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

• Published in: American Journal of Physiology: Cell Physiology Vol. 296; no. 2; p. C346
• Main Authors: Zhang, Fan, Dey, Deben, Branstrom, Robert, Forsberg, Lars, Lu, Ming, Zhang, Qimin, Sjoholm, Ake
• Format: Journal Article
• Language: English
• Published: United States 01.02.2009
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Calcium - metabolism; Cells, Cultured; Cytosol - metabolism; Diabetes Mellitus - drug therapy; Diabetes Mellitus - 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; Insulin-Secreting Cells - enzymology; Islets of Langerhans - drug effects; Islets of Langerhans - enzymology; Islets of Langerhans - metabolism; KATP Channels - drug effects; KATP Channels - metabolism; Medicin och hälsovetenskap; Mice; Mice, Inbred Strains; NADP - metabolism; Obesity - drug therapy; Obesity - enzymology; Peroxisome Proliferator-Activated Receptors - agonists; Peroxisome Proliferator-Activated Receptors - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Pioglitazone; Protein Kinase Inhibitors - pharmacology; Signal Transduction - drug effects; Thiazolidinediones - pharmacology; Time Factors; Tissue Culture Techniques; Up-Regulation
• ISSN: 0363-6143; 1522-1563; 1522-1563
• DOI: 10.1152/ajpcell.00444.2008

1 Diabetes Research Center, Department of Internal Medicine, Karolinska Institutet, South Hospital, Stockholm, Sweden; 2 Bexel Pharmaceuticals, Inc., Union City, California; and 3 Department 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 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 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 [Ca 2+ ] i mediated through Ca 2+ 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 Address for reprint requests and other correspondence: Q. Zhang and Å. Sjöholm, Diabetes Research Center, Dept. of Internal Medicine, Karolinska Institutet, South Hospital, SE-11883 Stockholm, Sweden (e-mail: qimin.zhang{at}ki.se )