Glimepiride

Sulfonylurea Receptor (SUR) Binding Kinetics and Affinity

This compound binds to the sulfonylurea receptor (SUR) subunit, which is a regulatory component of the KATP channel. The interaction of sulfonylureas with SUR leads to the inhibition of channel activity. diabetesjournals.orgdrugbank.com

Differential Binding to SUR1 and SUR2A Subunits

KATP channels are composed of Kir6.x-type subunits (specifically Kir6.2 in pancreatic beta cells) and SUR subunits. Different isoforms of SUR exist, including SUR1, SUR2A, and SUR2B, which are expressed in different tissues and confer distinct drug sensitivities. SUR1 is predominantly found in pancreatic beta cells, while SUR2A is primarily expressed in cardiac and skeletal muscle. diabetesjournals.orgnih.govarchivesofmedicalscience.com this compound has been shown to block KATP channels containing both SUR1 and SUR2A subunits. diabetesjournals.orgdrugbank.com Studies using recombinant KATP channels expressed in Xenopus oocytes have shown that this compound inhibits Kir6.2/SUR1, Kir6.2/SUR2A, and Kir6.2/SUR2B channels. nih.govnih.gov

Kinetic Parameters of Binding: Exchange Rate and Affinity

Compared to some other sulfonylureas like glibenclamide, this compound exhibits different binding kinetics to the sulfonylurea receptor in beta-cell membranes. This compound generally shows a lower binding affinity to isolated beta-cell membranes and intact beta-cells compared to glibenclamide, typically 3- to 4-fold lower. nih.govthieme-connect.comresearchgate.net However, this compound is reported to have a significantly higher exchange rate (both association and dissociation rates) with the sulfonylurea receptor than glibenclamide. researchgate.netnih.gov Specifically, it has a faster rate of association (2.5- to 3-fold higher) and dissociation (8- to 9-fold higher) from the receptor compared to glibenclamide. researchgate.net This faster exchange rate may contribute to a reduced risk of hypoglycemia observed with this compound compared to some older sulfonylureas. researchgate.net

Data on the high-affinity inhibition of different KATP channel subtypes by this compound, as measured by IC50 values in inside-out patches, are presented below:

For comparison, the IC50 values for glibenclamide are approximately 4 nM for SUR1 and 27 nM for SUR2A. nih.gov This indicates that this compound has a similar potency to glibenclamide at SUR1 but is more potent at SUR2A. nih.gov

Identification of Specific Binding Proteins (e.g., 65-kDa and 140-kDa polypeptides)

Studies utilizing photoaffinity labeling techniques with radiolabeled sulfonylureas have aimed to identify the specific proteins within the beta-cell membrane to which these drugs bind. Photoaffinity labeling of beta-cell membrane proteins with radiolabeled this compound has identified a 65-kDa binding protein. nih.govthieme-connect.comnih.govnih.gov In contrast, glibenclamide predominantly labels a 140-kDa protein under similar conditions. nih.govthieme-connect.comnih.govnih.gov

These findings suggest that this compound and glibenclamide may interact with different components or sites within the KATP channel complex. Some research suggests that the 65-kDa protein is the binding site for this compound, while the 140-kDa protein is the binding site for glibenclamide. portico.orgdiabetix-francoindian.com However, other studies suggest that this compound, like glibenclamide, binds to the 140 kDa sulfonylurea receptor subunit. nih.gov

Further studies involving competitive binding and photoaffinity labeling experiments where this compound inhibits the labeling of the 140-kDa protein by glibenclamide and vice versa suggest allosteric interactions between these binding proteins or subunits within the KATP channel complex. nih.govthieme-connect.comnih.govportico.org This indicates that the 65-kDa and 140-kDa proteins, potentially subunits of the KATP complex, can influence each other's binding characteristics and regulate the channel's open/closed state through allosteric mechanisms. nih.govthieme-connect.comportico.org

KATP Channel Modulation and Membrane Depolarization

The binding of this compound to the SUR subunit of the KATP channel leads to the closure of the channel. patsnap.comdrugbank.com This closure reduces the efflux of potassium ions from the beta cell. Under normal physiological conditions, open KATP channels maintain the beta cell membrane in a hyperpolarized state. By blocking these channels, this compound causes a decrease in potassium permeability, leading to depolarization of the beta cell membrane. patsnap.comdiabetesjournals.orgdrugbank.comscielo.org This depolarization is a critical step in initiating insulin secretion. Whole-cell patch clamp experiments have demonstrated that this compound induces depolarization of beta cells, consistent with its KATP channel blocking activity. nih.govthieme-connect.com

Calcium Influx and Exocytosis of Insulin Vesicles

Membrane depolarization induced by KATP channel closure triggers the opening of voltage-dependent calcium channels located on the beta cell membrane. patsnap.comdrugbank.comscielo.org This opening allows for an influx of extracellular calcium ions into the beta cell cytoplasm. patsnap.comdrugbank.comscielo.org The resulting increase in intracellular calcium concentration is a key signal that triggers the movement and fusion of insulin-containing secretory granules with the plasma membrane, a process known as exocytosis. drugbank.comscielo.org This exocytosis leads to the release of insulin into the bloodstream. Thus, this compound's action on KATP channels ultimately facilitates the calcium influx necessary for insulin vesicle exocytosis and subsequent insulin secretion. patsnap.comdrugbank.comscielo.orgresearchgate.net

Influence on Glucose Transport and Utilization

This compound influences the processes of glucose transport and utilization in insulin-responsive tissues through several mechanisms.

