Search Results (121)

Metformin, the most widely prescribed oral antihyperglycemic agent, is established as the first-line therapy for type 2 diabetes mellitus (T2DM) owing to its efficacy, affordability, and safety. Increasing evidence indicates that its benefits extend beyond glycemic control, encompassing cardiovascular protection and diabetes prevention in individuals at elevated cardiometabolic risk. Mechanistic studies demonstrate that metformin exerts pleiotropic effects through activation of AMP-activated protein kinase, modulation of the gut microbiota, inhibition of pro-inflammatory and oxidative stress pathways, and improvements in endothelial function, lipid metabolism, and insulin sensitivity. These actions address core drivers of atherosclerosis and metabolic dysfunction, many of which occur independently of glucose lowering. In patients with T2DM, the cardiovascular benefits of metformin are well recognized, including reductions in all-cause mortality and cardiovascular events. In individuals without diabetes but at high cardiovascular risk—such as those with prediabetes, obesity, or metabolic syndrome—evidence is more limited, as most data are derived from subgroup analyses or trials with surrogate endpoints. Nonetheless, consistent signals suggest that metformin may delay the progression from prediabetes to overt diabetes and potentially confer vascular protection, particularly in carefully selected high-risk populations. Clinical trials and meta-analyses have demonstrated that metformin reduces incident diabetes by approximately one quarter in high-risk adults, with stronger effects observed in younger, overweight individuals, women with prior gestational diabetes, and those treated for longer durations. However, uncertainties remain regarding its long-term cost-effectiveness, optimal dosing strategies, and cardiovascular benefits in non-diabetic populations. The ongoing VA-IMPACT trial (NCT02915198) is expected to clarify whether metformin reduces major cardiovascular events in prediabetic patients with atherosclerotic disease. Taken together, metformin represents more than an antidiabetic drug. Its pleiotropic mechanisms, favorable safety profile, and low cost support its potential integration into broader cardiometabolic prevention strategies, including primary prevention. Expanding its role beyond diabetes management may offer a cost-effective, widely accessible intervention with significant public health impact. Full article

Background/objectives: Chronic degenerative complications of diabetes, such as atherosclerotic cardiovascular disease and chronic kidney disease, contribute to an increased morbimortality in patients with type 2 diabetes (T2D), and thus, a multifactorial approach becomes essential. Among the classes of antihyperglycemic agents with beneficial pleiotropic cardiorenal effects, the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have proven to reduce the risk of major adverse cardiovascular (CV) and renal events. This study aims to assess the impact of treatment with GLP-1 RA on CV risk factors, insulin sensitivity, and renal function in Romanian patients with T2D. Methods: In an observational retrospective study, 150 patients with T2D were evaluated at the start of therapy with a GLP-1 RA and then after 6 and 12 months. Results: After 12 months of treatment, 59.3% of patients succeeded in achieving weight loss of over 5% of their initial weight, and 24.7% of patients achieved weight loss of over 10% of their initial weight, with the most significant decrease being measured in the first 6 months. HbA1c has shown a similar profile, with a significant reduction in the first 6 months of treatment, continued at a slower rate in the following 6 months. Additionally, the lipid profile, blood pressure values, and uric acid values, alongside the triglyceride/high-density lipoprotein cholesterol (TG/HDLc) ratio and the triglyceride–glucose (TyG) index have improved in these T2D patients treated with GLP-1 RA, while their eGFR decrease was slower than the one expected for similar populations without such a pharmacologic agent in their regimen. Conclusions: Treatment with GLP-1 RA in patients with T2D is associated with an improved cardiovascular–kidney–metabolic risk profile, ameliorated glycemic control, reduced weight, lower insulin resistance, and slower kidney disease progression. Full article

