Rosiglitazone

Ligand Binding and Receptor Activation Kinetics of this compound

This compound binds to the ligand-binding domain of PPARγ, leading to its activation. Research indicates that this compound exhibits a high affinity for PPARγ. For instance, studies have reported an EC50 of 60 nM and a dissociation constant (Kd) of 40 nM for this compound's binding to PPARγ. medchemexpress.com Other studies have reported a Kd of 0.4 ± 0.1 µM (400 nM) for PPARγ. frontiersin.org Kinetic analyses have shown that this compound binds to PPARγ2 quickly, with an association rate constant (ka) of 24 M⁻¹s⁻¹, and dissociates with a dissociation rate constant (kd) of 0.0867 s⁻¹. researchgate.net This rapid association and relatively easy dissociation characterize its binding kinetics. researchgate.net

Table 1: this compound Binding Kinetics to PPARγ

Nuclear Receptor Modulation and Transcriptional Regulation by this compound

Upon activation by this compound, PPARγ modulates the expression of a diverse array of genes involved in glucose and lipid metabolism. patsnap.com As a nuclear receptor, activated PPARγ preferentially binds with retinoid X receptor alpha (RXRA) to form a heterodimer, which then binds to specific DNA sequences known as PPARγ response elements (PPREs) in the promoter regions of target genes. pharmgkb.orgscielo.br This binding regulates the transcription of insulin-responsive genes, which are critical for controlling glucose production, transport, and utilization. drugbank.comfda.gov

This compound promotes PPARγ occupancy at numerous preexisting binding sites on DNA, an effect paralleled by an increased occupancy of the mediator subunit MED1. nih.gov This enhanced binding of PPARγ and MED1 correlates with increased transcription of nearby genes, indicating that this compound not only activates the receptor but also facilitates its association with DNA, leading to the recruitment of mediator complexes and subsequent gene activation. nih.gov While many adipocyte genes activated by TZDs contain PPARγ binding sites, this compound can both activate and repress genes. nih.govoup.com The specific outcome of gene modulation (activation or repression) can depend on the relative occupancies of PPARγ and CCAAT-enhancer binding protein alpha (C/EBPα) at gene promoters. nih.gov Beyond its metabolic effects, this compound also exerts anti-inflammatory actions by reducing nuclear factor kappa-B (NFκB) levels and increasing inhibitor of kappa-B (IκB) levels. drugbank.comnih.govpharmgkb.org

Insulin Signaling Cascade Enhancement

This compound significantly improves the insulin signaling cascade, particularly in insulin-sensitive tissues such as skeletal muscle and adipose tissue. diabetesjournals.orgresearchgate.net

Insulin-stimulated glucose uptake in adipocytes and skeletal muscle cells is critically dependent on the translocation of Glucose Transporter Type 4 (GLUT4) from intracellular storage compartments to the cell surface. nih.govdiabetesjournals.org In type 2 diabetes, the efficiency of this process is often compromised. nih.gov this compound enhances cell surface GLUT4 levels by increasing its endosomal recycling. nih.gov Furthermore, when applied during differentiation, this compound dose-dependently augments GLUT4 expression and promotes the formation of lipid droplets in adipocytes. nih.gov Importantly, this compound has been shown to restore insulin-induced GLUT4 translocation in adipocytes that have been rendered insulin-resistant in vitro. nih.govresearchgate.net Studies also indicate that this compound treatment can increase GLUT4 mRNA expression. researchgate.net

A crucial aspect of insulin signaling involves the tyrosine phosphorylation of Insulin Receptor Substrate (IRS) proteins, such as IRS-1 and IRS-2. diabetesjournals.orgnih.govoup.commdpi.com this compound enhances insulin signaling transduction by increasing IRS-1 tyrosine phosphorylation and promoting the association of the p85 subunit of Phosphatidylinositol 3-kinase (PI3K) with IRS-1. diabetesjournals.org It potentiates insulin-stimulated tyrosine phosphorylation of both IRS-1 and IRS-2. researchgate.netnih.gov Conversely, this compound has been shown to decrease inhibitory serine phosphorylation of IRS1, which is a key component of insulin resistance. oup.comnih.govsemanticscholar.org

The activation of PI3K, a downstream effector of IRS, is central to the insulin signaling pathway. researchgate.netnih.govoup.commdpi.com PI3K activation leads to the activation of Akt (also known as protein kinase B), which plays a pivotal role in glucose uptake, glycogen synthesis, and other metabolic processes. researchgate.netnih.govoup.commdpi.comresearchgate.net this compound treatment results in the activation of PI3K and Akt, contributing to improved insulin sensitivity. researchgate.netresearchgate.netnih.govnih.gov Beyond its effects on target tissues, this compound also has a direct potentiating effect on insulin secretion, mediated through PI3K activity. diabetesjournals.org Additionally, this compound increases the expression of the insulin receptor and enhances the insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-chain. researchgate.netnih.gov

Enhancement of Peripheral Insulin Sensitivity in Adipose Tissue, Skeletal Muscle, and Liver

This compound improves the body's sensitivity to insulin in peripheral tissues. fda.govebmconsult.com This action enhances glucose uptake and utilization, helping to control blood glucose levels. patsnap.com In animal models, this compound's antidiabetic activity was shown to be mediated by increased insulin sensitivity in the liver, muscle, and adipose tissues. fda.govebmconsult.com

Research in patients with type 2 diabetes demonstrated that three months of this compound treatment significantly improved insulin-stimulated glucose metabolism by 68% during low-dose insulin infusion and by 20% during high-dose insulin infusion. nih.govnih.govdiabetesjournals.org This improvement in insulin responsiveness is linked to the upregulation of the glucose transporter type 4 (GLUT4), which facilitates the transport of glucose into cells. patsnap.combvsalud.org this compound treatment has been shown to increase the expression of GLUT4 in adipose tissue. fda.govoup.com Studies in fatless mice revealed that this compound treatment normalized the decreases in insulin-stimulated glucose uptake and insulin receptor substrate (IRS)-1–associated phosphatidylinositol (PI) 3-kinase activity in skeletal muscle. diabetesjournals.org This suggests that this compound enhances insulin action in skeletal muscle primarily by repartitioning fat away from the muscle. diabetesjournals.org

Inhibition of Hepatic Gluconeogenesis

Pharmacological studies have demonstrated that this compound inhibits hepatic gluconeogenesis, the process of producing glucose in the liver. fda.govebmconsult.comeuropa.eu By activating PPARγ, this compound regulates the transcription of insulin-responsive genes that control glucose production. drugbank.com This leads to a reduction in the liver's output of glucose.