A key mechanism by which this compound enhances glucose uptake in peripheral tissues is by promoting the translocation and activation of Glucose Transporter 4 (GLUT4). wikipedia.orgwikipedia.orglipidmaps.orgnih.govuni.lu GLUT4 is the primary insulin-regulated glucose transporter found in adipocytes and skeletal muscle, responsible for facilitating glucose entry into these cells. guidetopharmacology.orgctdbase.org Research, including in vitro studies using murine 3T3 adipocytes and cultured human skeletal muscle cells, indicates that this compound increases the number of GLUT4 molecules in the plasma membrane, thereby enhancing glucose uptake. wikipedia.orgwikipedia.orglipidmaps.orgnih.govuni.lu This effect contributes to overcoming insulin resistance in these tissues. wikipedia.org While some studies suggest an acute effect on GLUT4 translocation, chronic exposure of rat cardiomyocytes to this compound has been shown to increase glucose uptake, potentially through enhanced expression of both GLUT1 and GLUT4 transporters. wikipedia.org

Beyond glucose transport, this compound also influences intracellular glucose metabolism by stimulating glycogenesis (the synthesis of glycogen) and lipogenesis (the synthesis of lipids) in peripheral tissues. In vitro studies, particularly in murine 3T3 adipocytes and rat diaphragm, have shown that this compound stimulates these processes. wikipedia.orgwikipedia.orglipidmaps.orgwikipedia.org Studies in cultured human skeletal muscle cells have further demonstrated that this compound increases insulin-stimulated glycogen synthesis in a dose-dependent manner. mybiosource.comsigmaaldrich.com This suggests that this compound not only facilitates glucose entry but also promotes its storage and utilization within muscle and fat cells. wikipedia.org

Glucose Transporter (GLUT4) Translocation and Activation in Adipocytes and Skeletal Muscle

Modulation of Insulin Signaling Cascades

This compound interacts with and modulates key components of the insulin signaling pathway, contributing to its insulin-sensitizing effects.

A significant finding regarding this compound's extrapancreatic action is its ability to activate the Phosphatidylinositol 3-Kinase (PI3K) and downstream Akt (Protein Kinase B) pathway. wikipedia.orgwikipedia.orgakrivisbio.comeasychem.orgguidetopharmacology.org This activation has been observed in various cell types, including rat adipocytes, skeletal muscle, endothelial cells, and osteoblasts. wikipedia.orgwikipedia.orgakrivisbio.comeasychem.orgguidetopharmacology.org The PI3K/Akt pathway is a critical signaling cascade initiated by insulin binding to its receptor, leading to a variety of metabolic effects, including glucose uptake and glycogen synthesis. uni.lu this compound's activation of this pathway is thought to be a key contributor to its insulin-like effects and its ability to enhance insulin sensitivity in peripheral tissues. sigmaaldrich.comwikipedia.orgwikipedia.orgakrivisbio.comeasychem.orgguidetopharmacology.org Inhibition of PI3K has been shown to abolish some of the stimulatory effects of this compound, highlighting the importance of this pathway in its action. wikipedia.orgguidetopharmacology.org

Upstream of the PI3K/Akt pathway, this compound has been shown to induce the tyrosine phosphorylation of Insulin Receptor Substrate (IRS)-1 and IRS-2 proteins. easychem.orgguidetopharmacology.orgnih.gov IRS proteins are key adaptor molecules that become tyrosine phosphorylated upon insulin receptor activation, serving as docking sites for various signaling molecules, including PI3K. uni.luguidetopharmacology.org Studies in isolated rat adipocytes suggest that this compound's induction of IRS-1 and IRS-2 tyrosine phosphorylation is part of an insulin-mimetic signaling cascade that involves the activation of nonreceptor tyrosine kinases such as pp59(Lyn) and pp125(Fak). nih.gov This tyrosine phosphorylation is essential for the subsequent activation of the PI3K pathway, thereby linking this compound's effects on IRS proteins to its downstream actions on glucose metabolism. uni.luguidetopharmacology.org

Compound Names and PubChem CIDs

Data Table: Summary of this compound's Extrapancreatic Effects

Association of PI3K with IRS-1 and -2

The insulin signaling pathway is crucial for glucose homeostasis, involving a cascade initiated by insulin binding to its receptor. This leads to the phosphorylation of Insulin Receptor Substrate (IRS) proteins, primarily IRS-1 and IRS-2. Phosphorylated IRS proteins then serve as docking sites for Phosphatidylinositol 3-kinase (PI3K). The association and activation of PI3K with IRS-1 and -2 are critical steps in downstream signaling, ultimately promoting glucose uptake and metabolism e-dmj.orgnih.gov. Studies have indicated that this compound can enhance PI3K and Akt activity, with these effects being more pronounced compared to other sulfonylureas like glibenclamide and tolbutamide scielo.org. This enhancement of the insulin downstream pathway appears to be significant in the pleiotropic effects of this compound scielo.org. Research in myotubes has shown that this compound mediates an effect via PI3K, an effect not shared by glibenclamide scielo.org. Furthermore, studies in insulin-resistant adipocytes and cardiomyocites have observed that this compound stimulates glucose influx, associated with enhanced translocation of GLUT1 and GLUT4 towards the plasma membrane scielo.org.

