BLX-1002, a novel thiazolidinedione with no PPAR affinity, stimulates AMP-activated protein kinase activity, raises cytosolic Ca2+, and enhances glucose-stimulated insulin secretion in a PI3K-dependent manner.

Abstract

BLX-1002 is a novel small thiazolidinedione with no apparent affinity to peroxisome proliferator-activated receptors (PPAR) that has been shown to reduce glycemia in type 2 diabetes without adipogenic effects. Its precise mechanisms of action, however, remain elusive, and no studies have been done with respect to possible effects of BLX-1002 on pancreatic beta-cells. We have investigated the influence of the drug on beta-cell function in mouse islets in vitro. BLX-1002 enhanced insulin secretion stimulated by high, but not low or intermediate, glucose concentrations. BLX-1002 also augmented cytoplasmic free Ca2+ concentration ([Ca2+](i)) at high glucose, an effect that was abolished by pretreatment with the Ca2+-ATPase inhibitor thapsigargin. In contrast, BLX-1002 did not interfere with voltage-gated Ca2+ channel or ATP-sensitive K+ channel activities. In addition, cellular NAD(P)H stimulated by glucose was not affected by the drug. The stimulatory effect of BLX-1002 on insulin secretion at high glucose was completely abolished by treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY-294002. Stimulation of the beta-cells with BLX-1002 also induced activation of AMP-activated protein kinase (AMPK) at high glucose. Our study suggests that BLX-1002 potentiates insulin secretion only at high glucose in beta-cells in a PI3K-dependent manner. This effect of BLX-1002 is associated with an increased [Ca2+](i) mediated through Ca2+ mobilization, and an enhanced activation of AMPK. The glucose-sensitive stimulatory impact of BLX-1002 on beta-cell function may translate into substantial clinical benefits of the drug in the management of type 2 diabetes, by avoidance of hypoglycemia.

• Authors: Fan Zhang, Deben Dey, Robert Bränström, Lars Forsberg, Ming Lu, Qimin Zhang, Ake Sjöholm
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 296 Issue 2 Pg. C346-54 (Feb 2009) ISSN: 1522-1563 [Electronic] United States
• PMID: 19052259 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BLX 1002
• Hypoglycemic Agents
• Insulin
• KATP Channels
• Peroxisome Proliferator-Activated Receptors
• Protein Kinase Inhibitors
• Thiazolidinediones
• NADP
• Phosphatidylinositol 3-Kinases
• AMP-Activated Protein Kinases
• Glucose
• Calcium
• Fenofibrate
• Pioglitazone

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Calcium (metabolism)
• Cells, Cultured
• Cytosol (metabolism)
• Diabetes Mellitus (drug therapy, enzymology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Synergism
• Enzyme Activation
• Fenofibrate (pharmacology)
• Glucose (metabolism)
• Hypoglycemic Agents (pharmacology)
• Insulin (metabolism)
• Insulin Secretion
• Insulin-Secreting Cells (drug effects, enzymology)
• Islets of Langerhans (drug effects, enzymology, metabolism)
• KATP Channels (drug effects, metabolism)
• Mice
• Mice, Inbred Strains
• NADP (metabolism)
• Obesity (drug therapy, enzymology)
• Peroxisome Proliferator-Activated Receptors (agonists, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Pioglitazone
• Protein Kinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)
• Thiazolidinediones (pharmacology)
• Time Factors
• Tissue Culture Techniques
• Up-Regulation