A significant finding associated with this compound treatment is the reduction of fat content within the liver. In one study, this compound treatment in patients with type 2 diabetes resulted in a 39-46% decrease in hepatic triglyceride content. nih.govoup.com This reduction in liver fat is strongly correlated with improved hepatic insulin sensitivity. oup.com In diabetic rats, this compound was shown to inhibit the increased expression of key gluconeogenic enzymes like phosphoenolpyruvate carboxykinase and glucose-6-phosphatase that can be induced by high-fructose diets. nih.gov This effect on gene expression is a key mechanism behind its ability to lower glucose production. nih.gov

Impact on Pancreatic Beta-Cell Function and Preservation

Beyond its effects on insulin sensitivity, this compound has been shown to positively impact the function and preservation of pancreatic beta-cells, which are responsible for producing insulin. e-dmj.orgbjd-abcd.com Studies suggest that thiazolidinediones can slow the progression of impaired glucose tolerance to type 2 diabetes by preserving beta-cell function. bjd-abcd.com In a study of patients with type 2 diabetes who were failing other oral medications, the addition of this compound for six months led to a significant recovery of first-phase insulin response to glucose. nih.gov Homeostasis model assessment (HOMA) estimates indicated that this compound improved beta-cell function from baseline by 49.5% to 60.0% in one 26-week study. oup.com

The mechanisms for this preservation are multifaceted. This compound helps reduce the toxic effects of high lipid levels on beta-cells, a phenomenon known as lipotoxicity. e-dmj.orgbjd-abcd.com In laboratory studies with human islets, this compound prevented the impairment of islet function caused by fatty acids and restored insulin content and glucose-stimulated insulin release. bjd-abcd.com It also upregulates the expression of genes important for beta-cell glucose sensing, such as GLUT2 and glucokinase. bjd-abcd.com Animal studies have shown that treatment with thiazolidinediones like this compound can reduce beta-cell death and preserve beta-cell mass. e-dmj.org

Table 1: Effects of this compound on Glucose Homeostasis in Patients with Type 2 Diabetes

Promotion of Adipogenesis and Adipocyte Differentiation

A primary effect of this compound is the promotion of adipogenesis, the process by which new fat cells (adipocytes) are formed from progenitor cells. nih.govnih.gov PPARγ is a master regulator of this process. mdpi.com this compound stimulates the differentiation of preadipocytes into mature adipocytes. patsnap.comstemcell.com These newly formed adipocytes are often smaller and more effective at storing fatty acids, which is a key part of its therapeutic effect. patsnap.com Studies in human mesenchymal stem cells have shown that exposure to this compound potentiates adipogenic differentiation, shifting the cells' development pathway towards becoming adipocytes. stemcell.com

Regulation of Circulating Free Fatty Acid Levels

A direct consequence of this compound's effects on adipose tissue is the regulation and reduction of circulating free fatty acid (FFA) levels. patsnap.comnih.gov Elevated FFAs are known to contribute to insulin resistance. jci.org By promoting adipogenesis and enhancing the ability of adipocytes to take up and store lipids, this compound effectively clears FFAs from the bloodstream. nih.govbjd-abcd.com

Table 2: Effects of this compound on Lipid Profile and Adipose Tissue Markers

Adipocyte Browning and Thermogenesis Modulation

This compound has been shown to play a significant role in the process of "browning" white adipose tissue (WAT), a phenomenon that could have implications for combating obesity. frontiersin.orgnih.gov This process involves the transdifferentiation of white adipocytes into "brite" or "beige" adipocytes, which share characteristics with brown adipocytes (BAT), most notably their ability to dissipate energy as heat through thermogenesis. mdpi.comresearchgate.net

The primary mechanism behind this effect is the activation of the peroxisome proliferator-activated receptor-gamma (PPARγ). frontiersin.orgresearchgate.net this compound is a selective agonist for PPARγ, a master regulator of adipogenesis. researchgate.netnih.govoup.com By activating PPARγ, this compound enhances the transcription of genes crucial for adipocyte browning. frontiersin.orgresearchgate.net Studies have demonstrated that this compound treatment induces the expression of key thermogenic genes such as Uncoupling Protein 1 (UCP1), Cidea, and Elovl3 in inguinal white adipose tissue (iWAT). frontiersin.org This leads to a noticeable reduction in the size of adipocyte lipid droplets, indicating a shift from energy storage to energy expenditure. frontiersin.org

Research indicates that this compound's pro-browning effect is linked to the inhibition of autophagy. frontiersin.orgresearchgate.net Furthermore, the activation of the MAPK and PI3K pathways at the maturation stage of adipocyte differentiation appears to be a significant part of the mechanism through which this compound induces browning. nih.govnih.gov In vitro studies have shown that for maximal browning and mitochondrial uncoupling in inguinal white adipocytes, a combination of a PPARγ activator like this compound and a β3-adrenoceptor agonist is required. nih.gov This suggests that while this compound primes the adipocytes for browning, a thermogenic stimulus is needed for full activation. nih.gov

Effects on LDL Cholesterol and LDL/HDL Ratio

The effects of this compound on lipid profiles, particularly low-density lipoprotein (LDL) cholesterol and the LDL/high-density lipoprotein (HDL) ratio, have been a subject of extensive research, with findings indicating a complex interplay of effects.