Background and Objectives: GLP-1 receptor agonists (GLP-1 RAs; ATC A10BJ) and dual GLP-1/GIP agonist (ATC A10BX16) have expanded rapidly due to strong evidence in type 2 diabetes, obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Their high acquisition costs and accelerating uptake make them key drivers of pharmaceutical expenditure. This study quantified national utilization and expenditure trends for antihyperglycemic drugs in Croatia (2017–2024), with a focus on GLP-1 RA and dual GLP-1/GIP agonists. Materials and Methods: Aggregate national data on dispensed medicines, valued at wholesale pharmacy prices, were obtained from HALMED’s annual ATC/DDD reports. Utilization was expressed as defined daily doses per 1000 inhabitants per day (DDD/1000/day). We analyzed the total A10 and key subclasses. The dual GLP-1/GIP agonist was only marketed in 2024. Compound annual growth rates (CAGR) were calculated. Results: The total antihyperglycemic utilization increased from 66.9 to 96.8 DDD/1000/day (a 44.7% rise), while the total A10 expenditure increased from EUR 54.2 million to EUR 96.5 million, indicating that expenditure growth outpaced utilization growth. GLP-1 receptor agonist expenditure increased from EUR 5.2 million (2018) to EUR 28.6 million (2024) (CAGR 33.0%), reaching 29.8% of total A10 expenditure in 2024. Expenditure for GLP-1-based agents grew faster than their DDD volume because per-DDD acquisition costs are substantially higher than for SGLT-2 inhibitors. These growth patterns are consistent with trajectories reported in higher-uptake EU health systems, suggesting convergence rather than an outlier position for Croatia. Conclusions: Croatia experienced a rapid shift towards GLP-1 RA-based antihyperglycemic pharmacotherapy, with GLP-1-based therapies exerting a disproportionate budget impact. For payers, these surveillance data support budget forecasting and negotiation of pricing and reimbursement conditions; clinicians can use them to benchmark and optimize evidence-aligned prescribing; and policymakers can apply them to monitor the diffusion and fiscal impact of high-cost therapies. Routine national ATC/DDD analysis, complemented by HZZO claims and primary-care datasets, is essential for guiding future pricing, reimbursement and formulary decisions. Full article

Background: Vaspin (also known as serpinA12) is a recent discovery among adipokines. It plays a significant role in obesity-related conditions, many of which are classified as chronic, inflammatory or lifestyle diseases. Due to its anti-inflammatory and insulin-sensitizing properties, vaspin has been investigated as a biomarker and potential therapeutic agent. Methods: A literature review was conducted using the MEDLINE and SCOPUS databases using the phrases “vaspin” and “serpinA12” to summarize the most recent and influential research concerning vaspin’s mechanisms and influence on various tissues. Results and Conclusions: Vaspin is notably involved in metabolic syndrome, and it is generally associated with mitigating conditions like insulin resistance and obesity-related chronic inflammation. In addition, its beneficial effects on endothelial and smooth muscle cells under hyperglycemic and hyperlipidemic conditions are also well documented. There is growing evidence that vaspin positively impacts cardiovascular health, reducing the risk of ischemic stroke and the development of atherosclerosis. Moreover, some studies suggest a direct influence of vaspin on the central nervous system, with its administration shown to reduce the expression of neuropeptide Y, a key regulator of food intake. Many of the reviewed sources highlight vaspin not only as a possible biomarker but also as a promising therapeutic candidate. However, despite intensive research on vaspin over the past 20 years, there are significant disparities between animal and in vitro studies versus human studies. A further limitation in the field is the lack of standardization in research methodologies, which contributes to inconsistent and sometimes contradictory results. Full article

