Search Results (1,787)

Background: Among individuals with type 2 diabetes (T2D), lifestyle improvements can restore glycemic control, yet few studies have examined deprescribing in settings where it was necessitated by improvements in health. This study aimed to (1) identify instances of medication deprescribing among adults with T2D in a primary care setting where patients had access to lifestyle medicine (LM), (2) document lifestyle changes among deprescribed patients, (3) assess changes in body mass index (BMI), glucose, and hemoglobin A1c (HbA1c) following deprescribing, and (4) assess the safety of deprescribing in the context of LM-informed care by identifying adverse events. Methods: A retrospective review of electronic health records (EHR) was conducted among 650 adults with a diagnosis of T2D per ICD-10 code at two primary care practices. To be included in the study, individuals had to be seen at least two times during the study period, from 2014 to 2023. Using a previously developed deprescribing framework, records were reviewed to identify deprescribing events. Among patients who were identified as deprescribed, BMI, glucose, and HbA1c, were extracted from the EHR, and age-, sex-, and time-adjusted differences in least squares means were calculated. Mentions of lifestyle change in provider notes in the EHR were also extracted pre- vs. post-deprescribing. Results: Forty-one deprescribing events were confirmed, totaling 6.3% of the study population. The most common medication changes included metformin dose reduction 34%, metformin discontinuation 19.5%, and insulin dose reduction 19.5%. Among patients with follow-up data, mean BMI decreased by 2.25 kg/m², p = 0.0003. Mean decreases of 25% in glucose and 13% in HbA1c were also observed, p < 0.0003 and p < 0.0013, respectively. Lifestyle modifications were specifically cited in 51% of records among deprescribed patients, most frequently related to diet and exercise. No serious adverse events were identified in patients who were deprescribed. Conclusions: In a primary care setting where patients had access to lifestyle medicine, a subset of adults with T2D experienced meaningful health improvements and were able to reduce glucose-lowering medications without any serious adverse events noted in the EHR. Full article

The ADA 2026 Standards of Care in Diabetes introduces pivotal updates that refine diagnostic and therapeutic workflows. Expanding upon the 2025 guidelines, the 2026 edition broadens continuous-glucose-monitoring (CGM) eligibility to include all individuals on insulin or non-insulin therapies where CGM aids management. Significant new guidance addresses hyperglycemia management in oncology, identifying metformin as the preferred first-line intervention for drug-induced glycemic excursions. Additionally, type 1-diabetes (T1D) risk stratification is refined; a confirmed single IA-2 autoantibody now warrants monitoring levels similar to the Stage 2 disease. Furthermore, prerequisites for automated-insulin-delivery (AID) initiation have been removed to streamline technology access. For laboratory professionals, these revisions emphasize the critical role of advanced glycemic metrics and precise autoantibody profiling in complex clinical contexts. Full article

Microbiome-targeted interventions have shown promise for metabolic health, yet clinical evidence remains inconsistent, particularly across stages of metabolic disease. This study evaluated the metabolic effects, safety, and tolerability of EDC-HHA01, a microbiome-informed, non-pharmacologic intervention, in adults with prediabetes (PD) or Type 2 Diabetes (T2DM). In a randomized, double-blind, placebo-controlled clinical trial, participants received EDC-HHA01 or placebo for six months. The study was adequately powered (≥80%) for the primary endpoint. Outcomes included changes in glycated hemoglobin (HbA1c), indices of insulin resistance, markers of metabolic endotoxemia, safety-related laboratory parameters, and exploratory patient-reported measures. Analyses were stratified by metabolic status and background metformin use. In participants with PD, EDC-HHA01 supplementation was associated with a statistically and clinically meaningful reduction in HbA1c compared with placebo, supported by concordant improvements in fasting insulin, insulin resistance indices, and reductions in endotoxemia markers. In participants with T2DM, changes were directionally similar but attenuated and did not reach statistical significance. The intervention was well tolerated, with no serious adverse events, high adherence, and no clinically relevant adverse changes in renal or lipid parameters. Exploratory patient-reported outcomes indicated favorable acceptability but were not interpreted as efficacy endpoints. EDC-HHA01 was associated with biologically coherent, stage-dependent metabolic effects, most evident in PD. These findings support further investigation of microbiome-informed strategies as metabolic support in early-stage dysregulation. Full article