Multiple studies have reported that this compound treatment leads to an increase in LDL cholesterol levels. gpnotebook.comtandfonline.comnatap.org A meta-analysis of post-hoc data revealed that combination therapy of this compound with metformin resulted in a weighted mean difference of 0.31 mmol/l higher LDL cholesterol compared to metformin alone. gpnotebook.com Similarly, when combined with a sulphonylurea, the weighted mean difference was 0.2 mmol/l higher than with a sulphonylurea alone. gpnotebook.com Short-term studies have consistently shown this increase in total and LDL cholesterol. nih.gov

However, the long-term effects on LDL cholesterol appear to be more nuanced. One prospective study following patients for 18 months observed that while LDL-C levels were significantly higher than baseline from months 3 to 12, they were not significantly different from baseline after 15 months. nih.gove-dmj.org This suggests a potential attenuation of the initial LDL-raising effect over time. nih.gov

In contrast to its effects on LDL, this compound consistently demonstrates a beneficial impact on HDL cholesterol, leading to an increase in its levels. gpnotebook.comtandfonline.comnih.govresearchgate.net This increase in HDL is more pronounced in individuals with lower baseline HDL concentrations. nih.gov

Regarding the LDL/HDL ratio, the combined effects on LDL and HDL cholesterol result in varied outcomes. While some studies report no significant change in the total cholesterol/HDL ratio, others suggest that despite the initial increase in LDL, the ratio may decrease below baseline with longer-term treatment. researchgate.net One comparative study found that while both this compound and another thiazolidinedione, pioglitazone, increased HDL cholesterol, the increase was greater with pioglitazone. diabetesjournals.org This same study also reported a smaller increase in LDL cholesterol with pioglitazone compared to this compound. diabetesjournals.org

Table 1: Effects of this compound on LDL and HDL Cholesterol from Clinical Studies This table is interactive. You can sort and filter the data.

Reductions in Glycated Hemoglobin A1c (HbA1c)

Clinical trials have consistently shown that this compound effectively lowers glycated hemoglobin A1c (HbA1c) levels, a crucial indicator of long-term glycemic control. In monotherapy, this compound has been shown to produce dose-dependent reductions in HbA1c. For instance, a 26-week study revealed that this compound at total daily doses of 4 mg and 8 mg led to placebo-corrected HbA1c reductions of 0.8% to 1.5%. nih.govnih.gov Another 26-week trial reported that this compound at 2 mg and 4 mg twice daily decreased mean HbA1c relative to placebo by 1.2 and 1.5 percentage points, respectively. nih.govoup.com In drug-naïve patients, approximately 33% of those treated with this compound achieved an HbA1c of 7% or less. nih.gov

The efficacy of this compound in reducing HbA1c is maintained over the long term. Studies with a duration of up to three years have shown a sustained improvement in HbA1c levels when this compound is used as monotherapy or in combination with other agents. europa.eu In a comparative study, this compound monotherapy demonstrated a similar reduction in HbA1c levels (around 0.8-0.9%) to metformin and glimepiride over a 48-week period in drug-naïve Korean patients with type 2 diabetes. e-dmj.org

Table 1: Reductions in Glycated Hemoglobin A1c (HbA1c) with this compound Monotherapy

Effects on Fasting and Post-Prandial Plasma Glucose

This compound exerts a significant glucose-lowering effect by reducing both fasting plasma glucose (FPG) and post-prandial plasma glucose (PPG) levels. europa.eu Short-term studies have demonstrated that this compound monotherapy leads to a significant reduction in FPG compared to baseline and placebo. nih.govnih.govresearchgate.net An 8-week study showed that this compound at doses of 4 mg, 8 mg, and 12 mg daily significantly decreased FPG compared to placebo. nih.gov Similarly, another 8-week trial found that all tested doses of this compound significantly reduced FPG from baseline. nih.govresearchgate.net

In addition to its effect on fasting glucose, this compound also effectively manages post-prandial hyperglycemia. Clinical trials have shown that this compound significantly reduces peak post-prandial glucose concentrations and post-prandial glucose excursion without increasing post-meal insulin levels. nih.govresearchgate.net This effect is a direct consequence of its insulin-sensitizing action. Some research suggests a potential genetic influence on the response to this compound, with certain genotypes showing a greater decrease in fasting and post-prandial glucose levels. pharmgkb.org

Table 2: Effects of this compound on Fasting Plasma Glucose (FPG)

Monotherapy Efficacy

When compared to other oral antidiabetic agents as monotherapy, this compound has shown comparable efficacy in glycemic control. In a 24-week study involving drug-naïve patients with type 2 diabetes, this compound (8 mg daily) demonstrated a similar reduction in HbA1c to vildagliptin (100 mg daily), although this compound had a greater effect on lowering fasting plasma glucose. medscape.com Another study comparing this compound with metformin and glyburide/glibenclamide in drug-naïve patients found that over a 52-week period, this compound monotherapy was comparable to metformin or glyburide in lowering glucose levels. drugbank.com A study in Korean patients also showed similar HbA1c reductions between this compound, metformin, and glimepiride after 48 weeks. e-dmj.org However, a 24-week trial in pediatric patients (10-17 years old) with type 2 diabetes failed to demonstrate the non-inferiority of this compound to metformin in improving HbA1c. europa.eueuropa.eu

Combination Therapy Outcomes (e.g., with Metformin, Sulfonylureas, Insulin)

Due to their complementary mechanisms of action, combining this compound with other antidiabetic agents often results in additive effects on glycemic control. europa.eu

With Metformin: The combination of this compound and metformin has been shown to be more effective at improving glycemic control, insulin sensitivity, and beta-cell function than metformin alone. researchgate.net Adding this compound to metformin therapy leads to significant improvements in HbA1c. researchgate.net

With Sulfonylureas: The addition of low-dose this compound to sulfonylurea therapy has been demonstrated to significantly improve glycemic control in patients with type 2 diabetes. openaccessjournals.com A fixed-dose combination of this compound and glimepiride has been shown to be effective, with data supporting the advantages of the combination over either drug as monotherapy. openaccessjournals.com

With Insulin: For patients inadequately controlled on insulin, the addition of this compound has resulted in significant, dose-related decreases in HbA1c. diabetesjournals.org In a 26-week trial, adding 8 mg of this compound daily to insulin therapy led to a mean reduction in HbA1c of 1.2%, with over half of the subjects achieving a reduction of at least 1.0%. diabetesjournals.org

Triple Therapy: Triple therapy regimens involving this compound have also been investigated. The combination of this compound, a sulfonylurea (like glibenclamide), and metformin has been shown to significantly improve metabolic control in patients with type 2 diabetes, even those who were previously on insulin. rssdi.in In insulin-naïve patients inadequately controlled on a sulfonylurea and metformin, adding either this compound or insulin glargine resulted in similar improvements in glycemic control, with about half of the participants in both groups reaching an HbA1c level below 7%. diabetesjournals.org

Table 3: Efficacy of this compound in Combination Therapy

Impact on Microvascular Complications

This compound's effect on the small blood vessels of the body has been a significant area of research, particularly concerning the common complications of diabetes: nephropathy (kidney disease), retinopathy (eye disease), and neuropathy (nerve damage).