According to the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC), type 2 diabetes mellitus (T2DM) remains a major public health issue with a considerable impact on human life, affecting over 38 million Americans of all ages, and an estimated 529 million people worldwide. It is a significant risk factor for polyneuropathy, eye problems, coronary artery disease (CAD), renal disease, heart disease, stroke, and peripheral artery disease (PAD). Nearly 9 million Americans with diabetes are unaware of their condition and, therefore, do not receive health care to prevent disease progression and complications. With T2DM being a condition that leads to increased demand for health care services due to its long-term, persistent nature and its incremental impact on the body, early diagnosis and timely initiation of effective treatments are essential. Despite the effect of metabolic memory in the development of diabetes-related complications, early intervention helps decelerate disease progression, reduce complications, and ultimately improve survival. Various blood-based biomarkers have been identified, which hold great promise to streamline the mechanisms underlying T2DM and its progression from insulin resistance and prediabetes to diabetes and end-stage diabetes. However, the greatest need is to identify and utilize reliable biomarkers that can help to assess pharmacological treatment response and guide efforts to improve insulin sensitivity, preserve pancreatic beta-cell function, and prevent or delay complications. This review explores the clinical utility of promising biomarkers and assess their potential to support more personalized pharmacological approaches tailored to the individual characteristics of T2DM patients. Full article

Background/Objectives: Fouquieria splendens Engelm. is a medicinal plant traditionally used in North America for treating metabolic disorders; however, its antihyperglycemic properties and safety profiles remain poorly studied. We investigated the phytochemical composition, oral acute toxicity, mutagenicity, and antihyperglycemic activity of the foliar ethanolic extract of F. splendens (EFS). Methods: Phytochemical analysis was performed using ultra-performance liquid chromatography–mass spectrometry. Acute toxicity and mutagenicity were evaluated following the OECD guidelines. Antihyperglycemic activity was assessed in streptozotocin-induced diabetic rats treated with EFS (200 mg/kg) alone or in combination with metformin for 30 days. Results: Eleven phenolic compounds were identified in the EFS, including ellagic acid, morin, apigenin, and luteolin 7-Oglucoside. EFS was non-mutagenic and had an LD₅₀ of >2000 mg/kg. This treatment significantly reduced blood glucose levels and enhanced the effect of metformin in diabetic rats. Histopathological analysis showed preserved morphology in the pancreatic, hepatic, and renal tissues of the treated animals. Conclusions: EFS exhibited significant antihyperglycemic activity and a favorable safety profile, supporting its potential as a complementary phytotherapeutic agent for diabetes management. These results highlight the pharmacological value of F. splendens and promote the exploration of native plants as adjuncts for chronic disease therapy. Full article

Cardiovascular (CV) disease, chronic kidney disease, obesity, and diabetes mellitus have reached epidemic proportions over the past few decades. Accumulating evidence highlights the strong interconnection between these conditions, leading to the definition of a broader disease entity known as cardio-renal-metabolic (CRM) syndrome. This newly recognized clinical entity presents important challenges in identifying the optimal treatment strategy within a holistic, patient-centered framework. In line with this, sodium glucose cotransporter 2 inhibitors (SGLT2is), owing to their multifaceted pharmacological effects, have been suggested as possible treatment options in the management of CRM. SGLT2is exert their antihyperglycemic effects by impeding the renal reabsorption of sodium and glucose, causing glycosuria and natriuresis. Research has confirmed that their unique beneficial effects extend beyond glycemic control, reducing CV death and hospitalizations in patients with heart failure, and the incidence of kidney failure in dedicated kidney outcome studies—regardless of diabetes status. Furthermore, these agents contribute to weight loss and blood pressure reduction. Their benefits appear to stem from a combination of factors, which include reduced oxidative stress, lower levels of inflammation, regulated neurohormonal activation, improved endothelial function, and enhanced metabolic efficiency. This review aims to provide a comprehensive analysis of the pathophysiological mechanisms underlying the effects of SGLT2is in CRM syndrome, synthesize evidence from landmark clinical trials, evaluate current experimental and diagnostic approaches, and provide the emerging role of SGLT2is in the treatment of this new clinical entity. Full article