Regulation of Hepatic Glucose Production

Hepatic glucose production (HGP) plays a significant role in maintaining fasting blood glucose levels. In type 2 diabetes, increased HGP contributes to hyperglycemia. This compound has been reported to have a mild impact on reducing hepatic glucose production, although this is not considered its main mechanism of action patsnap.com. In vitro studies have confirmed that this compound intervenes in glycogen metabolism. Experiments using Hep-G2 cells demonstrated that the drug enhances glycogen production by 30-40% when used in conjunction with insulin, seemingly induced by increased insulin receptor recycling and Protein Kinase-C (PKC) pathway activation scielo.org. Evidence suggests that PKC, particularly PKCε, might be related to this phenomenon, and PKCε is associated with insulin resistance in the liver scielo.org. Animal models have shown that this compound reduces insulin resistance and increases hepatic glucose disposal nih.gov.

Adipocytokine Release and Adipocyte Differentiation

Adipose tissue is not merely a storage site for energy but also an endocrine organ that secretes various adipocytokines influencing insulin sensitivity and glucose metabolism. This compound has been shown to interfere with the release of adipocytokines from adipocytes and influence their differentiation, contributing to its insulin-sensitizing activity researchgate.netingentaconnect.com. This effect may be dependent on or independent of SUR or DIGs (detergent-insoluble glycolipid-enriched raft domains) researchgate.net. Studies have demonstrated that this compound stimulates adipocyte differentiation through the enhancement of peroxisome proliferator-activated receptor gamma (PPAR-gamma) activity jst.go.jpresearchgate.net. This enhancement leads to increased secretion of adiponectin from adipose tissue, thereby reducing insulin resistance jst.go.jpresearchgate.net. This compound is reported to increase adiponectin gene expression in adipocytes, highlighting its important role in metabolic changes in diabetic patients jst.go.jp. Research indicates that this compound assembles complexes with PPARγ receptors, competing with rosiglitazone for its binding site scielo.org. This this compound-PPARγ complex modified mRNA levels of PPARγ-gene targets in 3T3-L1 adipocytes, including adiponectin scielo.org.

Molecular Docking and Computational Studies

Computational approaches, such as molecular docking and interactome analysis, provide valuable insights into the potential molecular targets and pathways influenced by this compound beyond its known interaction with SUR1.

Prediction of Binding to Soluble Epoxide Hydrolase (sEH) and Epoxyeicosatrienoic Acid (EET) Levels

Molecular docking studies have explored the potential binding of this compound to various proteins. Notably, this compound has exhibited good molecular docking with soluble epoxide hydrolase (sEH) nih.govresearchgate.netoup.com. sEH is an enzyme involved in the metabolism of epoxyeicosatrienoic acids (EETs) to less active dihydroxyeicosatrienoic acids (DHETs) researchgate.netdntb.gov.ua. EETs are endogenous lipid mediators with various beneficial effects, including anti-inflammatory and cardiovascular protective properties researchgate.netdntb.gov.ua. Inhibition of sEH can lead to increased levels of EETs researchgate.netdntb.gov.ua. Studies suggest that the cardiovascular protective effect of this compound may be related to an increase in EET levels through sEH inhibition nih.govresearchgate.netoup.com.

Interactome Analysis of Drug Target Receptors and Intermediate Proteins

Interactome analysis helps to understand the complex network of protein-protein interactions influenced by a drug. Computational assessment has generated this compound interactomes, depicting the multiple intermediary connections between its drug target receptors and various downstream proteins nih.gov. This compound's interactome was initiated via its drug target receptor, KCNJ11 (which encodes the Kir6.2 subunit of the KATP channel), and extended to other proteins through a network of intermediate protein edges nih.gov. Analysis of drug interactomes reveals that the genes involved are implicated in various cellular functions nih.gov. Target overlap analysis between this compound and other compounds has identified common hub genes, including ESR1, EGFR, PIK3CA, CYP2C9, and SRC, indicating potential areas of interaction and influence on various pathways samipubco.com.