Diabetic Nephropathy

Diabetic nephropathy is a leading cause of end-stage renal disease. Research into this compound has explored its potential to protect kidney function in patients with type 2 diabetes. Animal studies suggested that this compound could prevent diabetic nephropathy. drugbank.com Clinical trials in humans have aimed to quantify these effects. One study investigated the influence of this compound on renal hemodynamics and proteinuria in type 2 diabetic patients with existing renal insufficiency and overt diabetic nephropathy. clinicaltrials.govclinicaltrials.gov The primary goal was to assess changes in renal plasma flow, glomerular filtration rate, and the degree of protein in the urine. clinicaltrials.govclinicaltrials.gov Another trial noted that in patients with diabetic nephropathy, short-term treatment with this compound was found to reduce albuminuria. nih.gov

Table 1: Effects of this compound on Diabetic Nephropathy Markers

Diabetic Retinopathy

Diabetic retinopathy is a major cause of vision loss in adults. The potential of this compound to slow the progression of this complication has been investigated, with some studies suggesting a benefit. A longitudinal medical record review followed patients for a mean of 2.8 years to assess whether this compound could delay the onset of proliferative diabetic retinopathy (PDR), the most advanced stage of the disease. nih.gov In patients with severe nonproliferative diabetic retinopathy (NPDR) at the start of the study, those treated with this compound showed a significantly lower rate of progression to PDR compared to a control group. nih.govarvojournals.org

However, not all studies have found a protective effect. A community-based study following patients for a median of 3.6 years reported that this compound was associated with an increased need for intensive eye treatments like laser therapy and vitrectomy. nih.gov

Table 2: this compound and Progression to Proliferative Diabetic Retinopathy

Diabetic Neuropathy

Diabetic neuropathy is a common and often distressing complication of diabetes. Pre-clinical studies using animal models have shown that this compound may have a protective effect on nerves. openaccessjournals.comopenaccessjournals.com In streptozotocin-induced diabetic mice, this compound treatment was found to reduce diabetic neuropathy, an effect that appeared to be independent of its impact on blood sugar levels. nih.govoup.com The treatment was observed to lessen oxidative stress and prevent thermal hypoalgesia. nih.govoup.com

In human studies, the evidence is more complex. One trial found that in insulin-treated patients with type 2 diabetes, the presence of autonomic neuropathy could predispose them to this compound-induced vascular leakage. nih.gov This suggests a potential interaction between the drug and pre-existing nerve damage. nih.gov

Table 3: Pre-clinical Findings on this compound and Diabetic Neuropathy

Influence on Macrovascular Outcomes

The impact of this compound on large blood vessel complications, such as heart attack and stroke, has been a subject of extensive research and debate. While the drug was developed to improve glycemic control, its effects on cardiovascular risk factors and outcomes have been closely scrutinized.

Some studies have suggested potential benefits on markers of cardiovascular health. For instance, this compound has been shown to improve endothelium-dependent vasodilation, a measure of blood vessel health, in patients with type 2 diabetes. diabetesjournals.org It has also been associated with increases in high-density lipoprotein (HDL) cholesterol, often referred to as "good" cholesterol, and reductions in small, dense low-density lipoprotein (LDL) cholesterol particles. nih.gov Furthermore, some research indicated a modest blood pressure-lowering effect. diabetesjournals.orgnih.gov

A Cochrane review of 18 trials with a median follow-up of 26 weeks, however, concluded that the published studies did not provide clear evidence that this compound positively influenced patient-oriented outcomes like mortality or morbidity from cardiovascular events. nih.gov The review noted that while some surrogate markers for cardiovascular risk were improved, this did not translate into a demonstrated reduction in actual cardiovascular events in the trials analyzed. nih.gov The United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP) study, two major trials in type 2 diabetes, also did not find a reduction in cardiovascular endpoints through improved metabolic control alone. nih.gov

Table 4: Summary of this compound's Effects on Macrovascular Risk Factors

Role of Cytochrome P450 Enzymes (CYP2C8, CYP2C9) in this compound Biotransformation

Cytochrome P450 (CYP) isoenzymes play a crucial role in the biotransformation of this compound. In human liver, CYP2C8 is primarily responsible for the hydroxylation and N-demethylation of this compound nih.govchem960.comscispace.comuni.luncats.iouni.lu. While CYP2C9 contributes as a minor pathway, its involvement has also been noted nih.govchem960.comuni-freiburg.descispace.comuni.luncats.iouni.lunih.gov. The enzymatic activity of CYP2C8 for this compound is approximately four-fold higher than that of CYP2C9 uni.lu.

Major Metabolites and Their Potency

The major products formed during this compound metabolism are N-desmethyl this compound and para-hydroxy this compound nih.govuni.luscispace.comuni.luuni.lu. N-desmethyl this compound is the predominant metabolite found in plasma and undergoes further hydroxylation before entering phase II metabolism uni.lu. Para-hydroxy this compound is primarily detected in plasma as a conjugated metabolite, specifically this compound-para-O-sulfate uni.lu. Both of these major metabolites are subsequently excreted as sulfated or glucuronidated conjugates uni.lu.

Interactions with CYP2C8 and CYP2C9 Inhibitors and Inducers

Co-administration of this compound with CYP2C8 inhibitors can lead to a significant increase in this compound plasma concentrations nih.govchem960.com. For example, gemfibrozil, a known CYP2C8 inhibitor, has been shown to increase the area under the plasma concentration-time curve (AUC) of this compound by up to 127% when co-administered chem960.com. In some instances, gemfibrozil has been observed to increase this compound AUC by as much as 2.8-fold and prolong its elimination half-life.

