title: 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.affiliation: Diabetes Research Center, Dept. of Internal Medicine, Karolinska Institutet, South Hospital, SE-11883 Stockholm, Sweden.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Deben
authors.initials: D
authors.lastname: Dey
authors.forename: Robert
authors.initials: R
authors.lastname: Bränström
authors.forename: Lars
authors.initials: L
authors.lastname: Forsberg
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ake
authors.initials: A
authors.lastname: Sjöholm
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000201:enzymology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation; D011345:Fenofibrate / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009249:NADP / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000077205:Pioglitazone; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D046509:Tissue Culture Techniques; D015854:Up-Regulation
chemical_list: C542815:BLX 1002; D007004:Hypoglycemic Agents; D007328:Insulin; D054086:KATP Channels; D047492:Peroxisome Proliferator-Activated Receptors; D047428:Protein Kinase Inhibitors; D045162:Thiazolidinediones; D009249:NADP; D019869:Phosphatidylinositol 3-Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D002118:Calcium; D011345:Fenofibrate; D000077205:Pioglitazone