Investigation of Signaling Pathways (e.g., EGF receptor, EphrinB-EPHB, EPO, FGF, mTOR, p53, S1P1)

Computational and network pharmacology analyses have implicated this compound in influencing several signaling pathways. While direct interactions with all listed pathways (EphrinB-EPHB, EPO, FGF, p53, S1P1) were not explicitly detailed in the provided search results in the context of this compound, the interactome analysis and target overlap studies point to connections with key proteins within broader signaling networks. For example, EGFR (Epidermal Growth Factor Receptor) and PIK3CA (encoding the p110α subunit of PI3K) were identified as common hub genes in interactome analysis involving this compound samipubco.com. The EGFR signaling pathway is a complex network involved in cell proliferation, differentiation, and survival, often involving the PI3K-Akt-mTOR cascade mdpi.combio-rad-antibodies.comnih.govbio-rad.comembopress.org. mTOR (mammalian Target of Rapamycin) is a major downstream effector of the IRS-1/PI3K/Akt insulin signaling pathway, involved in regulating metabolism, protein synthesis, and cell growth nih.govnih.gov. While a direct regulatory effect of this compound on mTOR or p53 was not found in the provided snippets, the connections to PI3K and the broader insulin signaling pathway suggest potential indirect influences. The identification of SRC as a common hub gene also links this compound's potential influence to pathways involving Src family kinases, which are intimately associated with PI3K scielo.orgsamipubco.com. Further research is needed to fully elucidate this compound's specific interactions and functional consequences within each of these complex signaling pathways.

Compound List and PubChem CIDs

Data Tables

While detailed quantitative data for creating interactive tables for each specific interaction mentioned was limited within the provided snippets, the following summarizes some research findings that could conceptually be presented in tables:

Research Findings on this compound's Extrapancreatic Effects

Interactome Analysis Insights

Note: The intermediate protein edges represent the complexity of the signaling network connecting the initial drug target to the final node (BDNF in this specific study).

Common Hub Genes in this compound and Phytochemical Interactome

These tables summarize key findings from the provided text and illustrate how data could be presented. More detailed interactive tables would require access to the specific quantitative data from the referenced studies.

Glucose-Lowering Efficacy in Type 2 Diabetes Mellitus

The clinical efficacy of this compound in type 2 diabetes mellitus has been demonstrated through its impact on key glycemic parameters, including fasting plasma glucose (FPG), post-prandial glucose (PPG), and glycosylated hemoglobin (HbA1c) mims.commims.comwikidata.orgmims.com.

Reduction in Fasting Plasma Glucose (FPG) and Post-Prandial Glucose (PPG)

Studies have shown that this compound is effective in reducing both FPG and PPG levels in patients with type 2 diabetes mims.commims.comwikidata.orgmims.com. By stimulating insulin release, particularly in response to glucose, this compound helps to regulate blood sugar levels throughout the day wikipedia.orgmims.commims.com. The reduction in FPG reflects improved basal glucose control, while the decrease in PPG indicates better handling of glucose after meals mims.commims.com.

Glycosylated Hemoglobin (HbA1c) Reduction

Glycosylated hemoglobin (HbA1c) is a crucial marker reflecting average blood glucose levels over the preceding two to three months mims.com. Research consistently shows that this compound treatment leads to a significant reduction in HbA1c levels in patients with type 2 diabetes mims.commims.commims.commims.comwikidata.orgmims.com. This reduction signifies improved long-term glycemic control, which is essential for preventing or delaying diabetes-related complications.

Interactive Data Table: Illustrative HbA1c Reduction with this compound Monotherapy (Example Data)

Note: This table presents illustrative data based on typical findings in clinical research on this compound monotherapy and should be interpreted as representative examples of HbA1c reduction observed in studies mims.commims.commims.commims.comwikidata.orgmims.com. Specific outcomes may vary depending on study design, patient characteristics, and treatment duration.

Comparative Pharmacodynamic Profiles with Other Sulfonylureas (e.g., Glibenclamide, Glipizide, Gliclazide)

This compound is a second-generation sulfonylurea, and its pharmacodynamic profile has been compared to other agents in the same class, such as glibenclamide, glipizide, and gliclazide wikipedia.orgmims.commims.comwikidata.orgwikipedia.orgwikipedia.orgwikidata.org. While all sulfonylureas stimulate insulin secretion, differences exist in their binding characteristics to the KATP channel and their extrapancreatic effects wikipedia.orgmims.com.

Compared to glibenclamide, this compound is associated with a lower incidence of hypoglycemia wikipedia.org. Glibenclamide may interfere with the normal homeostatic suppression of insulin secretion in response to hypoglycemia, whereas this compound does not wikipedia.org. Gliclazide has been shown to selectively bind to sulfonylurea receptors (SUR-1) on pancreatic beta-cells and has been suggested to provide cardiovascular protection as it does not bind to SUR-2A receptors in the heart wikipedia.org. Glipizide also works by stimulating insulin release and increasing tissue sensitivity to insulin mims.comwikipedia.org.

Interactive Data Table: Comparative Pharmacodynamic Aspects of Sulfonylureas (Illustrative)

Note: This table provides an illustrative comparison of pharmacodynamic aspects based on available information wikipedia.orgmims.commims.commims.comwikidata.orgwikipedia.orgwikipedia.orgwikidata.orgwikipedia.org. Binding selectivity and relative hypoglycemia risk can be complex and influenced by various factors.

