It remains unclear how ␣-ketoisocaproate (KIC) and leucine are metabolized to stimulate insulin secretion. Mitochondrial BCATm (branched-chain aminotransferase) catalyzes reversible transamination of leucine and ␣-ketoglutarate to KIC and glutamate, the first step of leucine catabolism. We investigated the biochemical mechanisms of KIC and leucine-stimulated insulin secretion (KICSIS and LSIS, respectively) using Although leucine oxidation and KIC transamination were blocked in BCATm ؊/؊ islets, KIC oxidation was unaltered.These data indicate that KICSIS requires transamination of KIC and glutamate to leucine and ␣-ketoglutarate, respectively. LSIS does not require leucine catabolism and may be through leucine activation of glutamate dehydrogenase. Thus, KICSIS and LSIS occur by enhancing the metabolism of glutamine/glutamate to ␣-ketoglutarate, which, in turn, is metabolized to produce the intracellular signals such as ATP and NADPH for insulin secretion.To maintain glucose homeostasis in response to a meal, insulin secretion is precisely stimulated by nutrients such as glucose, amino acids, and free fatty acids as well as incretin hormones such as glucagon-like peptide-1. Nutrients are thought to stimulate insulin secretion through metabolic secretion coupling to generate metabolic signals, i.e. second messengers or coupling factors. Extensive research has been conducted to determine how nutrients are metabolized to generate these coupling factors, e.g. ATP and NADPH. Although leucine and ␣-ketoisocaproate (KIC) 3 are potent insulin secretagogues (1), the underlying mechanisms of leucine and KIC-stimulated insulin secretion (LSIS and KICSIS, respectively) remain elusive. A key question is whether their oxidative decarboxylation is required for induction of insulin secretion.
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 KATP 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 KATP channels like other KCOs. This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia.
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