Prior intervention studies for increasing prediabetes treatment uptake have largely focused on individual barriers with few multi-level interventions that address clinician- and system-level barriers.
OBJECTIVE
To measure the effectiveness of a multi-level intervention on uptake of prediabetes treatment in a primary care clinic.
DESIGN
Pragmatic study of the START (Screen, Test, Act, Refer and Treat) Diabetes Prevention intervention.
PARTICIPANTS
The START Diabetes Prevention intervention was implemented in a suburban primary care clinic outside of Baltimore compared to a control clinic in the same area over a 12-month period.
INTERVENTION
START Diabetes Prevention intervention included a structured workflow, shared decision-making resources and electronic health record clinical decision support tools.
MAIN MEASURES
Uptake of prediabetes treatment, defined as Diabetes Prevention Program referral, metformin prescription and/or medical nutrition referral within 30 days of any PCC visit.
KEY RESULTS
We demonstrated greater uptake of preventive treatment among patients with prediabetes in the intervention clinic vs. control clinic receiving usual care (11.6% vs. 6.7%, p<0.001). More patients in the intervention vs. control clinic reported their PCC discussed prediabetes with them (60% vs. 48%, p=0.002) and more felt overall that they understood what their doctor was telling them about prediabetes and that their opinion was valued. The START Diabetes Prevention Strategy had greater acceptability and usefulness to PCCs at the study end compared to baseline.
CONCLUSIONS
A low-touch multi-level intervention is effective in increasing prediabetes treatment uptake. The intervention was also acceptable and feasible for clinicians, and enhanced patient understanding and discussions of prediabetes with their clinicians.
PubMed: 38947005
DOI: 10.1101/2024.06.10.24308653 -
PRiMER (Leawood, Kan.) 2024Metformin is one of the primary pharmacologic agents for managing type 2 diabetes mellitus (T2DM). However, it has been associated with interference in vitamin B12...
BACKGROUND AND OBJECTIVES
Metformin is one of the primary pharmacologic agents for managing type 2 diabetes mellitus (T2DM). However, it has been associated with interference in vitamin B12 absorption and deficiency. Vitamin B12 deficiency and T2DM can present diagnostic challenges for polyneuropathy. Diagnosis is essential for guiding treatment, yet the use of vitamin B12 level testing in this population may have dwindled over time amid changing practice guidelines. This study examines trends over time in the use of vitamin B12 level testing among patients on metformin.
METHODS
This retrospective trend analysis used data from TriNetX, a real-world, longitudinal clinical database. Patients treated with metformin from 2000 to 2020 were identified using Rx Concept Unique Identifier codes. The number of patients who underwent vitamin B12 level testing at any time after 1 month from metformin initiation was tabulated. Patients were grouped by the year of B12 level testing. Trends in B12 level testing were assessed using the Jonckheere-Terpstra statistical test (<.05).
RESULTS
Out of 4,203,020 patients prescribed metformin, 1,055,995 (25.1%) underwent B12 level testing. The highest proportion of patients tested was in 2000 to 2002 (39.6%), while the lowest proportion was in 2018 to 2020 (20.1%). B12 testing utilization declined significantly by 19.5% from 2000-2002 to 2018-2020 (=.001).
CONCLUSIONS
In this study, we found that the use of vitamin B12 level testing in patients on metformin has significantly declined over the years, potentially impacting early detection of B12 deficiency. Future studies with more granular data from real-life practice are recommended to understand the precise reasons and impact of this trend.
PubMed: 38946756
DOI: 10.22454/PRiMER.2024.278059 -
Annales Pharmaceutiques Francaises Jun 2024The present work represents a reverse-phase high-performance liquid chromatography method in addition to stability studies for sequential estimation of Remogliflozin...
OBJECTIVE
The present work represents a reverse-phase high-performance liquid chromatography method in addition to stability studies for sequential estimation of Remogliflozin Etabonate, Vildagliptin, and Metformin HCl in tablet formulation.
METHOD
The mentioned method utilizes a Phenomenex Luna C18 column (250 × 4.6 mm, 5 μm). It consists of a column oven's temperature of 35 ͦ C. Mobile phase includes a mixture of 50% Phosphate buffer (pH - 6.8) and 50% Acetonitrile along with a flow rate of 0.8 mL/min and 20 minutes of run time. The injection volume was 20 μL. 217 nm is a detection wavelength, and a PDA detector is used for detection.
RESULTS
The suggested technique was proven and validated per the ICH Q2(R1) guideline. The combination was put under stress conditions that included acid, base, thermal, photolytic, and oxidative degradation. The combination was considerably degraded under oxidative, acidic, and basic circumstances for deterioration, and the degradation results were accurately identified from the observed peaks, demonstrating the method's effectiveness in detecting stability.
CONCLUSION
The technique was quick, precise, sensitive, and accurate; as a result, it may be used in quality control laboratories and the pharmaceutical industry for routine quality monitoring of tablets containing all three medications.
PubMed: 38945392
DOI: 10.1016/j.pharma.2024.06.006 -
European Journal of Obstetrics,... Jun 2024Isntroduction. Polycystic ovary syndrome (PCOS) is a multifaceted endocrine-gynecological condition affecting a substantial number of women during their reproductive... (Review)
Review
Comparative efficacy of metformin combined with cabergoline versus metformin alone in patients with PCOS and hyperprolactinemia: A systematic review and meta-analysis of randomized controlled trials.