Impact on Insulin and C-Peptide Levels

This compound's primary mechanism of action involves stimulating insulin release from pancreatic beta cells wikipedia.orgmims.com. This leads to an increase in circulating insulin levels mims.comwikidata.org. C-peptide is a byproduct of insulin production, and its levels can be used as an indicator of endogenous insulin secretion wikidata.org. Studies have shown that this compound treatment results in increased C-peptide levels, confirming its effect on stimulating the pancreas to produce insulin mims.comwikidata.org.

Monotherapy Studies in Patients with Inadequate Glycemic Control

This compound has been investigated as monotherapy in patients with type 2 diabetes mellitus who have inadequate glycemic control through diet and exercise alone. Clinical trials have demonstrated that this compound monotherapy can improve glycemic control. In one multicenter, randomized, double-blind, placebo-controlled study involving treatment-naive or minimally treated adults with type 2 diabetes and a mean baseline HbA1c of over 9%, this compound (titrated from 1 to 8 mg) over 22 weeks resulted in significant improvements in fasting plasma glucose and HbA1c compared to placebo. The this compound group showed an average HbA1c reduction of -1.1% compared to placebo. Reductions in HbA1c of -1.2%, -1.8%, and -1.8% were observed in the 1 mg, 4 mg, and 8 mg this compound groups, respectively, compared to placebo. medcentral.com Another study comparing this compound, metformin, and rosiglitazone monotherapy in drug-naive Korean patients with type 2 diabetes found that all three drugs similarly decreased HbA1c levels by 0.8-0.9% by the end of the study. e-dmj.org Approximately 60% of participants in this study achieved an HbA1c level below 7.0% with monotherapy, though only about 30% reached below 6.5%. e-dmj.org

Combination Therapy with Other Antihyperglycemic Agents (e.g., Metformin, Insulin)

This compound can be used in combination with other antihyperglycemic agents when glycemic control is not adequately achieved with this compound alone or other monotherapies. nih.gov Combination therapy with this compound and metformin has been evaluated. One study compared a fixed-dose combination of this compound and metformin with this compound monotherapy in patients with type 2 diabetes already on basal insulin therapy. The group receiving the this compound/metformin combination showed a significantly greater decrease in HbA1c and 2-hour postprandial glucose compared to the this compound monotherapy group. nih.gov

The combination of this compound and insulin has also been investigated. A retrospective study indicated that the combination of insulin and oral this compound in patients with type 2 diabetes led to a more significant improvement in HbA1c control compared to insulin alone, with HbA1c decreasing from 8.5 ± 0.6% to 7.4 ± 0.8%. frontiersin.org This combination also resulted in a notable decrease in the required insulin dosage. frontiersin.org Another study exploring the efficacy of continuing this compound in combination with basal-prandial insulin therapy in patients with a long duration of type 2 diabetes found that continuing this compound may remain beneficial, partly by enhancing insulin secretion. nih.gov

Data from a study on dapagliflozin added to this compound in patients with inadequately controlled type 2 diabetes on sulfonylurea monotherapy showed that adding dapagliflozin to this compound significantly reduced HbA1c, fasting plasma glucose, post-challenge plasma glucose, and weight compared with placebo added to this compound over 24 weeks, and this efficacy was maintained at 48 weeks. springermedizin.de

Efficacy in Special Populations (e.g., Elderly, Patients with Renal/Hepatic Impairment)

Studies suggest that this compound can be used in older patients and those with renal compromise. researchgate.net However, caution is advised in elderly patients due to the potential for prolonged hypoglycemia, and conservative dose titration is recommended with careful monitoring. medscape.com

In patients with renal impairment, the pharmacokinetics, efficacy, and safety of this compound have been investigated. An initial dosage of 1 mg daily is recommended in patients with type 2 diabetes and renal impairment to reduce hypoglycemia risk, with careful titration based on glycemic response. medcentral.com While this compound is metabolized by the liver to active metabolites that can accumulate in renal disease, studies have shown that this compound is safe and effective with clearly definable pharmacokinetics in diabetic patients with renal impairment with an initial creatinine clearance above 10 mL/min. nih.govnih.gov Increased plasma elimination of this compound with decreasing kidney function is thought to be related to altered protein binding. nih.gov However, some sources indicate that the use of this compound is contraindicated in patients with a glomerular filtration rate (GFR) of <60 mL/min due to the risk of severe and prolonged hypoglycemia from the accumulation of active metabolites. nih.govsmw.ch

The use of this compound in patients with hepatic impairment has not been extensively studied, and it is not recommended in severe impairment. medscape.com If used, therapy should be initiated at 1 mg daily and titrated carefully. medscape.com A study comparing this compound and linagliptin in patients with non-alcoholic fatty liver disease and type 2 diabetes found no significant differences between the two drugs in improving hepatic and renal functions or reducing blood lipid levels over 6 months. archivesofmedicalscience.com

Impact on Cardiovascular Mortality and Morbidity

Research has explored the impact of this compound on cardiovascular outcomes. The CAROLINA (Cardiovascular Outcome Study of Linagliptin Versus this compound in Type 2 Diabetes) trial compared the cardiovascular outcomes of linagliptin (a DPP-4 inhibitor) and this compound in patients with early type 2 diabetes at increased cardiovascular risk. This study indicated no major differences in cardiovascular outcomes between linagliptin and this compound. medscape.combjd-abcd.com The CAROLINA trial provided reassurance regarding the cardiovascular safety of sulfonylureas, including this compound. medscape.combjd-abcd.com

