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This Article Full Text Full Text (PDF) All Versions of this Article: 296/2/C346    most recent 00444.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhang, F. Articles by Sjöholm, A. Search for Related Content PubMed PubMed Citation Articles by Zhang, F. Articles by Sjöholm, A.

RECEPTORS AND SIGNAL TRANSDUCTION

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

¹Diabetes Research Center, Department of Internal Medicine, Karolinska Institutet, South Hospital, Stockholm, Sweden; ²Bexel Pharmaceuticals, Inc., Union City, California; and ³Department of Molecular Medicine and Surgery, Unit of Endocrine Surgery, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden

Submitted 27 August 2008 ; accepted in final form 25 November 2008

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 β-cells. We have investigated the influence of the drug on β-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 β-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 β-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 β-cell function may translate into substantial clinical benefits of the drug in the management of type 2 diabetes, by avoidance of hypoglycemia.

calcium; diabetes; islet; phosphatidylinositol 3-kinase; adenosine 5'-monophosphate