Background/Objectives: Metformin has been proposed as a potential treatment for hyperprolactinemia irrespective of etiology. Previous studies suggest that vitamin D deficiency attenuates the prolactin-lowering effect of metformin in women. This study examined whether vitamin D status modifies the effects of this agent on prolactin and other anterior pituitary hormones in men with iatrogenic hyperprolactinemia. Methods: Seventy-five adult men with antipsychotic-induced hyperprolactinemia and type 2 diabetes or prediabetes were enrolled. Participants were assigned to three equal groups based on vitamin D status and supplementation: vitamin D-naive men with sufficient levels (group 1), vitamin D-naive men with deficiency (group 2), and men with sufficient vitamin D levels receiving oral supplementation for at least six months (group 3). All participants received metformin (3 g/day) for six months. Plasma 25-hydroxyvitamin D, markers of glucose metabolism, total and monomeric prolactin, TSH, gonadotropins, ACTH, testosterone, and IGF-1 were measured at baseline and after treatment. Results: Baseline characteristics were comparable among groups except for 25-hydroxyvitamin D levels. Seventy participants completed the study. Metformin improved glycemic control and insulin sensitivity in all groups, with greater effects in men with sufficient vitamin D status. Reductions in total and monomeric prolactin were observed only in groups 1 and 3 and were associated with baseline prolactin concentrations and pretreatment 25-hydroxyvitamin D levels. These changes were accompanied by modest increases in LH and testosterone, and improvements in sexual functioning. Vitamin D levels and other hormonal parameters remained unchanged. The magnitude of the metformin effect did not differ between groups 1 and 3. Conclusions: Adequate vitamin D status is necessary for metformin to reduce prolactin levels in men with iatrogenic hyperprolactinemia. Full article

Background: The pathophysiological mechanisms of Abdominal Aortic Aneurysm (AAA) are not elucidated. Alterations in mitochondrial function, such as a reduction in oxidative phosphorylation (OXPHOS), have been observed at genome level and functionally in vascular smooth muscle cells. Metformin reduces AAA development and growth in diabetic patients, but the precise mechanisms are not known. In this paper we aim to demonstrate the feasibility of measuring mitochondrial functional capacity ex vivo in intact murine aneurysmal tissue and confirm a decrease in OXPHOS, and to determine if the protective effect of metformin on AAA is mediated by mitochondrial function. Methods: AAA was induced in ApoE KO mice by administration of angII (1000 ng/kg/min) through osmotic minipumps. Metformin was administered in drinking water at a dose of 100 mg/kg/day. The abdominal aorta was isolated in situ and mitochondrial functional capacity was analyzed ex vivo in whole permeabilized tissue by high-resolution respirometry. Results: Mitochondrial respiration was successfully measured ex vivo in whole aneurysmal tissue. Mitochondrial function was impaired in angII-treated mice, with decreased fold change in Complex I and Complex I+II oxygen consumption, relative to basal levels. Complex II oxygen consumption was also decreased in angII-treated mice. Rescue treatment of mice with metformin did not affect or restore mitochondrial function. Conclusions: Mitochondrial function can be evaluated in murine whole aneurysmal tissue, providing a method for a physiological approach to the study of mitochondrial function in AAA. Mitochondrial function is impaired in AAA. However, rescue treatment with metformin is not sufficient to recover mitochondrial function and seems not to be the mechanism behind prevention of aneurysm. Full article

Background: There is growing recognition that certain medical conditions, such as type 2 diabetes (T2D), can be effectively addressed through comprehensive lifestyle changes, thereby reducing reliance on medications; however, little guidance exists on deprescribing following lifestyle change. This study aimed to develop a framework that can be used to better define and standardize across research studies which medication changes in T2D care can be classified as deprescribing. Methods: An iterative development process began with a review of medication data exported from electronic health records (EHR) for n = 650 patients with T2D, 18–89 years, from two primary care practices with LM board-certified physicians. Included patients were seen during the period of 15 May 2014 to 13 March 2023. All reported T2D medications were grouped into the following categories: insulin, non-insulin, or metformin. A consensus-based review process was employed, facilitated by weekly meetings with the research team, whereby patients were classified as “potentially deprescribed,” “not deprescribed,” or “unclear” (not enough information based on limited, exported EHR data). Patients identified as potentially deprescribed or “unclear” were then further assessed through a more detailed review of their EHR. Results: Using the results of this chart review, a framework was developed to identify types of deprescribing, as follows: (1) insulin dose reduced; (2) change from insulin to other non-insulin medication; (3) insulin discontinued; (4) non-insulin T2D medication stopped; (5) dose reduced of the same non-insulin T2D medication; (6) change from any non-insulin medication to metformin or multiple medications + metformin to metformin only; (7) metformin stopped; (8) metformin dose reduced. A total of n = 193 patients were identified as having been potentially deprescribed based on the exported EHR data, and after a more detailed review of individual EHR records, 41 were confirmed as deprescribed. Conclusions: This study is the first to present a novel framework for classifying deprescribing in the context of positive health outcomes. The framework will facilitate future research evaluating the impact of lifestyle changes on diabetes management and promote comparability across settings for medication outcomes. Future research is needed to apply this framework to quantify deprescribing across various settings with greater precision. Full article

