Related Experiment Videos

Fenofibrate, troglitazone, and 15-deoxy-Delta12,14-prostaglandin J2 close KATP channels and induce insulin secretion

Kenju Shimomura1, Hiroyuki Shimizu, Mizuho Ikeda

  • 1Department of Medicine and Molecular Science, Gunma University School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511 Japan. kenju.shimomura@physiol.ox.ac.uk

The Journal of Pharmacology and Experimental Therapeutics
|June 18, 2004
PubMed

Insights

Peroxisome proliferator-activated receptor (PPAR) ligands, including PPAR-alpha and PPAR-gamma agonists, inhibit KATP channels and stimulate insulin secretion in pancreatic beta-cells. These findings suggest direct interaction with the beta-cell membrane.

Area of Science:

  • Molecular Endocrinology
  • Pancreatic Beta-Cell Physiology

Background:

  • Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands are known to stimulate insulin secretion via Ca2+ influx, but mechanisms remain unclear.
  • The effects of PPAR-alpha ligands on pancreatic beta-cells are largely unknown.
  • Understanding these interactions is crucial for metabolic disease research.

Purpose of the Study:

  • To investigate the effects of PPAR-alpha ligands (fenofibrate, fenofibric acid) and PPAR-gamma ligands (troglitazone, 15-deoxy-Delta12,14-prostaglandin J2) on KATP channel activity.
  • To determine the impact of these ligands on insulin secretion from pancreatic beta-cells.
  • To elucidate the direct interaction of PPAR ligands with beta-cell membranes.

Main Methods:

  • Utilized whole-cell patch clamp technique to assess KATP channel activity in HIT-T15 cells.
  • Measured [3H]glibenclamide binding to evaluate ligand interaction with KATP channels.
  • Quantified insulin secretion from HIT-T15 cells following ligand exposure.

Main Results:

  • Fenofibrate, fenofibric acid, troglitazone, and 15-deoxy-Delta12,14-PGJ2 significantly reduced KATP channel currents.
  • PPAR-alpha and PPAR-gamma ligands inhibited [3H]glibenclamide binding, indicating direct interaction with the channel.
  • All tested ligands stimulated insulin secretion from HIT-T15 cells.

Conclusions:

  • PPAR-alpha and PPAR-gamma ligands directly interact with the pancreatic beta-cell membrane.
  • These ligands modulate KATP channel activity and enhance insulin secretion.
  • Findings provide insights into the mechanisms underlying PPAR-mediated metabolic regulation.

Related Concept Videos

Dipeptidyl Peptidase 4 Inhibitors01:23

Dipeptidyl Peptidase 4 Inhibitors

Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a significant...
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...
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: 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...
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),...