| First Author | Zhang F | Year | 2009 |
| Journal | Am J Physiol Cell Physiol | Volume | 296 |
| Issue | 2 | Pages | C346-54 |
| PubMed ID | 19052259 | Mgi Jnum | J:146323 |
| Mgi Id | MGI:3837269 | Doi | 10.1152/ajpcell.00444.2008 |
| Citation | Zhang F, et al. (2009) 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. Am J Physiol Cell Physiol 296(2):C346-54 |
| abstractText | 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 Ca(2+) concentration ([Ca(2+)](i)) at high glucose, an effect that was abolished by pretreatment with the Ca(2+)-ATPase inhibitor thapsigargin. In contrast, BLX-1002 did not interfere with voltage-gated Ca(2+) 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 [Ca(2+)](i) mediated through Ca(2+) 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. |