Conversely, CYP2C8 inducers can substantially decrease this compound plasma concentrations nih.gov. Rifampin, a CYP2C8 inducer, has been reported to decrease this compound plasma concentrations by 66% and its AUC by 65%, while also reducing its elimination half-life by 62%.

While CYP2C9 contributes to this compound metabolism, clinically significant interactions with CYP2C9 substrates or inhibitors are generally not anticipated uni-freiburg.de. This compound itself acts as a moderate inhibitor of CYP2C8 (IC50 = 18 µM) and a weak inhibitor of CYP2C9 (IC50 = 50 µM) scispace.comuni.lu. At high doses, thiazolidinediones, including this compound, may potentially cause clinically significant drug-drug interactions with other CYP2C8 substrates ncats.io.

Observed Clinical Significance of Interactions

The observed pharmacokinetic interactions with CYP2C8 inhibitors and inducers carry clinical significance. When CYP2C8 inhibitors are co-administered, a decrease in the this compound dose may be necessary due to the potential for an increased risk of dose-related adverse reactions. Conversely, if CYP2C8 inducers are co-administered, an increase in the this compound dose may be required to maintain therapeutic efficacy. Close monitoring of glycemic control is strongly recommended during concomitant administration of this compound with either CYP2C8 inhibitors or inducers to ensure appropriate therapeutic management. The full clinical relevance of these interactions in patients with type 2 diabetes is still under evaluation, but a cautious approach involving dose adjustments, such as reducing the this compound dosage by half when treated with gemfibrozil, is considered prudent.

Table 1: Key Drug-Drug Interactions Affecting this compound Pharmacokinetics

Fluid Retention and Edema

Bone Fractures, particularly in Women

Clinical evidence from various studies and meta-analyses consistently indicates an increased risk of bone fractures with this compound use, especially in women wikidata.orgscribd.comfishersci.cafishersci.canih.gov. This heightened risk has been observed across different healthcare registries and confirmed in randomized controlled trials wikidata.org.

Detailed research findings highlight that the increased fracture risk is predominantly observed in the extremities, including the radius/ulna, humerus, tibia/fibula, ankle, and foot wikidata.orgfishersci.cafishersci.ca. In contrast, studies have not consistently shown an increased risk for hip/femur or vertebral fractures wikidata.orgfishersci.cafishersci.ca. The manifestation of this increased risk typically occurs beyond 12 months of exposure to this compound fishersci.ca.

Comparative studies, such as the A Diabetes Outcome Progression Trial (ADOPT), demonstrated that women treated with this compound experienced a higher incidence of fractures compared to those receiving other antidiabetic medications like metformin or glyburide fishersci.cafishersci.ca. For instance, the cumulative incidence of fractures in women at 5 years in the ADOPT trial was 15.1% with this compound, significantly higher than 7.3% with metformin and 7.7% with glyburide fishersci.ca.

Table 1: Cumulative Incidence of Fractures in Women at 5 Years (ADOPT Trial) fishersci.ca

A meta-analysis of 10 randomized controlled trials further supported these findings, reporting an odds ratio of 1.45 (95% CI 1.18–1.79) for increased fracture risk with the use of this compound and pioglitazone wikidata.org.

Hormonal Imbalance and Menstrual Dysfunction

Preclinical studies have indicated the occurrence of hormonal imbalance with this compound probes-drugs.orgfishersci.be. However, clinical studies have generally not observed significant undesirable effects directly associated with menstrual disorders in the broader patient population probes-drugs.orgfishersci.be.

Conversely, in women with insulin resistance and anovulation, particularly those diagnosed with Polycystic Ovary Syndrome (PCOS), this compound's primary mechanism of improving insulin sensitivity can lead to a beneficial effect: the resumption of ovulation probes-drugs.orgfishersci.be. This improvement in insulin sensitivity is also associated with reductions in plasma androgen levels, including both free and total testosterone, and an amelioration of the hyperandrogenism often observed in PCOS patients nih.govhznu.edu.cn. Clinicians should be aware of the potential for pregnancy in such patients due to restored fertility probes-drugs.orgfishersci.be.

Anemia

Anemia has been reported as an adverse event in patients treated with this compound in clinical studies probes-drugs.orglcms.cz. The incidence of anemia varies depending on whether this compound is used as monotherapy or in combination with other antidiabetic agents.

Table 2: Incidence of Anemia in Clinical Studies probes-drugs.org

Patients with low hemoglobin levels prior to initiating this compound therapy are at an increased risk of developing anemia during treatment fishersci.belcms.cz. While hemodilution was traditionally considered a potential cause for the observed reductions in red blood cell count and hemoglobin levels, more recent studies suggest that these changes are not correlated with alterations in total body water or body weight uni.lu.

Sarcopenia and Muscle Metabolism Research

Autophagy and Apoptosis Regulation

This compound has been shown to modulate the intricate processes of autophagy and apoptosis in various cell types. In the context of traumatic brain injury (TBI), research indicates that this compound treatment can significantly reduce neuronal apoptosis and autophagy, leading to improved functional recovery in rat models. nih.govnih.gov These neuroprotective effects are associated with a decrease in the protein expression of inflammatory markers such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). nih.gov

In the realm of oncology, this compound has been observed to induce both apoptosis and autophagy in pituitary tumor cells. researchgate.net Specifically, in GH3 cells, a rat pituitary tumor cell line, this compound treatment increased the expression of key autophagy-related proteins like Beclin 1, ATG5, and ATG7, while reducing p62 levels, which suggests the activation of autophagic processes. researchgate.net

Furthermore, in pancreatic beta-cells, this compound demonstrates a protective role against palmitate-induced apoptosis by inducing autophagy. researchgate.net This pro-survival function is mediated through the activation of AMP-activated protein kinase (AMPK). Inhibition of this autophagic process was found to augment palmitate-induced cell death, highlighting the importance of autophagy in the protective effects of this compound on beta-cells. researchgate.net In monocytic cells, higher concentrations of this compound were found to induce apoptosis, potentially through a PPARγ-independent mechanism linked to endoplasmic reticulum stress. ajol.info