UNLABELLED
Isntroduction. Polycystic ovary syndrome (PCOS) is a multifaceted endocrine-gynecological condition affecting a substantial number of women during their reproductive years. Metformin (MET) has been shown to improve ovarian function in PCOS-related conditions, while cabergoline is recognized for its powerful and sustained ability to reduce prolactin levels. This study investigates the potential impact of combining cabergoline with metformin while comparing it with metformin alone in the treatment of PCOS alongside hyperprolactinemia.
METHOD
To gather data, we searched PubMed, Google Scholar, ScienceDirect, and Cochrane Central. Eligible studies were randomized controlled trials involving patients with PCOS and hyperprolactinemia. Outcome measures included changes in the levels of prolactin, testosterone, DHEAS, BMI and menstrual irregularities. RevMan version 5.4 was used to analyze outcomes.
RESULT
This study incorporated three Randomized Controlled Trials (RCTs) involving 405 participants in total. Patients receiving a combination of metformin and cabergoline experienced significant reductions in prolactin and testosterone levels (p= <0.0001 and p=<0.0001, respectively). Conversely, alterations in DHEAS levels and BMI did not reach statistical significance (p = 0.19 and p = 0.71, respectively). Notably, women solely prescribed metformin exhibited significantly higher rates of menstrual irregularities compared to those receiving both metformin and cabergoline (p=<0.0001).
CONCLUSION
Our analysis underscores the synergistic effect achieved by pairing metformin and cabergoline in patients with PCOS and hyperprolactinemia. However, we encountered only a restricted number of studies meeting our criteria. It is imperative to consistently assess the combined effects of metformin and cabergoline to gain deeper insights into their effectiveness in addressing PCOS and hyperprolactinemia.
PubMed: 38945085
DOI: 10.1016/j.ejogrb.2024.06.037 -
Mymensingh Medical Journal : MMJ Jul 2024Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a rare congenital disorder that affects the female reproductive system and is characterized by an underdeveloped or...
Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a rare congenital disorder that affects the female reproductive system and is characterized by an underdeveloped or absent uterus and vagina. A 17-year-old unmarried female was admitted into the Department of Endocrinology, Mymensingh Medical College Hospital, Bangladesh in November 2023 for evaluation of primary amenorrhea and poorly controlled diabetes mellitus. She was the 5th issue of non-consanguineous marriage delivered at term by normal vaginal delivery. Her growth pattern and developmental milestones were normal. She had no history of galactorrhea, chronic or cyclic pelvic pain, thyroid dysfunction, excessive exercise, psychiatric illness, or drug abuse. There was no history of such type of illness in her family. She was diagnosed with diabetes mellitus two years back without classic symptoms, and at that time, her blood glucose was 22 mmol/L. She was prescribed metformin and gliclazide. She had no history of hypoglycemia, hyperglycemic crises, or hospital admission. On examination, her body build and nutritional status were normal. Anemia, jaundice, edema, dehydration, lymphadenopathy, acne, hirsutism, acanthosis nigricans, abdominal striae and vitiligo were absent. Her blood pressure was 110/70 without the postural drop, thyroid gland was not enlarged, anthropometric measurements were normal and BMI was 18.4 kg/m2. Her tanner stage was P5 & B4. Genital examination revealed normal female external genitalia, and a blind vaginal pouch was found. Other systemic examinations revealed no abnormality. On laboratory reports, her blood glucose was uncontrolled (HbA1c-10.2%) with glycosuria. Thyroid function test and gonadal hormones were normal. Ultrasonogram of the abdomen revealed uterus, cervix, and upper part of the vagina are absent, and an ectopic left kidney.
Topics: Humans; Female; Adolescent; Amenorrhea; 46, XX Disorders of Sex Development; Congenital Abnormalities; Mullerian Ducts; Diabetes Mellitus
PubMed: 38944743
DOI: No ID Found -
Diabetes Research and Clinical Practice Jun 2024Effective diabetes management remains suboptimal in low-resourced countries including Ghana. We determined the effectiveness of hospital-community link diabetes...
OBJECTIVE
Effective diabetes management remains suboptimal in low-resourced countries including Ghana. We determined the effectiveness of hospital-community link diabetes management intervention on glycaemic control and other outcomes.
METHODS
A retrospective study design, using secondary data from the Ghana-Netherlands for Health Foundation diabetes programme. The z-test was used for proportions, to compare parameters between baseline (2017) and endpoint (2022). The Friedman test was used to assess changes in blood glucose levels, and the multivariable Logistic regression to identify factors associated with blood glucose control.
RESULTS
Analyses of 251 clinical records showed decline in median blood glucose levels across six years from 8.8 mmol/L (7.2-12.9) in 2017 to 6.5 mmol/L (5.7-7.2) (p = 0.001) in 2022, recording 43 % increase in patients attaining glycaemic control in 2022 (p = 0.001). The Friedman test showed significant reduction in glucose levels (χ = 319.2, p = 0.001), with an effect size of 0.25 using the Kendall test. The logistic regression analyses revealed that patients on metformin and Glibenclamide combination were more likely to achieve glycaemic control than those on metformin monotherapy (adjusted OR = 7.30, 95 % CI 2.31-23.01, p = 0.001).
CONCLUSION
The intervention achieved significant reduction in blood glucose levels. Patients with diabetes benefit from the hospital-community link diabetes management intervention regarding glycaemic control.
PubMed: 38944249
DOI: 10.1016/j.diabres.2024.111762