Obesity-associated carcinogenesis offers a model to explore the transition from metabolic dysregulation to genomic instability and carcinogenesis. Adenosine 5′-monophosphate-activated protein kinase (AMPK), the principal cellular energy sensor, coordinates adenosine triphosphate (ATP) production with metabolic demand; however, in obesity, AMPK activity is impaired, resulting in reduced ATP, elevated Adenosine Monophosphate (AMP), and cellular energy stress. Deoxyribonucleic Acid (DNA) polymerases ε (Pol ε) and δ (Pol δ) maintain replication fidelity via a 3′→5′ exonuclease proofreading activity that removes misincorporated nucleotides. Elevated AMP directly binds and selectively inhibits the exonucleases, conserving energy at the expense of genomic accuracy. As a result, replication errors escape correction and accumulate, some conferring a selective advantage and driving carcinogenic evolution. Therapeutic and lifestyle interventions that activate AMPK—including weight loss, exercise, metformin, and aspirin—restore ATP production, lower AMP, and relieve inhibition of exonuclease proofreading, thereby preserving genomic integrity and slowing mutation-driven carcinogenesis. This framework reveals two core biological principles: 1. Energy metabolism and DNAreplication fidelity are mechanistically coupled at the DNA polymerase active site. 2. The mutation rate is an adaptive metabolic phenotype, modulated by AMP levels. These concepts redefine the metabolic–genetic interface in carcinogenesis and highlight AMPK activation as a rational target for obesity-associated cancer prevention. Full article

Gestational Diabetes Mellitus (GDM) is the most common metabolic complication of pregnancy, affecting approximately 14% of pregnancies globally. Despite the frequent normalization of glycemic parameters immediately after delivery, GDM is an important precursor of subsequent chronic disease, increasing the risk of type 2 diabetes (T2DM). Current international guidelines suggest just a strictly observational approach during the immediate puerperium, recommending metabolic screening only between 6 and 12 weeks postpartum. This has contributed to the creation of a therapeutic “orphan window” where women receive no specific metabolic support, leaving their metabolic status unassessed and unmanaged. We postulate that the immediate postpartum period represents a critical window of “metabolic plasticity” where the abrupt cessation of placental hormones offers a unique opportunity to restore insulin sensitivity and promote “beta-cell rest” before the onset of irreversible dysfunction. Consequently, this narrative review and perspective examines the epidemiological urgency of the GDM-to-T2DM transition and provides a biological rationale for early pharmacological or nutraceutical intervention. Specifically, we discuss the limitations of metformin and present the hypothesis of myo-inositol combined with alpha-lactalbumin as a safe, lactation-compatible “bridging therapy” to preserve beta-cell function, improve compliance, and modify the natural history of diabetes in this high-risk population, highlighting that this theoretical proposal requires validation through future clinical trials. Full article

Background/Objectives: Herbal formulas are unsuitable for routine dietary use. This study evaluates Qige Pipa Decoction (QPD), a food–medicine homologous formula containing edible components, comparing its anti-diabetic effects with the classic Gegen Qinlian Decoction (GQD) to explore its potential as a sustainable dietary intervention for T2DM. Methods: T2DM mice received QPD, GQD, or metformin for 6 weeks. Parameters included glycemic control, histopathology, gut microbiota (16S rRNA), serum metabolomics, liver transcriptomics, and chemical profiling (UPLC-Q-TOF-MS). Results: Both formulas comparably improved glycemia and insulin resistance. QPD uniquely enriched beneficial gut bacteria (e.g., Roseburia) and suppressed pro-inflammatory taxa. Metabolomics revealed decreased Carnitine C20:1 and increased phospholipids in the QPD group. Transcriptomics showed QPD enriched the AGE-RAGE signaling pathway. Chemically, QPD showed relatively higher signal intensities for glycosides and organic acids, while GQD showed relatively higher signal intensities for alkaloids. Conclusions: QPD exhibits anti-diabetic efficacy similar to GQD but through distinct regulatory mechanisms. Its food-medicine homologous composition provides a theoretical rationale for its exploration as a sustained dietary adjunct. However, the absence of safety biomarkers in this study precludes definitive conclusions regarding long-term tolerability, necessitating dedicated toxicological assessment in future trials. Full article