Mitochondrial Dynamics and Biogenesis

This compound has been identified as a significant inducer of mitochondrial biogenesis in several tissues. In the brain, it has been shown to stimulate the generation of new mitochondria in a manner independent of the apolipoprotein E (ApoE) isozyme. nih.gov This is achieved by inducing both mitochondrial DNA (mtDNA) and the expression of estrogen-stimulated related receptor alpha (ESRRA), a key regulator of mitochondrial biogenesis. nih.gov

This compound also exerts protective effects on endothelial cells against radiation-induced mitochondrial dysfunction. frontiersin.org By promoting mitochondrial biogenesis, it helps to maintain oxidative phosphorylation and reduce apoptosis in irradiated endothelial cells. frontiersin.org The effects of this compound on mitochondrial dynamics are also sex-dependent, with studies showing that it enhances mitochondrial biogenesis in the white adipose tissue of male rats more significantly than in females. mdpi.com

Endoplasmic Reticulum Stress Response

This compound has been shown to ameliorate endoplasmic reticulum (ER) stress in various pathological conditions. In granulosa cells, which are crucial for follicular development, this compound can protect against palmitic acid-induced cell death by inhibiting ER stress. nih.gov It also rescues these cells from ER stress induced by tunicamycin, a known ER stress inducer. nih.gov The protective mechanism involves the restoration of the cAMP/PKA/CREB pathway, which is inhibited by palmitic acid. nih.gov

In the context of neurodegenerative diseases, this compound has been found to rescue human neural stem cells from amyloid-beta-induced ER stress. nih.gov This protective effect is mediated through a PPARγ-dependent signaling pathway. The activation of this pathway is critical for protecting against ER disequilibrium and mitochondrial deficiency associated with Alzheimer's disease. nih.gov

Furthermore, PPARγ ligands like this compound can reduce ER stress and inflammation by targeting the expression of Nogo-B receptor (NGBR). frontiersin.org Studies have shown that this compound increases NGBR expression in hepatic cells and human umbilical vein endothelial cells (HUVECs), and the inhibitory effect of this compound on ER stress is weakened when NGBR is knocked down. frontiersin.org This suggests that NGBR is a key target of PPARγ activation in the mitigation of ER stress. frontiersin.org

Oxidative Stress Markers

This compound has demonstrated a consistent ability to reduce markers of oxidative stress across various studies. In overweight, non-diabetic individuals, treatment with this compound for six months resulted in a significant decrease in plasma peroxides. nih.gov This was accompanied by improvements in insulin sensitivity and a reduction in inflammatory markers. nih.gov

In animal models of diabetic nephropathy, this compound has been shown to reduce both plasma and kidney markers of protein oxidation and lipid peroxidation to near-normal levels. nih.gov This effect was observed even in insulin-treated diabetic mice, suggesting a direct antioxidant effect independent of its glucose-lowering properties. nih.gov

Similarly, in spontaneously hypertensive rats, this compound administration led to a marked decrease in the expression of oxidative stress markers such as inducible nitric oxide synthase (iNOS) and gp47phox in the hippocampus. spandidos-publications.com This was associated with a reduction in apoptotic cells, indicating a neuroprotective role through the attenuation of oxidative stress. spandidos-publications.com Studies in patients with type 2 diabetes have also shown that this compound can decrease markers of oxidative stress, such as malondialdehyde (MDA) and 8-iso-prostaglandin F2α, while increasing the levels of antioxidants like superoxide dismutase (SOD) and total antioxidant capacity. researchgate.netscielo.br

Vascular Calcification and Remodeling

The effects of this compound on vascular calcification and remodeling are complex and appear to be context-dependent. In vitro studies have shown that this compound can attenuate the calcification of vascular smooth muscle cells (VSMCs) under high glucose conditions. mdpi.com This is achieved by downregulating the expression of pro-calcific markers like Runx-2, osteocalcin, and BMP-2, while upregulating the mineralization inhibitor MGP. mdpi.com The protective effect against calcification is blocked by a PPARγ antagonist, indicating a direct role of PPARγ. mdpi.com

Clinical studies using intravascular ultrasound have provided mixed results regarding the effect of this compound on arterial remodeling in patients with coronary atherosclerosis. jacc.org Furthermore, in postmenopausal women with type 2 diabetes, this compound treatment has been investigated for its effects on circulating osteogenic precursor cells, which may play a role in both bone remodeling and vascular calcification. oup.com

Endothelial Dysfunction

This compound has been consistently shown to improve endothelial function in various populations. In patients with metabolic syndrome, a 12-month treatment with this compound led to significant improvements in flow-mediated vasodilation and a reduction in markers of inflammation like high-sensitivity C-reactive protein (hs-CRP), IL-6, and IL-18. diabetesjournals.org

The mechanisms underlying the beneficial vascular effects of this compound involve both PPARγ- and PPARδ-dependent pathways. nih.gov In a rat model of metabolic syndrome, this compound was found to improve impaired vasorelaxation by increasing the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), leading to increased nitric oxide production. nih.gov These effects were blocked by inhibitors of both PPARγ and PPARδ, suggesting a dual mechanism of action. nih.gov

Senescence and Aging Research

Recent preclinical studies have illuminated the potential of this compound in mitigating aspects of the aging process. Cellular senescence, a state of irreversible cell cycle arrest, contributes to age-related tissue dysfunction. frontiersin.org Senescent cells accumulate with age and secrete a variety of inflammatory molecules, collectively known as the senescence-associated secretory phenotype (SASP). frontiersin.org

A 2020 study demonstrated that low-dose this compound treatment in aging mice improved insulin sensitivity, a key factor in metabolic aging. nyulangone.org The treated mice also exhibited reduced inflammation, fibrosis, and atrophy in various tissues. nyulangone.org Gene expression analysis revealed a decrease in inflammatory genes and an increase in genes associated with mitochondrial function and genomic stability. nyulangone.org Notably, the median lifespan of the treated mice was extended by 11 percent. nyulangone.org Furthermore, the treatment was associated with improved cognitive function and reduced anxiety-like behaviors. nyulangone.org

In a cellular model of photoaging, pretreatment with this compound was found to counteract senescence-like phenotypes in murine dermal fibroblasts exposed to UVB irradiation. nih.gov The compound significantly reduced the number of senescent cells, preserved normal cell shape, and decreased the degradation of type I collagen by inhibiting matrix metalloproteinases (MMPs). nih.gov It also counteracted cell-cycle arrest and repressed the expression of p53 and p21, proteins involved in senescence induction. nih.gov These effects were linked to a significant decrease in reactive oxygen species (ROS) accumulation and an increase in the antioxidant enzyme catalase. nih.gov

These findings suggest that this compound may exert its anti-aging effects by targeting cellular senescence and its associated inflammation and oxidative stress.