Background/Objectives: Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that regulate blood glucose by preventing the degradation of active incretin hormones. Although clinically effective, this drug class is associated with adverse effects, creating the need for new molecular scaffolds with improved safety and efficacy. Methods: We evaluated the antihyperglycemic activity of β-aminohydrazine and β-amino-N-acylhydrazone derivatives (LASSBio-2123, 2125, 2129, and 2130) using a combined in vivo and in silico approach. Male C57BL/6 mice underwent glucose tolerance tests (GTT) and dexamethasone-induced insulin resistance protocols. Hepatic and skeletal muscle glycogen levels, as well as GLUT4 mRNA expression, were quantified. In silico studies included ADMET predictions and molecular docking analyses against aldose reductase and glucokinase enzymes. MTT was performed on the pancreatic cell line MIN6 (Mus musculus). Results: Among the compounds tested, LASSBio-2129 demonstrated the most promising profile, with favorable ADMET parameters, metabolic stability, and high docking affinity for aldose reductase and glucokinase. In vivo, LASSBio-2129 (10 mg/kg, i.p.) reduced blood glucose, increased hepatic and muscle glycogen storage, and upregulated GLUT4 mRNA expression in skeletal muscle. Additionally, LASSBio-2129 improved insulin sensitivity in the dexamethasone-induced insulin resistance model, with effects comparable to sitagliptin. Conclusions: The combined pharmacological, docking, and ADMET analyses identified LASSBio-2129 as aldose reductase inhibitor candidate and glucokinase activator. Its ability to improve glucose tolerance, enhance glycogen storage, and increase GLUT4 expression highlights its potential as a promising molecule for the treatment of type 2 diabetes mellitus. Full article

Background: Sodium–glucose cotransporter-2 inhibitors (SGLT2is), initially developed as antihyperglycemic agents, have emerged as multifunctional therapeutics with profound cardiorenal and metabolic benefits. Their unique insulin-independent mechanism, targeting renal glucose reabsorption, distinguishes them from conventional antidiabetic drugs. Mechanisms and Clinical Evidence: SGLT2is induce glycosuria, reduce hyperglycemia, and promote weight loss through increased caloric excretion. Beyond glycemic control, they modulate tubuloglomerular feedback, attenuate glomerular hyperfiltration, and exert systemic effects via natriuresis, ketone utilization, and anti-inflammatory pathways. Landmark trials (DAPA-HF, EMPEROR-Reduced, CREDENCE, DAPA-CKD) demonstrate robust reductions in heart failure (HF) hospitalizations, cardiovascular mortality, and chronic kidney disease (CKD) progression, irrespective of diabetes status. Adipose Tissue and Metabolic Effects: SGLT2is mitigate obesity-associated adiposopathy by shifting macrophage polarization (M1 to M2), reducing proinflammatory cytokines (TNF-α, IL-6), and enhancing adipose tissue browning (UCP1 upregulation) and mitochondrial biogenesis (via PGC-1α/PPARα). Modest weight loss (~2–4 kg) occurs, though compensatory hyperphagia may limit long-term effects. Emerging Applications: Potential roles in non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and neurodegenerative disorders are under investigation, driven by pleiotropic effects on metabolism and inflammation. Conclusions: SGLT2is represent a paradigm shift in managing T2DM, HF, and CKD, with expanding implications for metabolic syndrome. Future research should address interindividual variability, combination therapies, and non-glycemic indications to optimize their therapeutic potential. Full article

Diabetes mellitus (DM) is a global health challenge marked by chronic hyperglycemia, which can result in complications such as diabetic cardiomyopathy. Sitagliptin, an oral anti-hyperglycemic drug, has demonstrated efficacy in alleviating cardiovascular complications associated with DM. This study explored the impact of Sitagliptin’s potential as a therapeutic agent, functioning not only to control blood sugar levels but also to enhance vascular health and strengthen cardiac resilience in diabetes. The investigation focused on alterations in the vascular endothelial growth factor (VEGF) and its receptor-1 (FLT-1) signaling pathways, as well as its potential to suppress inflammation and oxidative stress. A number of rats received a single dose of streptozotocin (STZ) 55 mg/kg (i.p.) to induce DM. Sitagliptin was administered orally (100 mg/kg/90 days) to normal and diabetic rats, after which samples were collected for investigation. Sitagliptin significantly mitigated weight loss in diabetic rats. Its administration significantly reduced blood glucose levels and improved serum troponin I and CK-MB levels. Heart sections from diabetic rats showed a marked increase in mTOR, VEGF, and FLT-1 immune reaction, while sitagliptin-treated diabetic rats’ heart sections showed moderate immune reactions. Sitagliptin’s protective effect was also associated with reduced inflammation, and apoptotic markers. In conclusion, Sitagliptin is suggested to offer beneficial effects on the vascular health of cardiac blood vessels, thereby potentially reducing myocardial stress in diabetic patients. Full article