Effects on Ischemic Preconditioning

This compound has been studied for its effects on ischemic preconditioning, a protective mechanism that can limit damage during an ischemic event. Compared to some other sulfonylureas like glibenclamide, this compound appears to have minimal effects on ischemic preconditioning of cardiac myocytes. researchgate.net Studies in isolated rat hearts have shown that while glibenclamide abolishes the cardioprotective effect of ischemic preconditioning, this compound does not. ahajournals.orgucl.ac.ukahajournals.org This difference may be attributed to this compound not blocking mitochondrial KATP channels, which are believed to play a crucial role in preconditioning protection, in contrast to glibenclamide. ahajournals.orgucl.ac.ukahajournals.org Furthermore, this compound treatment has been reported to facilitate the cardioprotective effect elicited by ischemic preconditioning in the diabetic heart, independent of changes in blood glucose. nih.gov

Role in Patients with Chronic Heart Failurenih.govdiabetesjournals.orgjapsonline.com

Research has explored the impact of this compound on cardiovascular outcomes, particularly in patients with type 2 diabetes and chronic heart failure. A prospective cohort study analyzed data from over 21,000 inpatients with type 2 diabetes and chronic heart failure. The findings suggested that patients who continued this compound treatment after discharge experienced fewer heart failure rehospitalizations or emergency admissions. The study reported a hazard ratio (HR) of 0.42 (95% confidence interval [CI] 0.36–0.50) for heart failure rehospitalizations or emergency admissions in the this compound group compared to the non-glimepiride group. Furthermore, this compound use was associated with lower cardiovascular mortality (HR 0.34; 95% CI 0.24–0.48) and all-cause mortality (HR 0.47; 95% CI 0.35–0.63) in this patient population. researchgate.netnih.govoup.com

The same study also indicated that higher doses of this compound (2–4 mg/day) were associated with lower cardiovascular mortality compared to lower doses (1 mg/day). researchgate.netnih.govoup.comresearchgate.net The potential cardiovascular protective effect of this compound may be linked to an increase in epoxyeicosatrienoic acid (EET) levels through the inhibition of soluble epoxide hydrolase (sEH). researchgate.netnih.govoup.comresearchgate.net

Another clinical trial, the CAROLINA (Cardiovascular Outcome Study of Linagliptin versus this compound in Patients with Type 2 Diabetes) trial, compared linagliptin (a DPP-4 inhibitor) with this compound in over 6,000 patients with type 2 diabetes. This study found no significant difference in major adverse cardiovascular events or heart failure hospitalizations between the two treatment groups over a median follow-up of 6.3 years. diabetesjournals.orge-dmj.org

Data Table: Outcomes in Patients with T2D and Chronic Heart Failure (Propensity Score Matched Cohort)

*Based on data from a prospective cohort study nih.govoup.com.

Interactions with Other Antihyperglycemic Agents

When this compound is coadministered with other antihyperglycemic agents, a synergistic effect on lowering blood glucose can occur, potentially increasing the risk of hypoglycemia. medicalnewstoday.com This includes combinations with insulin or other oral antidiabetic medications. medicalnewstoday.commedscape.comhres.ca Dosage adjustments and close monitoring are often required when initiating or discontinuing other antidiabetic agents in patients receiving this compound. medscape.com

Interactions with Other Medications Affecting Metabolism or Excretion

This compound is primarily metabolized by the cytochrome P450 2C9 (CYP2C9) enzyme in the liver. medcentral.commdpi.comnih.gov Therefore, medications that inhibit or induce CYP2C9 activity can affect this compound plasma concentrations. medcentral.comhres.ca

Inhibitors of CYP2C9: Drugs that inhibit CYP2C9 (e.g., fluconazole) can decrease the metabolism of this compound, leading to increased plasma concentrations and a higher risk of hypoglycemia. medcentral.comnih.gov

Inducers of CYP2C9: Conversely, drugs that induce CYP2C9 (e.g., rifampin) can increase the metabolism of this compound, potentially leading to decreased plasma concentrations and a reduction in its glucose-lowering effect, resulting in worsening glycemic control. medcentral.comhres.ca A study reported a 33% reduction in the area under the curve (AUC) of this compound when coadministered with rifampicin. mdpi.com

Other medications can also interact with this compound through different mechanisms, such as competing for plasma protein binding sites or affecting renal excretion. For instance, aspirin may increase the effect of this compound through plasma protein binding competition. nih.gov Colesevelam has been reported to increase the clearance of this compound. mdpi.com Hydrochlorothiazide may decrease the effect of this compound through pharmacodynamic antagonism. nih.gov

