Racecadotril is an enkephalinase inhibitor used to treat abdominal discomfort in the clinic. The blood-glucose lowering action of racecadotril has been observed in rats; however, the mechanisms remain obscure. 8-week-old Wistar rats were intravenously injected with racecadotril and the levels of insulin in the brain were measured. Additionally, brain homogenates were co-incubated with racecadotril or thiorphan to evaluate insulin degrading enzyme (IDE) activity. Otherwise, rats were pretreated by intracerebroventricular (i. c. v.) injection of insulin antibody or glibenclamide at a dose sufficient to inhibit K (ATP) channels prior to injection of racecadotril. Moreover, rats were vagotomized to evaluate the role of the cholinergic nerve. Racecadotril significantly decreased the plasma glucose in rats; this action of racecadotril was abolished by i. c. v. pretreatment with insulin antibody or glibenclamide. Also, i. c. v. injection of thiorphan, the active form of racecadotril, lowered blood glucose, but this effect disappeared in the presence of the insulin antibody. In rat brain homogenates, racecadotril and thiorphan inhibited IDE activity and increased the cerebral insulin level. The blood-glucose lowering action of racecadotril or thiorphan was diminished in vagotomized rats. Our results suggest that racecadotril lowers blood glucose mainly through inhibition of IDE activity and increases endogenous insulin in the brain. Subsequently, the increased insulin might activate insulin receptor, which opens the K (ATP) channel and induces peripheral insulin release through the vagal nerve. Thus, we provide the new finding that racecadotril has the ability to inhibit IDE in rat brain.

Glucose enhances mitochondrial function, insulin secretion and Myc expression in β-cells. β-cell-specific Myc knockout mice show glucose intolerance, hypoinsulinemia and lack of adaptive β-cell mass expansion following high-fat diet feeding. However, whether Myc regulates GSIS and mitochondrial function in β-cells is unknown. Here, we tested the effects of the Myc activity inhibitor 10058-F4 (1RH) in GSIS, mitochondrial function and metabolism in islets using islet perifusion, Seahorse and metabolomics/transcriptomics approaches. Mouse and human islets incubated 6h with 40µM 1RH displayed impaired phase 1 and phase 2 insulin secretion induced by 11mM glucose. Insulin secretion was not affected in the presence of 25mM KCl suggesting that Myc is required for glucose- but not membrane depolarization-induced insulin secretion. Since adequate mitochondrial function is essential for GSIS, we measured oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) to analyze mitochondrial respiration and glycolytic flux in these islets. 1RH significantly reduced OCR, ECAR and glucose-induced ATP production. Conversely, the Myc inducer harmine (10µM), increased basal OCR, ATP production, and ECAR and partially reversed 1RH effects on mitochondrial function. RNAseq of mouse islets treated with 1RH in 11mM glucose revealed reduced expression of both oxidative phosphorylation and β-cell signature genes but enhanced gene expression of glycolysis, ROS, fatty acid metabolism and autophagy/mitophagy pathways. Metabolomics analysis of mouse islets treated with 1RH in 11mM glucose confirmed the reduction in ATP and highlighted the accumulation of L-palmitoylcarnitine and palmitic acid suggesting inefficient β-oxidation. In conclusion, Myc is required for GSIS and mitochondrial function in β-cells. Impaired Myc action can lead to unbalanced metabolism and autophagy/mytophagy leading to β-cell dysfunction. Disclosure G.Lu: None. R.Kang: None. P.Diaz-pozo: None. J.Lee: None. M.Li: None. V.M.Victor: None. D.Scott: None. A.Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd. Funding National Institutes of Health (R01DK126450)

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