Diabetic foot ulcers (DFUs), which affect approximately 15% of individuals with diabetes mellitus (DM), result from complex molecular disturbances involving chronic hyperglycemia, immune dysfunction, and infection. At the molecular level, chronic hyperglycemia promotes the formation of advanced glycation end products (AGEs), activates the AGE-RAGE-NF-κB axis, increases oxidative stress, and impairs macrophage polarization from the pro-inflammatory M1 to the reparative M2 phenotype, collectively disrupting normal wound healing processes. The local wound environment is further worsened by antibiotic-resistant polymicrobial infections, which sustain inflammatory signaling and promote extracellular matrix degradation. The rising threat of antimicrobial resistance complicates infection management even further. Recent studies emphasize that optimal glycemic control using antihyperglycemic agents such as metformin, Glucagon-like Peptide 1 receptor agonists (GLP-1 receptor agonists), and Dipeptidyl Peptidase 4 enzyme inhibitors (DPP-4 inhibitors) improves overall metabolic balance. These agents also influence angiogenesis, inflammation, and tissue regeneration through pathways including AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and vascular endothelial growth factor (VEGF) signaling. Evidence indicates that maintaining glycemic stability through continuous glucose monitoring (CGM) and adherence to antihyperglycemic treatment enhances antibiotic effectiveness by improving immune cell function and reducing bacterial virulence. This review consolidates current molecular evidence on the combined effects of glycemic and antibiotic therapies in DFUs. It advocates for an integrated approach that addresses both metabolic and microbial factors to restore wound homeostasis and minimize the risk of severe outcomes such as amputation. Full article

Oxidative stress has been directly implicated in the pathogenesis of various skin disorders, making it a promising target for therapeutic intervention. Bauhinia forficata Link (BFL), commonly referred to as “plant insulin,” is well known for its antioxidant and antihyperglycemic properties; however, its potential role in skin protection remains unexplored. In this study, we investigated the protective effects of BFL against H₂O₂-induced oxidative stress and inflammation in HaCaT keratinocytes. The major phytochemical constituents of BFL were identified by high-performance liquid chromatography (HPLC). Its antioxidant capacity was evaluated using 2,2′-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-Diphenyl-1-picrylhydrazyl (DPPH), oxygen radical absorbance capacity (ORAC), and superoxide dismutase (SOD). In an H₂O₂-induced oxidative stress model, we assessed intracellular reactive oxygen species (ROS) levels and apoptosis using flow cytometry. Cellular respiration was analyzed using a Seahorse XFp analyzer, while molecular mechanisms were examined by reverse transcription polymerase chain reaction (RT-PCR) and western blotting. Our results demonstrated that BFL significantly reduced intracellular ROS levels and apoptosis, primarily by activating the nuclear factor erythroid 2–related factor 2 (Nrf2)/PINK1 pathway, which promoted mitochondrial quality control and redox homeostasis. Additionally, BFL suppressed inflammatory responses by downregulating the nuclear factor-κB (NF-κB) signaling pathway and reducing the secretion of pro-inflammatory cytokines interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-α). These findings suggest that BFL is a potent antioxidant and anti-inflammatory agent, with potential as an adjunctive therapy for oxidative stress-related skin conditions. Full article

