Related Experiment Videos

Antidiabetic sulfonylureas modulate farnesoid X receptor activation and target gene transcription

Ramona Steri1, Mahmut Kara, Ewgenij Proschak

  • 1Institute of Pharmaceutical Chemistry/ZAFES/LiFF, Goethe-University Frankfurt Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.

Future Medicinal Chemistry
|March 24, 2011
PubMed
Abstract

Insights

Glibenclamide and glimepiride, common antidiabetic drugs, were found to interact with the farnesoid X receptor (FXR). These sulfonylureas may act as FXR ligands, influencing glucose and lipid homeostasis pathways.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Biochemistry

Background:

  • Sulfonylureas (glibenclamide, glimepiride) are oral antidiabetic agents that stimulate insulin release via pancreatic ATP-dependent potassium channels.
  • The farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, lipid, and glucose metabolism.

Purpose of the Study:

  • To investigate the potential effects of sulfonylureas on farnesoid X receptor (FXR) signaling.
  • To explore the molecular interactions between sulfonylureas and FXR.

Main Methods:

  • Reporter-gene assays to assess FXR activation.
  • Real-time quantitative PCR (qPCR) to measure FXR target gene expression.
  • Computational methods including molecular docking and molecular dynamics simulations.

Main Results:

  • Glibenclamide and glimepiride modulated FXR activation in reporter-gene assays.
  • These sulfonylureas induced FXR target genes in HepG2 cells.
  • Molecular docking and dynamics simulations revealed glibenclamide binding to the FXR ligand-binding domain and helix 12.

Conclusions:

  • Glibenclamide and glimepiride show potential as ligands for the farnesoid X receptor (FXR).
  • These drugs can modulate FXR activation and signaling pathways.
  • This suggests a potential additional mechanism of action for sulfonylureas beyond insulin secretion.

Related Concept Videos

Oral Hypoglycemic Agents: Sulfonylureas01:17

Oral Hypoglycemic Agents: Sulfonylureas

Sulfonylureas are oral hypoglycemic agents utilized in treating type 2 diabetes. They are characterized by their unique sulfonylurea chemical structure. The family of sulfonylureas is divided into generations. First-generation sulfonylureas, including tolbutamide (Orinase), chlorpropamide (Diabinese), and tolazamide (Tolinase), trigger insulin release from pancreatic β cells and enhance peripheral tissues' insulin sensitivity. The second-generation members, such as glipizide (Glucotrol),...
Oral Hypoglycemic Agents: Glinides01:06

Oral Hypoglycemic Agents: Glinides

Repaglinide (Prandin) and Nateglinide (Starlix), known as glinides, are oral insulin secretagogues that stimulate insulin release from pancreatic β cells by closing the ATP-sensitive potassium channels (KATP channel). Repaglinide controls insulin release from pancreatic β cells by managing potassium efflux. It shares two binding sites with sulfonylureas and also has a unique site, indicating overlapping mechanisms of action. With a rapid onset and a 4-7 hour duration, it effectively manages...
Oral Hypoglycemic Agents: Biguanides and Glitazones01:26

Oral Hypoglycemic Agents: Biguanides and Glitazones

Biguanides, particularly metformin (Glucophage), are insulin sensitizers that enhance glucose uptake, thereby reducing insulin resistance. Unlike sulfonylureas, metformin doesn't prompt insulin secretion, which helps to curb hypoglycemia risk. Metformin is beneficial in treating conditions like polycystic ovary syndrome due to its insulin-resistance reduction capability. The drug's primary action involves curtailing hepatic gluconeogenesis, a significant contributor to high blood glucose levels...
Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by the...
Transducer Mechanism: Nuclear Receptors01:31

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
Oral Hypoglycemic Agents: α-Glucosidase Inhibitors01:19

Oral Hypoglycemic Agents: α-Glucosidase Inhibitors

α-glucosidase inhibitors, including acarbose (Precose), miglitol (Glyset), and voglibose (Voglib) (primarily available in Asia), are drugs that control blood sugar levels by delaying the digestion of starch and disaccharides. They achieve this by inhibiting α-glucosidase enzymes in the intestine, which slow the absorption of carbohydrates in the intestine, which in turn leads to a prolonged release of the glucoregulatory hormone GLP-1 from intestinal L-cells.
Acarbose and miglitol are typically...