Chronic Kidney Disease (CKD) is a global health crisis, projected to be the fifth leading cause of death by 2040. Its progression is driven by a reinforcing loop of mitochondrial dysfunction, oxidative stress, and chronic inflammation. The AMPK-NRF2–FOXO axis serves as a central “redox-metabolic rheostat” that maintains renal homeostasis but is commonly dysfunctional in CKD. Herein, we explore the molecular crosstalk within this network, where AMPK acts as a metabolic and redox sensor, NRF2 governs the cytoprotective response, and FOXO isoforms regulate autophagy, antioxidative defense, and senescence. We highlight the functional paradoxes within the axis and evaluate the benefits and drawbacks of nutraceuticals and pharmacological agents, such as NRF2 inducer bardoxolone methyl, underscoring the necessity for context-dependent modulation. Furthermore, we examine the AMPK–NRF2–FOXO axis within the current clinical management, according to the 2024/2026 KDIGO guidelines. These guidelines reflect a shift toward a multi-targeted pharmacological approach involving metformin, SGLT2 inhibitors, GLP-1 receptor agonists, finerenone, and hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors. Full article

Background: Chronic kidney disease (CKD) affects up to 40% of patients with diabetes mellitus and has important implications for metformin safety. Although estimated glomerular filtration rate (eGFR)-based dosing is recommended, there is no consensus on the optimal estimating equation, which may lead to inconsistent treatment decisions. Methods: This retrospective study analyzed 46,788 Thai patients with diabetes from 2014 to 2024. eGFR was calculated using five equations, and CKD stages and metformin eligibility were evaluated according to U.S. FDA and KDIGO guidelines. Results: Median eGFR differed significantly across equations (p-value < 0.001), with the highest values observed using CKD-EPI 2009 and the lowest using Cockcroft–Gault. Among 30,805 metformin users, 0.6–3.7% had eGFR < 30 mL/min/1.73 m² depending on the equation used. Agreement with CKD-EPI 2009 ranged from 96 to 99 than 1% (≈3% with Cockcroft–Gault) were unnecessarily excluded from metformin therapy. CKD-EPI 2021 yielded approximately 4.5 mL/min/1.73 m² higher eGFR values, reclassifying 19% of patients to a better CKD stage. Conclusions: Differences among eGFR equations affect CKD staging and metformin eligibility. CKD-EPI 2009, CKD-EPI 2021, S-MDRD, and Thai GFR showed good agreement, whereas Cockcroft–Gault may underestimate renal function, potentially excluding patients who could safely continue metformin. Until outcome data are available, the widely used CKD-EPI equation remains the preferred reference due to its consistency with other standard equations. Further prospective studies are needed to evaluate the clinical impact of equation choice on metformin management. Full article

Background: Ovarian cancer (OC) is characterized by aggressive progression, high metastatic potential, and frequent resistance to conventional chemotherapy, highlighting the need for novel combination-based therapeutic strategies. Metformin has emerged as a promising antineoplastic agent; however, its efficacy may be enhanced through combination with bioactive compounds. This study aimed to investigate the antineoplastic effects of metformin in SKOV3 human OC cells and to evaluate whether these effects could be potentiated by boric acid (BA) and resveratrol, with particular emphasis on their modulatory impact on key inflammatory and tumor-associated biomarkers, including interleukin-17 (IL-17), nuclear factor kappa-B (NF-κB), and midkine (MDK). Methods: SKOV3 cells were treated with metformin, BA, and resveratrol as monotherapies or in combination. Cell viability was assessed using a colorimetric assay, while migratory capacity was evaluated by wound healing analysis. The expression levels of IL-17, NF-κB, and MDK were quantified in cell lysates, and p21 protein expression was analyzed by immunocytochemistry. Results: All treatments induced concentration- and time-dependent reductions in cell viability. Combination treatments, particularly metformin with boric acid or resveratrol, produced more pronounced inhibitory effects on cell survival and migration compared with single-agent treatments. Inflammatory and tumor-associated biomarkers, including IL-17, NF-κB, and MDK, were significantly modulated following treatment. Additionally, increased p21 expression was observed in treated cells, indicating enhanced cell cycle regulatory activity. Conclusions: These findings indicate that BA and resveratrol enhance the antineoplastic activity of metformin in SKOV3 OC cells by suppressing proliferative and migratory capacities and modulating inflammatory mediators such as IL-17, NF-κB, and MDK. However, since toxicity assessments in non-cancerous cells were not performed, the safety profile of this combination remains unclear and requires further investigation in non-cancerous models. Full article