Type 2 Diabetes (T2D) is a complex metabolic disorder that affects multiple organs, leading to severe complications in the pancreas, kidneys, liver, and heart. Prolonged hyperglycemia, along with oxidative stress and chronic inflammation, plays a crucial role in accelerating tissue damage, significantly increasing the risk of diabetic complications such as nephropathy, hepatopathy, and cardiovascular disease. This review evaluates the protective effects of various antidiabetic treatments on organ tissues affected by T2D, based on findings from experimental animal models. Metformin, a first-line antidiabetic agent, has been widely recognized for its ability to reduce inflammation and oxidative stress, thereby mitigating diabetes-induced organ damage. Its protective role extends beyond glucose regulation, offering benefits such as improved mitochondrial function and reduced fibrosis in affected tissues. In addition to traditional therapies, new classes of antidiabetic drugs, including sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists not only improve glycemic control but also exhibit nephroprotective and cardioprotective properties by reducing glomerular hyperfiltration, oxidative stress, and inflammation. Similarly, GLP-1 receptor agonists have been associated with reduced hepatic steatosis and enhanced cardiovascular function. Preclinical studies suggest that tirzepatide, a dual GLP-1/gastric inhibitory polypeptide receptor agonist may offer superior metabolic benefits compared to conventional GLP-1 agonists by improving β-cell function, enhancing insulin sensitivity, and reducing fatty liver progression. Despite promising preclinical results, differences between animal models and human physiology pose a challenge. Further clinical research is needed to confirm these effects and refine treatment strategies. Future T2D management aims to go beyond glycemic control, emphasizing organ protection and long-term disease prevention. Full article

Background: Hyperglycemic changes in the cellular biological properties of retinal pigment epithelium cells are involved in the pathophysiology of diabetic retinopathy (DR). To assess the effects of the new anti-diabetic agent imeglimin (Ime) on DR, the pharmacological effects of Ime and those of metformin (Met) in combination with the PPARα agonist GW7646 (GW) on adult retinal pigment epithelium (ARPE19) cells cultured in high-glucose conditions were compared. Methods: Cell viability, levels of reactive oxygen species (ROS), monolayer barrier function measured by transepit very much helial electrical resistance (TEER), and metabolic functions determined by an extracellular flux analyzer were evaluated. Results: While glucose concentrations did not alter cell viability regardless of the presence of Met or Ime, levels of ROS were significantly increased by the high-glucose conditions, and increased levels of ROS were significantly alleviated by the combination of Ime and GW but not by Met alone. Similarly, TEER values were increased by high-glucose conditions, but the effects of high-glucose conditions were dramatically enhanced by the combination of Ime and GW. Furthermore, a metabolic assay showed that an energetic shift was induced by the combination of Ime and GW, whereas energy status became quiescent with Met or Ime alone. Conclusions: The collective results suggest that Ime in combination with GW has synergetic effects on high-glucose-induced cellular biological changes in ARPE19 cells. Full article

With the increasing prevalence of diabetes and its growing impact on maternal and fetal health, management during pregnancy has become critical. This review describes the pathophysiology of insulin resistance during pregnancy, adverse outcomes correlated with diabetic pregnancies, and current management strategies. We investigate two leading approaches to managing pregnant patients with diabetes—lifestyle intervention and drug treatment. Lifestyle intervention, including dietary counseling, exercise regimens, patient education, and self-administered blood glucose monitoring, has demonstrated promising results in the management and prevention of gestational diabetes mellitus (GDM). Early intervention and treatment of at-risk patients have been critical for positive outcomes. Drug treatment, focusing on the utilization of insulin, insulin analogs, and antihyperglycemic agents has shown efficacy in achieving glycemic control and improving maternal and neonatal outcomes. These findings indicate that a combination of early lifestyle intervention and targeted drug treatment yields the most benefit in managing diabetes in pregnancy. To augment treatment, continuous glucose monitoring and telemedicine have become valuable tools in managing diabetes during pregnancy. Future research should aim to develop more effective antihyperglycemic agents, improve telehealth accessibility, and enhance preconception care for women at risk of developing GDM. By addressing these areas, we can significantly reduce the adverse outcomes associated with diabetes in pregnancy and improve overall maternal and fetal health. Full article