Impact of CYP2C9 Polymorphisms on Pharmacokinetics and Pharmacodynamics

Polymorphisms in the CYP2C9 gene are known to influence the metabolism of this compound. medscape.comhres.caresearchgate.netwikidata.orgnih.gov The CYP2C9 gene exhibits different phenotypes based on enzyme activity, including normal metabolizers (CYP2C9 1/1), intermediate metabolizers (CYP2C9 1/3), and poor metabolizers (CYP2C9 3/3). mdpi.com

Studies have shown that individuals with certain CYP2C9 variant alleles, particularly CYP2C9 3/3, have significantly lower clearance of this compound compared to those with the CYP2C9 1/1 genotype. mdpi.comingentaconnect.comnih.govresearchgate.net This reduced metabolism can lead to higher plasma concentrations of this compound. nih.govresearchgate.net For example, a study reported a 3-fold increase in the AUC for the CYP2C9 3/3 genotype compared to CYP2C9 1/1 after a 2 mg this compound dose. mdpi.com Another study in a Japanese population showed that the AUC for this compound in CYP2C9 1/3 subjects was approximately 2.5-fold higher than in CYP2C9 1/1 subjects. nih.govresearchgate.net This lower hydroxylation activity in individuals with the CYP2C9 1/3 polymorphism can result in elevated plasma levels and a stronger pharmacological effect. nih.govresearchgate.net

The increased exposure to this compound in poor metabolizers due to CYP2C9 polymorphisms may lead to a greater reduction in HbA1c levels. nih.govresearchgate.net However, it may also increase the risk of hypoglycemia. mdpi.comhres.ca

Genetic Factors Influencing Therapeutic Efficacy and Adverse Events

Beyond CYP2C9, other genetic factors may also influence the therapeutic efficacy and the likelihood of adverse events associated with sulfonylureas, including this compound. ingentaconnect.comnih.govconicet.gov.ar

Genes encoding proteins involved in insulin secretion and action, such as the sulfonylurea receptor 1 (SUR1, encoded by the ABCC8 gene) and the potassium inward rectifier Kir6.2 (encoded by the KCNJ11 gene), which constitute the ATP-sensitive potassium (KATP) channels in pancreatic beta cells, have been investigated for their impact on sulfonylurea response. wikipedia.orgingentaconnect.comnih.govconicet.gov.arviamedica.pl Specific genetic variants in ABCC8 and KCNJ11 have been correlated with variations in sulfonylurea response. ingentaconnect.comconicet.gov.arviamedica.pl For example, the E23K polymorphism in the KCNJ11 gene has been associated with an increased risk of sulfonylurea therapeutic failure. conicet.gov.ar

Polymorphisms in other genes, such as Transcription factor 7-like 2 (TCF7L2), have also been linked to the likelihood of sulfonylurea therapy failure. ingentaconnect.comconicet.gov.ar Additionally, polymorphisms in genes like insulin receptor substrate 1 (IRS1) and Calpain 10 (CAPN10) have been associated with sulfonylurea drug response. ingentaconnect.com

While research highlights the potential influence of these genetic factors on this compound response, larger population studies are needed to fully elucidate the contribution of specific polymorphisms to variability in therapeutic effectiveness and adverse events. ingentaconnect.com

Studies on Adipocytes, Muscle Cells, and Hepatocytes

This compound has demonstrated insulin-mimetic effects in adipocytes and muscle cells. In 3T3 adipocytes, this compound stimulated lipogenesis and glucose transport, exhibiting greater effectiveness than glyburide in certain aspects. portico.orgnih.govscielo.orghres.ca This stimulation of glucose transport is linked to enhanced translocation and dephosphorylation of GLUT4, a critical glucose transporter, suggesting a potential molecular mechanism for its action in both normal and insulin-resistant adipocytes. portico.orgnih.govscielo.orghres.ca

Studies using isolated rat diaphragms, a muscle model, also indicated that this compound stimulated glucose transport and glycogenesis, achieving a notable percentage of the maximum insulin effect. portico.orgnih.gov In cultured human skeletal muscle cells, this compound was found to increase insulin-stimulated glycogen synthesis in a dose-dependent manner, an effect seemingly mediated via the PI3 kinase pathway and not observed with glibenclamide, highlighting a potential distinct mechanism for this compound's insulin-sensitizing effect in these cells. diabetesjournals.org

In isolated rat hepatocytes, this compound has been shown to inhibit hepatic glucose output by increasing the concentration of fructose-2,6-biphosphate. hres.ca It may also enhance insulin-mediated glucose utilization in hepatocytes and has been reported to stimulate the activity of key enzymes in the glycolytic and glycogen synthetic pathways, such as phosphofructokinase and glycogen synthase. portico.org Furthermore, in vitro studies with hepatocytes revealed that this compound concentration-dependently inhibited gluconeogenesis and ketogenesis from alanine and stimulated the TCA cycle. hres.ca

Investigations on Pancreatic Islets

The primary mechanism of this compound involves stimulating insulin release from pancreatic beta cells through binding to the 65 kDa protein component of the KATP channel in their membranes. portico.orgnih.gov Studies using isolated perfused rat pancreases have shown that this compound strongly stimulates beta-cell activity, leading to a characteristic biphasic insulin release with an initial sharp peak followed by a prolonged second phase. nih.gov The extent of this insulin release is influenced by environmental glucose concentrations, with reduced glucose levels significantly decreasing hormone release. nih.gov this compound did not affect alpha-cell activity (glucagon release) in these studies. nih.gov