Microbiome Interactions

The gut microbiome is increasingly recognized for its role in modulating drug efficacy and bioavailability. nih.govpharmaceutical-journal.comucl.ac.uk For this compound, research indicates that its interaction with the gut microbiota is complex and may not always involve direct alteration of the microbial composition.

One key mechanism through which the gut microbiome can influence drug availability is bioaccumulation, where bacteria accumulate a drug intracellularly without metabolizing it. nih.gov Studies have identified this compound as a drug susceptible to bioaccumulation by certain gut bacteria, including Enterococcus sp., Lactobacillus sp., and Bifidobacterium sp. nih.govpharmaceutical-journal.comucl.ac.uk This process can restrict the amount of this compound available for absorption by the host. nih.gov

The metabolic actions of this compound are thought to be mediated in part through gut-derived PPAR-γ signaling. researchgate.net This suggests that while this compound may not directly reshape the gut microbial community, its therapeutic effects are still intertwined with host-microbiota interactions in the intestine.

Chronopharmacology

Chronopharmacology explores how the timing of drug administration can influence its efficacy and safety by aligning with the body's natural circadian rhythms. mdpi.com The nuclear receptor PPARγ, the target of this compound, exhibits a circadian expression pattern in key metabolic tissues like the liver and adipose tissue, suggesting that the effects of this compound could be time-dependent. mdpi.com

Research in mice has shown that disrupting circadian rhythms, for instance through reversed feeding schedules, can lead to metabolic disturbances. mdpi.com In such models, the administration of the related PPARγ agonist, pioglitazone, was more effective at restoring the expression of clock genes and reducing inflammation when given in the evening (7 PM) compared to the morning (7 AM). mdpi.com This indicates a potent chronopharmacological effect for this class of drugs. mdpi.com

A recent study investigated the chronotherapeutic effects of this compound on the interaction between macrophages and vascular smooth muscle cells (VSMCs), which is crucial in vascular diseases. nih.gov The study found that administering this compound to LPS-induced M1 macrophages at different time points altered the rhythmic release of inflammatory cytokines like TNF-α. nih.gov This, in turn, influenced the phenotypic switching of VSMCs. nih.gov The timing of this compound treatment was shown to affect the oscillation of clock genes such as Bmal1, Per1, Per2, and CRY in macrophages. nih.gov

While some sources suggest that the hypoglycemic effects of this compound are independent of administration time, the growing body of evidence on the circadian regulation of its target, PPARγ, and its downstream effects points towards the potential benefits of optimizing administration timing. medscape.org

Systems Biology and Computational Pharmacology Approaches

Systems biology and computational pharmacology are transforming drug discovery by integrating large-scale biological data to understand drug action within complex cellular networks. mountsinai.org These approaches move beyond the traditional "one drug, one target" paradigm to a more holistic view of how drugs affect entire biological systems. tcmsp-e.com

For this compound, these methodologies have been employed to elucidate its mechanisms of action and to identify potential drug combinations that could enhance efficacy or mitigate adverse effects. By analyzing databases like the FDA's Adverse Event Reporting System (FAERS) and electronic health records, researchers have been able to identify drugs that, when co-administered with this compound, may reduce the risk of side effects such as heart attacks. mountsinai.org For example, this approach identified the drug exenatide as significantly reducing the heart attack rate in this compound users. mountsinai.org

Network pharmacology, a branch of systems biology, has been used to predict the targets of this compound and its related compounds. nih.gov By constructing and analyzing molecular interaction networks, researchers can identify key pathways affected by the drug. nih.gov One such study predicted that the calcium signaling pathway is a significant regulatory pathway for a this compound compound, which may be relevant to its effects on diabetes and associated cognitive impairment. nih.gov

These computational approaches have also been instrumental in understanding the synergistic effects of drug combinations. A network-based method successfully identified the combination of metformin and this compound (Avandamet) as an effective treatment for Type 2 Diabetes by analyzing the gene expression profiles of the individual drugs and predicting the profile of the combination. nih.gov

Artificial Intelligence in Drug Discovery and Development

Artificial intelligence (AI) and machine learning (ML) are accelerating the drug discovery process by enabling rapid analysis of vast biological and chemical datasets. researchgate.netmdpi.com These technologies are applied to various stages, from target identification and validation to predicting drug efficacy and toxicity. researchgate.netresearchgate.net

Nanotechnology for Targeted Delivery Systems

Nanotechnology offers promising solutions to improve the delivery of therapeutic agents like this compound, potentially enhancing their bioavailability and reducing dosing frequency. researchgate.net By encapsulating drugs within nanoparticles, it is possible to achieve sustained release and target specific sites within the body. researchgate.net

Several nanotechnology-based systems are being explored for the delivery of antidiabetic drugs, including this compound. These include polymeric nanoparticles (PNPs), liposomes, and solid lipid nanoparticles (SLNs). mdpi.com For this compound, gelatin nanoparticles have been developed using a two-step desolvation method. researchgate.net These nanoparticles demonstrated a high drug encapsulation efficiency of 82-90% and provided sustained release of the drug over 32 hours in in-vitro studies. researchgate.net This sustained release profile could potentially maintain therapeutic concentrations for longer durations, improving patient compliance. researchgate.net

Transdermal delivery is another area where nanotechnology is being applied to improve the administration of this compound. researchgate.net Formulating this compound into a transdermal patch could help bypass the first-pass metabolism that oral drugs undergo, thereby increasing its bioavailability. researchgate.net Various advanced systems like transferosomal gels, microemulsions, and microneedles are being investigated to enhance the transport of drugs across the skin barrier. researchgate.net The goal is to provide a continuous and controlled delivery of the drug, which can be particularly beneficial for managing chronic conditions like diabetes. researchgate.net

Cellular and Gene Therapy Interactions

The interaction of this compound with cellular and gene therapies is an expanding area of investigation, particularly in the context of cancer and other diseases. Research has shown that this compound can modulate the expression of specific genes, which may enhance or complement the effects of certain therapies.

