Abstract
Here, we examined the chronic effects of two cannabinoid receptor-1 (CB1) inverse agonists, rimonabant and ibipinabant, in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia. Rimonabant and ibipinabant (10 mg·kg⁻¹·day⁻¹) elicited body weight-independent improvements in insulinemia and glycemia during 10 wk of chronic treatment. To elucidate the mechanism of insulin lowering, acute in vivo and in vitro studies were then performed. Surprisingly, chronic treatment was not required for insulin lowering. In acute in vivo and in vitro studies, the CB1 inverse agonists exhibited acute K channel opener (KCO; e.g., diazoxide and NN414)-like effects on glucose tolerance and glucose-stimulated insulin secretion (GSIS) with approximately fivefold better potency than diazoxide. Followup studies implied that these effects were inconsistent with a CB1-mediated mechanism. Thus effects of several CB1 agonists, inverse agonists, and distomers during GTTs or GSIS studies using perifused rat islets were unpredictable from their known CB1 activities. In vivo rimonabant and ibipinabant caused glucose intolerance in CB1 but not SUR1-KO mice. Electrophysiological studies indicated that, compared with diazoxide, 3 μM rimonabant and ibipinabant are partial agonists for K channel opening. Partial agonism was consistent with data from radioligand binding assays designed to detect SUR1 K(ATP) KCOs where rimonabant and ibipinabant allosterically regulated ³H-glibenclamide-specific binding in the presence of MgATP, as did diazoxide and NN414. Our findings indicate that some CB1 ligands may directly bind and allosterically regulate Kir6.2/SUR1 K(ATP) channels like other KCOs. This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP-Binding Cassette Transporters / agonists*
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Allosteric Regulation
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Animals
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Anti-Obesity Agents / adverse effects
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Anti-Obesity Agents / chemistry
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Anti-Obesity Agents / pharmacology*
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Anti-Obesity Agents / therapeutic use
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Cell Line, Transformed
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Chlorocebus aethiops
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Cricetinae
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Glucose Intolerance / chemically induced
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Glucose Intolerance / metabolism
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Humans
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Hypoglycemic Agents / adverse effects
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacology*
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Hypoglycemic Agents / therapeutic use
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Islets of Langerhans / drug effects
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Islets of Langerhans / metabolism
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Ligands
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Male
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Membrane Transport Modulators / adverse effects
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Membrane Transport Modulators / chemistry
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Membrane Transport Modulators / pharmacology*
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Membrane Transport Modulators / therapeutic use
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Mice
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Mice, Knockout
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Mice, Obese
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Potassium Channels, Inwardly Rectifying / agonists*
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Potassium Channels, Inwardly Rectifying / genetics
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Potassium Channels, Inwardly Rectifying / metabolism
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Rats
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Rats, Zucker
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Receptor, Cannabinoid, CB1 / agonists*
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Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
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Receptor, Cannabinoid, CB1 / genetics
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Receptor, Cannabinoid, CB1 / metabolism
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Receptors, Drug / agonists*
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Receptors, Drug / genetics
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Receptors, Drug / metabolism
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Recombinant Proteins / agonists
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Stereoisomerism
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Sulfonylurea Receptors
Substances
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ABCC8 protein, human
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ATP-Binding Cassette Transporters
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Abcc8 protein, mouse
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Abcc8 protein, rat
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Anti-Obesity Agents
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Hypoglycemic Agents
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Ligands
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Membrane Transport Modulators
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Potassium Channels, Inwardly Rectifying
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Receptor, Cannabinoid, CB1
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Receptors, Drug
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Recombinant Proteins
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Sulfonylurea Receptors