Preconception care is globally recognized as essential for optimizing pregnancy outcomes; however, in Japan, comprehensive data on medication-related potential exposure to pregnancy-contraindicated medications among women of reproductive age remain limited. We conducted a retrospective cross-sectional descriptive study using data from Japan’s National Database of Health Insurance Claims (fiscal year 2022) to assess the potential exposure to pregnancy-contraindicated medications among women of reproductive age. Outpatient prescriptions for oral medications dispensed to women aged 15–49 years were analyzed. In total, 270 medications classified as contraindicated during pregnancy were identified, of which 75 were also contraindicated for women planning pregnancy. Of these, 58 active ingredients were restricted in both phases. Notably, 212 medications were uniquely contraindicated during pregnancy, highlighting the broader contraindication profiles during fetal development than during the preconception period. Despite these contraindications, high prescription volumes were observed for medications such as loxoprofen sodium hydrate, sodium valproate, and metformin hydrochloride among women of reproductive age. These findings illustrate a high baseline utilization of pregnancy-contraindicated medications among women of reproductive age. As most women in this demographic are neither pregnant nor actively planning conception, these volumes primarily reflect standard care rather than inappropriate prescribing. In conclusion, pharmacists serve as an important supplementary safety net by routinely confirming pregnancy status to prevent inadvertent exposure. Full article

Introduction: Aging affects both metabolic and circadian systems, leading to disruptions in energy homeostasis and phase shifts in the circadian clock. Metformin, a widely used antihyperglycemic drug, exerts anti-aging effects by modulating key pathways in the liver and also influences the liver circadian clock. However, the optimal medication strategy, including dosage and timing, that achieves significant anti-aging effects while minimizing negative impacts on the circadian clock remains unclear. This study aims to identify a rational metformin administration strategy considering both aspects. Methods: An extended mathematical model of the liver circadian clock incorporating metformin regulation was developed, and numerical simulations were performed to evaluate different dosing times and feeding conditions. Results: Metformin administration at different times produced distinct effects on both the circadian clock and anti-aging outcomes. Administration during the increasing phase of CLOCK-BMAL1 concentration showed positive effects on the circadian clock and effective anti-aging properties. Regarding feeding patterns, a fed-like state was not conducive to anti-aging, whereas fasting was beneficial. Conclusions: These findings highlight the importance of dosing time and feeding styles in optimizing metformin efficacy and provide insights into its potential pharmacological applications in anti-aging therapy. Full article

Diabetes mellitus (DM) is a major disorder contributing to human mortality and morbidity globally. The use of medicinal plants in the management of diabetes is gaining global popularity due to their accessibility and cost-effectiveness. In this study, we evaluated the ameliorative potential of Vernonia amygdalina leaves crude extract (CE), free phenol (FP), and bound phenol (BP) fractions (50 mg/kg body weight) in a rat model of streptozotocin (STZ)-induced type 1 diabetes (T1DM). The effects of these treatments for 28 days on glucose, insulin, glycated hemoglobin, hepatic injury indices, and lipid profile were assessed in the serum. Furthermore, redox biomarkers (liver) and inflammatory mediators (serum and liver) were analyzed. Our results indicated that CE, FP, and BP fractions of Vernonia amygdalina inhibited the deleterious effects of T1DM by attenuating hyperglycaemia, insulin deficiency, hepatic injury, and dyslipidemia. Also, CE, FP, and BP fractions differentially improved antioxidant enzymes activity and reduced oxidative and inflammatory markers production. Specifically, CE showed superior effects compared with FP, BP, and metformin across multiple biomarkers, including glycated hemoglobin, α-amylase, α-glucosidase, hepatic glycogen, total cholesterol, LDL-cholesterol, protein carbonyl, SOD, IL-1β, and IL-10. The antidiabetic effects produced by CE, FP, and BP fractions of Vernonia amygdalina may be ascribed to the presence of different bioactive phytochemicals as revealed by HPLC analysis. Overall, our data would suggest a potential therapeutic role for Vernonia amygdalina leaves extracts in addressing hepatic complications due to T1DM. Full article