In human colon cancer cells, for instance, this compound has been observed to inhibit cell adhesion and migration. plos.org When combined with a JNK inhibitor, AS601245, these effects were even more pronounced. plos.org Microarray analysis revealed that this combined treatment significantly downregulated the expression of the ARHGEF7/β-PIX gene. plos.org Transfection experiments confirmed that β-PIX protein is a key player in the inhibition of cell migration, suggesting a potential synergistic interaction between PPARγ ligands like this compound and anti-inflammatory agents. plos.org

Furthermore, in pancreatic cancer, this compound has been identified as a promising agent for targeting cancer stem cells (CSCs). It upregulates the expression of Epithelium-specific ETS factor family member 3 (EHF), which in turn suppresses pancreatic cancer stemness by downregulating CXCR4. nih.gov This suggests a potential role for this compound in sensitizing cancer cells to other therapies by modulating key signaling pathways.

A study on non-segmental vitiligo proposed that this compound may promote pigmentation by upregulating the PPAR-γ and EDNRB genes, suggesting its potential use in combination with other treatments for this condition. springermedizin.de

CRISPR Applications in Functional Genomics

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology has revolutionized functional genomics, allowing for precise gene editing to study the function of specific genes. frontiersin.orgki.se While direct studies combining this compound with CRISPR for functional genomics are still emerging, the existing research on this compound's effects on gene expression provides a strong foundation for future CRISPR-based investigations.

Functional genomics aims to understand the complex interplay of genes and proteins and how they contribute to different phenotypes. frontiersin.org CRISPR-based screens can be used to identify genes that are essential for cellular processes or that confer resistance or sensitivity to drugs like this compound. scilifelab.se For example, a CRISPR screen could be designed to identify genes that mediate the effects of this compound on adipogenesis or insulin sensitivity.

Integrative analyses of CRISPR screening datasets are already being used to prioritize prescription drugs for repurposing. nih.gov This approach could be applied to identify new therapeutic uses for this compound by understanding its interactions with host factors in various diseases.

Stem Cell Research and Regenerative Medicine

This compound has demonstrated significant effects on stem cell differentiation and proliferation, making it a valuable tool in regenerative medicine research. scivisionpub.comstemcell.com Its ability to influence the fate of various stem cell lineages is a key area of interest.

This compound is a potent inducer of adipocyte differentiation from mesenchymal stem cells (MSCs). stemcell.commdpi.comstemcell.com Studies have shown that it promotes the differentiation of adipose tissue-derived mesenchymal stem cells (ASCs) in various species, including horses, sheep, dogs, mice, and humans. mdpi.com An optimized protocol using this compound was found to improve the adipogenic capacity and viability of ASCs compared to traditional methods. mdpi.com

Conversely, this compound has been shown to decrease osteoblastogenesis (bone formation) in human mesenchymal stem cells. stemcell.com This reciprocal regulation of adipogenesis and osteogenesis highlights the critical role of PPARγ in lineage commitment.

In the context of neural stem cells, this compound has been found to stimulate their proliferation while inhibiting neuronal differentiation in embryonic mouse models. stemcell.com Furthermore, it promotes endothelial differentiation and inhibits smooth muscle differentiation in angiogenic progenitor cells. stemcell.com

Recent research from UCLA has shed light on how this compound works at a molecular level to improve glucose metabolism. ucla.edu In obese, diabetic mice, the drug was found to trigger fat stem cells to produce new, smaller fat cells, which are more efficient at storing energy and regulating metabolism. ucla.edu This finding could lead to the development of new therapies for type 2 diabetes that focus on promoting healthy fat cell differentiation. ucla.edu

Omics Technologies (Genomics, Proteomics, Metabolomics)

"Omics" technologies provide a comprehensive view of the molecular changes induced by drugs like this compound. Genomics, proteomics, and metabolomics studies have been instrumental in elucidating the broad-spectrum effects of this compound. tarbaweya.orgacs.orgnih.govmdpi.com

Genomics and Transcriptomics: Gene expression analyses have revealed that this compound treatment in diabetic subjects alters the expression of genes involved in cell cycle control and adipogenesis. diabetesjournals.org Specifically, the expression of the transcription factor E2F4 was decreased, while the MAGE protein necdin was increased in adipose tissue. diabetesjournals.org These changes are thought to contribute to improved insulin sensitivity by promoting the formation of smaller, more insulin-sensitive adipocytes. diabetesjournals.org In models of mineralization, this compound was found to regulate distinct clusters of target genes, influencing pathways related to both bone and vascular health. nih.gov

Proteomics: Proteomic studies have complemented genomic findings by analyzing changes at the protein level. In the liver of obese mice, this compound was found to partially normalize the levels of enzymes involved in amino acid metabolism. tarbaweya.org An integrative analysis of transcriptomics, proteomics, and metabolomics in insulin-resistant mice identified key protein hubs, such as SDHB and SUCLG1, in white adipose tissue that are affected by this compound. acs.org

Metabolomics: Metabolomics, the study of small molecule metabolites, provides a functional readout of cellular activity. oup.com In diabetic mice, this compound treatment led to significant changes in the metabolome of the liver, muscle, and adipose tissue. nih.gov Multivariate analysis established relationships between these metabolic changes and the observed alterations in gene expression, providing a holistic view of this compound's mechanism of action. nih.gov For example, a link was found between differential gene expression in the liver and the content of liver trioleate. nih.gov