While this compound binds to the KATP channel, some studies suggest it has a lower binding affinity and causes less insulin release compared to glibenclamide in normal dogs and humans in vivo. portico.org However, in various animal models and in vitro studies using isolated perfused pancreases and perifused islets of rats and mice, this compound has been shown to release comparable or even higher amounts of insulin than glibenclamide. portico.org

Innovative research has also explored modified versions of this compound for targeted insulin release. A "photoswitchable" this compound prototype, JB253, is activated by blue light. In vitro studies with rodent and human pancreatic islet cells demonstrated that exposure to blue light triggered near-instantaneous insulin release, which rapidly ceased upon removal of the light source. pharmaceutical-journal.com

Osteoblast Proliferation and Differentiation Studies

Beyond its glucose-lowering effects, this compound's potential impact on bone cells has been investigated. Studies have indicated that this compound can induce the proliferation and differentiation of rat osteoblasts. actaorthop.orgphysiology.orgplos.orgresearchgate.net This effect is believed to be linked to its ability to activate the PI3K/Akt pathway. actaorthop.orgplos.orgresearchgate.netmedkoo.com

In a high glucose microenvironment (16.5 mM glucose), which typically inhibits osteogenic differentiation and proliferation of rat osteoblasts, this compound significantly enhanced these processes. plos.orgresearchgate.net This enhancement was associated with the activation of endothelial nitric oxide synthase (eNOS) via the PI3K/Akt pathway. plos.orgresearchgate.net Inhibition of PI3K activity suppressed the this compound-induced expression of key osteogenic markers such as RUNX2, OCN, and ALP mRNA, as well as ALP activity and calcium accumulation. plos.orgresearchgate.net

The following table summarizes some key in vitro findings:

Studies in Rats and Other Animal Species

Studies in various animal models, including rats, mice, and dogs, have shown that this compound leads to a rapid and pronounced decrease in blood glucose. portico.orgnih.gov In vivo studies indicate that this compound can significantly reduce HbA1c, blood glucose, and fasting insulin levels through extrapancreatic activities. portico.orgnih.gov

In monosodium glutamate (MSG)-induced obese insulin-resistant rats, this compound treatment for 4 weeks improved insulin sensitivity, increased GLUT4 protein content and glucose utilization in oxidative skeletal muscle, and increased phospho-glycogen synthase kinase (p-GSK3) and glycogen content in the liver. doi.orgresearchgate.net These findings provide in vivo evidence for this compound's insulin-sensitizing effect in muscle and liver. doi.orgresearchgate.net

The Spontaneously Diabetic Torii (SDT) rat, a non-obese model of type 2 diabetes characterized by reduced insulin secretory capacity, has also been used to study this compound. Following oral administration, SDT rats exhibited significantly higher maximum plasma concentrations and area under the curve for this compound compared to non-diabetic Sprague-Dawley rats. ingentaconnect.com However, additional insulin secretion after this compound treatment was markedly reduced in SDT rats, suggesting that this compound might be less effective in type 2 diabetic patients with severely impaired insulin secretory capacity. ingentaconnect.com

Animal studies have also investigated this compound's effects on bone. In ovariectomized rats, this compound was able to reverse bone resorption induced by estrogen deficiency while stimulating bone formation. researchgate.net

Euglycemic Clamp Studies to Assess Insulin Sensitivity

Euglycemic clamp studies are a standard method for quantifying insulin sensitivity in vivo. In rats, euglycemic clamp studies have indicated that this compound enhances insulin action in peripheral tissues, suggesting a beneficial effect on insulin sensitivity. portico.org this compound has been shown to increase the metabolic clearance of glucose at submaximal insulin levels in normal rats. portico.org

In a study utilizing euglycemic and hyperinsulinemic clamps in normal dogs, oral administration of this compound for 7 days resulted in a significant increase in hepatic glucose uptake. portico.org

The following table summarizes some key in vivo findings in animal models:

Islet Transplantation Models

Preclinical studies investigating this compound have extended to evaluating its potential involvement in the prevention of diabetes within the context of islet transplantation models. Research utilizing the BioBreeding (BB) rat, a model prone to spontaneous autoimmune diabetes, has included investigations into this compound's effects alongside islet transplantation. nih.govportico.org These studies aimed to understand if this compound could play a role in preserving beta cell function or preventing the autoimmune destruction that necessitates transplantation. While the specific, detailed findings regarding this compound's direct effects on the survival, function, or immune response towards transplanted islets in these models are not extensively detailed in the readily available literature, the inclusion of this compound in such studies suggests an exploration of its potential benefits in a transplantation setting, possibly related to its known effects on beta cell function and potentially its reported immunomodulatory activity. nih.govportico.org The BB rat model is particularly relevant as it mimics the autoimmune destruction of beta cells seen in Type 1 Diabetes, the primary indication for islet transplantation. nih.gov